Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, 72063-72103 [2014-28241]
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Vol. 79
Thursday,
No. 233
December 4, 2014
Part II
Department of Health and Human Services
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Food and Drug Administration
21 CFR Part 201
Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling;
Pregnancy, Lactation, and Reproductive Potential: Labeling for Human
Prescription Drug and Biological Products—Content and Format; Draft
Guidance for Industry; Availability; Final Rule and Notice
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Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6246,
Silver Spring, MD 20993–0002, 301–
796–3432; or Stephen Ripley, Center for
Biologics Evaluation and Research,
Food and Drug Administration, 10903
New Hampshire Ave., Bldg. 71, Rm.
7301, Silver Spring, MD 20993–0002,
240–402–7911.
SUPPLEMENTARY INFORMATION:
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. FDA–2006–N–0515 (formerly
Docket No. 2006N–0467)]
RIN 0910–AF11
Content and Format of Labeling for
Human Prescription Drug and
Biological Products; Requirements for
Pregnancy and Lactation Labeling
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Final rule.
The Food and Drug
Administration (FDA) is amending its
regulations governing the content and
format of the ‘‘Pregnancy,’’ ‘‘Labor and
delivery,’’ and ‘‘Nursing mothers’’
subsections of the ‘‘Use in Specific
Populations’’ section of the labeling for
human prescription drug and biological
products. The final rule requires the
removal of the pregnancy categories A,
B, C, D, and X from all human
prescription drug and biological product
labeling. For human prescription drug
and biological products subject to the
Agency’s 2006 Physician Labeling Rule,
the final rule requires that the labeling
include a summary of the risks of using
a drug during pregnancy and lactation,
a discussion of the data supporting that
summary, and relevant information to
help health care providers make
prescribing decisions and counsel
women about the use of drugs during
pregnancy and lactation. The final rule
eliminates the ‘‘Labor and delivery’’
subsection because information about
labor and delivery is included in the
‘‘Pregnancy’’ subsection. The final rule
requires that the labeling include
relevant information about pregnancy
testing, contraception, and infertility for
health care providers prescribing for
females and males of reproductive
potential. The final rule creates a
consistent format for providing
information about the risks and benefits
of prescription drug and/or biological
product use during pregnancy and
lactation and by females and males of
reproductive potential. These revisions
will facilitate prescriber counseling for
these populations.
DATES: This rule is effective June 30,
2015. See section IV of this document
for the implementation dates of this
final rule.
FOR FURTHER INFORMATION CONTACT:
Kathy Schreier, Center for Drug
Evaluation and Research, Food and
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SUMMARY:
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Table of Contents
Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the
Regulatory Action in Question
Costs and Benefits
I. Background
A. History of FDA-Approved Pregnancy
and Lactation Labeling for Prescription
Drugs
B. Development of the Proposed Rule
C. The Proposed Rule
D. Mental Models Research
II. Overview of the Final Rule Including
Significant Changes to the Proposed Rule
A. Overview
B. Significant Changes to the Proposed
Rule
III. Comments on the Proposed Rule
A. Proposed Rule as a Whole
B. Specific Provisions of the Proposed Rule
IV. Implementation
V. Legal Authority
A. Statutory Authority
B. First Amendment
VI. Environmental Impact
VII. Summary of Final Regulatory Impact
Analysis
A. Introduction
B. Summary of Costs and Benefits
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. References
Executive Summary
Purpose of the Regulatory Action
FDA is amending its regulations
governing the content and format of the
‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and
‘‘Nursing mothers’’ subsections of the
‘‘Use in Specific Populations’’ section
(under § 201.57 (21 CFR 201.57)) and
the ‘‘Precautions’’ section (under
§ 201.80 (21 CFR 201.80)) of the labeling
for human prescription drug and
biological products (both referred to as
‘‘drugs’’ or ‘‘drug products’’ in this final
rule). In this rulemaking, the Agency is
finalizing many of the provisions in the
proposed rule issued on May 29, 2008
(73 FR 30831).
This rulemaking is part of a broad
effort by the Agency to improve the
content and format of prescription drug
labeling. The final rule creates a
consistent format for providing
information about the risks and benefits
of drug use during pregnancy and
lactation and by females and males of
reproductive potential. FDA’s revisions
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to the content and format requirements
for prescription drug and biological
product labeling are authorized by the
Federal Food, Drug, and Cosmetic Act
(the FD&C Act) and by the Public Health
Service Act (PHS Act).
Summary of the Major Provisions of the
Regulatory Action in Question
The final rule requires that for the
labeling of certain drug products (as
described in the ‘‘Implementation’’
section of this document), the
subsections ‘‘Pregnancy,’’ ‘‘Nursing
mothers,’’ and ‘‘Labor and delivery’’ be
replaced by three subsections entitled
‘‘Pregnancy,’’ ‘‘Lactation,’’ and
‘‘Females and Males of Reproductive
Potential.’’ The final rule also requires
the removal of the pregnancy categories
A, B, C, D, and X from all drug product
labeling.
‘‘Pregnancy’’
The final rule merges the current
‘‘Pregnancy’’ and ‘‘Labor and delivery’’
subsections into a single ‘‘Pregnancy’’
subsection of labeling. If there is a
scientifically acceptable pregnancy
exposure registry for the drug, the
‘‘Pregnancy’’ subsection must contain a
specified statement about the existence
of the registry, followed by contact
information needed to enroll or to
obtain information about the registry.
The Agency has concluded that
including information about pregnancy
exposure registries in prescription drug
labeling will encourage participation in
registries, thereby improving data
collection in pregnant women. Under
‘‘Pregnancy,’’ the final rule also requires
that the labeling include a summary of
the risks of using a drug during
pregnancy. If data demonstrate that a
drug is not absorbed systemically, the
‘‘Risk Summary’’ must contain only a
specified statement regarding this fact. If
data demonstrate that the drug is
absorbed systemically, the ‘‘Risk
Summary’’ must include risk statements
based on data from all relevant sources
(human, animal, and/or pharmacologic),
that describe, for the drug, the risk of
adverse developmental outcomes.
The labeling must also contain
relevant information, if it is available, to
help health care providers make
prescribing decisions and counsel
women about the use of the drug during
pregnancy; this could include
information on disease-associated
maternal and/or embryo/fetal risk, dose
adjustments during pregnancy and the
postpartum period, maternal adverse
reactions, fetal/neonatal adverse
reactions, and/or the effect of the drug
on labor or delivery. FDA believes that
including such information supports
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health care providers’ understanding of
drug product risks and benefits and
facilitates informed prescribing
decisions and patient counseling. The
labeling must also describe the data that
are the basis for the risk statements and
clinical information included in the
‘‘Pregnancy’’ subsection of labeling.
‘‘Lactation’’
The final rule requires that the
‘‘Lactation’’ subsection of labeling
contain a summary of the risks of using
a drug during lactation. If data
demonstrate that the drug is not
absorbed systemically, this summary
must contain only a specified statement
regarding this fact. If data demonstrate
that the drug is absorbed systemically
by the mother, this summary must
include, to the extent it is available,
relevant information on the presence of
the drug in human milk, effects of the
drug on the breast-fed child, and effects
of the drug on milk production. For
drugs absorbed systemically, a risk and
benefit statement must appear at the end
of the summary of risks, unless
breastfeeding is contraindicated during
drug therapy. FDA has determined that
the inclusion of a risk and benefit
statement will provide a useful
framework for health care providers to
use when making prescribing decisions
for a lactating patient.
The ‘‘Lactation’’ subsection must also
include, to the extent information is
available, relevant information
concerning ways to minimize drug
exposure in the breast-fed child in
certain situations and concerning
available interventions for monitoring or
mitigating the adverse reactions
presented elsewhere in the labeling. In
addition, the labeling must also include
pertinent information about the data
that are the basis for the risk summary
and clinical information included in the
‘‘Lactation’’ subsection of labeling.
‘‘Females and Males of Reproductive
Potential’’
FDA determined that because there
was no consistent placement in the
labeling of information about pregnancy
testing, contraception, and infertility, it
was difficult for health care providers to
find this important information that can
affect decisionmaking before or during
pregnancy. Thus, the final rule requires
that the ‘‘Females and Males of
Reproductive Potential’’ subsection
include relevant information when
pregnancy testing or contraception is
required or recommended before,
during, or after drug therapy or when
there are human or animal data that
suggest drug-associated fertility effects.
Removal of Pregnancy Categories
Through experience and stakeholder
feedback, FDA learned that the
pregnancy categories were confusing
and did not accurately and consistently
communicate differences in degrees of
fetal risk. In addition, FDA learned that
the pregnancy categories were heavily
relied upon by clinicians but were often
misinterpreted and misused in that
prescribing decisions were being made
based on the pregnancy category, rather
than an understanding of the underlying
information that informed the
assignment of the pregnancy category.
FDA believes that a narrative structure
for pregnancy labeling, rather than a
category system, is best able to capture
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and convey the potential risks of drug
exposure based on animal or human
data, or both. FDA has determined that
retaining the pregnancy categories is
inconsistent with the need to accurately
and consistently communicate
differences in degrees of fetal risk.
Therefore, the final rule requires the
removal of the pregnancy categories A,
B, C, D, and X from all drug product
labeling.
Costs and Benefits
We estimate that over 10 years with
a 7 percent discount rate, the present
value of one-time costs of the rule equal
$52.4 million and the present value of
the annual costs equal $14.4 million;
with a 3 percent discount rate, the
present value of one-time costs equal
$60.1 million and the present value of
the annual costs equal $18.2 million.
The present value of the total costs
equal $66.8 million with a 7 percent
discount rate and $78.2 million with a
3 percent discount rate. The annualized
costs of the rule total $9.5 million with
a 7 percent discount rate and $9.2
million with a 3 percent discount rate.
The final rule will address issues raised
by experts and stakeholders and
improve the quality of the affected
sections of prescription drug labeling.
Better quality prescribing information
will enhance the usefulness of the
labeling. The public health benefits of
the final rule would result from
improved health outcomes. However,
because we have no information about
how improved labeling will affect
prescriber behavior and patient
outcomes, we are unable to quantify the
benefits of the final rule.
SUMMARY OF BENEFITS AND COSTS OF THE FINAL RULE
Total benefits
Present value
of total costs
with 3 percent
discount rate
($ mil)
Present value
of total costs
with 7 percent
discount rate
($ mil)
Total
annualized
costs over 10
years with 3
percent
discount
rate
($ mil)
Total
annualized
costs over 10
years with 7
percent
discount
rate
($ mil)
Not estimated ...................................................................................................
78.2
66.8
9.2
9.5
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I. Background
In the Federal Register of May 29,
2008 (73 FR 30831), FDA issued a
proposed rule to amend the content and
format of the ‘‘Pregnancy,’’ ‘‘Labor and
delivery,’’ and ‘‘Nursing mothers’’
subsections of the ‘‘Use in Specific
Populations’’ section of labeling for
human prescription drug and biological
products, which appear in § 201.57. The
proposed rulemaking was part of a
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broad effort by the Agency to improve
the content and formatting of
prescription drug labeling.
A. History of FDA-Approved Pregnancy
and Lactation Labeling for Prescription
Drugs
Under sections 502 and 505 of the
FD&C Act (21 U.S.C. 352 and 355), FDA
has responsibility for ensuring that
prescription drug and biological
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products (both referred to as ‘‘drugs’’ or
‘‘drug products’’ in this final rule) are
accompanied by labeling (including
prescribing information) that
summarizes scientific information
concerning their safe and effective use.
FDA regulations on labeling for use
during pregnancy, during labor and
delivery, and by nursing mothers were
originally issued in 1979 as part of a
rule prescribing the content and format
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for labeling for human prescription
drugs (part 201 (21 CFR part 201)) (44
FR 37434, June 26, 1979) (the 1979
regulations).1 The requirements on
content and format of labeling for drug
products were revised on January 24,
2006, in the final rule on ‘‘Requirements
on Content and Format of Labeling for
Human Prescription Drug and Biological
Products’’ (71 FR 3922), commonly
referred to as the ‘‘Physician Labeling
Rule’’ (PLR).2 As part of the January
2006 revision, the subsections of the
labeling on pregnancy, labor and
delivery, and nursing mothers were
moved from the ‘‘Precautions’’ section
under § 201.57 to the ‘‘Use in Specific
Populations’’ section. The content of
these sections in part 201 was not
revised, but the sections were
redesignated as § 201.57(c)(9)(i) through
(c)(9)(iii). The previous labeling
regulation (adopted in 1979) was
redesignated as § 201.80, and applies to
products not affected by the January
2006, revisions. In redesignated
§ 201.80, the subsections on pregnancy,
labor and delivery, and nursing mothers
are § 201.80(f)(6) through (f)(8).
The 1979 regulations provided, at
what was redesignated in 2006 as
§ 201.57(c)(9)(i) and § 201.80(f)(6)(i),
that unless a drug was not absorbed
systemically and was not known to have
a potential for indirect harm to a fetus,
a ‘‘Pregnancy’’ subsection must be
included within the ‘‘Precautions’’
section of the labeling. The 1979
regulations required that the
‘‘Pregnancy’’ subsection contain
information on the drug’s teratogenic
effects and other effects on reproduction
and pregnancy and, when available, a
description of human studies with the
drug and data on its effects on later
growth, development, and functional
maturation of the child. The 1979
regulations also required that each
product be classified under one of five
pregnancy categories (A, B, C, D, or X)
on the basis of risk of reproductive and
developmental adverse effects or, for
certain categories, on the basis of such
risk weighed against potential benefit.3
With regard to labor and delivery, the
1979 regulations stated, at what was
redesignated in 2006 as § 201.57(c)(9)(ii)
and § 201.80(f)(7), that under certain
circumstances, the labeling must
1 Thus, the labeling for drugs originally approved
before 1979 may not contain the information
required by those regulations regarding pregnancy,
labor and delivery, and nursing mothers.
2 FDA’s regulations governing the content and
format of labeling for human prescription drug and
biological products are contained in §§ 201.56,
201.57, and 201.80.
3 For further discussion of the pregnancy
categories, see 73 FR 30831 at 30832 through 30833.
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include information on the effects of the
drug on, among other things, the mother
and the fetus, the duration of labor and
delivery, and the effect of the drug on
the later growth, development, and
functional maturation of the child.
With regard to labeling on lactation,
the 1979 regulations required, at what
was redesignated in 2006 as
§ 201.57(c)(9)(iii) and § 201.80(f)(8), that
a ‘‘Nursing mothers’’ subsection be
included in the ‘‘Precautions’’ section of
the labeling. The ‘‘Nursing mothers’’
subsection provided that if a drug was
absorbed systemically, the labeling must
contain information about excretion of
the drug in human milk and effects on
the nursing infant, as well as a
description of any pertinent adverse
effects observed in animal offspring.
The ‘‘Nursing mothers’’ subsection
required the use of certain standard
statements depending on whether the
drug was known to be excreted in
human milk and whether it was
associated with serious adverse
reactions.4
B. Development of the Proposed Rule
Over a number of years after the 1979
regulations were issued, FDA received
feedback on the issues and concerns
with the ‘‘Pregnancy,’’ ‘‘Labor and
delivery,’’ and ‘‘Nursing mothers’’
subsections of prescription drug
labeling as defined by the 1979
regulations. In response to this
feedback, FDA held a part 15 public
hearing, conducted focus groups, and
convened two advisory committees to
provide expert input. During this
process, many stakeholders stated that
these subsections of prescription drug
labeling lacked clarity, often failed to
provide meaningful clinical information
about drug exposure during pregnancy
and lactation, and did not address the
potential maternal and fetal
consequences of discontinuing needed
maternal drug therapy during
pregnancy. Experts and other
stakeholders noted that the pregnancy
categories, although highly relied upon
by health care providers, were often
misinterpreted and misused. FDA also
sought input on the development of a
model format for these subsections of
labeling, and the resulting model served
as the basis for the May 29, 2008,
proposed rule (73 FR 30831). The
preamble to the proposed rule contains
a detailed discussion about the
background of the development of the
proposed rule and additional details
4 For further discussion of the history of both the
‘‘Pregnancy’’ and the ‘‘Nursing mothers’’
subsections of prescription drug labeling, see 73 FR
30831 at 30833.
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regarding the 1979 regulations
governing labeling of drug products for
use during pregnancy, during labor and
delivery, and while nursing (73 FR
30831 at 30832–30838).
C. The Proposed Rule
FDA proposed to amend the content
and format of the ‘‘Pregnancy,’’ ‘‘Labor
and delivery,’’ and ‘‘Nursing mothers’’
subsections of the ‘‘Use in Specific
Populations’’ section of physician
labeling for prescription drug products
subject to § 201.57. The Agency’s
proposed changes were intended to
create a consistent format for providing
information about the effects of a drug
on pregnancy and lactation that would
be useful for decisionmaking by health
care providers and their patients. With
respect to the ‘‘Pregnancy,’’ ‘‘Labor and
delivery,’’ and ‘‘Nursing mothers’’
subsections of the ‘‘Precautions’’ section
of prescription drug labeling for drug
products subject to § 201.80, the Agency
proposed only to remove the pregnancy
category from the ‘‘Pregnancy’’
subsection.
1. Proposed Provisions for New and
Recently Approved Drugs
FDA proposed the following format
and content changes to the
‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and
‘‘Nursing mothers’’ subsections of
prescription drug labeling for products
subject to § 201.57.
• Merge the current ‘‘Pregnancy’’ and
‘‘Labor and delivery’’ subsections into a
single ‘‘Pregnancy’’ subsection
designated 8.1 under the section ‘‘8 Use
in Specific Populations.’’
• Rename the ‘‘Nursing mothers’’
subsection as ‘‘Lactation’’ designated
with the identifying number 8.2 under
the section ‘‘8 Use in Specific
Populations.’’
• Reserve the identifying number 8.3
for future use.
• Replace the format and content of
the ‘‘Pregnancy’’ subsection in its
entirety with the following:
Æ If there is a pregnancy exposure
registry for the drug, the telephone
number or other information needed to
enroll in the registry or to obtain
information about the registry must be
included at the beginning of the
‘‘Pregnancy’’ subsection of labeling.
Æ Require the inclusion of a general
statement about background risk,
specifically ‘‘All pregnancies have a
background risk of birth defect, loss, or
other adverse outcome regardless of
drug exposure. The fetal risk summary
below describes (name of drug)’s
potential to increase the risk of
developmental abnormalities above the
background risk.’’
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Æ Under the subheading ‘‘Fetal Risk
Summary,’’ require the labeling to
contain a risk conclusion and a
narrative description of the risk(s) (if the
risk conclusion is based on human
data).
Æ Require the fetal risk summary to
characterize the likelihood that the drug
increases the risk of developmental
abnormalities and other risks in
humans.
Æ Require that if data demonstrate
that a drug is not systemically absorbed,
the fetal risk summary contain only the
following statement: (Name of drug) is
not absorbed systemically from (part of
body) and cannot be detected in the
blood. Maternal use is not expected to
result in fetal exposure to the drug.
Æ When both human and animal data
are available, require that risk
conclusions based on human data be
presented before risk conclusions based
on animal data. Require that a risk
conclusion based on human data be
followed by a narrative description of
the risks.
Æ When human data are sufficient to
reasonably determine the likelihood that
the drug increases the risk of fetal
developmental abnormalities or specific
developmental abnormalities, require
the labeling to contain one of two risk
conclusions: Human data do not
indicate that (name of drug) increases
the risk of (type of developmental
abnormality or specific developmental
abnormality) or Human data indicate
that (name of drug) increases the risk of
(type of developmental abnormality or
specific developmental abnormality).
Æ When human data are available but
not sufficient to reasonably determine
the drug’s effects on fetal developmental
abnormalities, require the labeling to
characterize the likelihood that the drug
increases the risk of developmental
abnormalities as low, moderate, or high.
Æ Require that when the data on
which the risk conclusion is based are
animal data, the fetal risk summary
characterize the likelihood that the drug
increases the risk of developmental
abnormalities using one of the following
risk conclusions: Not predicted to
increase the risk, low likelihood of
increased risk, moderate likelihood of
increased risk, high likelihood of
increased risk, or insufficient animal
data on which to assess the likelihood
of increased risk.
Æ When human data are available,
require that in addition to the risk
conclusion(s), the fetal risk summary be
followed by a brief narrative description
of the risks of developmental
abnormalities as well as on other
relevant risks associated with the drug.
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Æ Require the fetal risk summary to
refer to the ‘‘Contraindications’’ and/or
‘‘Warnings and Precautions’’ sections of
the labeling if there is any information
in those sections on an increased risk to
the fetus from exposure to the drug.
Æ Require under the subheading
‘‘Clinical Considerations’’ the inclusion
of information about the known or
predicted risks to the fetus from
inadvertent exposure to the drug,
including human or animal data on
dose, timing, and duration of exposure.
If there are no data to assess the risk
from inadvertent exposure, require the
labeling to so state.
Æ Require under the subheading
‘‘Clinical Considerations’’ the inclusion
of information related to prescribing
decisions for pregnant women,
including the risk, if known, to the
pregnant woman and the fetus from the
disease or condition the drug is
indicated to treat and the potential
influence of drug treatment on that risk;
information about dosing adjustments
during pregnancy; if use of the drug is
associated with any maternal adverse
reactions that are unique to pregnancy
or if known adverse reactions occur
with increased frequency or severity in
pregnant women, a description of such
adverse reactions; if it is known or
anticipated that treatment of the
pregnant woman will cause a
complication in the fetus or the neonate,
a description of the complication, the
severity and reversibility of the
complication, and general types of
interventions, if any, that may be
needed.
Æ If the drug has a recognized use
during labor or delivery, whether or not
that use is stated as an indication in the
labeling, or is expected to affect labor or
delivery, require the inclusion of
available information about the effect of
the drug on the mother; the fetus/
neonate; the duration of labor and
delivery; the possibility of
complications, including interventions,
if any, that may be needed; and the later
growth, development, and functional
maturation of the child.
Æ Require the inclusion of a ‘‘Data’’
subheading that, for human data,
describes positive and negative
experiences during pregnancy,
including developmental abnormalities,
and, to the extent applicable, the
number of subjects and duration of the
study. For animal data, require under
the subheading ‘‘Data’’ a description of
the relationship of the exposure and
mechanism of action in the animal
species to the anticipated exposure and
mechanism of action in humans.
• Replace the ‘‘Nursing mothers’’
subsection with ‘‘Lactation’’ and replace
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the content requirements of ‘‘Nursing
mothers’’ in its entirety with the
following:
Æ Require that the labeling of all
drugs contain a ‘‘Lactation’’ subsection.
Æ Under the subheading ‘‘Risk
Summary,’’ if the data demonstrate that
the drug does not affect the quantity
and/or quality of human milk and there
is reasonable certainty either that the
drug is not detectable in human milk or
that the amount of drug consumed
through breast milk will not adversely
affect the breast-fed child, the labeling
must state: The use of (name of drug) is
compatible with breastfeeding. After
this statement (if applicable), the
labeling must summarize the drug’s
effect on milk production, what is
known about the presence of the drug in
human milk, and the effects on the
breast-fed child.
Æ The source(s) of the data (e.g.,
human, animal, in vitro) that are the
basis for the ‘‘Risk Summary’’ must be
stated. When there are insufficient data
or no data to assess the drug’s effect on
milk production, the presence of the
drug in human milk, and/or the effects
on the breast-fed child, the ‘‘Risk
Summary’’ must so state.
Æ If the drug is not systemically
absorbed, require that the subheading
‘‘Risk Summary’’ contain only the
following statement: (Name of drug) is
not absorbed systemically from (part of
body) and cannot be detected in the
mother’s blood. Therefore, detectable
amounts of (name of drug) will not be
present in breast milk. Breastfeeding is
not expected to result in fetal exposure
to the drug.
Æ If the drug is absorbed systemically,
require the following under the
subheading ‘‘Risk Summary’’:
D A description of the effects of the
drug’s impact on milk production,
including the effect of the drug on the
quality and quantity of milk, including
milk composition, and the implications
of these changes to the breast-fed child.
D A description of the presence of the
drug in human milk in one of the
following ways: (1) The drug is not
detectable in human milk, (2) the drug
has been detected in human milk, (3)
the drug is predicted to be present in
human milk, (4) the drug is not
predicted to be present in human milk,
or (5) the data are insufficient to know
or predict whether the drug is present
in human milk.
D Require that if studies demonstrate
that the drug is not detectable in human
milk, the ‘‘Risk Summary’’ state the
limits of the assay used.
D Require that if the drug has been
detected in human milk, the ‘‘Risk
Summary’’ give the concentration
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detected in milk in reference to a stated
maternal dose (or, if the drug has been
labeled for pediatric use, in reference to
the pediatric dose), an estimate of the
amount of the drug consumed daily by
the infant based on an average daily
milk consumption of 150 milliliters per
kilogram of infant weight per day, and
an estimate of the percentage of the
maternal dose excreted in human milk.
D Require the inclusion of
information about the likelihood and
seriousness of known or predicted
effects on the breast-fed child from
exposure to the drug in human milk
based on the pharmacologic and
toxicologic profile of the drug, the
amount of drug detected or predicted to
be found in human milk, and agerelated differences in absorption,
distribution, metabolism, and
elimination.
Æ Under the subheading ‘‘Clinical
Considerations,’’ require the labeling to
provide the following information to the
extent it is available: Information
concerning ways to minimize the
exposure of the breast-fed child to the
drug, such as timing the dose relative to
breastfeeding or pumping and
discarding milk for a specified period;
information about potential drug effects
in the breast-fed child that could be
useful to caregivers, including
recommendations for monitoring or
responding to these effects; information
about dosing adjustments during
lactation.
Æ Require that the labeling include,
under the subheading ‘‘Data,’’ an
overview of the data that are the basis
for the ‘‘Risk Summary’’ and ‘‘Clinical
Considerations.’’
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2. Pregnancy Categories and
Implementation
FDA proposed to require the new
content and format changes for
prescription drug labeling for all
applications (including new drug
applications (NDAs), biologics license
applications (BLAs), or efficacy
supplements) required to comply with
the PLR, i.e., for drug products for
which an application was approved on
or after June 30, 2001. FDA proposed
that holders of applications approved
before June 30, 2001 (i.e., applications
not subject to the PLR), would not be
required to implement the new content
and format changes. Instead, if the
labeling for such applications contains a
pregnancy category, the application
holders would be required to remove
the pregnancy category designation by 3
years after the effective date of the final
rule.
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D. Mental Models Research
In a separate but related effort, FDA
contracted with a third party research
firm to conduct a Mental Models
Research study in 2009 to better
understand the decisionmaking
processes of health care providers
prescribing drugs to pregnant and
lactating women with chronic
conditions (Ref. 1). Mental Models
Research is an established risk analysis
approach that evaluates, using a
structured interview, decisionmaking
practices that require the synthesis of
complex issues. The specific objectives
of this study, which involved interviews
with 54 health care providers, were to
understand how health care providers
used FDA-approved prescribing
information (in the labeling format in
place at the time of the study in 2009),
in order to determine the factors that
influence their treatment decisions for
pregnant and lactating women with
chronic conditions, and to define
measures that could be used to quantify
the value of prescribing information as
a tool for these decision makers.
The findings from the Mental Models
Research were consistent with the
feedback the Agency received during its
work on the proposed and final rules.
For example, the research showed that
the pregnancy categories were relied
upon by many health care providers
almost to the exclusion of other
information found in the labeling. It also
showed that providers often relied on
secondary sources to find the pregnancy
category for a particular product rather
than using the product’s labeling.
Interviewees made suggestions for
improving prescribing information,
including simplifying the information
presented, centralizing the relevant
information, and making the
information included in labeling
clinically relevant.
II. Overview of the Final Rule,
Including Significant Changes to the
Proposed Rule
A. Overview
In this rulemaking, the Agency
finalizes many of the provisions in the
May 2008 proposed rule. In addition,
the final rule reflects revisions the
Agency made in response to comments
on the May 2008 proposed rule. FDA
has also made editorial and
organizational changes to clarify
provisions. For the purposes of this
rulemaking, the term ‘‘drug’’ or ‘‘drug
product’’ is used to refer to human
prescription drugs and biological
products that are regulated as drugs.
The final rule requires that for the
labeling of certain products (as
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described in the ‘‘Implementation’’
section of this document), the
subsections ‘‘Pregnancy,’’ ‘‘Nursing
mothers,’’ and ‘‘Labor and delivery’’ be
replaced by three subsections entitled
‘‘Pregnancy,’’ ‘‘Lactation,’’ and
‘‘Females and Males of Reproductive
Potential.’’ Information previously
placed in ‘‘Labor and delivery’’ is
required to be included in the
‘‘Pregnancy’’ subsection of labeling. The
final rule requires ‘‘Risk Summary’’
subheadings in the ‘‘Pregnancy’’ and
‘‘Lactation’’ subsections of labeling. The
‘‘Pregnancy Exposure Registry’’
subheading under ‘‘Pregnancy’’ is only
required if there is such a registry. The
‘‘Clinical Considerations’’ and ‘‘Data’’
subheadings are required under
‘‘Pregnancy’’ and under ‘‘Lactation’’
only to the extent relevant information
is available. If data demonstrate that the
drug is systemically absorbed, the ‘‘Risk
Summary’’ in the ‘‘Pregnancy’’
subsection requires a statement
regarding the background risk, in
addition to certain other information,
and the ‘‘Risk Summary’’ in the
‘‘Lactation’’ subsection of labeling
requires the inclusion of a risk and
benefit statement, unless breastfeeding
is contraindicated. The ‘‘Females and
Males of Reproductive Potential’’
subsection is not required if none of the
subheadings are applicable. However,
when pregnancy testing and/or
contraception is required or
recommended before, during, or after
drug therapy and/or when there are
human and/or animal data that suggest
drug-associated fertility effects, the
‘‘Females and Males of Reproductive
Potential’’ subsection requires the
inclusion of such information under the
subheadings ‘‘Pregnancy Testing,’’
‘‘Contraception,’’ and ‘‘Infertility,’’
respectively. The final rule also requires
statements acknowledging when data on
various labeling elements either are not
available or do not establish the
presence or absence of drug-associated
risk In addition, the final rule requires
removal of pregnancy categories from all
drug product labeling, including those
products for which an application was
approved before June 30, 2001.
B. Significant Changes to the Proposed
Rule
The final rule reflects revisions to the
proposed rule in response to comments
received on the proposed rule, as
discussed in detail in section III of this
document. FDA made the following
organizational and content-based
changes to the proposed rule:
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1. Pregnancy
• The final rule revises the proposed
rule to clarify that the ‘‘Risk Summary’’
subheading is always required in the
‘‘Pregnancy’’ subsection of labeling. The
subheading ‘‘Pregnancy Exposure
Registry’’ is only required when such a
registry exists; the ‘‘Clinical
Considerations’’ and ‘‘Data’’
subheadings are required when relevant
information is available. If the ‘‘Clinical
Considerations’’ subheading is required,
the following headings under it are also
required to the extent relevant
information is available: ‘‘Diseaseassociated maternal and/or embryo/fetal
risk,’’ ‘‘Dose adjustments during
pregnancy and the postpartum period,’’
‘‘Maternal adverse reactions,’’ ‘‘Fetal/
Neonatal adverse reactions,’’ and ‘‘Labor
or delivery.’’ Similarly, if the ‘‘Data’’
subheading is required, the headings
‘‘Human Data’’ and ‘‘Animal Data’’ are
required under it to the extent relevant
information is available.
• The final rule revises the proposed
‘‘Pregnancy Exposure Registry’’
subheading as follows:
Æ Requires that contact information
and a standard statement on the
pregnancy exposure registry will be
included under its own subheading
‘‘Pregnancy Exposure Registry’’ if there
is a pregnancy registry that is
scientifically acceptable.
Æ Eliminates the phrase ‘‘must be
stated at the beginning of the
‘Pregnancy’ subsection of the labeling.’’
Æ Revises the phrase ‘‘telephone
number or other information needed to
enroll’’ to ‘‘contact information needed
to enroll.’’
Æ Adds a requirement that the
following statement be included in
labeling before the contact information
for the pregnancy exposure registry:
There is a pregnancy exposure registry
that monitors pregnancy outcomes in
women exposed to (name of drug)
during pregnancy.
• The final rule revises the proposed
‘‘Fetal Risk Summary’’ as follows:
Æ Changes the title of the subheading
‘‘Fetal Risk Summary’’ to ‘‘Risk
Summary.’’
Æ Eliminates the requirement that the
following background risk statement be
included in the labeling before the fetal
risk summary: All pregnancies have a
background risk of birth defect, loss, or
other adverse outcome regardless of
drug exposure. The fetal risk summary
below describes (name of drug)’s
potential to increase the risk of
developmental abnormalities above the
background risk.
Æ Replaces the proposed standardized
background risk statement with the
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requirement that, if the drug is
systemically absorbed, the labeling state
the percentage range of live births in the
United States with a major birth defect
and the percentage range of pregnancies
in the United States that end in
miscarriage, regardless of drug
exposure. The final rule also requires
that if such information is available for
the population(s) for which the drug is
labeled, it must also be included.
Æ Replaces the term ‘‘developmental
abnormalities’’ with the term ‘‘adverse
developmental outcomes.’’ The final
rule defines ‘‘adverse developmental
outcomes’’ as structural abnormalities,
embryo-fetal and/or infant mortality,
functional impairment, and alterations
to growth.
Æ Clarifies that, when applicable, risk
statements must include a crossreference to additional details located
under the ‘‘Data’’ subheading of
‘‘Pregnancy.’’
Æ Revises the statement required
when a drug is not systemically
absorbed as follows:
D Replaces the phrase ‘‘from (part of
the body)’’ with ‘‘following (route of
administration)’’ to describe how the
drug enters the body.
D Replaces the phrase ‘‘cannot be
detected in the blood’’ with ‘‘maternal
use is not expected to result in fetal
exposure to the drug.’’
Æ Adds a requirement that when use
of the drug is contraindicated during
pregnancy, this must be stated first in
the ‘‘Risk Summary.’’
Æ Requires that risk statements be
presented in the following order: Based
on human data, based on animal data,
based on pharmacology.
• The ‘‘Risk conclusions based on
human data’’ in the ‘‘Risk Summary’’ is
revised as follows:
Æ Replaces the term ‘‘risk
conclusions’’ with ‘‘risk statement.’’
Æ Eliminates the term ‘‘sufficient
human data’’ and the proposed rule’s
requirement that the labeling contain
one of the following standardized risk
conclusions about sufficient human
data: Human data do not indicate that
(name of drug) increases the risk of
(type of developmental abnormality or
specific abnormality) and Human data
indicate that (name of drug) increases
the risk of (type of developmental
abnormality or specific abnormality).
Æ Replaces the standardized risk
conclusions based on human data with
the requirement that when human data
are available that establish the presence
or absence of any adverse
developmental outcome(s) associated
with maternal use of the drug, the Risk
Summary must summarize the specific
developmental outcome, its incidence,
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and the effects of dose, duration of
exposure, and gestational timing of
exposure. The final rule also requires
that if the human data indicate that
there is an increased risk for a specific
adverse developmental outcome in
infants born to women exposed to the
drug during pregnancy, this risk must be
quantitatively compared to the risk for
the same outcome in infants born to
women who were not exposed to the
drug but who have the disease or
condition for which the drug is
indicated to be used. When risk
information is not available for women
with these condition(s), then the risk for
the specific outcome must be compared
to the rate at which the outcome occurs
in the general population.
Æ Requires that the ‘‘Risk Summary’’
must state when there are no human
data or when available human data do
not establish the presence or absence of
drug-associated risk.
Æ Eliminates the term ‘‘other human
data’’ and the requirement that when
there are other human data, the
likelihood that the drug increases the
risk of developmental abnormalities
must be characterized as low, moderate,
or high.
• The ‘‘Risk conclusions based on
animal data’’ in the ‘‘Risk Summary’’ is
revised as follows:
Æ Replaces the term ‘‘risk
conclusions’’ with ‘‘risk statement.’’
Æ Eliminates the requirement that
animal data be characterized as ‘‘not
predicted to increase the risk,’’ ‘‘low
likelihood of increased risk,’’ ‘‘moderate
likelihood of increased risk,’’ or ‘‘high
likelihood of increased risk.’’
Æ Requires that when animal data are
available, the labeling must summarize
the findings in animals and based on
these findings, describe, for the drug,
the potential risk of any adverse
developmental outcome(s) in humans.
The final rule requires that the risk
statement include: The number and
type(s) of species affected, the timing of
exposure, animal doses expressed in
terms of human exposure or dose
equivalents, and outcomes for pregnant
animals and offspring. When animal
studies do not meet current standards
for nonclinical developmental toxicity
studies, the labeling must so state. The
final rule requires that when there are
no animal data, the ‘‘Risk Summary’’
must so state.
• Adds a ‘‘Risk statement based on
pharmacology’’ to the ‘‘Risk Summary,’’
requiring that when the drug has a wellunderstood mechanism of action that
may result in drug-associated adverse
developmental outcome(s), the ‘‘Risk
Summary’’ must explain the mechanism
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of action and the potential associated
risks.
• Eliminates the ‘‘Narrative
description of human data’’ requirement
from the ‘‘Risk Summary.’’
• Removes the requirement that the
‘‘Risk Summary’’ refer to the
‘‘Contraindications’’ or ‘‘Warnings and
Precautions’’ sections of the labeling
when those sections contain
information on an increased risk to the
fetus from exposure to the drug.
• The final rule revises the ‘‘Clinical
Considerations’’ component as follows:
Æ Requires headings, to the extent
relevant information is available, for
‘‘Disease-associated maternal and/or
embryo/fetal risk,’’ ‘‘Dose adjustments
during pregnancy and the postpartum
period,’’ ‘‘Maternal adverse reactions,’’
‘‘Fetal/Neonatal adverse reactions,’’ and
‘‘Labor or delivery’’.
Æ Eliminates the ‘‘Inadvertent
exposure during pregnancy’’ heading.
Æ Eliminates the ‘‘Prescribing
decisions for pregnant women’’ heading.
Æ Revises ‘‘risk, if known, to the
pregnant woman and the fetus from the
disease or condition the drug is
indicated to treat’’ (which was the
language used in the proposed rule
under the ‘‘Prescribing decisions for
pregnant women’’ heading) to ‘‘serious
known or potential risk to the pregnant
woman and/or the embryo/fetus
associated with the disease or condition
for which the drug is indicated to be
used’’ and places this information under
the new heading ‘‘Disease-associated
maternal and/or embryo/fetal risk.’’
Æ Under ‘‘Dose adjustments during
pregnancy and the postpartum period,’’
requires the inclusion of information
about dose adjustments during
pregnancy and the postpartum period if
supported by pharmacokinetic data.
Æ Under ‘‘Dose adjustments during
pregnancy and the postpartum period,’’
removes the requirement that, if there
are no data on dosing in pregnancy, the
labeling must so state.
Æ Under ‘‘Maternal adverse
reactions,’’ replaces the proposed
requirement that the ‘‘labeling must
describe any interventions that may be
needed (e.g., monitoring blood glucose
for a drug that causes hyperglycemia in
pregnancy)’’ with the requirement that
the labeling include a description of
available intervention(s) for monitoring
or mitigating the reaction.
Æ Adds a requirement that the
labeling include relevant information
about fetal/neonatal adverse reactions
under the heading ‘‘Fetal/Neonatal
adverse reactions’’.
Æ Under ‘‘Fetal/Neonatal adverse
reactions,’’ replaces the phrase ‘‘will
cause a complication in the neonate’’
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with ‘‘increases or may increase the risk
of an adverse reaction in the fetus or
neonate.’’
Æ Under ‘‘Fetal/Neonatal adverse
reactions,’’ replaces ‘‘the severity and
reversibility of the complication’’ with
‘‘the potential severity and reversibility
of the adverse reaction,’’ and replaces
‘‘general types of interventions, if any,
that may be needed’’ with ‘‘available
intervention(s) for monitoring or
mitigating the reaction.’’
Æ Under ‘‘Fetal/Neonatal adverse
reactions,’’ adds a requirement that the
labeling must describe, if known, the
effect of dose, timing, and duration of
exposure on the risk.
Æ Revises the heading ‘‘Drug effects
during labor or delivery’’ to ‘‘Labor or
delivery.’’
Æ Under ‘‘Labor or delivery,’’ revises
‘‘[i]f the drug has a recognized use
during labor or delivery, whether or not
the use is stated as an indication in the
labeling, or if the drug is expected to
affect labor or delivery’’ to ‘‘[i]f the drug
is expected to affect labor or delivery.’’
Æ Under ‘‘Labor or delivery,’’ revises
‘‘the possibility of complications,
including interventions, if any, that may
be needed’’ to ‘‘the increased risk of
adverse reactions, including their
potential severity and reversibility.’’
Æ Under ‘‘Labor or delivery,’’ adds a
requirement that the labeling provide
information about available
intervention(s) that can mitigate effects
and/or adverse reactions.
Æ Under ‘‘Labor or delivery,’’ clarifies
that the information described under
that heading is not required for drugs
approved only for use during labor and
delivery.
Æ Under ‘‘Labor or delivery,’’
eliminates the requirement that the
labeling include information about the
effect of the drug on the later growth,
development, and functional maturation
of the child.
• The final rule revises the ‘‘Data’’
subheading of labeling as follows:
Æ Replaces ‘‘provide an overview of
the data that were the basis for the fetal
risk summary’’ with ‘‘describe the data
that are the basis for the Risk Summary
and Clinical Considerations.’’
Æ Requires the inclusion of the
subheading ‘‘Data,’’ and the headings
‘‘Human Data’’ and ‘‘Animal Data,’’ to
the extent available information is relied
on in the Risk Summary and Clinical
Considerations subheadings.
Æ Separates the requirements for
human data from the requirements for
animal data.
Æ For human data, requires that the
labeling describe adverse developmental
outcomes, adverse reactions, and other
adverse effects and, to the extent
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applicable, the types of studies or
reports, number of subjects and duration
of each study, exposure information,
and limitations of the data. Requires
that both positive and negative study
findings be included.
Æ For animal data, retains the
requirement that the labeling describe
the types of studies, animal species,
dose, duration and timing of exposure,
and adds the requirement that the
labeling also describe study findings,
presence or absence of maternal
toxicity, and limitations of the data.
Adds the requirement that the
description of maternal and offspring
findings must include information on
the dose-response and severity of
adverse developmental outcomes.
Requires that animal doses or exposures
be described in terms of human dose or
exposure equivalents and that the basis
for those calculations must be included.
2. Lactation
• The final rule revises the ‘‘Risk
Summary’’ as follows:
Æ Requires that when relevant human
or animal lactation data are available,
the ‘‘Risk Summary’’ must include a
cross-reference to ‘‘Data’’ in the
‘‘Lactation’’ subsection.
Æ Removes the proposed
standardized statement ‘‘The use of
(name of drug) is compatible with
breastfeeding.’’
Æ Requires that when human data are
available, animal data must not be
included unless the animal model is
specifically known to be predictive for
humans.
Æ Requires that when use of a drug is
contraindicated during breastfeeding,
this information must be stated first in
the ‘‘Risk Summary.’’
Æ Revises the standardized statement
required when the drug is not absorbed
systemically from (Name of drug) is not
absorbed systemically from (part of
body) and cannot be detected in the
mother’s blood. Therefore, detectable
amounts of (name of drug) will not be
present in breast milk. Breastfeeding is
not expected to result in fetal exposure
to the drug to (Name of drug) is not
absorbed systemically by the mother
following (route of administration) and
breastfeeding is not expected to result in
exposure of the child to (name of drug).
Æ Revises the order of the types of
information required if the drug is
systemically absorbed as follows: (1)
Presence of drug in human milk, (2)
effects of drug on the breast-fed child,
and (3) effects of drug on milk
production.
Æ Replaces proposed standardized
statements regarding the presence of the
drug in human milk with a requirement
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that the ‘‘Risk Summary’’ state whether
the drug and/or its active metabolites
are present in human milk, and when
there are no data to assess this, the
‘‘Risk Summary’’ must so state.
Æ Under ‘‘Presence of drug in human
milk,’’ requires that if studies
demonstrate the presence of the drug
and/or its active metabolites in human
milk, the ‘‘Risk Summary’’ must state
the concentration of the drug and/or its
active metabolites in human milk and
the actual or estimated daily dose for an
infant fed exclusively with human milk.
The estimated amount of drug and/or its
active metabolites ingested by the infant
must be compared to the labeled infant
or pediatric dose, if available, or to the
maternal dose.
Æ Under ‘‘Presence of drug in human
milk,’’ retains the requirement that if
studies demonstrate that the drug and/
or its active metabolite(s) are not
detectable in human milk, the Risk
Summary must state the limits of the
assay used.
Æ Under ‘‘Presence of drug in human
milk,’’ adds the requirement that if
studies demonstrate the presence of the
drug and/or its active metabolite(s) in
human milk but the drug and/or its
active metabolite(s) are not expected to
be systemically bioavailable to the
breast-fed child, then the ‘‘Risk
Summary’’ must describe the
disposition of the drug and/or its active
metabolites.
Æ Adds a requirement that if only
animal lactation data are available, the
‘‘Risk Summary’’ must state only
whether or not the drug and/or its active
metabolite(s) were detected in animal
milk and specify the animal species.
Æ Under ‘‘Effects of drug on the
breast-fed child,’’ the final rule:
D Adds a requirement that the ‘‘Risk
Summary’’ include available
information on the known or predicted
effects on the child from exposure to the
drug and/or its active metabolite(s)
through human milk or from contact
with breast or nipple skin from a topical
product.
D Requires the inclusion of
information about systemic and/or local
adverse reactions.
D Requires that the ‘‘Risk Summary’’
state if there are no data to assess the
effects of the drug and/or its active
metabolite(s) on the breast-fed child.
Æ Under ‘‘Effects of drug on milk
production,’’ the final rule:
D Replaces the proposed requirement
that the ‘‘Risk Summary’’ describe the
effect of the drug on the quality and
quantity of milk, including milk
composition, and the implications of
these changes to the milk on the breastfed child, with the requirement that the
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‘‘Risk Summary’’ must describe the
effects of the drug and/or its active
metabolite(s) on milk production.
D Adds a requirement that when there
are no data to assess the effects of the
drug and/or its active metabolite(s) on
milk production, the ‘‘Risk Summary’’
must so state.
Æ The final rule adds the requirement
that for drugs absorbed systemically,
unless breastfeeding is contraindicated
during drug therapy, the following risk
and benefit statement must appear at the
end of the ‘‘Risk Summary’’: The
developmental and health benefits of
breastfeeding should be considered
along with the mother’s clinical need for
(name of drug) and any potential
adverse effects on the breast-fed child
from the drug or from the underlying
maternal condition.
• Under ‘‘Clinical Considerations,’’
the final rule:
Æ Revises the provisions of the
proposed rule to require that the
labeling include information concerning
ways to minimize exposure to the drug
and/or its active metabolite(s) in the
breast-fed child in situations where the
following conditions are present: The
drug and/or its active metabolite(s) are
present in human milk in clinically
relevant concentrations; do not have an
established safety profile in infants; and
are used either intermittently, in single
doses, or for short courses of therapy.
Æ Adds a requirement that, when
applicable, the labeling must describe
ways to minimize a breast-fed child’s
oral intake of topical drugs applied to
the breast or nipple skin.
Æ Under ‘‘Monitoring for adverse
reactions,’’ replaces the proposed
requirement that the labeling include
information about potential drug effects
in the breast-fed child that could be
useful to caregivers, including
recommendations for monitoring or
responding to those effects, with a
requirement that the labeling must
describe available intervention(s) for
monitoring or mitigating the adverse
reaction(s) presented in the ‘‘Risk
Summary.’’
Æ Eliminates the proposed
requirement that the labeling include
information about dosing adjustments
during lactation.
• Under ‘‘Data,’’ the final rule
replaces the phrase ‘‘provide an
overview of the data’’ with the phrase
‘‘describe the data.’’
3. Females and Males of Reproductive
Potential
• Adds ‘‘8.3 Females and Males of
Reproductive Potential’’ subsection
requiring that when pregnancy testing
and/or contraception are required or
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recommended before, during, or after
drug therapy and/or when there are
human and/or animal data that suggest
drug-associated fertility effects, this
subsection of labeling must contain this
information under the subheadings
‘‘Pregnancy Testing,’’ ‘‘Contraception,’’
and ‘‘Infertility,’’ in that order.
III. Comments on the Proposed Rule
The Agency received 72 comments on
the proposed rule. Comments were
received from prescription drug
manufacturers, trade organizations
representing prescription drug
manufacturers and other interested
parties, professional associations and
organizations representing health care
providers, health care and consumer
advocacy organizations, individual
physicians, pharmacists, consumers,
and others.
Most of the comments supported
FDA’s goal of improving the format and
content of the ‘‘Pregnancy,’’ ‘‘Labor and
delivery,’’ and ‘‘Nursing mothers’’
subsections of prescription drug
labeling, and several of these comments
stated that the proposed rule would
address shortcomings of the previous
labeling regulations. Other comments
noted that the proposed rule would
improve the accessibility of relevant
information, thereby enabling better
informed medical decisions regarding
the risks and benefits of prescription
drug use by pregnant and lactating
women. Although a number of
comments supported all of FDA’s
proposed revisions, many comments
opposed particular aspects of the
proposed rule.
To make it easier to identify
comments and our responses, the word
‘‘Comment’’ and a comment number
appear in parentheses before each
comment’s description, and the word
‘‘Response’’ in parentheses precedes
each response. Similar comments are
grouped together under the same
number. Specific issues raised by the
comments and the Agency’s responses
follow.
A. Proposed Rule as a Whole
1. Plain Language and Intended
Audience
(Comment 1) Several comments
suggested that the language used in the
pregnancy and lactation subsections of
prescription drug labeling should be
clear and accessible to a variety of
audiences. One comment stated that
because the intended audience for
prescription pregnancy and lactation
labeling is females of reproductive
potential and their health care
providers, this portion of prescription
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drug labeling should not include overly
technical information. Another
comment suggested that to make the
information more accessible to the
general public, FDA should include a
plain language summary of the
pregnancy and lactation subsections.
Two comments suggested that because
females of reproductive potential may
read the ‘‘Pregnancy’’ and ‘‘Lactation’’
subsections of labeling, FDA should
include a statement that encourages
patients to always consult a health care
provider before discontinuing
medication. Another comment
questioned how patients would access
the proposed information and asked
whether it would be included in
patient-specific information that
patients receive at the pharmacy.
Several other comments suggested that
the final rule should aim to create userfriendly labeling that contains a concise
and accurate presentation of
information that is of clinical relevance.
(Response) FDA acknowledges that
some females of reproductive potential
may use prescribing information in the
‘‘Pregnancy’’ and ‘‘Lactation’’
subsections of prescription drug
labeling. The intended audience of
prescription drug labeling, however, is
health care providers, and it is the
responsibility of the prescribing health
care provider to communicate pertinent
information regarding drug risks and
benefits and proper use to his or her
patient. For this reason, we have
determined that it is not appropriate to
require a summary of the ‘‘Pregnancy’’
and ‘‘Lactation’’ subsections of labeling
as a mechanism for all patients to
readily access full prescribing
information, or a statement that
encourages patients to always consult a
health care provider before
discontinuing medication. We note that
in addition to the professional labeling
that is the subject of this rulemaking,
some drugs also have FDA-approved
patient labeling specifically written for
the consumer, such as Medication
Guides (see 21 CFR part 208). Whether
the information required under the final
rule will be included in FDA-approved
patient labeling for an individual drug
will be decided on a case-by-case basis
in accordance with the applicable FDA
regulations and guidance.
2. Scope of the Rule
(Comment 2) Several comments
suggested that FDA expand the scope of
the rule in various ways. Two comments
suggested that the rule be expanded to
include nonprescription products. Four
comments suggested that the proposed
content changes also apply to drugs for
which an application was approved
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before June 30, 2001, although a
separate comment agreed with the
proposal to limit the rule to drugs for
which an application was approved on
or after June 30, 2001. One comment
suggested that the rule be expanded to
include vaccine products (we discuss
this suggestion later in our response to
Comment 8). Two other comments
suggested that the rule provide
incentives to industry to perform
studies on the use of drugs and
biological products during pregnancy
and lactation. One comment suggested
that depression should not be treated
pharmacologically during pregnancy,
whereas a separate comment suggested
that FDA ban the use of all drugs and
vaccines during pregnancy. Another
comment suggested that the
presentation of the information required
under the rule be standardized as much
as possible with applicable coding
schema for ease of implementation in
databases or electronic health record
systems.
(Response) FDA has considered these
comments and declines to expand the
scope of the final rule in any of the
suggested ways. This final rule amends
our labeling regulations in §§ 201.57
and 201.80, which apply only to
prescription drug and biological
products. It is therefore not within the
scope of this rulemaking to address
pregnancy and lactation labeling for
nonprescription drug products.
The primary purpose of this final rule,
and prescription drug labeling in
general, is to facilitate informed
prescribing and safe and effective
product use. FDA recognizes the
importance of use of labeling
information in electronic health records
and other databases and agrees that, if
possible, the presentation of information
in labeling should facilitate its
accessibility. However, this final rule is
not designed to standardize the required
information with a coding schema for
use in databases or electronic health
record systems. It is also beyond the
scope of this rule to address incentives
for collecting data on the use of drugs
and biological products during
pregnancy and lactation.
FDA does not make recommendations
about whether particular diseases or
conditions should or should not be
treated pharmacologically, though we
specifically decline the suggestion to
ban the use of all drugs during
pregnancy. We note that many diseases
and conditions are associated with
adverse pregnancy outcomes when not
appropriately managed during
pregnancy, and under-treating or not
treating a pregnant woman’s medical
condition may put the woman’s health
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in danger, and is often associated with
greater risk to the developing fetus than
the risk of exposure to a maternal drug.
FDA also declines the suggestion that
the content changes required by this
final rule also apply to drugs for which
an application was approved before
June 30, 2001. In developing this rule,
FDA considered the scientific,
economic, and practical implications of
alternative approaches, including
requiring implementation of the content
and format requirements for the
‘‘Pregnancy,’’ ‘‘Lactation,’’ and
‘‘Females and Males of Reproductive
Potential’’ subsections of labeling for all
drugs, regardless of approval date. FDA
concluded that requiring the content
and format changes only for drugs for
which an application was approved on
or after June 30, 2001, (as described in
the ‘‘Implementation’’ section of this
document) best balanced the public
health benefits and the economic and
other costs of these labeling changes. In
addition, this approach provides
conformity with the rest of prescription
drug labeling and the scope is consistent
with the scope of the PLR. FDA,
however, encourages voluntary
compliance with these content and
format changes for drugs for which an
application was approved before June
30, 2001.
3. Combining the ‘‘Pregnancy’’ and
‘‘Lactation’’ Subsections
(Comment 3) One comment suggested
that the ‘‘Pregnancy’’ and ‘‘Lactation’’
subsections should be combined for
certain drugs. The comment explained
that combining these sections would be
useful, for example, in helping health
care providers counsel women who take
selective serotonin reuptake inhibitors
(SSRIs) for the treatment of perinatal
depression because clinicians have to
consider the effects of the medication
during both pregnancy and the
postpartum period.
(Response) FDA disagrees. The risk
and benefit considerations for drug
product use are different between
pregnant and lactating patients, and we
have determined that the information is
best presented in separate but adjacent
subsections of labeling. FDA believes
that if the sections were combined it
would be more difficult for a health care
provider who has either a pregnant or a
lactating patient to locate the
information relevant to the prescribing
decision. For anticipatory counseling,
for which the health care provider is
discussing the use of the drug with a
pregnant patient who in the future may
be lactating, we believe that having
‘‘Lactation’’ denoted in a separate,
numbered, indexed, and searchable
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subsection of labeling will not make it
harder for a prescriber to find this
information.
4. Updates
In the preamble to the proposed rule,
FDA stated that under § 201.56(a) ‘‘the
labeling must be updated when new
information becomes available that
causes the labeling to become
inaccurate, false, or misleading’’ (73 FR
30831 at 30841). The Agency also
explained that ‘‘[w]hen new human data
concerning the use of a drug during
pregnancy becomes available, if that
information is clinically relevant, FDA
believes that it is necessary for the safe
and effective use of the drug and,
therefore, the pregnancy subsection of
the labeling must be updated to include
that information. Failure to include
clinically relevant new information
about the use of a drug during
pregnancy could cause the drug’s
labeling to become inaccurate, false, or
misleading’’ (73 FR 30831 at 30841).
(Comment 4) Several comments
requested that FDA clarify its
expectations for the process and timing
of updating the ‘‘Pregnancy’’ and
‘‘Lactation’’ subsections of labeling after
new data become available. Two of
these comments stated that the data
should be updated regularly or
continually. Another comment stated
that the labeling should be updated
annually. Several other comments
requested that FDA define the quantity
and quality of data that necessitates that
the labeling be updated. One of these
comments suggested that FDA state in
the final rule that the labeling should be
updated if the benefit-risk profile
changes because of new information,
and that labeling changes should be
done according to ‘‘current labeling
regulations.’’ Another comment
questioned whether health care
providers will be informed of changes to
the ‘‘Pregnancy’’ and ‘‘Lactation’’
subsections of labeling. One comment
suggested that sponsors electronically
post supplemental information before
updated printed labeling is available,
and another suggested using
surveillance systems to facilitate
obtaining updated safety information.
Two comments expressed specific
concern that the ‘‘Lactation’’ subsection
of drug labeling will not be updated
frequently enough to be useful for
clinicians. One of these comments
stated that it is critical to routinely
update labeling as human lactation data
becomes available. A separate comment
suggested including references in
labeling to online resources regarding
lactation data to provide prescribers and
patients with updated information.
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(Response) The requirements for
labeling updates described in
§ 201.56(a) apply to this final rule as
follows: The labeling must be
informative and accurate and neither
promotional in tone nor false or
misleading in any particular. In
accordance with §§ 314.70 and 601.12 of
the chapter, the labeling must be
updated when new information
becomes available that causes the
labeling to become inaccurate, false, or
misleading (§ 201.56(a)(2)). With respect
to the comment about updating labeling
as human lactation data becomes
available, although § 201.56(a)(3) states
that the labeling must be based
whenever possible on data derived from
human experience, it also requires that
conclusions based on animal data but
necessary for safe and effective use of
the drug in humans must be identified
as such and included with human data
in the appropriate section of the
labeling.
Because studies are not usually
conducted in pregnant women prior to
approval, most of the data regarding use
in pregnancy and lactation will be
collected in the postmarketing setting.
Accordingly, in order that a drug
product does not become misbranded,
the labeling must be updated when new
information becomes available that
causes the labeling to become
inaccurate, false, or misleading.
Applicants are responsible for following
the medical literature and also for
updating labeling as new published and
unpublished data become available.
FDA declines the suggestion to include
references to online resources regarding
drug use during lactation because the
information has not been reviewed by
FDA.
Office of New Drugs at the Center for
Drug Evaluation and Research, includes
staff with expertise in obstetrics,
lactation, pediatrics, clinical pharmacy,
and regulatory science. The DPMH is
available for consultation by all FDA
drug product review divisions to whom
the final rule applies for all issues
related to labeling content and for
review of data on the use of drugs
during pregnancy and lactation. The
DPMH, by working across review
divisions, helps to ensure consistent
application of FDA pregnancy and
lactation labeling regulations to
different drug products. The DPMH also
provides consultation services to and
works collaboratively with other Offices
and Centers at FDA. FDA intends to
provide staff with education and
training on the changes in the labeling
regulations.
5. Responsibility for Drafting and
Reviewing Labeling
(Comment 5) One comment requested
that FDA clarify whether industry or
FDA would be responsible for writing
and reviewing the new labeling. The
comment also questioned whether FDA
would provide staff with the training
and expertise to make necessary
judgments. Another comment expressed
concern about the potential for
inconsistent implementation of the new
rule by FDA’s review divisions. This
comment suggested that to increase
labeling consistency, the Agency should
establish a group of FDA specialists that
review pregnancy and lactation labeling.
(Response) As with all prescription
drug labeling, both the manufacturer
and FDA reviewers will play a shared
role in determining the new labeling
content. The Division of Pediatrics and
Maternal Health (DPMH), within the
7. Guidance on Formulating Labeling
(Comment 7) FDA received one
comment requesting that the Agency
provide clear guidance to manufacturers
regarding how to formulate the
pregnancy and lactation labeling
subsections.
(Response) Concurrent with the
publication of this final rule, FDA is
issuing a draft guidance for industry on
‘‘Pregnancy, Lactation, and
Reproductive Potential: Labeling for
Human Prescription Drug and Biological
Products—Content and Format’’ (the
draft guidance on pregnancy and
lactation labeling).5 The draft guidance
is intended to assist applicants in
drafting the ‘‘Pregnancy,’’ ‘‘Lactation,’’
and ‘‘Females and Males of
Reproductive Potential’’ subsections of
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6. Process for Development of the
Proposed Rule
(Comment 6) One comment stated
that FDA should have included
pharmacists in the focus tests used
during development of the proposed
rule.
(Response) FDA acknowledges the
critical role that pharmacists play in
communicating drug information both
to patients and health care providers.
However, during the development of the
proposed rule, FDA’s priority was to
understand the information health care
providers need to most effectively make
prescribing decisions that consider both
the risk and benefit to the mother and
her fetus or child. Therefore, the focus
testing was limited to health care
providers who both care for and
prescribe for pregnant and lactating
women.
5 This guidance, when finalized, will represent
FDA’s current thinking on this topic.
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labeling for prescription drug products.
It provides recommendations for
applicants revising labeling of already
approved products and for applicants
drafting labeling for new products that
will be submitted as part of an NDA or
BLA.
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8. Blood Products and Vaccines
(Comment 8) FDA received two
comments regarding the applicability of
the proposed rule to certain biological
products. One comment requested that
the final rule be expanded to include
vaccine products. The other comment
stated that blood products are not
affected by the rule and requested that
this be noted when the final rule is
published.
(Response) This final rule applies to
vaccine products. Vaccine products are
prophylactic biological products that are
developed and labeled to prevent
specific diseases in specific
populations. The types of information
that must be communicated about a
vaccine, in general, parallel the types of
information that must be communicated
about a drug or therapeutic biologic
through labeling to facilitate safe and
effective use, although there are some
unique considerations for vaccines
addressed in the draft guidance on
pregnancy and lactation labeling, which
is being published concurrently with
this final rule.
We disagree that blood products are
not affected by the final rule. The final
rule applies to any biological products,
including blood products, that are
subject to the PLR.
9. Numbering of ‘‘Pregnancy’’ and
‘‘Lactation’’ Subsections
(Comment 9) FDA proposed that the
identifying numbers and titles for the
new labeling content under the section
‘‘8 Use in Specific Populations’’ would
be 8.1 for ‘‘Pregnancy’’ and 8.2 for
‘‘Lactation.’’ FDA stated in the proposed
rule that the identifying number 8.3
would be available for future use (73 FR
30831 at 30838). Two comments
pointed out that under this proposal, the
next subsections after ‘‘8.2 Lactation’’
will be ‘‘8.4 Pediatric Use’’ and ‘‘8.5
Geriatric Use.’’ These comments stated
that the absence of subsection 8.3 may
be confusing and suggested that FDA
renumber the subsections. One
comment requested that FDA clarify
whether the Agency has a specific use
in mind for 8.3 and, if it does not,
suggested that the Agency renumber the
subheadings to ‘‘8.3 Pediatric Use’’ and
‘‘8.4 Geriatric Use.’’ The comment
explained that if a future need for an
additional subsection arose, it could
become 8.5.
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(Response) As discussed in further
detail in section III.B of this document,
in this final rule, FDA designates 8.3 as
‘‘Females and Males of Reproductive
Potential.’’ Accordingly, we are no
longer reserving 8.3 for future use.
10. International Harmonization
(Comment 10) Two comments
suggested that prescription drug
labeling should be consistent at an
international level to reduce confusion
among health care providers, patients,
and regulators interpreting the risks and
benefits associated with drug use during
pregnancy and lactation.
(Response) FDA declines to adopt this
suggestion because it is beyond the
scope of this rule to address the
international harmonization of
prescription drug labeling. Although we
acknowledge the importance of working
with our international regulatory
colleagues to harmonize drug
development and drug regulatory
science where appropriate and
beneficial, we also recognize that there
is great variation internationally in
health care systems, access to care and
drugs, and the regulation and marketing
of drugs. The final rule reflects our
judgment regarding the most useful
pregnancy and lactation prescription
drug labeling for prescribers in the
United States, which may not be
applicable to prescribers in all other
countries.
11. Examples in an Appendix
(Comment 11) The proposed rule
included an appendix containing
examples, based on the proposed rule,
of pregnancy and lactation labeling for
fictitious drugs.
FDA received several comments
suggesting that the examples be revised
or expanded. One comment requested
that in the final rule, FDA provide
additional examples of sample labeling,
including examples for which extensive
data exists. Another comment suggested
that the information included in the
sample labeling for the fictitious drug
products did not reflect the amount of
data that is typically available. The
comment explained that the examples
would be more useful if they presented
situations where there is extensive data.
Several other comments pointed out
that the terminology in the examples
was not consistent with the terminology
in the proposed rule.
(Response) FDA has not included
sample drug labeling with the final rule.
The draft guidance on pregnancy and
lactation labeling, which is being
published concurrently with this final
rule, provides information about how to
interpret and apply the rule to labeling
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development. Labeling development is a
detailed and iterative process unique to
each prescription drug product, a
process that is driven by the product’s
characteristics and actions, the efficacy
and safety data submitted to the Agency,
and the conditions and populations for
and in which the product is intended to
be used. Accordingly, FDA has
concluded that the development of
fictitious product labeling would not be
useful to drug developers or FDA
reviewers who will be responsible for
developing, revising, and approving
product labeling under this new final
rule.
12. Cross-Referencing
FDA proposed that when the risk
conclusion in the fetal risk summary is
based solely on animal data, it must
include a cross-reference to the ‘‘Data’’
component of the ‘‘Pregnancy’’
subsection, and the effects found in
animals must be described in the ‘‘Data’’
component (73 FR 30831 at 30842).
(Comment 12) One comment
suggested that any cross-references to
the ‘‘Data’’ or ‘‘Clinical Considerations’’
components made anywhere in labeling
specify whether the cross- reference is
to the component in the ‘‘Pregnancy’’
subsection or the component in the
‘‘Lactation’’ subsection. Another
comment explained that the rule would
benefit from extensive use of crossreferencing within the text of each
section to ensure that the bases for the
risk conclusions are thoroughly
understood, regardless of whether the
risk conclusions are based on human or
animal data, for both the ‘‘Pregnancy’’
and ‘‘Lactation’’ subsections.
(Response) FDA agrees that any crossreferences to components of ‘‘8.1
Pregnancy’’ or ‘‘8.2 Lactation’’ must
specify whether the cross-reference is to
the component in the ‘‘Pregnancy’’
subsection or the component in the
‘‘Lactation’’ subsection. Accordingly, in
the final rule, when applicable, risk
statements in the ‘‘Pregnancy’’
subsection must include a crossreference to additional details in the
relevant portion of the ‘‘Data’’
subheading in the ‘‘Pregnancy’’
subsection. Also in the final rule, when
relevant human and/or animal lactation
data are available, the ‘‘Risk Summary’’
must include a cross-reference to the
relevant portion of ‘‘Data’’ in the
‘‘Lactation’’ subsection.
13. Need for Educational Campaign
(Comment 13) FDA received one
comment suggesting that the Agency
develop educational campaigns for
patients and health care providers
regarding the changes to pregnancy and
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lactation drug labeling brought about by
this rulemaking.
(Response) FDA is developing
educational materials for FDA staff,
health care providers, and patients to
inform them about the changes in these
labeling regulations and how these
changes will have a positive impact on
labeling regarding the use of drugs and
biologics during pregnancy and
lactation. The draft guidance on
pregnancy and lactation labeling is
being published concurrently with this
final rule; however, additional materials
may be completed following this date.
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14. Inventory
(Comment 14) FDA received one
comment requesting that the final rule
address how distributors should manage
drug products in their inventory that
have outdated labeling. The comment
suggested that product inventory
without the revised labeling should
remain in the supply chain until the
labeled product’s expiration date,
regardless of whether the product bears
the new labeling.
(Response) For previously approved
products, the implementation plan gives
sponsors a minimum of 3 years after the
effective date of this final rule to submit
labeling with the new content and
format. As we explained in the
preamble to the proposed rule, FDA
believes that this 3-year period will
allow industry sufficient time to use up
any existing labeling stock such that
none will remain in the supply chain
after the product bears the new labeling
(73 FR 30831 at 30846).
15. Highlights
FDA’s regulations require that all
prescription drug labeling described in
§ 201.56(b)(1) contain ‘‘Highlights of
prescribing information’’ (§ 201.57(a)).
(Comment 15) Two comments
requested that FDA clarify which
elements of the ‘‘Pregnancy’’ and
‘‘Lactation’’ subsections are likely to be
included in the ‘‘Highlights of
prescribing information.’’ One of the
comments expressed hope that adoption
of the rule will promote standardization
with respect to which elements are
elevated to the ‘‘Highlights of
prescribing information,’’ thereby
facilitating consistent interpretation and
implementation of the rule’s
requirements among FDA reviewers and
review divisions.
(Response) The requirements for
placement of information in the
‘‘Highlights of prescribing information’’
are specified in § 201.57(a). This final
rule does not revise or change the
requirements for the ‘‘Highlights of
prescribing information.’’ Additional
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discussion of FDA’s recommendations
on the content of the ‘‘Highlights of
prescribing information’’ may be found
in FDA’s guidance for industry on
‘‘Labeling for Human Prescription Drug
and Biological Products—Implementing
the PLR Content and Format
Requirements’’ (February 2013).6
October 5, 2011). Based on this analysis,
to the extent that the discussion in the
proposed rule relied on the discussion
about preemption in the preamble to the
PLR, we conclude that the statements
we made regarding preemption in the
preamble to the proposed rule are also
not justified.
16. Preemption of State Law
In the preamble to the proposed rule,
FDA included a discussion in the
Federalism section that referred to a
more extensive discussion and analysis
in the PLR regarding the preemption of
product liability lawsuits.
(Comment 16) Comments expressed
different views about this discussion.
One comment suggested that in the final
rule FDA revise the preamble to
eliminate any reference to the
preemption of product liability lawsuits.
Another comment expressed its
appreciation of FDA’s view that the rule
would preempt state laws that conflict
with its requirements. This comment
also expressed its support for FDA’s
intention to consult with State and local
officials in an effort to avoid conflict
between State law and federally
protected interests.
(Response) FDA’s statement regarding
preemption in the proposed rule relied
on statements made in the preamble to
the PLR (71 FR 3922). In the preamble
to the PLR, FDA discussed its views on
the preemptive effect of both that
regulation’s codified provisions and the
FD&C Act. Subsequent to the
publication of the May 2008 proposed
rule, the Supreme Court, in Wyeth v.
Levine (555 U.S. 555 (2009)), addressed
the preamble to the PLR and held that
a State tort claim that an NDA-approved
drug should have had a stronger
warning was not preempted by the
FD&C Act or FDA’s labeling
requirements. Following the Court’s
decision in Wyeth, FDA concluded that
the position on preemption we
articulated in the preamble to the PLR
cannot be justified under legal
principles governing preemption
(Preemption Review, 76 FR 61565,
B. Specific Provisions of the Proposed
Rule
6 U.S. Food and Drug Administration, ‘‘Guidance
for Industry, Labeling for Human Prescription Drug
and Biological Products—Implementing the PLR
Content and Format Requirements,’’ (February
2013), available at https://www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM075082.pdf. Many guidances are
referenced throughout this document. The guidance
referred to in this footnote, as well as others
referenced throughout the remainder of the
document, can be found on the FDA Drugs
guidance Web page at https://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/
Guidances/default.htm. We update guidances
periodically. To make sure you have the most
recent version of a guidance, check the FDA Drugs
guidance Web page.
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1. 8.1 Pregnancy
a. Comments related to the pregnancy
subsection as a whole.
i. Order of subsections—FDA
proposed that information appear in
subsection ‘‘8.1 Pregnancy’’ in the
following order: (1) Pregnancy exposure
registry (if applicable), (2) general
statement about background risk, (3)
fetal risk summary, (4) clinical
considerations, and (5) data (proposed
§ 201.57(c)(9)(i)). In the proposed rule,
FDA sought comment on how these
elements should be ordered to optimize
the clinical usefulness of this labeling
subsection (73 FR 30831 at 30839).
Specifically, FDA asked whether the
‘‘Fetal Risk Summary’’ should precede
the pregnancy exposure registry
information and the statement about
background risk.
(Comment 17) Comments expressed
different opinions about the proposed
order of information in the ‘‘Pregnancy’’
subsection of labeling. Three comments
agreed with the proposed order. One of
these comments explained that the
proposed order will maximize a
physician’s ability to find and
understand important pregnancy-related
information about a given drug product.
Another comment explained that
placing the pregnancy exposure registry
information first is preferable because if
this information were placed after the
‘‘Risk Summary,’’ it may be interpreted
to imply that the pregnancy exposure
registry exists because of the data in the
fetal risk summary. One comment
supported placing the pregnancy
exposure registry information first so
that it will appear more visible in
labeling.
Many comments disagreed with the
proposed order and suggested a variety
of alternatives. Six comments suggested
that the ‘‘Fetal Risk Summary’’
subheading be placed first because it
contains the most important and useful
information. One of these comments
pointed out that past FDA advisory
committees have suggested that
summary information should be placed
first. Two comments suggested that the
‘‘Background Risk Statement’’ should be
first followed by the ‘‘Fetal Risk
Summary.’’ These comments explained
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that the most important information
should be placed first, as recommended
by FDA advisory committees. Three
comments suggested that the pregnancy
exposure registry information be placed
last. Another comment suggested that
the information be placed in the
following order: Pregnancy exposure
registry information, clinical
considerations, fetal risk summary, data,
and background risk statement.
(Response) FDA has determined that
placing the pregnancy exposure registry
information first under ‘‘8.1 Pregnancy’’
best balances the objectives of this
rulemaking. Although we agree that the
‘‘Risk Summary’’ information is most
important to prescribers and we
acknowledge that the advisory
committee expressed a preference for
placing the most important information
first, it is also clear that stakeholders
desire greater quality and quantity of
human data in pregnancy labeling. FDA
believes that the benefits of prominently
placing information about pregnancy
registry availability at the beginning of
‘‘8.1 Pregnancy’’ outweigh the
downsides of a minor decreased
prominence of the ‘‘Risk Summary’’
information, which appears
immediately after the information under
‘‘Pregnancy Exposure Registry.’’ Many
health care providers are still learning
about pregnancy exposure registries and
their purpose. We have concluded that
routinely placing this information first
in pregnancy labeling may increase
pregnancy registry enrollment, the
quality of human data that emerge from
these studies, and the quality of
pregnancy labeling (including the ‘‘Risk
Summary’’) that follows. Because we
agree that the information under ‘‘Risk
Summary’’ is most important to
prescribers, we also decline the
suggestion to place the ‘‘Risk Summary’’
after ‘‘Clinical Considerations.’’ The
‘‘Pregnancy’’ subsection will include, in
this order, information under
‘‘Pregnancy Exposure Registry,’’ as
applicable, ‘‘Risk Summary,’’ ‘‘Clinical
Considerations,’’ as applicable, and
‘‘Data,’’ as applicable.
ii. Removal of the pregnancy
categories—FDA proposed to remove
the pregnancy categories from all
prescription drug labeling. As discussed
in greater detail in section I of this
document, in 1979 FDA adopted a
pregnancy category system that was
used to convey risk and benefit
information related to potential or
documented human teratogenic risk and
potential maternal/fetal benefits
associated with drug treatment during
pregnancy. Under the 1979 regulations,
each drug product was identified with
a pregnancy category: A, B, C, D, or X.
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Categories were not used to characterize
the risks and benefits associated with
drug treatment by lactating women.
FDA proposed to remove pregnancy
categories from all prescription drug
labeling because we determined that the
categories were confusing and did not
accurately and consistently
communicate differences in degrees of
fetal risk (73 FR 30831 at 30846).
(Comment 18) Comments expressed
different opinions about whether the
elimination of the pregnancy category
system, in full or in part, would
improve or diminish the usefulness of
the Pregnancy subsection of
prescription drug labeling. FDA
received 11 comments from medical
associations, women’s and reproductive
health advocacy organizations,
toxicologists, individual health care
practitioners, pharmacists, and drug
manufacturers specifically supporting
our proposal to retire the pregnancy
category system. Several of these
comments explained that the categories
were confusing or misleading. One of
the comments stated that although the
use of pregnancy categories is easier for
some practitioners, it results in
miscommunication and errors in
decisionmaking. Another comment
explained that reliance on the categories
may result in poorly informed clinical
decisionmaking.
FDA received 16 comments from
physicians, pharmacists, pharmacy
associations, nurses, manufacturers,
drug safety consultants, and individual
consumers, requesting that FDA either
retain the pregnancy category system or
replace the pregnancy category system
with another standardized schema.
Many of these comments suggested that
FDA add the additional narrative
information as proposed, but also retain
the category system. Two of these
comments explained that the pregnancy
categories are simple and effective, and
the new information may confuse
patients or prescribers. Another
comment stated that without a
standardized schema, there will not be
a consistent and useful format for
decisionmaking. Other comments
agreed that the pregnancy categories
need to be revised but suggested that
FDA develop new standardized
statements or categories or revise the
bases for the current categories. Two
comments urged FDA to maintain an
‘‘X’’-like category for drugs where the
risks outweigh any benefit to a pregnant
or nursing patient, and one comment
urged FDA to maintain an ‘‘X’’-like
category so that providers and patients
could easily identify those drugs that
are contraindicated for the mother,
fetus, and/or a breastfeeding infant.
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A separate comment supported FDA’s
proposal to eliminate the pregnancy
categories but thought they should be
retained until the implementation of the
final rule is complete.
(Response) FDA has determined that
retaining the pregnancy categories is
inconsistent with the need to accurately
and consistently communicate
differences in degrees of fetal risk. As
discussed in the proposed rule, the
current pregnancy category system has
long been criticized as being confusing
and overly simplistic (73 FR 30831 at
30833–30834). Through experience and
stakeholder feedback, FDA learned that
the pregnancy categories were heavily
relied upon by clinicians but
misinterpreted, misunderstood, and
erroneously used as a grading system
where fetal risk increased from A to X.
The categories gave the incorrect
impression that drugs in the same
category carried the same risk or
potential for human adverse
developmental outcomes. In addition,
the categories did not discriminate
among risk information obtained from
nonclinical animal studies and
postmarketing human studies and did
not discriminate among drugs
associated with adverse outcomes of
differing severity or incidence.
Stakeholders also pointed out that the
pregnancy categories focused on
structural abnormalities and thus did
not adequately address the full range of
potential developmental toxicities.
As described in greater length in the
preamble of the proposed rule, FDA
carefully explored a multitude of
models to determine whether the former
pregnancy category system or a different
pregnancy category system could
accurately and consistently
communicate differences in degrees of
fetal risk (73 FR 30831 at 30833–30837).
FDA found that when it applied these
criteria to actual animal and human data
findings for drugs with known risk
profiles, none of the models produced
clinically informative and reliable
differentiations of risk (73 FR 30831 at
30838). Prescribing and drug-use
decisions during pregnancy require
consideration of not only fetal risk
information, but also of various clinical
and individual factors, including
maternal drug effects, the severity of
maternal disease, maternal tolerance of
the drug, coexisting maternal
conditions, the impact of maternal
disease on the fetus, and available
alternative therapies. FDA concluded
that continuing to use a category system
to characterize the risks of drug use
during pregnancy would not be
appropriate because of the complexity
of medical decisionmaking regarding
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drug use during pregnancy (73 FR 30831
at 30838).
FDA continues to believe that a
narrative structure for pregnancy
labeling is best able to capture and
convey the potential risks of drug
exposure based on animal or human
data, or both. This perspective is
consistent with FDA’s approach to other
aspects of product labeling. For
example, numeric or letter or other
categorical gradations of risk have never
been used for safety labeling because
safety and risk are complex constructs
in clinical medicine. For similar
reasons, FDA does not apply symbol or
letter designations of risk to other
potential toxicities or adverse effects
expected with drug product use.
For the reasons discussed previously,
FDA declines the suggestion to maintain
pregnancy category X. We note,
however, that labeling must clearly
identify populations in which use of a
drug is contraindicated. The labeling
regulations in § 201.57 clearly describe
the information that must be included
in the ‘‘Contraindications’’ section and
all contraindications from the full
prescribing information are always
listed in the ‘‘Highlights of prescribing
information’’ (§ 201.57(c)(5)). Therefore,
when use of a drug is contraindicated in
pregnancy, this information must be
stated in the ‘‘Contraindications’’
section and listed in the ‘‘Highlights of
prescribing information,’’ as well as, per
the previous discussion, stated first
under the ‘‘Risk Summary’’ subheading
of the ‘‘Pregnancy’’ subsection of
labeling.
To the extent that the comment
suggests that the pregnancy categories
should be retained for applications
subject to § 201.80 until the
implementation of the new content and
format requirements is complete, we
decline this suggestion; we believe it is
more consistent with the Agency’s
overall concerns with respect to
removing the pregnancy categories to
implement that change within a shorter
timeframe that nevertheless provides
sufficient time for compliance. We
would like to clarify that for
applications required to implement the
new content and format requirements,
the pregnancy categories are required to
be removed at the time the labeling is
revised regardless of whether this will
result in the labeling including a
pregnancy category for more than 3
years after the effective date of the final
rule (as described in the
‘‘Implementation’’ section of this
document in response to Comment 92).
Requiring that the labeling for some
applications be revised twice solely as
part of the implementation of this
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regulation would not be consistent with
the Agency’s goal to avoid
overburdening both the Agency and
industry.
b. Comments related to specific
provisions of 8.1 Pregnancy.
i. Pregnancy exposure registry—FDA
proposed that if there is a pregnancy
exposure registry for a product
described in § 201.56(b)(1) (i.e.,
prescription drug products for which an
application was approved after June 30,
2001), the telephone number or other
information necessary to enroll in the
registry or to obtain information about
the registry must be stated at the
beginning of the ‘‘Pregnancy’’
subsection of prescription drug labeling
(proposed § 201.57(c)(9)(i)(A)). For drug
products that do not have a pregnancy
exposure registry, the proposed rule did
not require the ‘‘Pregnancy’’ subsection
of prescription drug labeling to contain
any statement about pregnancy
exposure registries.
(Comment 19) Comments disagreed
about the mandatory inclusion of
pregnancy exposure registry
information. Many comments supported
the mandatory inclusion of pregnancy
exposure registry information in the
‘‘Pregnancy’’ subsection of prescription
drug labeling. These comments
explained, for example, that including
pregnancy exposure registry information
in labeling may ‘‘encourage patient
involvement in registries’’ and ‘‘pave
the way for improved registry use by
clinicians leading to better
documentation of drug effects and use
during pregnancy.’’
One comment stated that including a
reference to an existing pregnancy
registry should not be mandatory.
(Response) FDA believes that
appropriately conducted pregnancy
registries are an important mechanism
for the collection of clinically relevant
data concerning the effects of exposure
to drugs during pregnancy. The Agency
believes that including information
about pregnancy exposure registries in
prescription drug labeling will
encourage participation in registries,
thereby improving their usefulness.
Thus, if there is a pregnancy registry
that FDA has reviewed and found
scientifically acceptable, FDA is
requiring that the ‘‘Pregnancy’’
subsection of prescription drug labeling
include under its own subheading,
‘‘Pregnancy Exposure Registry,’’ a
standard statement concerning the
existence of the registry, as well as the
contact information necessary to enroll
in the pregnancy exposure registry or to
obtain information about the registry.
The Agency generally considers a
pregnancy exposure registry
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scientifically acceptable when it is
consistent with applicable FDA
guidance, including the guidance for
industry on ‘‘Establishing Pregnancy
Exposure Registries’’ (August 2002). If
there are changes to an existing
pregnancy registry or a new pregnancy
registry is initiated after drug approval,
labeling will need to be updated to
include this new information.
(Comment 20) Two comments sought
clarification regarding the standards for
including contact information for a
pregnancy exposure registry. One
comment stated that contact information
should only be included if the registry
is scientifically acceptable to the
sponsor and FDA. Another comment
asked whether contact information for
non-U.S. registries must be included.
(Response) As stated previously, if
there is a scientifically acceptable
pregnancy registry for a drug product,
FDA is requiring a standard statement
concerning the registry as well as
contact information needed to enroll in
the registry or obtain additional
information about it. For registries that
include U.S. populations, U.S. contact
information should be included in the
labeling, regardless of whether the
registry is maintained within the United
States or elsewhere.
(Comment 21) Four comments
suggested that the pregnancy exposure
registry information should have its
own component header.
(Response) FDA agrees with the
suggestion that the pregnancy exposure
registry information should have its
own component header. In the final
rule, contact information for an existing
pregnancy exposure registry and a
standard statement on the registry will
fall under the subheading ‘‘Pregnancy
Exposure Registry’’ in the ‘‘Pregnancy’’
subsection of prescription drug labeling.
Because of this change, FDA eliminated
the phrase ‘‘must be stated at the
beginning of the ‘Pregnancy’ subsection
of the labeling’’ from the final rule.
(Comment 22) Two comments stated
that it should be easier to enroll patients
in pregnancy exposure registries.
(Response) The importance of subject
recruitment into pregnancy exposure
registries and the need to build
awareness of pregnancy exposure
registries among health care providers
are both factors in FDA’s decision to
place information about existing
pregnancy exposure registries at the
beginning of § 201.57, ‘‘8.1 Pregnancy.’’
The actual process of enrolling patients,
however, is beyond the scope of this
rule.
(Comment 23) Comments expressed
disagreement about whether the
‘‘Pregnancy Exposure Registry’’
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subheading should be omitted from the
‘‘Pregnancy’’ subsection of prescription
drug labeling when there is no existing
registry for the drug. One comment
suggested that the ‘‘Pregnancy Exposure
Registry’’ subheading should not be
omitted even if there is no existing
registry for the drug, and that it should
include a statement that there is no
specific pregnancy exposure registry for
the drug. Another comment requested
that FDA consider incorporating a
statement that the subheading may be
omitted if there is no pregnancy
exposure registry.
(Response) FDA concludes that the
‘‘Pregnancy Exposure Registry’’
subheading should be omitted when
there is no pregnancy exposure registry.
We have determined that requiring the
‘‘Pregnancy Exposure Registry’’
subheading in labeling when there is no
pregnancy exposure registry for the drug
product, and the inclusion of a
statement indicating that no registry
exists, would not further the goal of
improving the collection of data in
pregnant women who are exposed to a
drug.
(Comment 24) One comment
suggested that the labeling should state
the purpose of the pregnancy exposure
registry and provide the contact
information necessary for enrollment.
(Response) FDA agrees that including
a statement in the labeling about the
purpose of the pregnancy exposure
registry would be useful. In the final
rule, FDA requires that if there is a
scientifically acceptable pregnancy
exposure registry for the drug, the
labeling must include a statement that
there is a pregnancy exposure registry
that monitors pregnancy outcomes in
women exposed to the drug during
pregnancy, and include contact
information needed to enroll in the
registry or to obtain information about
the registry. Because the purpose of all
pregnancy registries is to collect
clinically relevant human data that can
be used in a product’s labeling to
provide health care providers with
useful information for treating or
counseling patients who are pregnant or
anticipating pregnancy, we do not
believe it is necessary to include a more
specific statement in labeling about
their purpose.
(Comment 25) Two comments
suggested that pregnancy exposure
registry information be included in
‘‘Highlights’’ and in the ‘‘Patient
Counseling Information’’ section of
labeling. One comment requested that
FDA clarify in guidance whether the
Agency anticipates requesting more
pregnancy registries as a condition of
marketing approval.
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(Response) FDA believes that
including information about pregnancy
exposure registries in the ‘‘Patient
Counseling Information’’ section of
labeling would be useful. If the drug
product has a pregnancy exposure
registry, the availability of a pregnancy
exposure registry should be noted in the
‘‘Patient Counseling Information’’
section of labeling, and a cross-reference
should be included to ‘‘8.1 Pregnancy’’
for the contact information necessary to
enroll. The preamble to the PLR states
that ‘‘Highlights’’ summarizes the
information from the ‘‘Full Prescribing
Information’’ that is most important for
prescribing the drug safely and
effectively and organizes it into logical
groups to enhance accessibility,
retention, and access to the more
detailed information (71 FR 3922 at
3931). Information about the availability
of and contact information for a
pregnancy exposure registry are not
considered essential information for
prescribing and should not appear in
‘‘Highlights’’ (see FDA’s guidance for
industry on ‘‘Labeling for Human
Prescription Drug and Biological
Products—Implementing the PLR
Content and Format Requirements’’
(February 2013)). The question of
whether FDA anticipates requesting
more pregnancy exposure registries as a
condition of marketing approval is
outside the scope of this rule.
In the final rule, FDA revised the
phrase ‘‘telephone number or other
information needed to enroll’’ to
‘‘contact information needed to enroll.’’
FDA determined that this change would
allow for more flexibility in the type of
contact information included under this
portion of the labeling.
ii. Background risk statement—FDA
proposed that a general statement about
the background risk of adverse
pregnancy outcomes be included in
labeling. The proposed rule stated in
§ 201.57(c)(9)(i)(B) that the following
statement was required to be included
in the labeling: All pregnancies have a
background risk of birth defect, loss, or
other adverse outcome regardless of
drug exposure. The fetal risk summary
below describes (name of drug)’s
potential to increase the risk of
developmental abnormalities above the
background risk.
(Comment 26) Two comments
expressed support for the inclusion of a
background risk statement. One of these
comments noted that the statement will
be useful to clinicians when explaining
the fetal risks associated with drug use
during pregnancy.
Several comments suggested
modifying the background risk
statement. One comment suggested that
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applicants be given the option to
identify in the background risk
statement the specific risks described in
the fetal risk summary. The comment
proposed that the second sentence of
the background statement be modified
to state: ‘‘The fetal risk summary below
describes the potential of (name of drug)
to contribute to risk of (‘adverse
outcomes, including developmental
abnormalities’ or identify specific risks)
above background risk.’’
Several comments requested
clarification about whether the
background risk statement refers to the
general population or the population
with the disease. Two other comments
suggested that when the background
risk of adverse outcomes in the relevant
disease population is known to be
higher than in the general population,
this information should be included in
the background risk statement. One of
these comments suggested that relevant
literature citations should also be
included as appropriate.
One comment asked FDA to clarify
how it will determine the background
rate of adverse pregnancy outcomes.
Another comment suggested that FDA
and industry develop a standard
definition of background risk that would
provide a common explanation for all
labeling, both for the general population
and for any specific disease states or
conditions. This comment explained
that different reviewers may look at
different criteria for assessing
background risk (i.e., what constitutes a
developmental abnormality or a
congenital malformation), and a
standard definition would provide for
consistency. A separate comment stated
that the background risks of pregnancy
can vary by demographics, location,
ethnicity, and other variables. The
comment suggested that to maintain
uniform and standardized descriptions
of background risk, FDA should provide
industry with a guidance document
describing background risk.
One comment recommended against
requiring data in the background risk
statement. The comment explained that
background statistics change over time
as new evidence is made available and
accepted by the medical community.
Several comments suggested that FDA
revise or omit the second sentence of
the background risk statement. One of
the comments explained that the
sentence implies that the drug
necessarily has the potential to increase
the risk of developmental abnormalities
above the background risk.
(Response) In the final rule, FDA has
eliminated the proposed standardized
background risk statement. In its place,
the final rule requires that the labeling
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state the percentage range of live births
in the general population of the United
States with a major birth defect and the
percentage range of pregnancies in the
United States that end in miscarriage,
regardless of drug exposure. The final
rule also requires that if such
information is available for the
population(s) for which the drug is
labeled, it must also be included. The
final rule requires that the background
risk information appear in labeling
under the subheading ‘‘Risk Summary,’’
rather than as a standalone statement
under its own subheading (as in the
proposed rule).
The Agency has determined that
rather than including a standardized
general statement about background
risk, it is beneficial to include the
approximate background rates of major
birth defects and miscarriage. This will
provide some context to the risk
statement, and a basis for comparison
with risk estimates from studies in
pregnant women. Including the
approximate background rates allows
the prescriber to inform patients of the
risk of major birth defects and
miscarriage, regardless of drug
exposure. Accordingly, the final rule
requires that the labeling include the
approximate background rates of major
birth defects and miscarriage, regardless
of drug exposure, in the United States.
FDA agrees, however, that it is possible
that these numbers may change over
time. Therefore, the Agency did not
include any specific numbers in the
final rule. Instead, the Agency has
provided information, including
relevant literature citations, about
current background rates of major birth
defects and miscarriage in the draft
guidance on pregnancy and lactation
labeling, which is being published
concurrently with this final rule.
Although the literature citations are
included in the draft guidance, the
Agency does not believe it is either
necessary or appropriate to include
them in the labeling.
FDA agrees that the second sentence
in the proposed background risk
statement, which states that the fetal
risk summary describes the drug’s
potential to increase the risk of
developmental abnormalities above the
background risk, could have been
misinterpreted as meaning that the drug
is associated with an increased risk. As
discussed previously, the Agency has
removed the standardized background
risk statement, including the second
sentence, from the final rule.
iii. Fetal risk summary—FDA
proposed that under ‘‘Pregnancy,’’
prescription drug labeling include a
subheading ‘‘Fetal Risk Summary’’
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(§ 201.57(c)(9)(i)(C)). FDA proposed that
the section include a risk conclusion,
contain a narrative description of the
risk(s) (if the risk conclusion is based on
human data), and refer to any
contraindications or warnings and
precautions.
(Comment 27) One comment
expressed support for the proposed
‘‘Fetal Risk Summary,’’ explaining that
the proposed labeling requirements
increase the utility of the ‘‘Pregnancy’’
subsection by expanding the teratology
section to include information about
specific developmental abnormalities
such as incidence, seriousness,
reversibility, potential for correction,
and effect of dose, duration, and
gestational timing of exposure. Several
other comments suggested that the
proposed ‘‘Fetal Risk Summary’’ be
revised in various ways, discussed in
detail as follows.
Sources of data. FDA proposed that
all available data, including human,
animal, and pharmacologic data, that
are relevant to assessing the likelihood
that a drug will increase the risk of
developmental abnormalities and other
relevant risks must be considered
(Proposed § 201.57(c)(9)(i)(C)(1)).
(Comment 28) One comment
recommended that rather than
considering ‘‘all available data,’’ the
data sources for the ‘‘Fetal Risk
Summary’’ be limited to ‘‘scientifically
rigorous, organized data collection
schemes such as clinical or preclinical
studies, and registries.’’
(Response) FDA declines this
suggestion. For example, depending on
the safety signal, valuable information
may come from epidemiological studies
that are not prospective pregnancy
exposure registries. On occasion,
adverse event reporting or case series
reporting may raise enough concern
about a potential increased risk for a
specific structural malformation or
pattern of malformations, or a serious
adverse event, that the information
should be included in labeling.
(Comment 29) Maternal and neonatal
risk. One comment suggested that FDA
include information regarding maternal
and neonatal risks in the ‘‘Pregnancy’’
subsection of labeling. The comment
suggested that FDA add a ‘‘maternal risk
subsection,’’ preferably before the ‘‘Fetal
Risk Summary,’’ which would address
side effects and adverse reactions
associated with the use of a drug,
including those unique to pregnancy.
The comment explained that placing
this information higher on the label and
making it a separate subsection would
underscore the importance of the health
of the mother. The comment also
suggested that FDA include neonatal
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outcomes as well as fetal outcomes in
the ‘‘Fetal Risk Summary.’’
(Response) FDA agrees that
information on drug-associated maternal
risk is important, and in the final rule
has created a separate heading,
‘‘Maternal adverse reactions,’’ under
‘‘Clinical Considerations,’’ which
requires relevant information, to the
extent it is available, about drugassociated maternal adverse reactions
that are unique to or more frequent or
severe during pregnancy. FDA disagrees
that information on neonatal outcomes
as well as fetal outcomes should be
included in the ‘‘Risk Summary.’’
Rather, if available, this information is
included under its own heading, ‘‘Fetal/
Neonatal adverse reactions,’’ under
‘‘Clinical Considerations.’’ FDA believes
that consistent placement of this
information under a specified heading
under ‘‘Clinical Considerations’’ will
allow health care providers to easily
locate this information. FDA also
believes that this approach ensures that
maternal, fetal, and neonatal risks will
be captured and clearly conveyed in
prescription drug labeling.
Terms used to describe adverse fetal
outcomes. FDA proposed that the fetal
risk summary must characterize the
likelihood that the drug increases the
risk of developmental abnormalities in
humans (i.e., structural anomalies, fetal
and infant mortality, impaired
physiologic function, alterations to
growth) and other relevant risks (e.g.,
transplacental carcinogenesis)
(proposed § 201.57(c)(9)(i)(C)(1)).
(Comment 30) Several comments
suggested that the term ‘‘developmental
abnormalities’’ should be replaced with
a broader and more accurate term. One
comment suggested FDA replace the
term ‘‘developmental abnormalities’’
with the term ‘‘adverse outcomes,
including developmental
abnormalities.’’ This comment
explained that the phrase
‘‘developmental abnormalities’’ does not
include ‘‘other relevant risks (e.g.,
transplacental carcinogenesis)’’ that are
also required to be described in the
‘‘Fetal Risk Summary.’’ Several
comments suggested replacing the term
‘‘developmental abnormalities’’ with the
term ‘‘developmental effects’’ or
‘‘adverse developmental effects.’’ These
comments explained that in the field of
developmental toxicology, a
developmental abnormality would
imply, in general, a dysmorphogenic
effect (malformation or variation), rather
than the wider definition intended by
the proposed rule. Several comments
noted the importance of using
terminology consistently in labeling.
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(Response) FDA agrees that the terms
used to describe various developmental
effects or outcomes should be accurate
and understandable, and that standard
nomenclature in the field of
developmental toxicology should be
used to the extent that it exists. FDA
also agrees that terminology should be
used consistently in labeling. FDA
concludes that the term ‘‘developmental
abnormalities’’ is widely recognizable as
referring to structural defects
(malformations or variations), rather
than the full range of possible
manifestations of developmental
toxicity as FDA had intended.
Therefore, in the final rule, FDA has
included the following terms that
describe various developmental
toxicities, as explained in the following
list:
• ‘‘Adverse developmental
outcomes’’ has replaced ‘‘developmental
abnormalities’’ as the general term to
encompass all manifestations or types of
developmental toxicity.
• ‘‘Structural abnormalities’’ is used
to describe dysmorphology, which
includes malformations, variations,
deformations, and disruptions, rather
than the proposed ‘‘structural
anomalies.’’
• ‘‘Embryo-fetal and/or infant
mortality’’ is used to describe
developmental mortality, which
includes miscarriage, stillbirth, and
infant death (including neonatal death),
instead of the proposed ‘‘fetal and infant
mortality.’’
• ‘‘Functional impairment’’ is used to
describe functional toxicity, which
includes such outcomes as deafness,
endocrinopathy, neurodevelopmental
effects, and impairment of reproduction,
rather than ‘‘impaired physiologic
function.’’
• ‘‘Alterations to growth’’ is used to
describe such outcomes as growth
restriction, excessive growth, and
delayed and early maturations.
These terms and descriptions are
consistent with FDA’s guidance for
industry on ‘‘Reproductive and
Developmental Toxicities—Integrating
Study Results to Assess Concerns’’
(September 2011).
Relationship between animal and
human data. FDA proposed that when
both human and animal data are
available, risk conclusions based on
human data must be presented before
risk conclusions based on animal data
(proposed § 201.57(c)(9)(i)(C)(2)).
(Comment 31) A number of comments
suggested that FDA reexamine the
emphasis that the ‘‘Fetal Risk
Summary’’ places on human data as
compared to animal data.
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Several comments stated that because
there will be frequent conflicts between
human and animal data, FDA should
develop an overall approach to
characterize risk based on both human
and animal data. One of these comments
suggested that FDA consider the
European Medicines Agency’s (EMEA’s)
(now EMA’s) Integration Table for Risk
Assessment and Recommendation for
Use as an example of how to integrate
risk conclusions based on animal and
human data.
Two comments stated that the
proposed rule gives primary emphasis
to human studies, if they exist, while
downgrading the emphasis on animal
data. One of these comments explained
that the quality and statistical power of
human data often fall well short of
desirable, and suggested that human
data be accompanied by clear
acknowledgement of any deficiencies.
The other comment explained that
emphasizing minimal human data over
strong animal data can misrepresent the
fetal risk of a drug.
Two comments suggested that if
human data are ‘‘insufficient’’ (i.e., do
not meet the standard for inclusion in
proposed § 201.57(c)(9)(i)(C)(2)(i)), a risk
statement based on human data should
not precede a risk statement based on
animal data. One of these comments
explained that the most robust and
clinically relevant data should always
be presented first.
Several comments stated that if risk
conclusions are based on sufficient
human data, sponsors should not be
required to include animal data, even if
such data are available. One comment
also suggested that if sufficient human
data become available after the labeling
is approved, animal data should be
removed when the human data are
added to the labeling. This comment
explained that ‘‘a risk conclusion based
on animal data might not support, or
could flatly contradict, a risk conclusion
based on sufficient human data.’’
One comment suggested that FDA ban
all animal studies because human
studies are more accurate.
(Response) We continue to believe
that the ‘‘Risk Summary’’ is
appropriately based on both human and
animal data. Because of the importance
of human data, we also have determined
that when human data provide an
incomplete assessment, this should be
stated in the risk statement based on
human data. Specifically, the ‘‘Risk
Summary’’ must state when there are no
human data or when available human
data do not establish the presence or
absence of a drug-associated risk. FDA
believes that the use of narrative
summaries of the data will avoid
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conflicting characterizations of risk
magnitude.
FDA disagrees with the suggestion
that animal data be presented first in
cases where the human data are
insufficient. FDA also disagrees that the
most robust and clinically relevant
data—whether human data or animal
data—should always be presented first.
We have determined that to promote
consistency and to meet readers’
expectations that information will
always be found in the same place, a
fixed order of presentation must be
maintained. Moreover, we have
determined that human data should
precede animal data because it is the
most clinically relevant.
We note that the purpose of this
rulemaking is to facilitate informed
prescribing and safe and effective drug
product use; placing restrictions on or
encouraging any type of studies that
may be used as the basis for drug
labeling is beyond the scope of this rule.
Not systemically absorbed. FDA
proposed that if the drug is not
systemically absorbed, the fetal risk
statement must contain only the
following statement: (Name of drug) is
not absorbed systemically from (part of
body) and cannot be detected in the
blood. Maternal use is not expected to
result in fetal exposure to the drug
(proposed § 201.57(c)(9)(i)(C)(1)).
(Comment 32) One comment
suggested that this statement should
focus on the route of administration
rather than the part of the body.
(Response) FDA agrees that ‘‘part of
the body’’ could be misconstrued and
we have determined that the use of
‘‘route of administration’’ to describe
how the drug enters the body is more
consistent with labeling language that
addresses dosing and administration. In
the final rule, FDA has replaced ‘‘part of
the body’’ with ‘‘route of
administration.’’ FDA has determined
that ‘‘cannot be detected in the blood’’
is redundant and that the statement is
clear without this phrase. In the final
rule, FDA has eliminated that phrase.
(Comment 33) Standard statement for
certain drugs. FDA received one
comment suggesting that we develop a
standard statement for drugs that are
indicated for use only by males or by
females who are not of reproductive
potential.
(Response) FDA disagrees. We have
determined that a standard statement is
not needed. We believe it is appropriate
that the ‘‘Risk Summary’’ will be
included in labeling for all drugs,
regardless of their indicated population.
This will promote consistency in drug
labeling.
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Risk conclusions based on human
data. In the proposed rule, under the
subheading ‘‘Fetal Risk Summary,’’ FDA
proposed that when human data are
sufficient to reasonably determine the
likelihood that the drug increases the
risk of fetal developmental
abnormalities or specific developmental
abnormalities, the likelihood of
increased risk must be characterized
using one of the following risk
conclusions: Human data do not
indicate that (name of drug) increases
the risk of (type of developmental
abnormality or specific developmental
abnormality) or Human data indicate
that (name of drug) increases the risk of
(type of developmental abnormality or
specific abnormality) (proposed
§ 201.57(c)(9)(i)(C)(2)(i)). The proposed
rule defined the sources of ‘‘sufficient
human data’’ as clinical trials,
pregnancy exposure registries or other
large scale epidemiologic studies, or
case series reporting a rare event
(proposed § 201.57(c)(9)(i)(C)(2)(i)).
(Comment 34) Many comments
requested that FDA more clearly define
the criteria for ‘‘sufficient human data’’
and provide further guidance on the
quantity and quality of evidence
considered to be ‘‘sufficient human
data’’ rather than ‘‘other human data.’’
One comment requested that FDA
clarify the standards that constitute
‘‘sufficient human data,’’ including how
those standards were developed.
Another comment stated that there is no
agreement among experts as to how
much data are needed to reach a risk
conclusion and requested that FDA
clarify what is considered sufficient
human data to reasonably determine the
risk of developmental abnormalities.
Several comments questioned whether
data from an individual study could
ever constitute ‘‘sufficient human data.’’
These comments explained that
although individual clinical trials,
pregnancy exposure registries, largescale epidemiologic studies, and case
series can provide signals for potential
adverse pregnancy outcomes, an
individual study is not statistically
powered to fully assess the incidence
and form one of the proposed risk
conclusions. A separate comment stated
that even if human data has multiple
sources, there is often not enough
human data to make a risk conclusion.
This comment questioned how often the
risk statements based on sufficient
human data would be used. One
comment stated that the proposed rule
does not discuss who will determine
whether the data are sufficient or how
such a determination will be made. The
comment suggested that to increase
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consistent implementation across
review divisions, a dedicated group of
FDA specialists should review the
determination of whether the human
data are sufficient or insufficient for all
labeling subject to the rule. This
comment also requested that FDA
provide examples of sufficient and
insufficient data and that FDA caution
prescribers that such classifications
should not be considered as scientific
proof that a drug may or may not harm
a particular patient.
(Response) FDA agrees that the term
‘‘sufficient human data’’ is ambiguous
and has eliminated it from the final rule.
FDA has also eliminated from the final
rule the distinction between ‘‘sufficient
human data’’ and ‘‘other human data.’’
In the final rule, FDA requires that
when human data are available that
establish the presence or absence of any
adverse developmental outcome(s)
associated with maternal use of the
drug, the labeling must summarize the
specific developmental outcome; its
incidence; and the effects of dose,
duration of exposure, and gestational
timing of exposure. As stated
previously, the final rule also requires
that the ‘‘Risk Summary’’ state when
there are no human data or when
available human data do not establish
the presence or absence of drugassociated risk.
FDA has also determined that the
term ‘‘risk conclusion’’ is inappropriate
because the available data may not
always lead to a conclusion regarding
the drug’s risk to the fetus. Therefore, in
the final rule, FDA has replaced the
term ‘‘risk conclusion’’ with the term
‘‘risk statement.’’
(Comment 35) Several comments
suggested that the Agency revise the
proposed risk statements to make them
more straightforward and appropriately
qualify the nature of the data and the
inability to draw definitive conclusions
about an absence of risk based on them.
Two of these comments suggested that
the term ‘‘human data’’ be replaced with
the term ‘‘available human data.’’ One
comment suggested that the risk
conclusion ‘‘Human data do not
indicate that (name of drug) increases
the risk of (type of developmental
abnormality or specific developmental
abnormality)’’ be replaced with
‘‘Available human data indicate no
additional risk of (type of
developmental abnormality or specific
developmental abnormality) with (name
of drug).’’ One comment suggested that
the term ‘‘indicate’’ should be replaced
with the term ‘‘suggest.’’
(Response) In the final rule, FDA has
eliminated the requirement in the
proposed rule that standardized risk
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conclusions be used to characterize the
likelihood of increased risk. As
discussed previously, in the final rule,
FDA requires instead, under ‘‘Risk
statement based on human data,’’ that
when human data are available that
establish the presence or absence of any
adverse developmental outcome(s)
associated with maternal use of the
drug, the labeling must summarize the
specific developmental outcome; its
incidence; and the effects of dose,
duration of exposure, and gestational
timing of exposure. The final rule also
requires that if the data indicate that
there is an increased risk for a specific
adverse developmental outcome in
infants born to women exposed to the
drug during pregnancy, this risk must be
quantitatively compared to the risk for
the same outcome in infants born to
women who were not exposed to the
drug but who have the disease or
condition for which the drug is
indicated to be used. The final rule
requires that if the data indicate that
there is an increased risk for a specific
adverse developmental outcome in
infants born to women exposed to the
drug during pregnancy, but risk
information is not available for women
who were not exposed to the drug but
who have the disease or condition for
which the drug is indicated to be used,
then the risk for the specific outcome
must be compared to the rate at which
the outcome appears in the general
population.
(Comment 36) FDA also received
comments about the proposed sources
of sufficient human data. One comment
stated that sufficient data must be based
on large-scale epidemiologic studies or
clinical trials, and cannot be based on
pregnancy registries or case reports/
series requiring further evaluation. This
comment explained that most
pregnancy registries can only serve to
rule out a major teratogen and to
generally determine the similarity in
array of effects seen in large registries,
and they cannot provide a quantitative
estimate of population rates of
individual defects or abnormalities.
Another comment stated that a risk
conclusion cannot always be reached
based on the types of human data
described in the proposed rule, and
questioned whether there is a consistent
approach to sufficient human data as it
relates to case series reporting of a rare
event. This comment explained that
spontaneous reports should not be part
of the basis for this subsection. One
comment questioned how the labeling
will summarize seemingly contradictory
results of well-powered pregnancy
exposure registries or studies from
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which a definitive clinical conclusion
cannot be reached.
(Response) FDA recognizes that
because retrospective voluntary adverse
event reporting may be biased and
incomplete, spontaneous reports cannot
rule in or out a causal relationship
between drug exposure and clinical
outcome. However, multiple
spontaneous reports (or case series) of
rare events can be useful in suggesting
possible associations between adverse
events and drug exposure during
pregnancy that warrant further
investigation. Furthermore, FDA has
determined that data from studies with
small numbers of pregnancy exposures
may provide valuable information about
potential safety signals, especially when
corroborated by findings from other
studies.
(Comment 37) One comment
suggested that FDA eliminate the
proposed rule’s requirement that
sponsors specify all possible types of
developmental abnormalities or specific
abnormalities for which human data do
not indicate that the drug increases the
risk. The comment explained that such
a list could be lengthy and of little
clinical benefit to health care providers.
(Response) FDA did not intend to
imply that every potential type of
developmental abnormality must be
included in labeling when human data
are negative. We note that it is difficult
to be certain that a lack of findings
equates to a lack of risk because the
failure of a study to detect an
association between a drug exposure
and an adverse outcome may be related
to many factors, including a true lack of
an association between exposure and
outcome, a study of the wrong
population, failure to collect or analyze
the right data endpoints, and/or
inadequate power. The intent of this
final rule is to require accurate
descriptions of available data and
facilitate the determination of whether
the data demonstrate potential
associations between drug exposure and
an increased risk for developmental
toxicities.
FDA proposed that when there are
available human data that are not
sufficient to use one of the risk
conclusions for sufficient human data,
the likelihood that the drug increases
the risk of developmental abnormalities
must be characterized as low, moderate,
or high (proposed
§ 201.57(c)(9)(i)(C)(2)(ii)). In the
preamble to the proposed rule, FDA
sought comment on this subsection.
Specifically, FDA sought ‘‘comment on
whether, in situations with human data
that are not sufficient, rather than
classifying the risk as low, moderate, or
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high, the risk should instead be
characterized by specific statements
describing the findings, or whether the
findings should be described at all if
they are not readily interpretable.
Examples of specific statements would
be: ‘Limited data in humans show
(describe outcomes),’ or ‘Limited data in
humans show conflicting results
(describe study types, number of cases,
outcomes, and limitations)’’’ (73 FR
30831 at 30842).
(Comment 38) FDA received 10
comments from a variety of sources
expressing strong disagreement with the
proposal to use the terms ‘‘low,’’
‘‘moderate,’’ and ‘‘high’’ to characterize
the likelihood of increased risk of
adverse outcomes due to drug exposure
based on less than sufficient human
data. FDA received only one comment
supporting the proposal.
Four comments stated that the
proposal to classify risk as low,
moderate, or high based on insufficient
human data might produce the same
confusion as the current pregnancy
category system. These comments
explained that, as with the A, B, C, D,
X category system, the use of the
categories low, moderate, and high to
characterize the likelihood of increased
risk of adverse outcomes would
oversimplify the data and lump drugs
with various types and amounts of data
together without describing the basis for
the conclusions. Another comment
suggested that these characterizations
are subjective and would be confusing
to health care providers.
One comment recommended that
when the human data are insufficient,
FDA require the inclusion of the
following risk conclusion: ‘‘Insufficient
data—risk conclusion not established.’’
Another comment recommended that
FDA consider adopting something
similar to the EMA’s system. One
comment suggested that the ‘‘Risk
Summary’’ should include information
about the findings, such as the
gestational age of exposure, the target
organ or organ system, and the findings
should be characterized in terms of
structural, developmental, growth, or
functional abnormality. Another
comment recommended that when the
human data are not sufficient, the
labeling contain statements specific to
the findings rather than classifying the
risk as low, moderate, or high. One
comment suggested that when there are
insufficient data, the labeling should
include a statement explaining that it is
not possible to draw conclusions based
on insufficient human data. This
comment also expressed a preference for
referring to the data portion of the
labeling rather than including a more
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detailed narrative discussion of
insufficient human data in the fetal risk
summary.
(Response) As discussed previously,
FDA agrees that the term ‘‘sufficient
human data’’ is ambiguous and we have
removed the term from the final rule, as
well as the distinction between
‘‘sufficient human data’’ and ‘‘other
human data.’’ FDA also agrees that the
terms ‘‘low,’’ ‘‘moderate,’’ and ‘‘high’’
are subjective and should not be used to
describe human data that cannot
support a statement about fetal risk. The
final rule requires instead that when
human data are available that establish
the presence or absence of any adverse
developmental outcome(s) associated
with maternal use of the drug, the
labeling must summarize the specific
developmental outcome; its incidence;
and the effects of dose, duration of
exposure, and gestational timing of
exposure. As discussed earlier, the final
rule also requires that if the human data
indicate that there is an increased risk
for a specific adverse developmental
outcome in infants born to women
exposed to the drug during pregnancy,
this risk must be quantitatively
compared to the risk for the same
outcome in infants born to women who
were not exposed to the drug but who
have the disease or condition for which
the drug is indicated to be used. When
risk information is not available for
women with the disease or condition for
which the drug is indicated, then the
risk for the specific outcome must be
compared to the rate at which the
outcome occurs in the general
population. The final rule also requires
that the ‘‘Risk Summary’’ state when
there are no human data or when
available human data do not establish
the presence or absence of drugassociated risk.
Narrative description of risk(s) based
on human data. FDA proposed that
when there are human data, the risk
conclusion must be followed by a brief
description of the risks of
developmental abnormalities as well as
other relevant risks associated with the
drug. To the extent possible, this
description must include the specific
developmental abnormality (e.g., neural
tube defects); the incidence,
seriousness, reversibility, and
correctability of the abnormality; and
the effect on the risk of dose, duration
of exposure, and gestational timing of
exposure. When appropriate, the
description must include the risk above
the background risk attributed to drug
exposure and confidence limits and
power calculations to establish the
statistical power of the study to identify
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or rule out a specified level of risk
(proposed § 201.57(c)(9)(i)(C)(4)).
In the final rule, FDA has removed the
‘‘Narrative description of risk(s)’’
heading from the ‘‘Pregnancy’’
subsection. FDA has determined that
much of the information required under
that heading by the proposed rule was
duplicative of information now required
in the ‘‘Risk Summary.’’ As discussed
previously, when human data are
available that establish the presence or
absence of any adverse developmental
outcome(s) associated with maternal use
of the drug, the ‘‘Risk Summary’’ in the
‘‘Pregnancy’’ subsection must
summarize the specific developmental
outcome; its incidence; and the effects
of dose, duration of exposure, and
gestational timing of exposure. Because
this information is required to be
included in a narrative form in the
‘‘Risk Summary,’’ we determined that
including a separate ‘‘Narrative
description of risk(s)’’ heading in the
labeling was unnecessary. In addition,
as explained in the following comments
and our responses, some of the
information that was required by the
proposed rule to appear under
‘‘Narrative description of risk(s)’’ is
required by the final rule to appear
instead under ‘‘Clinical
Considerations.’’
(Comment 39) One comment
suggested that FDA add a statement to
the ‘‘Narrative description of risk(s)’’
portion of the ‘‘Pregnancy’’ subsection
of labeling that explains that
spontaneous abortions caused by a drug
could potentially mask the risk of
developmental abnormalities.
(Response) Although FDA
acknowledges that embryo-fetal death
(i.e., spontaneous abortion) does
sometimes occur due to severe
developmental abnormalities, the
Agency has determined that it is not
necessary to explicitly include such a
statement in labeling. Any increase in
spontaneous abortions attributed to drug
exposure above the background risk is
required to be described in the ‘‘Risk
Summary.’’
(Comment 40) One comment stated
that the term ‘‘seriousness’’ is
ambiguous and suggested replacing it
with the phrase ‘‘impact on health.’’
Two comments requested clarification
of the terms ‘‘reversibility’’ and
‘‘correctability.’’
(Response) FDA agrees that the term
‘‘seriousness’’ is not clear, and it is not
used in the final rule; it has been
replaced with a requirement that the
labeling describe the potential severity
of the adverse reaction. Information
about the reversibility of adverse
reactions should be included under the
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heading, ‘‘Fetal/Neonatal adverse
reactions,’’ under ‘‘Clinical
Considerations.’’ This portion of the
final rule requires that if it is known or
anticipated that maternal drug therapy
increases or may increase the risk of an
adverse reaction in the fetus or neonate,
the labeling must describe the adverse
reaction, the potential severity and
reversibility of the adverse reaction, and
available interventions for monitoring or
mitigating the reaction.
In response to the comments
requesting clarification of the terms
‘‘reversibility’’ and ‘‘correctability,’’
FDA considers a condition to be
reversible if it can self-correct with
routine care and nurturing or through an
intervention such as discontinuing the
drug. An example of a potentially
reversible drug effect in the neonate is
provided in the draft guidance on
pregnancy and lactation labeling, which
is being published concurrently with
the final rule. The term ‘‘correctable’’
has been removed from the final rule.
(Comment 41) One comment
suggested that FDA include in the
‘‘Narrative description of risk(s)’’
information about precautionary
measures that can be taken to prevent an
adverse outcome caused by the drug.
(Response) FDA agrees that
information about precautionary
measures to prevent an adverse drug
effect should be included in labeling. In
the final rule, under ‘‘8.1 Pregnancy,’’
‘‘Clinical Considerations,’’ ‘‘Maternal
adverse reactions,’’ FDA requires that if
the use of the drug is associated with a
maternal adverse reaction that is unique
to pregnancy or if a known adverse
reaction occurs with increased
frequency or severity in pregnant
women, the labeling must describe the
adverse reaction and available
intervention(s) for monitoring or
mitigating it. Also, in the final rule, FDA
requires that under ‘‘8.1 Pregnancy,’’
‘‘Clinical Considerations,’’ ‘‘Fetal/
Neonatal adverse reactions,’’ if it is
known or anticipated that maternal drug
therapy increases or may increase the
risk of an adverse reaction in the fetus
or neonate, the labeling must describe
the adverse reaction, the potential
severity and reversibility of the adverse
reaction, and available intervention(s)
for monitoring or mitigating the
reaction. For further discussion of these
requirements, see Comment 61 and our
response.
(Comment 42) One comment
suggested that FDA replace the phrase
‘‘risk attributed to drug exposure’’ in the
‘‘Narrative description of risk(s)’’ with
the phrase ‘‘a drug’s potential to
contribute to the risk of adverse
outcomes.’’
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(Response) As discussed previously,
the ‘‘Narrative description of risk(s)’’
heading was removed from the final
rule, and the phrase ‘‘risk attributed to
drug exposure’’ is not used elsewhere in
the final rule.
(Comment 43) Two comments stated
that confidence intervals and power
calculations should not be included in
labeling because they are too technical
and not useful for most prescribers.
(Response) FDA does not agree. Under
‘‘Data,’’ the final rule requires a
description of the limitations of any
data included in the labeling.
Confidence intervals and power
calculations are important for the
review and interpretation of the data. As
noted in the draft guidance on
pregnancy and lactation labeling, which
is being published concurrently with
the final rule, the confidence intervals
and power calculation, when available,
should be part of that description of
limitations.
(Comment 44) One comment
suggested that the ‘‘Narrative
description of risk(s)’’ include a
discussion about the uncertainties or
limitations of the ‘‘Fetal Risk Summary’’
when appropriate.
(Response) As discussed previously,
FDA has removed the ‘‘Narrative
description of risk(s)’’ heading from the
final rule. In the final rule, any
uncertainties or limitations of the data
are required to be stated in ‘‘Data.’’
(Comment 45) One comment
suggested that the ‘‘Narrative
description of risk(s)’’ cross-reference
‘‘Data’’ to direct readers to the
information upon which the narrative is
based.
(Response) As discussed previously,
the ‘‘Narrative description of risk(s)’’
was removed from the final rule.
Risk statement based on animal data.
FDA proposed to require that when the
data on which the risk conclusion is
based are animal data, the ‘‘Fetal Risk
Summary’’ must characterize the
likelihood that the drug increases the
risk of developmental abnormalities
using one of the following risk
conclusions: Not predicted to increase
the risk, low likelihood of increased
risk, moderate likelihood of increased
risk, high likelihood of increased risk, or
insufficient data (proposed
§ 201.57(c)(9)(i)(C)(3)(i)–
(c)(9)(i)(C)(3)(v)). In the preamble to the
proposed rule, the Agency sought
comment on whether these standardized
statements can adequately communicate
different levels of risk based on animal
data and their potential relevance to
human fetal effects or whether these
statements are likely to generate
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confusion among prescribers (73 FR
30831 at 30843).
(Comment 46) Comments expressed
different opinions about the proposal to
use standardized statements to
characterize animal data. FDA received
11 comments, primarily from
toxicologists, teratologists, and
organizations representing toxicologists
and teratologists, as well as a few
comments from drug manufacturers,
expressing strong disagreement with the
proposal to use risk statements to
characterize animal data. FDA received
three comments that supported using
standardized statements to characterize
the likelihood, based on animal data,
that a drug will increase the risk for a
known developmental abnormality.
These comments explained, for
example, that a standardized statement
indicating the possible correlation
between animal and human data would
be helpful to clinicians.
Two comments stated that the
proposed categories are confusing and
subject to variable interpretation. One of
these comments explained that it will be
very difficult to categorize the results of
multiple studies conducted for a single
drug into one of the proposed
categories, and there could be
disagreement about whether to
characterize the risk based on the
animal data as ‘‘low,’’ ‘‘moderate,’’ or
‘‘high.’’
Several comments stated that the
proposal to use category language to
describe animal data demonstrates a
misunderstanding of the function and
meaning of experimental animal
studies. These comments explained that
although animal data can identify the
potential of a therapeutic agent to cause
developmental toxicity, it cannot give
rise to an estimate of the probability of
human harm.
Two comments expressed concern
that the use of standardized risk
statements would amount to a category
system similar to the one that FDA
currently uses and would have all of its
associated problems.
Several comments expressed
particular concern with the proposal to
use these categories without an
accompanying narrative description of
the animal studies. One comment
suggested that the sample labels
provided in the Appendix of the
proposed rule illustrate the difficulty of
trying to characterize the risk to humans
based on animal data. Another comment
stated that ‘‘the terms ‘risk,’ ‘medium,’
and ‘high’ are highly charged terms’’
and expressed concern that the risk
statements will be over-interpreted by
anxious consumers and their clinicians.
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One comment suggested that rather
than using the proposed risk statements,
FDA should instead use the
standardized statements presented in
the draft reviewer guidance on
‘‘Integration of Study Results to Assess
Concerns about Human Reproductive
and Developmental Toxicities’’ (October
2001).
Most of the comments that disagreed
with the proposed standardized risk
statements suggested that the labeling
instead contain narrative statements
describing the animal data and its
potential relationship to human
pregnancy risk. One of these comments
explained that ‘‘succinct narrative
statements will promote a reasoned risk
assessment, facilitate comparisons
among drugs, and enhance risk
communication.’’ Several of these
comments suggested that the labeling
should describe animal data
qualitatively, including the number of
species with positive findings,
consistency of findings, and the type of
findings.
(Response) The Agency has
determined that the terms ‘‘not
predicted to increase the risk,’’ ‘‘low
likelihood of increased risk,’’ ‘‘moderate
likelihood of increased risk,’’ and ‘‘high
likelihood of increased risk’’ are
confusing and subject to different
interpretations. The Agency believes
that using standardized risk statements
may give the false impression that
animal data can provide a semiquantitative assessment of human risk.
The Agency also agrees that the use of
standardized risk statements to
characterize the risk of developmental
abnormalities based on animal data
would potentially have the same
drawbacks as the current pregnancy
category system. Therefore, in the final
rule, FDA removed the requirement that
a standardized risk statement be used to
describe human risk based on animal
data. Instead, the ‘‘Risk Summary’’
requires that when animal data are
available, the labeling must summarize
the findings in animals and, based on
these findings, describe, for the drug,
the potential risk of adverse
developmental outcomes in humans.
The final rule requires that the
statement include the number and
type(s) of species affected, timing of
exposure, animal doses expressed in
terms of human exposure or dose
equivalents, and outcomes for pregnant
animals and offspring. The final rule
also requires that when animal studies
do not meet current standards for
nonclinical developmental toxicity
studies or when there are no animal
data, the labeling must so state.
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(Comment 47) Two comments
suggested that labeling should include
language explaining the limitations of
using animal data to predict the
likelihood that the drug increases the
risk of developmental abnormalities.
(Response) FDA declines the
suggestion to include language in
labeling explaining the limitations of
using animal data to predict the
likelihood that the drug increases the
risk of developmental abnormalities,
because this is beyond the scope of this
rule, and is discussed in guidance
documents, such as FDA’s guidance for
industry on ‘‘Reproductive and
Developmental Toxicities—Integrating
Study Results to Assess Concerns’’
(September 2011).
(Comment 48) FDA proposed that the
‘‘Risk Summary’’ contain ‘‘risk
conclusions’’ based on animal data. One
comment suggested that the term ‘‘risk
conclusion’’ be replaced with the term
‘‘risk statement’’ because it is difficult to
reach any conclusions about fetal risk
posed by drugs based solely on animal
data.
(Response) FDA agrees. As with
human data, in the final rule, the
Agency has replaced the term ‘‘risk
conclusion’’ with the term ‘‘risk
statement’’ when discussing risks based
on animal data.
(Comment 49) Risk statement based
on pharmacology. One comment
suggested that FDA consider whether a
separate approach is appropriate for a
group of drugs, such as oncology
products, for which the pharmacological
and toxicological mechanisms are
similar. The comment suggested that for
cytotoxic drugs, FDA could use the
following standard risk statement:
‘‘(Drug name) is indicated for (cancer
type) and is generally used in terminally
ill patients. There are very limited data
on exposure in pregnant patients and,
therefore, no assessment of fetal or
maternal risk is available. The
mechanism of action of this drug is to
kill growing cells and it can be
anticipated that there is a risk to the
fetus at all stages of development.’’
(Response) FDA agrees that the
‘‘Pregnancy’’ subsection of labeling
should address situations in which a
drug may result in an increased risk of
adverse developmental outcomes based
on a well-understood mechanism of
action. The final rule requires that when
the drug has a well-understood
mechanism of action that may result in
adverse developmental outcome(s), the
‘‘Risk Summary’’ must explain the
mechanism of action and the potential
associated risks.
Contraindications, warnings, and
precautions. FDA proposed that the
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‘‘Fetal Risk Summary’’ refer to
information that is included in the
‘‘Contraindications’’ or ‘‘Warnings and
Precautions’’ section of labeling
regarding an increased risk to the fetus
from exposure to the drug (proposed
§ 201.57(c)(9)(i)(C)(5)).
(Comment 50) One comment
suggested that FDA specify that any
contraindications or warnings or
precautions that must be included in the
‘‘Fetal Risk Summary’’ are those that
relate to risk to the fetus.
(Response) In the final rule, FDA
removed the requirement that the ‘‘Risk
Summary’’ refer to information that is
included in the ‘‘Contraindications’’ or
‘‘Warnings and Precautions’’ section of
labeling regarding an increased risk to
the fetus from exposure to the drug. As
described in FDA’s draft guidance for
industry implementing the PLR, when a
topic is discussed in more than one
section of labeling, the section
containing the most important
information relevant to prescribing
should typically include a succinct
description and should cross-reference
sections that contain additional detail
(FDA’s guidance for industry on
‘‘Labeling for Human Prescription Drug
and Biological Products—Implementing
the PLR Content and Format
Requirements’’ (February 2013)).
Consistent with that principle, crossreferencing of information required
under the final rule will typically
appear in the section where the topic is
briefly summarized, e.g., ‘‘Warnings and
Precautions,’’ and will refer the reader
to the place in labeling where it will be
presented in greater detail, i.e.,
‘‘Pregnancy.’’ We note that because a
contraindication is important
information that needs to be
communicated to the health care
provider, the final rule requires that
when use of a drug is contraindicated
during pregnancy, this information must
be stated first in the ‘‘Risk Summary.’’
iv. Clinical considerations.
FDA proposed that the ‘‘Pregnancy’’
subsection of prescription drug labeling
include a ‘‘Clinical Considerations’’
component to provide guidance and
information to health care providers
about the use of the drug in three
distinct clinical situations: (1)
Counseling women who were
inadvertently exposed to the drug
during pregnancy, (2) making
prescribing decisions for pregnant
women, and (3) making prescribing
decisions during labor and delivery
(proposed § 201.57(c)(9)(i)(D)).
We received many comments on this
proposal. Based on those comments,
FDA has made some changes to the final
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rule. A description of each comment we
received and our responses follow.
(Comment 51) General comments.
Comments expressed different opinions
about the utility and appropriateness of
the proposed ‘‘Clinical Considerations’’
component. Many comments expressed
general support for including this
information. One comment stated that
‘‘Clinical Considerations’’ will help
clinicians and patients to consider all
aspects of the patient’s care when
deciding when and how to prescribe
drugs during pregnancy and in women
of childbearing potential. Another
comment stated that the title ‘‘Clinical
Considerations’’ encourages
professionals to make their own medical
judgments. A separate comment noted
that FDA refrained from interfering with
the physician’s discretion by framing
‘‘Clinical Considerations’’ as a practical
guide that assists the provider in
decisionmaking.
Some comments cautioned that
‘‘Clinical Considerations’’ was too
directive in its advice and requiring this
information intruded on the practice of
medicine and could increase physician
liability for failure to adhere to labeling
instructions. One comment stated that
‘‘Clinical Considerations’’ should not
dictate prescribing by a physician for
pregnant women. The comment
requested that FDA revisit this
provision to see whether the content can
be made more useful without advising
physicians how to practice medicine. In
particular, the comment suggested that
information about known alternative
therapies should be included.
Alternatively, the comment suggested
that FDA consider the use of a general
statement about clinical considerations
rather than an extensive, clinically
based discussion that may be unable to
incorporate risk and benefit
information. Another comment stated
that it is the health care provider’s
responsibility to keep abreast of the
latest information about the disease
state and its effect on pregnant women
and to apply that knowledge to
treatment of each individual patient,
and the professional labeling is not the
appropriate place for this information.
(Response) FDA disagrees both that
‘‘Clinical Considerations’’ is too
directive and that professional labeling
is not the appropriate place for this
information. As a Public Health Agency
with expertise in drug regulation and
safety, FDA has a responsibility to issue
regulations that facilitate the
development of drug labeling that
communicates how to safely and
effectively prescribe drugs in the
clinical setting. The Agency does not
regard ‘‘Clinical Considerations’’ as
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dictating prescribing decisions. Rather,
FDA views the ‘‘Clinical
Considerations’’ component of
‘‘Pregnancy’’ as providing information
that supports health care providers’
understanding of drug product risks and
benefits and facilitates informed
prescribing decisions and patient
counseling.
Inadvertent exposure. FDA proposed
that under the subheading ‘‘Clinical
Considerations,’’ the ‘‘Pregnancy’’
subsection of labeling include
information regarding known or
predicted risks to the fetus from
inadvertent exposure to the drug during
pregnancy (proposed
§ 201.57(c)(9)(i)(D)(1)). The proposed
rule would have required that: The
labeling must discuss the known or
predicted risks to the fetus from
inadvertent exposure to the drug
(exposure in early pregnancy before a
woman knows she is pregnant),
including human or animal data on
dose, timing, and duration of exposure.
If there are no human or animal data to
assess the risk from inadvertent
exposure, the labeling must so state.
(Comment 52) Comments expressed
different opinions about the necessity
and utility of including this
information.
Two comments supported including
information about inadvertent exposure.
One of these comments explained that
the proposed section improves a
physician’s ability to manage such
cases.
Two comments, however, suggested
that FDA consider removing this
requirement because it will be
duplicative of the information contained
in the ‘‘Fetal Risk Summary.’’ One of
these comments explained that
assuming equal exposure to the drug,
the known or predicted risks to the fetus
would be the same regardless of
whether the exposure was intentional or
not. This comment explained that
because fetal risks are already fully
described in the ‘‘Fetal Risk Summary,’’
including the same information under
‘‘inadvertent exposure during
pregnancy’’ would be redundant. The
comment suggested that the
‘‘inadvertent exposure during
pregnancy’’ component instead include
a cross-reference to the ‘‘Fetal Risk
Summary’’ and describe only
information not already described in the
‘‘Fetal Risk Summary,’’ in particular,
any information about ways to manage
or mitigate the effects of inadvertent
drug exposure. The other comment
explained that the risk of drug exposure
to the fetus early in pregnancy should
not be different between women who
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choose to become pregnant and those
whose pregnancies were unplanned.
Another comment suggested that FDA
either delete the statement ‘‘exposure in
early pregnancy before a woman knows
that she is pregnant’’ or retain it as an
example. This comment explained that
although inadvertent exposure is more
likely in early pregnancy, it may occur
at any time during pregnancy.
One comment asked for clarification
as to what is expected to be included in
this section. Specifically, this comment
questioned how the risk conclusions
from animal data in the ‘‘Fetal Risk
Summary’’ will be used to counsel
clinicians on the risk of inadvertent
exposure, and requested that FDA
provide examples of this section in an
Appendix.
(Response) The Agency agrees that the
proposed ‘‘inadvertent exposure during
pregnancy’’ component would have
required information about drug effects
on the fetus that is largely redundant of
the information that is required to be
included in the ‘‘Risk Summary’’ in the
‘‘Pregnancy’’ subsection of prescription
drug labeling. FDA has removed the
‘‘inadvertent exposure during
pregnancy’’ component from the final
rule.
Prescribing decisions for pregnant
women. FDA proposed that the
‘‘Clinical Considerations’’ portion of the
‘‘Pregnancy’’ subsection of prescription
drug labeling contain information about
prescribing decisions for pregnant
women, including the following: (1) The
risk, if known, to the pregnant woman
and the fetus from the disease or
condition the drug is indicated to treat;
(2) information about dosing
adjustments during pregnancy; (3)
information about maternal adverse
reactions associated with use of the
drug; and (4) information about any
known or anticipated complications in
the neonate from treatment of the
pregnant woman (proposed
§ 201.57(c)(9)(i)(D)(2)).
In the final rule, FDA removed the
heading ‘‘Prescribing decisions for
pregnant women.’’ FDA determined that
because the ‘‘inadvertent exposure’’
component was removed from the final
rule, the ‘‘Clinical Considerations’’
portion of the ‘‘Pregnancy’’ subsection
was shortened such that having a
separate heading for ‘‘Prescribing
decisions for pregnant women’’ was
unnecessary.
FDA received comments about the
information required in the proposed
rule under the heading ‘‘Prescribing
decisions for pregnant women.’’ A
description of each comment and our
responses follow.
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FDA proposed that the ‘‘Prescribing
decisions for pregnant women’’
component under ‘‘Clinical
Considerations’’ include information
about the risk, if known, to the pregnant
woman and the fetus from the disease
or condition the drug is indicated to
treat (proposed § 201.57(c)(9)(i)(D)(2)(i)).
(Comment 53) Comments disagreed
about whether the ‘‘Pregnancy’’
subsection of labeling should include
information about the effects of not
treating the woman’s underlying disease
or condition.
Two comments supported requiring
the inclusion of information about the
short- and long-term effects of not taking
a necessary drug to treat a chronic
disease or condition for the duration of
a pregnancy, as well as information
about the severity of the condition for
which the drug might be prescribed.
Two other comments, however,
disagreed with including information in
‘‘Clinical Considerations’’ about the
risks of not treating the mother’s
underlying disease or condition during
pregnancy. These comments stated that
prescription drug labeling is not the
appropriate place for health care
providers to learn about the risks of
diseases that drugs are indicated to
treat.
(Response) FDA has determined that
when relevant information is available
about the serious effects of not treating
conditions or diseases during
pregnancy, it must be included in this
section of labeling. In the final rule, this
requirement appears first under
‘‘Clinical Considerations’’ under the
heading ‘‘Disease-associated maternal
and/or embryo/fetal risk.’’ The wording
of this portion of the final rule was
revised to require that when there is a
serious known or potential risk to the
pregnant woman and/or the embryo/
fetus associated with the disease or
condition for which the drug is
indicated to be used, the labeling must
describe the risk.
(Comment 54) Other comments
suggested that the ‘‘Clinical
Considerations’’ component of the
proposed rule be altered in various
ways.
Two comments expressed concern
that descriptions of risks to the pregnant
patient or fetus posed by diseases or
conditions would vary among drugs that
are indicated to treat the same disease
or condition, thereby promoting
confusion. One of these comments
suggested that FDA develop diseasespecific text for developmental risks of
major disease classes, such as asthma,
hypertension, diabetes, and epilepsy,
which sponsors can use in their
prescription drug labeling. This
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comment also requested that the
information be updated on a timely
basis.
(Response) FDA agrees that it is
important that information provided in
labeling is consistent and up-to-date,
and we address this issue in our
response to Comment 4. FDA is not
mandating that labeling contain
consistent disease-specific text, as
knowledge of disease-associated risk
may change over time as more data
become available.
(Comment 55) One comment
suggested that FDA add a statement
under ‘‘Clinical Considerations’’
explicitly stating that untreated or
inadequately treated health conditions
(such as infections; chronic diseases
such as diabetes, hypertension, renal
and thyroid diseases; and psychiatric
disorders such as depression) can
adversely affect the health of the woman
and the outcomes of the pregnancy, and
that decisions about medication usage
must be balanced with the risks of
untreated and/or poorly managed health
conditions.
(Response) FDA disagrees with this
suggestion. We have determined that
requiring a general standardized
statement is less effective than
providing drug-specific information
about the risks of not treating the
condition or disease for which the drug
is indicated to be used.
(Comment 56) One comment
suggested that ‘‘Clinical Considerations’’
should provide information about how
to discontinue or switch medications
during pregnancy when necessary.
(Response) FDA agrees that when
such information is available, it may be
appropriate to include it in ‘‘Clinical
Considerations.’’ We note that this does
not require a change to the final rule,
because this is consistent with current
labeling practices.
(Comment 57) One comment
suggested that ‘‘Clinical Considerations’’
take into account the severity of the
disease, disorder, or condition to the
mother, and the availability and the
benefits and risks of alternative
therapies for which greater or lesser
knowledge may be known about their
use in pregnant women.
(Response) FDA disagrees with the
suggestion that the labeling address the
availability and the benefits and risks of
alternative therapies during pregnancy.
Because the comparative risks and
benefits for different therapies may vary
by patient, this determination must be
made by the prescribing health care
provider. FDA acknowledges, however,
that under certain circumstances it may
be appropriate to include a statement in
the labeling that pregnant women
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should consider alternative drug
therapies, and the appropriateness of
this would be evaluated on a case-bycase basis during the labeling review
process for a specific application.
Dosing adjustments during
pregnancy. FDA proposed that ‘‘Clinical
Considerations’’ provide information
about dosing adjustments during
pregnancy (proposed
§ 201.57(c)(9)(i)(D)(2)(ii)). The proposed
rule stated that this information must
also be included in the ‘‘Dosage and
Administration’’ and ‘‘Clinical
Pharmacology’’ sections of the labeling,
and that if there are no data on dosing
during pregnancy, the labeling must so
state.
(Comment 58) One comment
suggested that dosing information
should be restricted to the ‘‘Dosage and
Administration’’ section of labeling and
that ‘‘Clinical Considerations’’ should
cross-reference the ‘‘Dosage and
Administration’’ and ‘‘Clinical
Pharmacology’’ sections of the labeling
rather than repeat dosing adjustment
information in the ‘‘Pregnancy’’
subsection of labeling. The comment
also suggested replacing the phrase ‘‘no
data’’ because it could become outdated
and because, in some instances, there
may be data but it might not be
sufficient to support recommendations
for dosing adjustments.
(Response) We disagree with the
suggestion that all information about
dosing should be restricted to the
‘‘Dosage and Administration’’ section of
labeling. FDA has determined that it is
important that labeling information
relevant to the use of the drug during
pregnancy be included in the
‘‘Pregnancy’’ subsection. These issues
are discussed in the draft guidance on
pregnancy and lactation labeling, which
is being published concurrently with
the final rule. If there are
pharmacokinetic data that support dose
adjustment(s) during pregnancy and the
postpartum period, this information
must be provided under the heading,
‘‘Dose adjustments during pregnancy
and the postpartum period’’ in ‘‘Clinical
Considerations,’’ and there should be a
cross-reference to other sections of
labeling that include more details (e.g.,
‘‘Dosage and Administration’’ or
‘‘Clinical Pharmacology’’). Although in
the proposed rule FDA had required a
cross-reference to ‘‘Dosage and
Administration’’ and ‘‘Clinical
Pharmacology,’’ we have removed that
requirement. We believe, however, that
when appropriate, a cross-reference
should be included. This approach is
consistent with the regulations and
guidance applicable to the ‘‘Dosage and
Administration’’ section of labeling
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(§ 201.57(c)(3)) and FDA’s guidance for
industry on ‘‘Dosage and
Administration Section of Labeling for
Human Prescription Drug and Biological
Products—Content and Format’’ (March
2012), which require that the labeling
provide details on how to adjust or
modify the dosage in the ‘‘Dosage and
Administration’’ section of labeling,
including for specific patient
populations.
FDA agrees with the suggestion to
remove the phrase ‘‘no data’’ from the
final rule. In the final rule, we have
removed the requirement to state if
there are no data available on dose
adjustments during pregnancy and the
postpartum period. In addition, as noted
in the draft guidance on pregnancy and
lactation labeling, which is being
published concurrently with the final
rule, headings under ‘‘Clinical
Considerations’’ (including ’’Dose
adjustments during pregnancy and the
postpartum period’’) should be omitted
if there are no data available or the
available data are not relevant.
Maternal adverse reactions. FDA
proposed that ‘‘Clinical Considerations’’
contain information about maternal
adverse reactions that are unique to
pregnancy or adverse reactions that
occur with increased frequency or
severity in pregnant women. The
proposed rule required that the labeling
also describe any interventions that may
be needed, such as monitoring blood
glucose for a drug that causes
hyperglycemia in pregnancy (proposed
§ 201.57(c)(9)(i)(D)(2)(iii)).
(Comment 59) One comment
suggested that a cross-reference, ‘‘see
Pregnancy,’’ be added to the ‘‘Adverse
Reactions’’ section of labeling to ensure
that health care providers refer to this
section.
(Response) FDA disagrees with this
comment. The conventions for crossreferencing are explained in FDA’s
guidance for industry on ‘‘Labeling for
Human Prescription Drug and Biological
Products—Implementing the PLR
Content and Format Requirements’’
(February 2013). The suggestion that
this rule require a cross-reference from
the ‘‘Adverse Reactions’’ section to the
‘‘Pregnancy’’ subsection of labeling is
not consistent with the conventions set
forth in that guidance. In addition, not
every drug product will have
pregnancy-related adverse reactions;
thus, a required cross-reference is
unnecessary.
(Comment 60) One comment
suggested that ‘‘Clinical Considerations’’
refer to ‘‘available’’ interventions rather
than ‘‘needed’’ interventions to avoid
interfering with the practice of
medicine.
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(Response) FDA agrees with the
suggestion to replace the phrase
‘‘interventions that may be needed’’
with the phrase ‘‘available
interventions.’’ In the final rule, FDA
requires that if use of the drug is
associated with a maternal adverse
reaction that is unique to pregnancy or
if a known adverse reaction occurs with
increased frequency or severity in
pregnant women, the labeling must
describe the adverse reaction and
available intervention(s) for monitoring
or mitigating the reaction. This change
also allows for differences that may
exist in community standards of care
and available services across the United
States. We note that in the final rule we
removed the following language from
the codified: ‘‘e.g., monitoring blood
glucose for a drug that causes
hyperglycemia in pregnancy.’’
Fetal/Neonatal adverse reactions.
FDA proposed that ‘‘Clinical
Considerations’’ contain information
about any known or anticipated
complications in the neonate, including
any interventions that might be needed
(proposed § 201.57(c)(9)(i)(D)(2)(iv)).
(Comment 61) Two comments asked
FDA to clarify the meaning of the term
‘‘complication.’’ One comment
suggested that if FDA intended the term
‘‘complication’’ to mean adverse
reaction in the neonate, the Agency
should use the term ‘‘adverse reaction.’’
This comment also suggested that if an
adverse reaction/complication has been
described in the ‘‘Fetal Risk Summary,’’
only a cross-reference to
§ 201.57(c)(9)(i)(C) should be required to
appear in § 201.57(c)(9)(i)(D)(2)(iv).
Another comment suggested that FDA
state that a ‘‘complication’’ could be an
‘‘adverse drug reaction,’’ and suggested
that FDA state that the term ‘‘adverse
drug reaction’’ may be used when
appropriate.
(Response) FDA agrees that ‘‘adverse
reaction’’ is a more appropriate term
and that it is more consistent with the
other portions of the final rule. In the
final rule, the term ‘‘adverse reaction’’
(as defined in § 201.57(b)(7)) has
replaced ‘‘complication.’’ Additionally,
in the final rule FDA is requiring the
inclusion of information regarding fetal
adverse reactions in this section of
labeling. Although the proposed rule
only addressed adverse reactions
(referred to there as ‘‘complications’’) in
the neonate under what in the final rule
is required in § 201.57(c)(9)(i)(C), FDA
concludes that information intended to
inform prescribing decisions for
pregnant women appropriately includes
information on fetal adverse reactions as
well as neonatal adverse reactions. FDA
does not believe that there is a
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principled distinction between the
importance of such information with
respect to the fetus and with respect to
the neonate. The consistent location
under ‘‘Clinical Considerations’’ of
information about potential adverse
reactions in the fetus as well as in the
pregnant woman and the neonate, and
about available interventions, will make
the information in that subsection more
useful, as well as easier to identify for
prescribers and other health care
providers. Accordingly, the final rule
requires that if it is known or
anticipated that maternal drug therapy
increases the risk of an adverse reaction
in the fetus or the neonate, the labeling
must describe the adverse reaction, the
potential severity and reversibility of
the adverse reaction, and available
intervention(s) for monitoring or
mitigating the reaction.
FDA disagrees with the suggestion
that if an adverse reaction/complication
has been described in the ‘‘Fetal Risk
Summary,’’ only a cross-reference to
§ 201.57(c)(9)(i)(C) should be required to
appear in § 201.57(c)(9)(i)(D)(2)(iv). As
discussed in the draft guidance on
pregnancy and lactation labeling, which
is being published concurrently with
the final rule, the ‘‘Clinical
Considerations’’ portion of the labeling
is intended to describe fetal/neonatal
adverse reactions that are not adverse
developmental outcomes. Therefore,
because the two portions of the labeling
address different potential reactions/
outcomes, a cross-reference would not
be appropriate.
Additionally, in the final rule, FDA
added the requirement that the labeling
must describe, if known, the effect of
dose, timing, and duration of exposure
on the risk of an adverse reaction in the
fetus or neonate as FDA has concluded
that this information is important for
informing prescribing decisions.
Drug effects during labor or delivery.
FDA proposed that the ‘‘Clinical
Considerations’’ portion of pregnancy
labeling contain information about drug
effects during labor or delivery for drugs
that have a recognized use during labor
or delivery, whether or not the use is
stated as an indication in the labeling,
or are expected to affect labor or
delivery (proposed
§ 201.57(c)(9)(i)(D)(3)).
(Comment 62) One comment
supported the proposal to merge
information about labor and delivery
into the ‘‘Pregnancy’’ subsection of
labeling.
Another comment expressed concern
that including information about drugs
used during labor or delivery, including
drugs that are used off-label during
labor or delivery, conflicts with FDA’s
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long-standing position that off-label
information is not to be included in
labeling.
(Response) We note that, as stated in
the proposed rule (73 FR 30831 at
30844), the language proposed for this
heading contained only slight
modifications from that in existing
§ 201.57(c)(9)(ii). However, because
important safety information, whether
for an approved or unapproved use, may
be required to be included in labeling
(see, e.g., § 201.57(c)(6)(i)), we
concluded that it is not necessary to
include specific language regarding this
issue. Therefore, FDA has removed the
language regarding ‘‘drugs that have a
recognized use during labor or delivery,
whether or not the use is stated as an
indication in the labeling.’’ In the final
rule, FDA revised the heading ‘‘Drug
effects during labor or delivery’’ to
‘‘Labor or delivery,’’ which is consistent
with the level of specificity used in the
other headings under ‘‘Clinical
Considerations.’’
v. Data.
FDA proposed that the following
information be included in the
‘‘Pregnancy’’ subsection of labeling
under the subheading ‘‘Data’’:
(1) Under the subheading ‘‘Data,’’ the
‘‘Pregnancy’’ subsection of the labeling
must provide an overview of the data
that were the basis for the fetal risk
summary.
(2) Human and animal data must be
presented separately, and human data
must be presented first.
(3) The labeling must describe the
studies, including study type(s) (e.g.,
controlled clinical or nonclinical,
ongoing or completed pregnancy
exposure registries, other
epidemiological or surveillance studies),
animal species used, exposure
information (e.g., dose, duration,
timing), if known, and the nature of any
identified fetal developmental
abnormalities or other adverse effect(s).
Animal doses must be described in
terms of human dose equivalents and
the basis for those calculations must be
included.
(4) For human data, positive and
negative experiences during pregnancy,
including developmental abnormalities,
must be described. To the extent
applicable, the description must include
the number of subjects and the duration
of the study.
(5) For animal data, the relationship
of the exposure and mechanism of
action in the animal species to the
anticipated exposure and mechanism of
action in humans must be described. If
this relationship is not known, that
should be stated (proposed
§ 201.57(c)(9)(i)(E)).
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FDA received comments about the
information required under ‘‘Data’’ in
the proposed rule and made some
changes to the final rule. The following
discussion addresses these comments,
our responses, and the changes to the
final rule.
(Comment 63) References. One
comment suggested that under ‘‘Data,’’
the labeling should include references
for the cited data. The comment
explained that including references for
the data would allow clinicians and
other health care workers to further
research pregnancy issues.
(Response) We decline this
suggestion. FDA has determined that
prescription drug labeling is intended to
facilitate prescribing decisions and is
not intended as a research tool. We also
note that this final rule is a part of
labeling regulations, found at § 201.57,
which address the inclusion of
references in prescription drug labeling
(see § 201.57(c)(16)).
(Comment 64) Postmarketing
reporting of adverse reactions. One
comment stated that if specific numbers
of adverse event reports are included in
drug labeling, the labeling will need to
be constantly updated. The comment
suggested that the Agency instead
consider using quantitative measures of
frequency to produce a more stable
label.
(Response) FDA acknowledges that
the inclusion in labeling of actual
numbers of postmarketing reports for
particular adverse reactions is often not
appropriate. We agree that the number
of postmarketing reports of adverse
reactions changes over time and labeling
may become rapidly outdated. In
addition, postmarketing reports of
adverse reactions generally do not
establish an incidence or prevalence of
a particular outcome or definitively
demonstrate an association between
prenatal exposure to the drug in
question and the adverse developmental
outcome. However, FDA also recognizes
that there may be isolated situations in
which reporting of adverse reactions
corroborates other human data and, in
these situations, it may be appropriate
to list a specific number of cases with
the date when the reporting was
collected. FDA will consider whether
the labeling for a drug product should
include specific numbers of reports of
adverse reactions on a case-by-case basis
based on evaluating all available data
and principles of epidemiology and data
interpretation.
In the final rule, FDA replaced the
phrase ‘‘provide an overview of the
data’’ with ‘‘describe the data.’’ FDA
made this change to clarify our
intention that under the subheading
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‘‘Data,’’ the labeling must include a
more detailed description of the data
than might be understood from use of
the term ‘‘overview.’’ In the final rule,
FDA also added the requirement that
under ‘‘Data,’’ the labeling describe the
data that are the basis for the ‘‘Clinical
Considerations.’’ The proposed rule
stated that ‘‘Data’’ must describe the
data that were the basis for the fetal risk
summary, and did not address the data
that were the basis for ‘‘Clinical
Considerations.’’ FDA has determined
that there is no principled reason to
distinguish between the data under the
fetal risk summary and that underlying
‘‘Clinical Considerations.’’ Accordingly,
the final rule requires that under the
subheading ‘‘Data,’’ the labeling
describe the data that are the basis for
both the ‘‘Risk Summary’’ and ‘‘Clinical
Considerations.’’ This subheading,
therefore, is only required to the extent
that there are data that are the basis for
these two subheadings and the headings
under them.
FDA has also determined that the
information in labeling would be clearer
if human data and animal data appeared
separately under applicable headings. In
the final rule, FDA requires that human
and animal data be presented separately
under the headings ‘‘Human Data’’ and
‘‘Animal Data.’’
In the final rule, FDA requires that for
human data, the labeling must describe
adverse developmental outcomes,
adverse reactions, and other adverse
effects. To the extent applicable, the
labeling must describe the types of
studies or reports, number of subjects
and the duration of each study,
exposure information, and limitations of
the data. The final rule requires that
both positive and negative study
findings be included. The proposed rule
listed various types of studies. These
were removed from the final rule
because we determined that it is more
appropriate to discuss these elements in
guidance.
Animal data. FDA proposed that
human and animal data must be
presented separately, and human data
must be presented first.
(Comment 65) One comment
suggested that FDA omit the
requirement that human data must be
presented first. The comment explained
that the most robust data should be
presented first regardless of whether it
is animal or human data.
(Response) FDA declines this
suggestion. We have determined that to
promote consistency and to meet
readers’ expectations that information
will always be found in the same place,
a fixed order of presentation must be
maintained. Additionally, as discussed
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in the preamble to the proposed rule,
the importance of human data in
labeling was stressed by physicians who
participated in focus group testing of the
model labeling format and also by the
FDA advisory committee that provided
input on the proposed format (73 FR
30831 at 30841). FDA has determined
that human data should always be
presented first because human data are
often the most relevant to prescribers,
and animal data may not always be
applicable to humans.
FDA also proposed that animal doses
must be described in terms of human
dose equivalents and the basis for those
calculations must be included.
(Comment 66) Two comments
suggested that the final rule remove the
requirement to use ‘‘administered dose’’
as a comparator between animal and
human data and to replace it with
comparisons based on systemic
exposure, if available. One of these
comments explained that basing the
comparison on systemic exposure will
provide greater consistency within the
labeling and will also provide a way to
more easily make comparisons between
drugs.
(Response) FDA declines this
suggestion to restrict the comparison to
only those based on systemic exposure.
We agree that comparisons based on
systemic exposure could provide
consistency within labeling and
therefore the final rule requires that they
must be included when data are
available, but the data are not always
available for such a comparison. FDA
believes that including the human dose
equivalent may be more meaningful
information for health care providers,
particularly in the absence of data to
make comparisons based on systemic
exposure, and as such, in the final rule,
a comparison of the animal to human
doses must be included using the data
available.
The proposed rule required that for
animal data under the ‘‘Data’’
component the relationship of the
exposure and mechanism of action in
the animal species to the anticipated
exposure and mechanism of action in
humans be described. In the final rule,
we removed this requirement because
often this relationship is not known.
The final rule requires that animal doses
or exposures be described in terms of
human dose or exposure equivalents,
and that the basis for those calculations
be included.
2. 8.2 Lactation
FDA proposed that the ‘‘Nursing
mothers’’ subsection of prescription
drug labeling be replaced with the
subsection ‘‘Lactation’’ (proposed
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§§ 201.56(d)(1) and 201.57(c)(9)(ii)).
FDA proposed that the ‘‘Lactation’’
subsection of prescription drug labeling
contain the following subheadings:
‘‘Risk Summary,’’ ‘‘Clinical
Considerations,’’ and ‘‘Data’’ (proposed
§ 201.57(c)(9)(ii)). FDA received many
comments about the proposed
‘‘Lactation’’ subsection and made
changes to the final rule based on these
comments. The discussion that follows
addresses these comments, our
responses, and the changes FDA made
to the final rule.
a. General comments.
i. Support for ‘‘Lactation’’ subsection
(Comment 67) FDA received many
comments expressing support for the
proposed ‘‘Lactation’’ subsection. One
of these comments explained that it is
essential for drug labeling ‘‘to carry ’best
science’ information that enables
clinicians to efficiently and thoroughly
review what is known about the drug
and any reported health effects to the
breast-fed infant.’’ The comment stated
that the proposed rule would facilitate
more efficient consideration of the data.
(Response) We agree with these
comments, and our final rule requires
labeling to include a subsection on
lactation with risk and benefit
information related to breastfeeding and
the breast-fed infant.
ii. Drug alternatives
(Comment 68) One comment
suggested that a statement should be
included that many drugs for which we
may not have lactation data have a
suitable alternative for which we do
have data.
(Response) We decline to adopt this
comment. We do not believe it would be
appropriate to include this type of
statement in labeling. Because the
comparative risks and benefits will vary
among individual patients, a health care
provider, in consultation with his or her
patient, is in the best position to
determine whether there is a ‘‘suitable
alternative’’ for a particular drug.
iii. Validating data
(Comment 69) One comment
expressed concern about the potential
for bias or omissions with respect to
which data the sponsor includes and the
risk statements the sponsor uses to
characterize such data. The comment
encouraged FDA to employ all
reasonable means to validate the
sponsor’s collection, evaluation, and
subsequent conclusions regarding
lactation data.
(Response) FDA agrees. FDA will
review data available in literature and
sponsor-submitted data used for
developing the ‘‘Lactation’’ subsection
of drug labeling. We note that this does
not require a change to the final rule
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because FDA’s normal review process
for prescription drug labeling includes
validating the applicant’s collection,
evaluation, and subsequent conclusions
regarding data.
b. Risk summary
i. ‘‘Active metabolites’’
(Comment 70) Two comments
suggested that FDA revise the ‘‘Risk
Summary’’ so that it explicitly refers to
active metabolites of the drug, in
addition to the drug itself.
(Response) FDA agrees with this
comment. We also have determined that
it is appropriate to include information
about the effects of a drug and/or its
active metabolite(s) not only in the
‘‘Risk Summary,’’ but under other
subheadings in the ‘‘Lactation’’
subsection of labeling. Therefore, the
final rule has been revised to refer
explicitly to drugs and/or their active
metabolites.
ii. ‘‘Compatible with breastfeeding’’
FDA proposed that under the
subheading ‘‘Risk Summary,’’ if, as
described under § 201.57(c)(9)(ii)(A)(1)
through (c)(9)(ii)(A)(3) of the section,
the data demonstrate that the drug does
not affect the quantity and/or quality of
human milk and there is reasonable
certainty either that the drug is not
detectable in human milk or that the
amount of drug consumed via breast
milk will not adversely affect the breastfed child, the labeling must state: The
use of (name of drug) is compatible with
breastfeeding. After this statement (if
applicable), the risk summary must
summarize the drug’s effect on milk
production, what is known about the
presence of the drug in human milk,
and the effects on the breast-fed child
(proposed § 201.57(c)(9)(ii)(A)).
(Comment 71) Two comments
suggested that FDA eliminate the
statement, ‘‘The use of (name of drug)
is compatible with breastfeeding’’ from
the ‘‘Lactation’’ subsection of the final
rule. One of the comments explained
that it will be difficult to determine
whether a drug is compatible with
breastfeeding with such definitive
certainty, especially since the term
‘‘compatible’’ implies safety. Another
comment suggested that in the final rule
FDA should replace the statement
‘‘compatible with breastfeeding’’ with a
standardized statement that ‘‘sufficient’’
human data exist to indicate that the
drug does or does not adversely affect
the breast-fed child, followed by a
supportive narrative.
(Response) FDA agrees that the term
‘‘compatible’’ is not clearly defined and
implies that the use of a drug during
lactation is ‘‘safe.’’ No drug is
completely safe even in a person who is
not pregnant or breastfeeding. In
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addition to offering potential
therapeutic benefit(s), all drugs have
potential side effects and risks involved
with their use. The balance between
those benefits and risks is taken into
account not just at the approval stage,
but also helps direct diagnostic and
treatment recommendations for a
particular patient in a particular clinical
scenario. Accordingly, in the final rule
FDA removed the statement ‘‘The use of
(name of drug) is compatible with
breastfeeding.’’
Breastfeeding offers significant health
benefits to both the child and mother.
Different drugs and/or their active
metabolites pass into breast milk in
different concentrations; they may or
may not be orally bioavailable in the
infant, and they may or may not result
in significant adverse reactions in the
short term or adverse outcomes in the
long term. Often, all of the potential
risks related to drug treatment during
lactation are not known even though the
benefits of breastfeeding are known and
substantial.
FDA declines the suggestion to
include a standardized statement that
‘‘sufficient’’ human data exist to
indicate that the drug does or does not
adversely affect the breast-fed child,
followed by a supportive narrative.
However, the final rule requires that if
the drug is absorbed systemically, the
labeling must include, under ‘‘Risk
Summary,’’ available information, if
relevant, on the known or predicted
effects on the breast-fed child from
exposure to the drug and/or its active
metabolite(s), including systemic and/or
local adverse reactions. If the available
information is sufficient to determine
that use of the drug is contraindicated
during breastfeeding, this significant
information is required at the beginning
of the ‘‘Risk Summary.’’ The ‘‘Risk
Summary’’ must state when there are no
data to assess the effects of the drug on
the child.
FDA also revised the final rule to
require that if studies demonstrate the
presence of the drug and/or its active
metabolite(s) in human milk but the
drug and/or its active metabolite(s) are
not expected to be systemically
bioavailable to the breast-fed child, then
the ‘‘Risk Summary’’ must describe the
disposition of the drug and/or its active
metabolite(s). FDA added this
requirement to the final rule to identify
situations in which a drug and/or its
active metabolite(s) are present in
human milk but the breast-fed child
does not have any systemic exposure
because of degradation in the
gastrointestinal tract.
iii. Not systemically absorbed
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FDA proposed that if data
demonstrate that a drug is not
systemically absorbed, the fetal risk
summary must contain only the
following statement: (Name of drug) is
not absorbed systemically from (part of
body) and cannot be detected in the
mother’s blood. Therefore, detectable
amounts of (name of drug) will not be
present in milk. Breastfeeding is not
expected to result in fetal exposure to
the drug (proposed § 201.57(c)(9)(ii)(A)).
(Comment 72) One comment
suggested that the statement be revised
to focus on the route of administration
rather than on the part of the body
where the drug is administered. The
comment also suggested that the
language ‘‘cannot be detected in blood’’
could be omitted because it is
redundant with ‘‘not systemically
absorbed.’’
(Response) FDA agrees with this
comment and we removed the phrase
‘‘cannot be detected in blood’’ from the
final rule.
We also agree with the suggestion to
focus on the route of administration.
FDA agrees that ‘‘part of the body’’
could be misconstrued and we have
determined that the use of ‘‘route of
administration’’ to describe how the
drug enters the body is more consistent
with labeling language that addresses
dosing and administration. In the final
rule, FDA has replaced ‘‘part of the
body’’ with ‘‘route of administration.’’
(Comment 73) Another comment
suggested revising the language
‘‘systemically absorbed’’ to ‘‘has a
systemic effect’’ to include the action of
biological products (vaccines) that are
immune stimulants rather than
chemicals that are absorbed.
(Response) FDA declines the
suggestion to change the language
‘‘systemically absorbed’’ to ‘‘has a
systemic effect.’’ The terms
‘‘systemically absorbed’’ and ‘‘absorbed
systemically’’ refer to the absorption of
the drug or biological product from its
site of administration into serum and/or
other body tissues where the drug or
biological product, including a vaccine,
can reach its receptor or target cell and
exert its pharmacological or
immunological effect. A drug or
biological product that is not
systemically absorbed will not be
excreted into human milk and,
therefore, breastfeeding should not
result in the child’s exposure to the
drug. In the final rule, FDA has deleted
the sentence, ‘‘Therefore, detectable
amounts of (name of drug) will not be
present in breast milk.’’ The final rule
also replaces the sentence,
‘‘Breastfeeding is not expected to result
in fetal exposure to the drug’’ with
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‘‘breastfeeding is not expected to result
in exposure of the child to (name of
drug).’’
(Comment 74) Two comments noted
that the term ‘‘fetal’’ was used
improperly in this section of the
proposed rule.
(Response) FDA agrees and has
removed the term ‘‘fetal’’ from the
‘‘Lactation’’ subsection and replaced it
with the term ‘‘child.’’
iv. Presence of drug in human milk
FDA proposed that under the heading
‘‘Presence of drug in human milk’’:
(1) The risk summary must describe
the presence of the drug in human milk
in one of the following ways: The drug
is not detectable in human milk; the
drug has been detected in human milk;
the drug is predicted to be present in
human milk; the drug is not predicted
to be present in human milk; or the data
are insufficient to know or predict
whether the drug is present in human
milk;
(2) If studies demonstrate that the
drug is not detectable in human milk,
the risk summary must state the limits
of the assay used; and
(3) If the drug has been detected in
human milk, the risk summary must
give the concentration detected in milk
in reference to a stated maternal dose
(or, if the drug has been labeled for
pediatric use, in reference to the labeled
pediatric dose), an estimate of the
amount of the drug consumed daily by
the infant based on an average daily
milk consumption of 150 milliliters per
kilogram of infant weight per day, and
an estimate of the [percentage] of the
maternal dose excreted in human milk
(proposed § 201.57(c)(9)(ii)(A)(2)(i)–
(c)(9)(ii)(A)(2)(iii)). We received
comments about this portion of the
‘‘Lactation’’ subsection of the proposed
rule. The discussion that follows
addresses these comments, our
responses, and the changes FDA made
to this portion of the ‘‘Lactation’’
subsection of the final rule.
(Comment 75) Predicting whether
drug is present in human milk. Several
comments objected to the proposal that
the ‘‘Risk Summary’’ state that the drug
is ‘‘predicted’’ or ‘‘not predicted’’ to be
present in human milk. One of these
comments stated that avoiding
predictions and relying instead on
clinical data would better assist
providers. Two comments suggested
that the statements about whether the
drug is predicted or not predicted to be
present in human milk should be
omitted because the other proposed
descriptions effectively cover the range
of potential options.
(Response) FDA agrees that the terms
‘‘predicted’’ and ‘‘not predicted’’ should
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not be used in the ‘‘Risk Summary,’’ and
that a description of available data, if
relevant, on the presence of the drug
and/or its active metabolite(s) in human
milk should be used instead. In
addition, FDA has determined that, in
order to provide clarity in the ‘‘Risk
Summary,’’ in situations where there are
no data to assess whether the drug and/
or its active metabolite(s) are present in
human milk, the ‘‘Risk Summary’’ must
so state.
(Comment 76) Limits of the assay
used. Two comments suggested omitting
assay information if the presence of
drug in milk is not detectable. The
comments stated that assay information
is overly technical and unfamiliar for
many health care providers. In addition,
the comments explained that it would
be presumed that during its review of
the data, the review division at FDA
would consider the validity of studies,
including the assay’s reliability and
sensitivity, before approving the
inclusion in labeling of a statement that
the drug is not detectable in human
milk.
(Response) FDA declines this
comment. We have determined that the
limit of the assay is critical to
understanding the amount of the drug
and/or its active metabolite(s) that may
or may not be present in human milk.
We also believe that most health care
providers are capable of interpreting
this data when presented in labeling
and that health care providers are
familiar with the importance of assay
limits for all types of laboratory testing.
In the final rule, FDA has retained the
requirement from the proposed rule that
if studies demonstrate that the drug
and/or its active metabolite(s) are not
detectable in human milk, the ‘‘Risk
Summary’’ must state the limits of the
assay used.
(Comment 77) Concentration of the
drug detected in human milk. Two
comments expressed support for FDA’s
proposal that the ‘‘Lactation’’ subsection
of prescription drug labeling provide the
concentration of the drug detected in
human milk in reference to a stated
adult or labeled pediatric dose. One of
these comments suggested that the
labeling should also include the
milligrams per kilogram received per
day and the percentage of the weightequivalent therapeutic dose
administered to the mother. This
comment requested that the doses be
presented according to infant age ranges
when possible. A separate comment
suggested providing a calculation of the
estimated infant daily dose consumed as
compared to available pediatric dosing
rather than to maternal dosing, but
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added that clinicians may have
difficulty interpreting the calculations.
One comment stated that the
concentration of the drug detected in
milk should not be made in reference to
the maternal dose or the labeled
pediatric dose. The comment explained
that the concentration of a drug in milk
may vary widely depending upon
whether it reflects steady-state or a
single dose, and could vary based on the
timing between the ingestion of the drug
and taking the sample. The comment
suggested that an estimate of the amount
of the drug consumed daily by the
infant could be made in reference to the
maximum maternal daily dose or the
maximum labeled pediatric dose and
that ‘‘an estimate of the [percentage] of
the maternal dose excreted in human
milk’’ could be omitted.
One comment suggested that FDA
standardize the approach to presenting
drug concentrations in breast milk and
stated that this would ensure that
uniform data are presented by all
manufacturers, allowing for easy
comparisons between prescription
products. The comment also suggested
that FDA provide a guidance document
highlighting the value of breast milk
area under the curve (AUC)
concentrations, explaining that
providing standardized ways of
calculating weight-normalized drug
doses and average breast milk
consumption could better guide
manufacturers and help create a unified
approach to describing drug
concentrations in breast milk.
(Response) FDA addresses these
issues in the draft guidance for industry
on ‘‘Clinical Lactation Studies—Study
Design, Data Analysis, and
Recommendations for Labeling’’
(February 2005) (the draft guidance on
clinical lactation studies).
FDA agrees that it would be helpful
to clinicians to provide infant drug
exposure dosing in milligrams per
kilograms received per day so that a
clinician may compare it to a labeled
infant or pediatric dose if available.
However, because of the technical
considerations for calculating drug and/
or active metabolite levels in milk, FDA
is not requiring this in the final rule.
FDA has determined that the actual or
calculated infant daily dose must be
compared to the labeled infant or
pediatric dose, when available, and to
the maternal dose when pediatric
dosing is not available. When infant or
pediatric dosing is available for a drug
and pediatric pharmacokinetic data are
available for a drug and/or its active
metabolite(s), these data provide an
effective way to estimate comparative
exposure (and potentially comparative
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safety) of a breast-fed child versus a
child receiving a drug therapeutically.
Although not required by the final
rule, FDA agrees that data presented
according to infant age groups could be
useful given the changes in infant
hepatic and renal function during the
first few months of life, and infants’
increasing ability with age to metabolize
and clear drugs and/or their active
metabolites. These data may not always
be available, but when they are, their
presentation stratified by age would be
clinically relevant and should be
included in labeling.
(Comment 78) ‘‘No data.’’ One
comment suggested removing the phrase
‘‘no data’’ from the ‘‘Risk Summary’’ in
the ‘‘Lactation’’ subsection, because
there are rarely no data for a drug.
(Response) FDA disagrees with the
suggestion to remove the phrase ‘‘no
data’’ from the ‘‘Risk Summary.’’ Often,
there are no lactation data (either
human or animal) at the time of
approval of NDAs and BLAs.
v. Effects on milk production and
quality
FDA proposed that if the drug is
absorbed systemically, the risk summary
must describe the effect of the drug on
the quality and quantity of milk,
including milk composition, and the
implications of these changes to the
milk on the breast-fed child (proposed
§ 201.57(c)(9)(ii)(A)(1)).
(Comment 79) Several comments
stated that it is seldom feasible to
adequately study the effects of a drug on
the quality and quantity of breast milk,
and this information should only be
provided when available. One comment
explained that to be scientifically valid,
such evaluation requires a study before,
during, and after drug exposure. This
comment explained that further
complicating factors are substantial
inter- and intra-individual variation and
small study sample size.
One comment requested that FDA
include information about the effects of
the drug on the woman’s milk supply
and other issues that affect the process
of breastfeeding. The comment stated
that many women are advised against
taking medications that affect milk
supply while lactating but are not
informed that this is the reason they
should avoid these medications.
(Response) Although FDA agrees that
it is not always possible to determine
the effects of a drug and/or its active
metabolite(s) on milk production, we
have determined that when the relevant
data are available, this information must
be included in the labeling. In the final
rule, FDA requires that the ‘‘Risk
Summary’’ describe the effects of the
drug and/or its active metabolite(s) on
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milk production, and if there are no data
to assess the effects of the drug and/or
its active metabolite(s) on milk
production, the ‘‘Risk Summary’’ must
so state.
With respect to milk quality and
composition, there are currently no
established standards or documented
population variability for milk content.
It is also not known how much change
in various milk components would
reduce the known benefits of
breastfeeding relative to the risks of
exposure to a drug and/or its active
metabolite(s) through breast milk
combined with any potential effects on
milk composition and quality.
Accordingly, in the final rule, FDA has
removed the requirement that the ‘‘Risk
Summary’’ describe the effect of the
drug on the quality and composition of
milk, and the implications of these
changes to the milk on the breast-fed
child.
vi. Sufficient Data
(Comment 80) One comment noted
that the proposed rule does not require
sufficient data to reach conclusions in
the ‘‘Risk Summary’’ in the ‘‘Lactation’’
subsection, and suggested that FDA
discuss what constitutes sufficient data,
as it does in the ‘‘Pregnancy’’
subsection.
(Response) As discussed previously,
many comments disagreed with FDA’s
proposed use of the term ‘‘sufficient’’ in
the ‘‘Pregnancy’’ subsection of labeling.
The comments stated that the term was
not clearly defined in the proposed rule,
and suggested that it would be difficult
to apply the term consistently across
drug labeling. Based on FDA’s
consideration of these comments, the
final rule does not refer to ‘‘sufficient’’
data in either the ‘‘Pregnancy’’ or the
‘‘Lactation’’ subsection.
vii. Risk and Benefit Statement
(Comment 81) FDA received seven
comments noting that the proposed
‘‘Lactation’’ subsection did not require
the inclusion in labeling of any
information about the benefits of
breastfeeding. Some of these comments
recommended that FDA add such a
statement to the final rule to prevent
patients from unnecessarily foregoing or
discontinuing breastfeeding.
(Response) FDA acknowledges that
the proposed rule did not require the
inclusion of information about the
benefits of breastfeeding. The Agency
has determined that the inclusion in the
‘‘Lactation’’ subsection of labeling of a
risk and benefit statement will provide
a useful framework for health care
providers to use when making
prescribing decisions for lactating
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patients. In the final rule, FDA requires
that for drugs absorbed systemically,
unless breastfeeding is contraindicated
during drug therapy, a statement that
the developmental and health benefits
of breastfeeding should be considered
along with the mother’s clinical need for
the drug and any potential adverse
effects on the breast-fed child from the
drug or from the underlying maternal
condition, must be included at the end
of the ‘‘Risk Summary’’ in the
‘‘Lactation’’ subsection of labeling.
c. Clinical Considerations
FDA proposed that under the
subheading ‘‘Clinical Considerations,’’
the labeling must provide the following
information to the extent it is available:
(1) Information concerning ways to
minimize the exposure of the breast-fed
child to the drug, such as timing the
dose relative to breastfeeding or
pumping and discarding milk for a
specified period; (2) information about
potential drug effects in the breast-fed
child that could be useful to caregivers,
including recommendations for
monitoring or responding to these
effects; and (3) information about dosing
adjustments during lactation. This
information must also be included in
the ‘Dosage and Administration’ and
‘Clinical Pharmacology’ sections
(proposed § 201.57(c)(9)(ii)(B)(1)–
(c)(9)(ii)(B)(3)). FDA received comments
about the proposed ‘‘Clinical
Considerations’’ subheading. The
discussion that follows addresses these
comments, our responses, and FDA’s
changes to the final rule.
i. Other Therapies
In the Proposed rule, FDA included
sample labeling for several fictitious
drugs. In the ‘‘Clinical Considerations’’
portion of the ‘‘Lactation’’ subsection,
the ALPHAZINE sample stated that
‘‘Other medical therapies are available
for treatment of maternal hypertension.’’
(Comment 82) Two comments
disagreed with the inclusion of this
statement. The comments explained that
the statement is confusing because
although no comparator data are
presented, clinicians may infer that
other drugs in the class are safe and
effective.
(Response) We note that the language
to which these comments refer was
included in sample labeling included
with the proposed rule, and not in the
proposed rule itself. FDA included
sample labeling with the proposed rule
to serve as examples of how to apply the
requirements of the proposed rule in
different scenarios. We note that the
final rule does not include sample
labeling. FDA agrees, however, that
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statements such as, ‘‘Other medical
therapies are available for treatment of
maternal hypertension,’’ may be
confusing, and should not be included
in the ‘‘Pregnancy’’ or ‘‘Lactation’’
subsections of labeling.
ii. Minimizing Exposure to the BreastFed Child
(Comment 83) General comments.
Four comments disagreed with the
proposal to include information
regarding minimizing exposure of the
breast-fed child in the ‘‘Clinical
Considerations’’ portion of the
‘‘Lactation’’ subsection. These
comments explained that inclusion of
this information could discourage
women from breastfeeding even when
there is no reason for concern. One
comment noted that this information
should only be included when there is
information that breastfeeding should be
withheld during drug therapy and the
timing of pumping and discarding of
breast milk can be provided.
Alternatively, the comment suggested
stating when information regarding the
timing of pumping and discarding
breast milk cannot be provided. Another
comment noted that this information
should not be obligatory when data
suggest that there is not sufficient
excretion of the drug in milk to cause
concern for the infant. The comment
explained that including this
information when the ‘‘Risk Summary’’
and ‘‘Data’’ components have already
stated that the drug is compatible with
breastfeeding could give the false
impression that the drug is unsafe for
the child and may encourage women to
discontinue breastfeeding. One
comment noted that in cases when the
drug disappears from breast milk with a
known half-life, it is possible to
minimize infant exposure by
recommending dosing occur at certain
times related to feeding.
(Response) FDA notes that
information concerning minimizing
exposure to the breast-fed child must be
provided only to the extent it is
available and relevant. In addition, the
final rule was revised to clarify that
information concerning minimizing
drug exposure in the breast-fed child
must be included only if the drug and/
or its active metabolite(s) are present in
human milk in clinically relevant
concentrations; the drug does not have
an established safety profile in infants;
and the drug is used either
intermittently, in single doses, or for
short courses of therapy. As discussed
further in our response to Comment 84,
the final rule also requires that, when
applicable, the labeling describe ways to
minimize a breast-fed child’s oral intake
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of topical drugs applied to the breast or
nipple skin.
(Comment 84) Topical products. In
the proposed rule, FDA did not provide
for inclusion of data regarding topical
drugs that are not absorbed systemically
by the mother but that may transfer to
infants during breastfeeding. One
comment requested that FDA include a
standardized statement in the ‘‘Risk
Summary’’ about such drug products.
(Response) Situations in which a
topical pharmaceutical product can
result in infant exposure without
systemic absorption of the product into
maternal serum are limited to topicals
applied to the skin of the breast,
especially that of the nipple and areola.
For prescription drug products, these
topicals would most likely include
corticosteroids and anti-infectives. FDA
acknowledges that the proposed rule
did not accommodate a situation in
which a drug product does not result in
maternal systemic exposure but could
result in infant systemic exposure. In
response to this comment, FDA revised
the ‘‘Minimizing exposure’’ portion of
‘‘Clinical Considerations’’ to
accommodate the inclusion of
information about such products. In the
final rule, FDA added a requirement
that, when applicable, the labeling must
also describe ways to minimize a breastfed child’s oral intake of topical drugs
applied to the breast or nipple skin.
iii. Drug Effects in the Breast-Fed Child
and Monitoring for Adverse Reactions
FDA proposed that the ‘‘Clinical
Considerations’’ portion of the
‘‘Lactation’’ subsection of prescription
drug labeling include information about
potential drug effects in the breast-fed
child that could be useful to caregivers,
including recommendations for
monitoring or responding to these
effects (proposed
§ 201.57(c)(9)(ii)(B)(2)).
(Comment 85) FDA received one
comment about this portion of the
proposed ‘‘Clinical Considerations.’’
The comment suggested that FDA omit
the first part of this provision—
’’information about potential drug
effects in the breast-fed child’’—because
this information duplicates the
information required to appear in the
‘‘Risk Summary’’ under proposed
§ 201.57(c)(9)(ii)(A)(3), ‘‘Effects of drug
on the breast-fed child.’’ The comment
also stated that the term
‘‘recommendations’’ in the second part
of this provision could interfere with
the practice of medicine. The comment
suggested the following language:
‘‘Information about ways to monitor for,
or respond to, potential drug effects in
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72093
the breast-fed child that could be useful
to caregivers.’’
(Response) FDA acknowledges that
this portion of the proposed rule
appeared to require information
duplicative of information in the ‘‘Risk
Summary.’’ We removed the language,
‘‘information about potential drug
effects in the breast-fed child,’’ from the
‘‘Clinical Considerations’’ portion of the
‘‘Lactation’’ subsection of the final rule.
In the final rule, when relevant
information is available about potential
adverse effects in an infant due to
exposure to the maternal drug and/or its
active metabolite(s) through human
milk, this information must be included
in the ‘‘Risk Summary.’’ FDA also
concluded that it was not necessary to
characterize information about the
potential effects of a drug and/or its
active metabolite(s) on a breast-fed child
as being useful to caregivers because,
although caregivers sometimes read
prescription drug labeling, it is not
directed at them, and individual health
care providers are in the best position to
discuss with their patients information
that may be useful for the patients to
share with other caregivers. Therefore,
the reference to information that may be
useful to caregivers also has been
removed.
FDA acknowledges the comment
concerning the use of the term
‘‘recommendations’’ in the second part
of this provision, and in the final rule
has removed the term
‘‘recommendations for monitoring’’ and
replaced it with ‘‘available interventions
for monitoring or mitigating.’’ The final
rule requires that under ‘‘Clinical
Considerations’’ the labeling describe
information about available
interventions for monitoring or
mitigating the adverse reactions
described in the ‘‘Risk Summary.’’ We
note that this language is consistent
with the language in the ‘‘Pregnancy’’
subsection.
iv. Dose Adjustments
(Comment 86) One comment stated
that dose adjustment information
should not be included in the
‘‘Lactation’’ subsection. The comment
suggested that dosing information
generally should be restricted to the
‘‘Dosage and Administration’’ section of
labeling.
(Response) FDA agrees with the
suggestion that we omit information
about dose adjustments from the
‘‘Lactation’’ subsection of prescription
drug labeling, although this decision is
not based on a conclusion (as suggested
in the comment) that dosing information
generally should be restricted to the
‘‘Dosage and Administration’’ section of
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labeling. FDA has determined that other
than during the immediate postpartum
period when a woman’s physiology is
reverting from a pregnant to a
nonpregnant state, a lactating woman is
unlikely to require dose adjustments for
drugs. The physiological changes
associated with lactation are unlikely to
result in pharmacokinetic changes
significant enough to warrant maternal
dose adjustments. Therefore, FDA has
determined that all available and
relevant information about dose
adjustments during pregnancy and the
postpartum period must be included in
the ‘‘Pregnancy’’ subsection of labeling.
In the final rule, FDA has removed the
requirement that information about
dosing adjustments during lactation be
included in the ‘‘Lactation’’ subsection
of labeling.
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d. Data
FDA proposed that under the
subheading ‘Data,’ the ‘Lactation’
subsection of the labeling must provide
an overview of the data that are the
basis for the risk summary and clinical
considerations (proposed
§ 201.57(c)(9)(ii)(C)). FDA received
comments about this portion of the rule.
One comment expressed support for
presenting lactation data under ‘‘Data’’
when available. The other comments
and changes we made in response to
those comments are explained in this
section of the document.
(Comment 87) FDA received
comments requesting that the Agency
clarify when animal lactation data
should be included in labeling. Several
comments questioned the usefulness of
animal lactation data in the absence of
clinical data. One comment stated that
extrapolation of animal data to humans
may not be helpful without stating what
is known about the correlation to
humans.
Several comments stated that only
human data should be presented when
it is available. Two comments requested
that if, in cases where both human and
animal data are available, FDA decides
to retain the requirement that both kinds
of data be presented, the ‘‘Lactation’’
subsection be revised to state that
clinical data are to be presented before
preclinical data.
One comment requested additional
clarification regarding the quantity and
quality of animal data that would
support inclusion of the data in
labeling, and asked that FDA provide
sample labeling for a drug for which
only animal lactation data are available.
Another comment suggested that the
labeling state when there is an absence
of available or sufficient human and/or
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animal data in the ‘‘Lactation’’
subsection.
(Response) The preamble to the
proposed rule did not include a
discussion of animal lactation data, and
the inclusion of animal lactation data
was not addressed in the codified
section of the proposed rule. In the final
rule, under ‘‘Risk Summary,’’ FDA
defines situations for which animal
lactation data must and must not be
included in the ‘‘Lactation’’ subsection.
Animal lactation data can be helpful in
predicting whether a drug and/or its
active metabolite(s) will be present in
human milk; however, because of
species-specific differences in lactation
physiology, animal lactation data
typically do not reliably predict drug
levels in human milk. FDA added a
requirement to the final rule that when
relevant human lactation data are
available, animal data must not be
included unless the animal model is
specifically known to be predictive for
humans. In addition, under ‘‘Risk
Summary,’’ ‘‘Presence of drug in human
milk,’’ FDA clarified that if only animal
lactation data are available, the ‘‘Risk
Summary’’ must state only whether or
not the drug and/or its active
metabolite(s) were detected in animal
milk and specify the animal species.
Although animal data do not reliably
predict whether a drug and/or its active
metabolite(s) will be present in human
milk, in the absence of human data,
FDA determined that the fact that a drug
and/or its active metabolite(s) were or
were not detected in animal milk may
nevertheless be useful in informing
prescribing decisions.
In the final rule, FDA revised the
‘‘Data’’ portion of the ‘‘Lactation’’
subsection to require that the labeling
‘‘describe the data that are the basis for
the Risk Summary and Clinical
Considerations’’ and removed the
requirement that the labeling ‘‘provide
an overview of the data.’’ FDA made
this change to clarify that under ‘‘Data,’’
the labeling must include a more
detailed description of the data than
might be understood from use of the
term ‘‘overview,’’ as well as to maintain
consistency between the ‘‘Data’’
portions of the ‘‘Lactation’’ and
‘‘Pregnancy’’ subsections. Furthermore,
this subheading is only required to the
extent that there are data that are the
basis for the Risk Summary and Clinical
Considerations subheadings, and the
headings under them.
3. 8.3 Females and Males of
Reproductive Potential
In the final rule, FDA is adding a
requirement that information regarding
pregnancy testing, contraception, and
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infertility be relocated in labeling under
subsection ‘‘8.3 Females and Males of
Reproductive Potential.’’ FDA is adding
this requirement to the final rule based
on public comments regarding these
issues, and based on the Agency’s
conclusion that this information should
be presented in labeling in a consistent
location. Subsection ‘‘8.3 Females and
Males of Reproductive Potential’’
includes three subheadings, ‘‘Pregnancy
Testing,’’ ‘‘Contraception,’’ and
‘‘Infertility.’’ Each subheading should
only be included if it is applicable or if
relevant information is available, and
Section 8.3 should be omitted in its
entirety if none of the subheadings are
applicable. The comments are discussed
in detail in our responses to Comments
88, 89, and 90.
Information concerning pregnancy
testing, contraception, and infertility is
important for informing decisions made
by patients, in consultation with their
health care providers, regarding the use
of prescription drugs before or during
pregnancy. This information is in many
ways inherently linked to the scientific
and medical rationale underpinning the
Pregnancy subsection of prescription
drug labeling. However, in the course of
developing this final rule, and in
particular in evaluating comments 88,
89, and 90, FDA concluded that because
there was no consistent placement in
the labeling of information about
pregnancy testing, contraception, and
infertility, it was difficult for health care
providers to find this important
information. For example, clinical
advice on infertility might be found
with the discussion of animal data in
the ‘‘Nonclinical Toxicology’’ section, in
the ‘‘Adverse Reactions’’ section, or in
the ‘‘Warnings and Precautions’’
section. Contraception and pregnancy
testing recommendations for known or
suspected teratogens might be found in
the ‘‘Pregnancy’’ subsection or in the
‘‘Warnings and Precautions’’ section.
(Comment 88) FDA received one
comment suggesting that the new
labeling explicitly state that a woman
taking drugs with potential or known
adverse effects on pregnancy outcomes
should (1) consider using reliable
contraception if she does not intend to
become pregnant or (2) if she does
intend to become pregnant, seek
consultation with her health care
provider to discuss medical
management of her health condition
before becoming pregnant, if possible.
(Response) FDA agrees that when a
drug has a potential or known adverse
effect on pregnancy outcomes (e.g., is a
known or suspected human teratogen),
information regarding recommendations
or requirements regarding contraception
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use must be included in prescription
drug labeling. In the final rule, FDA
requires that when contraception is
required or recommended before,
during, or after drug therapy, this
information must be included under the
subheading ‘‘Contraception’’ in
subsection ‘‘8.3 Females and Males of
Reproductive Potential.’’ In addition, it
may be appropriate to include in this
subsection information concerning
counseling females of reproductive
potential about pregnancy planning.
Furthermore, the concerns expressed
in the comment regarding the inclusion
of information about contraception use
when taking a drug with potential or
known adverse effects on pregnancy
outcomes apply equally to information
about pregnancy testing, particularly
when a drug is a known or suspected
human teratogen. Therefore, FDA has
determined that information regarding
recommendations or requirements
concerning pregnancy testing before,
during, or after drug therapy must also
be included in prescription drug
labeling. In the final rule, FDA requires
that this information be included under
the subheading ‘‘Pregnancy Testing’’ in
subsection ‘‘8.3 Females and Males of
Reproductive Potential.’’
(Comment 89) FDA received three
comments noting that the ‘‘Pregnancy’’
subsection of the proposed rule only
addresses risks to the fetus when the
drug is administered to a pregnant
woman, and it does not address the
potential for manifestations of
developmental toxicity associated with
fetal drug exposure from transfer of drug
through semen to the maternal and fetal
circulations. One of the three comments
noted that the proposed rule does not
address the potential for manifestations
of developmental toxicity associated
with exposure resulting from transfer
through the semen or the need for male
contraception when a compound is
determined to have a predicted risk of
developmental toxicity and the transfer
of semen is unknown. This comment
suggested that statements addressing
this issue be added when the
information is required for the product.
One of the comments suggested that
FDA add a section to the final rule that
addresses prescribing information for
male patients with a partner of
reproductive potential or a pregnant
partner. Another comment suggested
that the risk conclusion statement
specify whether it is based on maternal
or paternal exposure when that
information is available.
(Response) FDA agrees that when
relevant information is available, this
information should be included in
labeling. In the final rule, FDA requires
that information about recommended or
required use of contraception by men be
included under the subheading
‘‘Contraception’’ in subsection ‘‘8.3
Females and Males of Reproductive
Potential.’’
(Comment 90) FDA received one
comment requesting that the Agency
clarify how and when animal data
described in subsection 13.1 of labeling
(‘‘Carcinogenesis, Mutagenesis,
Impairment of Fertility’’) that raises
concerns about mutagenesis,
impairment of fertility, or preimplantation loss should be included in
subsection ‘‘8.1 Pregnancy.’’ The
comment also requested that FDA
clarify when it would be appropriate to
move information from subsection 13.1
to subsection 8.1 or to cross-reference
subsection 13.1 in subsection 8.1.
(Response) As stated previously, FDA
concluded that it is important to include
information about drug-associated
fertility effects in labeling in a
consistent location and manner. In the
final rule, animal data that raise
concerns about drug-associated
impairment of fertility and/or preimplantation loss effects must be
included under ‘‘Infertility’’ in
72095
subsection ‘‘8.3. Females and Males of
Reproductive Potential.’’ In addition,
when there are contraception
recommendations based on animal
mutagenesis data, this information must
be included in subsection 8.3 under the
Contraception subheading. Because the
same concerns about drug-associated
fertility effects apply to human data,
FDA has determined that human data
that raise such concerns also must be
included in the ‘‘Infertility’’ subsection.
With respect to the question about
cross-referencing, subsection 8.3 should
cross-reference the applicable animal
data included in subsection 13.1,
consistent with FDA’s cross-referencing
regulations (e.g., § 201.57(c)(1),
(c)(6)(iv), and (c)(15)(ii)). The draft
guidance on pregnancy and lactation
labeling, which is being published
concurrently with this final rule,
addresses these issues.
IV. Implementation
FDA proposed that holders of
applications (including an NDA, BLA,
or efficacy supplement) approved before
June 30, 2001, would be required to
remove the pregnancy category from
their labeling within 3 years after the
effective date of this rule. These
applications are those that are not
subject to the requirements of the PLR.
For drugs with applications (including
an NDA, BLA, or efficacy supplement)
approved on or after June 30, 2001, FDA
proposed a phased-in implementation
plan that would stagger the required
dates these products would be required
to replace the content and formatting of
the pregnancy and lactation subsections
of their labeling with the new content
and formatting required by this rule.
These applications are those that are
subject to the requirements of the PLR.
Table 1 contains the implementation
plan that was included in the proposed
rule. In table 1, ‘‘Applications’’ includes
NDAs, BLAs, and efficacy supplements.
TABLE 1—IMPLEMENTATION PLAN
Applications required to conform to new pregnancy/lactation
content requirements
Time by which labeling with new pregnancy/lactation content must be
submitted to FDA for approval
New or Pending Applications
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Applications submitted on or after the effective date of the pregnancy
final rule.
Applications pending on the effective date of the pregnancy final rule ...
Time of submission.
4 years after the effective date of pregnancy final rule or at time of approval, whichever is later.
Approved Applications Subject to the Physician Labeling Rule
Applications approved any time from June 30, 2001, up to and including June 29, 2002, and from June 30, 2005, up to and including
June 29, 2007.
Applications approved any time from June 30, 2007, up to and including the effective date of the pregnancy final rule.
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3 years after the effective date of pregnancy final rule.
4 years after the effective date of pregnancy final rule.
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TABLE 1—IMPLEMENTATION PLAN—Continued
Applications required to conform to new pregnancy/lactation
content requirements
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Applications approved from June 30, 2002, up to and including June
29, 2005.
(Comment 91) Two comments stated
that the proposed implementation plan
was confusing. One of these comments
requested that FDA explain the rationale
supporting the implementation
schedule. Another comment stated the
proposed phased-in approach for
previously approved drugs may generate
confusion. The comment explained that
if drug labeling information and drug
reference materials contain pregnancy
information that is inconsistent between
newly approved and previously
approved drugs through a 3- to 5-year
period, confusion may limit the
understanding of the new labeling.
Comments disagreed about whether
the length of the implementation
schedule was reasonable. One comment
stated that the long implementation
timeline will delay the delivery of
complete information. Another
comment stated that FDA should
expedite the implementation schedule
for licensed drugs that are necessary to
maintain the health status of the mother
and could harm the fetus if the mother
is left untreated. This comment also
suggested that the Agency should make
supplemental information available in
advance of the printed label. Another
comment, however, expressed support
for the proposal to give sponsors 3 years
after the effective date of the rule to
remove the pregnancy categories.
(Response) The Agency has taken all
of these comments into consideration,
and has decided to maintain the
implementation schedule that was
published in the proposed rule. The
implementation schedule follows the
timetable used for implementation of
the PLR and works to balance the
anticipated workload for the review of
labels. The purpose of having a
staggered approach is to avoid
overburdening both the Agency and
industry. The implementation plan for
the final rule (also referred to as the
Pregnancy and Lactation Labeling Rule
(PLLR)) is modeled from the
implementation plan for the PLR and
experience acquired from that plan. The
PLLR implementation timeline also
depends on the PLR implementation
and the extent to which applications are
subject to the PLR.
(Comment 92) One comment
expressed concern that under the
proposed implementation schedule, the
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Time by which labeling with new pregnancy/lactation content must be
submitted to FDA for approval
5 years after the effective date of pregnancy final rule.
pregnancy categories will be removed
from the labeling for some drugs before
the new content required by the rule
will be added to the labeling, and this
could cause confusion among doctors
and patients.
(Response) We would like to clarify
that a holder of an application that is
not subject to the PLR, and thus, not
subject to the new content and format
requirements of this final rule, must
remove the pregnancy category from its
labeling within 3 years after the
effective date of this rule. A holder of
an application that is subject to the PLR
and thus, subject to the new content and
format requirements of this rule, is not
required to remove the pregnancy
category until such time that it is
required to submit revised labeling with
the new content and format, even if that
occurs more than 3 years after the
effective date of the final rule. FDA did
not intend to suggest that application
holders of previously approved
applications subject to the PLR might, in
some circumstances, be required to
revise labeling twice as a part of
implementation. Therefore, if a holder
of an application is subject to the PLR,
FDA does not anticipate that the
pregnancy category will be removed
from the labeling prior to submitting the
revised labeling with the new content
and format for that product under the
PLLR implementation schedule. In
conjunction with the publication of the
final rule, the Agency is planning to
launch an education campaign for all
stakeholders, including health care
providers and professional
organizations, to ensure that they are
well informed about the changes.
V. Legal Authority
A. Statutory Authority
FDA is revising its regulations on the
format and content of the ‘‘Pregnancy,’’
‘‘Labor and delivery,’’ and ‘‘Nursing
mothers’’ subsections of the ‘‘Use in
Specific Populations’’ section (under
§ 201.57) and the ‘‘Precautions’’ section
(under § 201.80) of the labeling for
human prescription drugs (in addition
to the list of headings and subheadings
under § 201.56(d)(1)).
FDA’s revisions to the content and
format requirements for prescription
drug labeling are authorized by the
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Frm 00034
Fmt 4701
Sfmt 4700
FD&C Act and by the PHS Act. Section
502(a) of the FD&C Act deems a drug to
be misbranded if its labeling is false or
misleading ‘‘in any particular.’’ Under
section 201(n) of the FD&C Act (21
U.S.C. 321(n)), labeling is misleading if
it fails to reveal facts that are material
with respect to consequences that may
result from the use of the drug under the
conditions of use prescribed in the
labeling or under customary or usual
conditions of use. Section 502(f) of the
FD&C Act deems a drug to be
misbranded if its labeling lacks
adequate directions for use and
adequate warnings against use in those
pathological conditions where its use
may be dangerous to health, as well as
adequate warnings against unsafe
dosage or methods or duration of
administration or application, in such
manner and form, as are necessary for
the protection of users. Section 502(j) of
the FD&C Act deems a drug to be
misbranded if it is dangerous to health
when used in the dosage or manner, or
with the frequency or duration,
prescribed, recommended, or suggested
in its labeling.
In addition, the premarket approval
provisions of the FD&C Act authorize
FDA to require that prescription drug
labeling provide the practitioner with
adequate information to permit safe and
effective use of the drug product. Under
section 505 of the FD&C Act, FDA will
approve an NDA only if the drug is
shown to be both safe and effective for
use under the conditions set forth in the
drug’s labeling. Section 701(a) of the
FD&C Act (21 U.S.C. 371(a)) authorizes
FDA to issue regulations for the efficient
enforcement of the FD&C Act.
Under 21 CFR 314.125, FDA will not
approve an NDA unless, among other
things, there is adequate safety and
effectiveness information for the labeled
uses and the product labeling complies
with the requirements of part 201.
Under § 201.100(d) of FDA’s
regulations, a prescription drug product
must bear labeling that contains
adequate information under which
licensed practitioners can use the drug
safely for their intended uses. This final
rule amends the regulations specifying
the format and content for such labeling.
Section 351 of the PHS Act (42 U.S.C.
262) provides legal authority for the
Agency to regulate the labeling and
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Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations
shipment of biological products.
Licenses for biological products are to
be issued only upon a showing that they
meet standards ‘‘designed to insure the
continued safety, purity, and potency of
such products’’ prescribed in
regulations (section 351(d) of the PHS
Act). The ‘‘potency’’ of a biological
product includes its effectiveness (21
CFR 600.3(s)). Section 351(b) of the PHS
Act prohibits false labeling of a
biological product. FDA’s regulations in
part 201 apply to all prescription drug
products, including biological products.
B. First Amendment
FDA’s requirements for the content
and format of the ‘‘Pregnancy’’ and
‘‘Lactation’’ subsections of labeling for
prescription drug products are
constitutionally permissible because
they are reasonably related to the
government’s interest in ensuring the
safe and effective use of prescription
drug products and because they do not
impose unjustified or unduly
burdensome disclosure requirements. In
the PLR, FDA explained in greater depth
why that rule passes muster under the
First Amendment (see 71 FR 3922 at
3964, January 24, 2006). That analysis is
equally applicable to this final rule, and
we hereby adopt that discussion by
reference.
VI. Environmental Impact
The Agency has determined under 21
CFR 25.30(h) that this action is of a type
that does not individually or
cumulatively have a significant effect on
the human environment. Therefore,
neither an environmental assessment
nor an environmental impact statement
is required.
VII. Summary of Final Regulatory
Impact Analysis
mstockstill on DSK4VPTVN1PROD with RULES2
A. Introduction
FDA has examined the impacts of the
final rule under Executive Order 12866,
Executive Order 13563, the Regulatory
Flexibility Act (5 U.S.C. 601–612), and
the Unfunded Mandates Reform Act of
1995 (Public Law 104–4). Executive
Orders 12866 and 13563 direct Agencies
to assess all costs and benefits of
available regulatory alternatives and,
when regulation is necessary, to select
regulatory approaches that maximize
net benefits (including potential
economic, environmental, public health
and safety, and other advantages;
distributive impacts; and equity). The
Agency believes that this final rule is
not a significant regulatory action under
Executive Order 12866.
The Regulatory Flexibility Act
requires Agencies to analyze regulatory
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18:24 Dec 03, 2014
Jkt 235001
options that would minimize any
significant impact of a rule on small
entities. Because our analysis suggests
that some small prescription drug
manufacturers and prescription drug
repackagers and relabelers will incur
costs that total more than 1 percent of
their annual income in some years, the
Agency finds that the final rule will
have a significant economic impact on
a substantial number of small entities.
Section 202(a) of the Unfunded
Mandates Reform Act of 1995 requires
that Agencies prepare a written
statement, which includes an
assessment of anticipated costs and
benefits, before proposing ‘‘any rule that
includes any Federal mandate that may
result in the expenditure by State, local,
and tribal governments, in the aggregate,
or by the private sector, of $100,000,000
or more (adjusted annually for inflation)
in any one year.’’ The current threshold
after adjustment for inflation is $141
million, using the most current (2013)
Implicit Price Deflator for the Gross
Domestic Product. FDA does not expect
this final rule to result in any 1-year
expenditure that would meet or exceed
this amount.
The first regulations on the content
and format of prescription drug labeling
were established in 1979, including the
requirement to assign drugs to one of
five pregnancy categories. Over time,
however, labeling became long,
repetitive, and difficult to use. With the
PLR in 2006, the Agency began to apply
modern principles of effective
communication to improve the quality
of prescription drug labeling. However,
the PLR left the content of the
‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and
‘‘Nursing mothers’’ subsections of the
‘‘Use in Specific Populations’’ section
untouched. This decision gave the
Agency sufficient time to meet with
experts and stakeholders to develop a
regulatory framework that encourages
applicants to prepare content that
clearly communicates available
information about prescription drug use
during pregnancy and lactation, and in
females and males of reproductive
potential. With this final rule, the
Agency specifically addresses the
content and format of these subsections.
B. Summary of Costs and Benefits
The final regulatory impact analysis
of the final rule (Ref. 2) is available at
https://www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/
EconomicAnalyses/default.htm. Table 2
presents a summary of the annualized
costs and benefits of the final rule over
10 years. With a 7 percent discount rate,
annualized costs equal about $9.5
million; with a 3 percent discount rate,
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Frm 00035
Fmt 4701
Sfmt 4700
72097
annualized costs equal about $9.2
million.
The final rule will require that
applicants comply with new labeling
content and format requirements for
affected subsections for prescription
drug and biological product labeling
subject to the PLR under § 201.57(c)(9)
(PLR labeling) and will require that
applicants remove the pregnancy
category from all prescription drug and
biological product labeling subject to
§ 201.80(f)(6)(i) (non-PLR labeling). The
‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and
‘‘Nursing mothers’’ subsections of the
‘‘Use in Specific Populations’’ section
will be replaced by the ‘‘Pregnancy,’’
‘‘Lactation,’’ and ‘‘Females and Males of
Reproductive Potential’’ subsections.
New information will be required to
summarize the key information needed
by health care providers treating females
and males of reproductive potential.
The information in these subsections
will be presented in a narrative,
following a standardized order and
format with clear subheadings.
The primary objectives of the final
rule are to improve labeling by updating
the content and format of these
subsections of prescription drug product
labeling, and to remove the pregnancy
category system. The Agency concluded
that following a standardized structure
is essential for effective communication.
The final rule is needed to ensure that
these subsections contain the most upto-date information available and
provide prescribers with clinically
relevant data that they can use in their
decisionmaking processes. Consistent
with the approach taken by the PLR, the
Agency intends to provide applicants
with clear guidance about the required
content and format. Concurrent with the
publication of this final rule, FDA is
issuing a draft guidance for industry on
‘‘Pregnancy, Lactation, and
Reproductive Potential: Labeling for
Human Prescription Drug and Biological
Products—Content and Format.’’
The level of effort needed to comply
with the requirements of the final rule
will depend on the type of labeling (PLR
or non-PLR labeling) and the length of
time the product has been marketed.
Applicants and persons responsible for
existing prescription drug and biological
product labeling will incur one-time
costs to revise existing labeling in years
3, 4, and 5. Applicants submitting new
BLAs, NDAs, and certain efficacy
supplements will incur one-time costs
to gather and organize new content
required by the final rule at the time
they prepare labeling for the application
or supplement. In addition, we estimate
the additional annual printing costs for
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Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations
longer PLR labeling that will include
new content.
We estimate that the total cost of the
rule over 10 years will equal about $88.7
million. The present value of the total
costs will equal $78.2 million with a 3
percent discount rate and $66.8 million
with a 7 percent discount rate. Over 10
years, the annualized present value will
equal $9.2 million with a 3 percent
discount rate and $9.5 million with a 7
percent discount rate.
TABLE 2—ECONOMIC DATA: COSTS AND BENEFITS ACCOUNTING STATEMENT
Units
Category
Benefits:
Annualized ............
Monetized
$millions/year ....
Annualized ............
Quantified ..............
Qualitative .............
Primary
estimate
Low
estimate
High
estimate
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
From/To:
From:
From/To:
Discount
rate
(percent)
Notes
7
........................
........................
........................
........................
........................
3
7
3
........................
........................
........................
........................
........................
........................
Improved quality of prescription drug labeling for
health care providers
Costs:
Annualized ............
Monetized
$millions/year ....
Annualized ............
Quantified ..............
Qualitative .............
Transfers:
Federal Annualized
Monetized
$millions/year ....
Other Annualized ..
Monetized
$millions/year ....
Period
covered
(years)
Year
dollars
$9.5
........................
........................
2011
7
10
........................
9.2
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
2011
........................
........................
........................
3
7
3
........................
10
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
........................
7
........................
........................
........................
........................
........................
........................
3
........................
........................
To:
........................
........................
........................
........................
7
........................
........................
........................
........................
........................
........................
3
........................
........................
From:
To:
Effects:
State, Local or Tribal Government: No effect
Small Business: The final rule will have significant impacts on some small pharmaceutical manufacturers and prescription
drug repackagers and relabelers.
Wages: No effect
Growth: No effect
mstockstill on DSK4VPTVN1PROD with RULES2
VIII. Paperwork Reduction Act of 1995
This final rule contains information
collection requirements that are subject
to review by the Office of Management
and Budget (OMB) under the Paperwork
Reduction Act of 1995 (the PRA) (44
U.S.C. 3501–3520). The title,
description, and respondent description
of the information collection provisions
are shown in the following paragraphs
with an estimate of the total reporting
and disclosure burdens. Included in the
estimate is the time for reviewing
instructions, searching existing data
sources, gathering and maintaining the
data needed, and completing and
reviewing each collection of
information.
VerDate Sep<11>2014
18:24 Dec 03, 2014
Jkt 235001
Title: Content and Format of Labeling
for Human Prescription Drug and
Biological Products; Requirements for
Pregnancy and Lactation Labeling
Description: The final rule amends
FDA regulations concerning the content
and format of the ‘‘Pregnancy,’’ ‘‘Labor
and delivery,’’ and ‘‘Nursing mothers’’
subsections of the ‘‘Use in Specific
Populations’’ section of the labeling for
human prescription drugs. The final
rule requires that labeling include,
among other things, a summary of the
risks of using a drug during pregnancy
and lactation and a discussion of the
data supporting that summary. The
labeling also includes relevant
information to help health care
providers make prescribing decisions
PO 00000
Frm 00036
Fmt 4701
Sfmt 4700
and counsel women about the use of
drugs during pregnancy and lactation.
The final rule eliminates the current
pregnancy categories A, B, C, D, and X.
In addition, the ‘‘Labor and delivery’’
subsection has been eliminated because
information on labor and delivery is
included in the ‘‘Pregnancy’’ subsection.
The final rule also requires that the
labeling include relevant information
about pregnancy testing, contraception,
and infertility for health care providers
prescribing for females and males of
reproductive potential. The final rule is
intended to create a consistent format
for providing information about the
risks and benefits of prescription drug
and/or biological product use during
E:\FR\FM\04DER2.SGM
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Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations
pregnancy and lactation and by females
and males of reproductive potential.
Under § 201.57(c)(9)(i) and (c)(9)(ii),
holders of approved applications are
required to provide new labeling
content in a new format—that is, to
rewrite the pregnancy and lactation
portions of each drug’s labeling. Under
§ 201.57(c)(9)(iii), these application
holders are also required to include a
new subsection 8.3, ‘‘Females and Males
of Reproductive Potential,’’ which
requires that when pregnancy testing or
contraception is required or
recommended before, during, or after
drug therapy or when there are human
or animal data that suggest drugassociated fertility effects, this
subsection must contain this
information. These application holders
are required to submit supplements
requiring prior approval by FDA before
distribution of the new labeling, as
required in § 314.70(b) or § 601.12(f)(1).
Under § 201.80(f)(6)(i), holders of
approved applications are required to
remove the pregnancy category
designation (e.g., ‘‘Pregnancy Category
C’’) from the ‘‘Pregnancy’’ subsection of
the ‘‘Precautions’’ section of the
labeling. These application holders
must report the labeling change in their
annual reports, as required in
§ 314.70(d) or § 601.12(f)(3).
The new content and format
requirements of the final rule apply to
all applications that are required to
comply with the PLR, including: (1)
Applications submitted on or after the
effective date of the final rule; (2)
applications pending on the effective
date of the final rule; and (3)
applications approved from June 30,
2001, to the effective date of the final
rule.
The following submissions under the
final rule are subject to the PRA:
• Applications submitted on or after
the effective date of the final rule
(§§ 314.50, 314.70(b), 601.2,
601.12(f)(1));
• Amendments to applications
pending on the effective date of the final
rule (§§ 314.60, 601.2, 601.12(f)(1));
• Supplements to applications
approved from June 30, 2001, to the
effective date of the final rule
(§§ 314.70(b), 601.12(f)(1));
• Annual reports for applications
approved before June 30, 2001, that
contain a pregnancy category, to report
removal of the pregnancy category letter
in their labeling (§§ 314.70(d),
601.12(f)(3)).
The information collection
requirements and burden estimates are
summarized in tables 3 and 4 of this
document. The burden estimates are
based on data and timeframes used for
section VII of this document (Summary
of Final Regulatory Impact Analysis)
and for the final regulatory impact
analysis of the final rule (available at
https://www.fda.gov/AboutFDA/
ReportsManualsForms/Reports/
EconomicAnalyses/default.htm). FDA
estimates that approximately 4,000
applications containing labeling
consistent with this rulemaking will be
submitted to FDA during the 10-year
period on or after the effective date of
the final rule by approximately 390
applicants and repackagers and
relabelers. The estimate of 4,000
applications includes labeling for
approximately 800 applications
submitted under section 505(b) of the
FD&C Act or section 351 of the PHS Act,
and 1,200 applications submitted under
section 505(j) of the FD&C Act, and
revised labeling from repackagers and
relabelers for approximately 2,000 drug
products. This estimate also includes
labeling amendments submitted to FDA
for applications pending on the effective
date of the final rule. Based on data
provided in section VII of this document
and in the final regulatory impact
analysis of the final rule, FDA estimates
that for future approvals it will take
applicants approximately 40 hours to
prepare and submit labeling consistent
with this rulemaking. The estimate of 40
hours applies only to the requirements
of this rulemaking and does not indicate
the total hours required to prepare and
submit complete labeling for these
applications. The information collection
burden to prepare and submit labeling
72099
in accordance with §§ 201.56, 201.57,
and 201.80 is approved by OMB under
control numbers 0910–0572 and 0910–
0001.
In addition, FDA estimates that
approximately 10,150 supplements to
applications approved from June 30,
2001, to the effective date of the final
rule, or pending on the effective date,
will be submitted to FDA during the
third, fourth, and fifth years after the
effective date to update labeling in
accordance with this final rule. This
estimate includes approximately 1,080
NDA, BLA, and efficacy supplements,
approximately 1,320 ANDA
supplements, and labeling supplements
from repackagers and relabelers for
approximately 7,750 drug products.
FDA estimates that approximately 390
application holders and repackagers and
relabelers will submit these
supplements, and that it will take
approximately 120 hours to prepare and
submit each supplement.
FDA also estimates that
approximately 5,500 annual reports will
be submitted to FDA during the third
year after the effective date for
applications approved before June 30,
2001, that contain a pregnancy category
(5,500 includes annual reports for
approximately 1,340 NDAs and BLAs
and approximately 4,160 ANDAs
containing labeling changes resulting
from this rulemaking). FDA estimates
that approximately 320 application
holders will submit these annual
reports, and that it will take
approximately 40 hours for each
submission.
As indicated in tables 3 and 4 of this
document, we estimate that the total
hours resulting from the information
collection in this rulemaking will be
approximately 1,598,000 hours. The
costs associated with this rulemaking,
including labor costs, are discussed in
section VII of this document and in the
final regulatory impact analysis of the
final rule.
Description of Respondents: Persons
and businesses, including small
businesses and manufacturers.
TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN 1
mstockstill on DSK4VPTVN1PROD with RULES2
Type of submission
(21 CFR section)
Number of
respondents
Supplements to applications approved 6/30/
01 to effective date (§§ 314.70(b),
601.12(f)(1)).
Annual report submission of revised labeling
for applications approved before 6/30/01
that contain a pregnancy category
(§§ 314.70(d), 601.12(f)(3)).
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18:24 Dec 03, 2014
Jkt 235001
PO 00000
Number of
responses per
respondent
390
26
320
17
Frm 00037
Fmt 4701
Average
burden per
response
Total annual
responses
10,150 (Submitted 3rd, 4th,
and 5th years after effective date).
5,500 (Submitted 3rd year
after effective date).
Sfmt 4700
E:\FR\FM\04DER2.SGM
04DER2
Total
hours
120
1,218,000
40
220,000
72100
Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations
TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued
Number of
respondents
Type of submission
(21 CFR section)
Total .......................................................
1 There
Number of
responses per
respondent
Total annual
responses
Average
burden per
response
........................
........................
...............................................
........................
Total
hours
1,438,000
are no capital costs or operating and maintenance costs associated with this information collection.
TABLE 4—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1
Type of submission
(21 CFR section)
Number of
respondents
Number of
disclosures
per
respondent
New NDAs/ANDAs/BLAs/efficacy supplements
submitted on or after effective date, including
amendments to applications pending on effective date (§§ 314.50, 314.60, 314.70(b), 601.2,
601.12(f)(1)).
390
10
1 There
Average
burden per
disclosure
Total
ours
4,000 (Submitted during
10-year period after
effective date).
40
160,000
are no capital costs or operating and maintenance costs associated with this information collection.
The information collection provisions
of this final rule have been submitted to
OMB for review, as required by section
3507(d) of the PRA. Prior to the effective
date of this final rule, FDA will publish
a notice in the Federal Register
announcing OMB’s decision to approve,
modify, or disapprove the information
collection provisions in this final rule.
An Agency may not conduct or sponsor,
and a person is not required to respond
to, a collection of information unless it
displays a currently valid OMB control
number.
IX. Federalism
FDA has analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. FDA has
determined that this final rule does not
contain policies that have substantial
direct effects on the States, on the
relationship between the National
Government and the States, or on the
distribution of power and
responsibilities among the various
levels of government. Accordingly, the
Agency has concluded that the rule does
not contain policies that have
federalism implications as defined in
the Executive order and, consequently,
a federalism summary impact statement
is not required.
mstockstill on DSK4VPTVN1PROD with RULES2
Total annual
disclosures
X. References
In addition to the references placed
on display in the Division of Dockets
Management for the proposed rule
under Docket No. FDA–2006–N–0515
(formerly Docket No. 2006N–0467), the
following references are on display in
the Division of Dockets Management
under Docket No. FDA–2006–N–0515
(formerly Docket No. 2006N–0467) and
may be seen by interested persons
between 9 a.m. and 4 p.m., Monday
VerDate Sep<11>2014
18:24 Dec 03, 2014
Jkt 235001
through Friday, and are available
electronically at https://
www.regulations.gov. (FDA has verified
all Web site addresses in this reference
section, but we are not responsible for
any subsequent changes to the Web sites
after this document publishes in the
Federal Register.)
1. Decision Partners, LLC, ‘‘Evaluation of
How Best to Communicate to Healthcare
Providers about the Risks and Benefits of
Prescription Drug Use for Pregnant and
Nursing Women: A Mental Models
Research Report,’’ September 2009
(available at https://www.fda.gov/
AboutFDA/ReportsManualsForms/
Reports/EconomicAnalyses/default.htm).
2. Final Regulatory Impact Analysis for
Docket No. FDA–2006–N–0515 (formerly
Docket No. 2006N–0467) (available at
https://www.fda.gov/AboutFDA/Reports
ManualsForms/Reports/Economic
Analyses/default.htm and at https://
www.regulations.gov).
3. U.S. Food and Drug Administration,
‘‘Guidance for Industry, Warnings and
Precautions, Contraindications, and
Boxed Warning Sections of Labeling for
Human Prescription Drug and Biological
Products—Content and Format,’’ 2011.
4. Kweder, S.L., ‘‘Drugs and Biologics in
Pregnancy and Breastfeeding: FDA in the
21st Century.’’ Birth Defects Research
Part A: Clinical and Molecular
Teratology. 82(9):605–609, September
2008.
5. Adam, M.P., J.E. Polifka, and J.M.
Friedman, ‘‘Evolving Knowledge of the
Teratogenicity of Medications in Human
Pregnancy.’’ American Journal of
Medical Genetics Part C: Seminars in
Medical Genetics. 157C(3):175–182,
August 15, 2011.
6. Law, R., P. Bozzo, G. Koren, et al. ‘‘FDA
Pregnancy Risk Categories and the CPS.
Do They Help or Are They a
Hindrance?’’ Canadian Family
Physician. 56:239–241, March 2010.
PO 00000
Frm 00038
Fmt 4701
Sfmt 4700
7. U.S. Food and Drug Administration
‘‘Guidance for industry, Establishing
Pregnancy Exposure Registries,’’ 2002.
8. U.S. Food and Drug Administration
‘‘Guidance for Industry, Reproductive
and Developmental Toxicities—
Integrating Study Results to Assess
Concerns,’’ 2011.
9. Rynn, L., J. Cragan, and A. Correa, ‘‘Update
on Overall Prevalence of Major Birth
Defects—Atlanta, Georgia, 1978–2005.’’
Centers for Disease Control and
Prevention Morbidity and Mortality
Weekly Report. 57(01):1–5, January 11,
2008.
10. American College of Obstetricians and
Gynecologists Frequently Asked
Questions: Miscarriage and Molar
Pregnancy, 2011 (available at https://
www.acog.org/∼/media/For%20Patients/
faq090.pdf?dmc=1&ts=20140130T
1655496642).
11. U.S. Food and Drug Administration,
‘‘Reviewer Guidance, Evaluating the
Risks of Drug Exposure in Human
Pregnancies,’’ 2005.
12. U.S. Food and Drug Administration,
‘‘Guidance for industry, Considerations
for Developmental Toxicity Studies for
Preventive and Therapeutic Vaccines for
Infectious Disease Indications,’’ 2006.
13. U.S. Food and Drug Administration,
‘‘Guidance for industry, M3 (R2)
Nonclinical Safety Studies for the
Conduct of Human Clinical Trials and
Marketing Authorization for
Pharmaceuticals and the International
Conference on Harmonisation S5 (R2)
Guideline: Detection of Toxicity to
Reproduction for Medicinal Products
and Toxicity to Male Fertility,’’ 2010.
14. Tracy, T.S., et al. ‘‘Temporal Changes in
Drug Metabolism (CYP1A2, CYP2D6 and
CYP3A Activity) During Pregnancy.’’
American Journal of Obstetrics and
Gynecology. 192(2):633–639, February
2005.
15. Anderson, G.D., ‘‘Pregnancy-Induced
Changes in Pharmacokinetics.’’ Clinical
Pharmacokinetics. 44(10):989–1008,
2005.
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16. American Academy of Pediatrics Policy
Statement. ‘‘Breastfeeding and the Use of
Human Milk.’’ Pediatrics. 129(3):e827–
841, 2012.
17. Sachs, H.C. and Committee on Drugs.
‘‘The Transfer of Drugs and Therapeutics
Into Human Breast Milk: An Update on
Selected Topics.’’ Pediatrics.
132(3):e796–809, September 2013.
18. U.S. Food and Drug Administration,
‘‘Draft Guidance for industry Clinical
Lactation Studies—Study Design, Data
Analysis, and Recommendations for
Labeling,’’ 2005.
19. Proposed Pregnancy and Lactation
Labeling Rule (available at https://
www.fda.gov/Drugs/Development
ApprovalProcess/Development
Resources/Labeling/ucm093307.htm).
20. Public Comments on Proposed Pregnancy
and Lactation Labeling Rule (available at
https://www.regulations.gov/#!docket
Detail;D=FDA-2006-N-0515).
List of Subjects in 21 CFR Part 201
Drugs, Labeling, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, 21 CFR part 201 is
amended as follows:
PART 201—LABELING
1. The authority citation for 21 CFR
part 201 continues to read as follows:
■
Authority: 21 U.S.C. 321, 331, 351, 352,
353, 355, 358, 360, 360b, 360gg–360ss, 371,
374, 379e; 42 U.S.C. 216, 241, 262, 264.
§ 201.56
[Amended]
2. Amend § 201.56 in paragraph (d)(1)
by removing from the list of headings
and subheadings the subheadings ‘‘8.2
Labor and delivery’’ and ‘‘8.3 Nursing
mothers’’ and adding in their places the
subheadings ‘‘8.2 Lactation’’ and ‘‘8.3
Females and Males of Reproductive
Potential’’, respectively.
■ 3. Amend § 201.57 by revising
paragraphs (c)(9)(i), (ii), and (iii) to read
as follows:
■
§ 201.57 Specific requirements on content
and format of labeling for human
prescription drug and biological products
described in § 201.56(b)(1).
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*
*
*
*
*
(c) * * *
(9) * * *
(i) 8.1 Pregnancy. This subsection of
the labeling must contain the following
information in the following order
under the subheadings ‘‘Pregnancy
Exposure Registry,’’ ‘‘Risk Summary,’’
‘‘Clinical Considerations,’’ and ‘‘Data’’:
(A) Pregnancy exposure registry. If
there is a scientifically acceptable
pregnancy exposure registry for the
drug, contact information needed to
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18:24 Dec 03, 2014
Jkt 235001
enroll in the registry or to obtain
information about the registry must be
provided following the statement:
‘‘There is a pregnancy exposure registry
that monitors pregnancy outcomes in
women exposed to (name of drug)
during pregnancy.’’
(B) Risk summary. The Risk Summary
must contain risk statement(s) based on
data from all relevant sources (human,
animal, and/or pharmacologic) that
describe, for the drug, the risk of
adverse developmental outcomes (i.e.,
structural abnormalities, embryo-fetal
and/or infant mortality, functional
impairment, alterations to growth).
When multiple data sources are
available, the statements must be
presented in the following order:
Human, animal, pharmacologic. The
source(s) of the data must be stated. The
labeling must state the percentage range
of live births in the United States with
a major birth defect and the percentage
range of pregnancies in the United
States that end in miscarriage,
regardless of drug exposure. If such
information is available for the
population(s) for which the drug is
labeled, it must also be included. When
use of a drug is contraindicated during
pregnancy, this information must be
stated first in the Risk Summary. When
applicable, risk statements as described
in paragraphs (c)(9)(i)(B)(1) and (2) of
this section must include a crossreference to additional details in the
relevant portion of the ‘‘Data’’
subheading in the ‘‘Pregnancy’’
subsection of the labeling. If data
demonstrate that a drug is not
systemically absorbed following a
particular route of administration, the
Risk Summary must contain only the
following statement: ‘‘(Name of drug) is
not absorbed systemically following
(route of administration), and maternal
use is not expected to result in fetal
exposure to the drug.’’
(1) Risk statement based on human
data. When human data are available
that establish the presence or absence of
any adverse developmental outcome(s)
associated with maternal use of the
drug, the Risk Summary must
summarize the specific developmental
outcome(s); their incidence; and the
effects of dose, duration of exposure,
and gestational timing of exposure. If
human data indicate that there is an
increased risk for a specific adverse
developmental outcome in infants born
to women exposed to the drug during
pregnancy, this risk must be
quantitatively compared to the risk for
the same outcome in infants born to
women who were not exposed to the
drug but who have the disease or
condition for which the drug is
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Fmt 4701
Sfmt 4700
72101
indicated to be used. When risk
information is not available for women
with the disease or condition for which
the drug is indicated, the risk for the
specific outcome must be compared to
the rate at which the outcome occurs in
the general population. The Risk
Summary must state when there are no
human data or when available human
data do not establish the presence or
absence of drug-associated risk.
(2) Risk statement based on animal
data. When animal data are available,
the Risk Summary must summarize the
findings in animals and based on these
findings, describe, for the drug, the
potential risk of any adverse
developmental outcome(s) in humans.
This statement must include: The
number and type(s) of species affected,
timing of exposure, animal doses
expressed in terms of human dose or
exposure equivalents, and outcomes for
pregnant animals and offspring. When
animal studies do not meet current
standards for nonclinical developmental
toxicity studies, the Risk Summary must
so state. When there are no animal data,
the Risk Summary must so state.
(3) Risk statement based on
pharmacology. When the drug has a
well-understood mechanism of action
that may result in adverse
developmental outcome(s), the Risk
Summary must explain the mechanism
of action and the potential associated
risks.
(C) Clinical considerations. Under the
subheading ‘‘Clinical Considerations,’’
the labeling must provide relevant
information, to the extent it is available,
under the headings ‘‘Disease-associated
maternal and/or embryo/fetal risk,’’
‘‘Dose adjustments during pregnancy
and the postpartum period,’’ ‘‘Maternal
adverse reactions,’’ ‘‘Fetal/Neonatal
adverse reactions,’’ and ‘‘Labor or
delivery’’:
(1) Disease-associated maternal and/
or embryo/fetal risk. If there is a serious
known or potential risk to the pregnant
woman and/or the embryo/fetus
associated with the disease or condition
for which the drug is indicated to be
used, the labeling must describe the
risk.
(2) Dose adjustments during
pregnancy and the postpartum period. If
there are pharmacokinetic data that
support dose adjustment(s) during
pregnancy and the postpartum period, a
summary of this information must be
provided.
(3) Maternal adverse reactions. If use
of the drug is associated with a maternal
adverse reaction that is unique to
pregnancy or if a known adverse
reaction occurs with increased
frequency or severity in pregnant
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Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations
women, the labeling must describe the
adverse reaction and available
intervention(s) for monitoring or
mitigating the reaction. The labeling
must describe, if known, the effect of
dose, timing, and duration of exposure
on the risk to the pregnant woman of
experiencing the adverse reaction.
(4) Fetal/Neonatal adverse reactions.
If it is known or anticipated that
treatment of the pregnant woman
increases or may increase the risk of an
adverse reaction in the fetus or neonate,
the labeling must describe the adverse
reaction, the potential severity and
reversibility of the adverse reaction, and
available intervention(s) for monitoring
or mitigating the reaction. The labeling
must describe, if known, the effect of
dose, timing, and duration of exposure
on the risk.
(5) Labor or delivery. If the drug is
expected to affect labor or delivery, the
labeling must provide information about
the effect of the drug on the pregnant
woman and the fetus or neonate; the
effect of the drug on the duration of
labor and delivery; any increased risk of
adverse reactions, including their
potential severity and reversibility; and
must provide information about
available intervention(s) that can
mitigate these effects and/or adverse
reactions. The information described
under this heading is not required for
drugs approved for use only during
labor and delivery.
(D) Data—(1) ‘‘Data’’ subheading.
Under the subheading ‘‘Data,’’ the
labeling must describe the data that are
the basis for the Risk Summary and
Clinical Considerations.
(2) Human and animal data headings.
Human and animal data must be
presented separately, beneath the
headings ‘‘Human Data’’ and ‘‘Animal
Data,’’ and human data must be
presented first.
(3) Description of human data. For
human data, the labeling must describe
adverse developmental outcomes,
adverse reactions, and other adverse
effects. To the extent applicable, the
labeling must describe the types of
studies or reports, number of subjects
and the duration of each study,
exposure information, and limitations of
the data. Both positive and negative
study findings must be included.
(4) Description of animal data. For
animal data, the labeling must describe
the following: Types of studies, animal
species, dose, duration and timing of
exposure, study findings, presence or
absence of maternal toxicity, and
limitations of the data. Description of
maternal and offspring findings must
include dose-response and severity of
adverse developmental outcomes.
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Animal doses or exposures must be
described in terms of human dose or
exposure equivalents and the basis for
those calculations must be included.
(ii) 8.2 Lactation. This subsection of
the labeling must contain the following
information in the following order
under the subheadings ‘‘Risk
Summary,’’ ‘‘Clinical Considerations,’’
and ‘‘Data’’:
(A) Risk summary. When relevant
human and/or animal lactation data are
available, the Risk Summary must
include a cross-reference to the ‘‘Data’’
subheading in the ‘‘Lactation’’
subsection of the labeling. When human
data are available, animal data must not
be included unless the animal model is
specifically known to be predictive for
humans. When use of a drug is
contraindicated during breastfeeding,
this information must be stated first in
the Risk Summary.
(1) Drug not absorbed systemically. If
data demonstrate that the drug is not
systemically absorbed by the mother,
the Risk Summary must contain only
the following statement: ‘‘(Name of
drug) is not absorbed systemically by
the mother following (route of
administration), and breastfeeding is not
expected to result in exposure of the
child to (name of drug).’’
(2) Drug absorbed systemically. If the
drug is absorbed systemically, the Risk
Summary must describe the following to
the extent relevant information is
available:
(i) Presence of drug in human milk.
The Risk Summary must state whether
the drug and/or its active metabolite(s)
are present in human milk. If there are
no data to assess this, the Risk Summary
must so state. If studies demonstrate
that the drug and/or its active
metabolite(s) are not detectable in
human milk, the Risk Summary must
state the limits of the assay used. If
studies demonstrate the presence of the
drug and/or its active metabolite(s) in
human milk, the Risk Summary must
state the concentration of the drug and/
or its active metabolite(s) in human milk
and the actual or estimated daily dose
for an infant fed exclusively with
human milk. The actual or estimated
amount of the drug and/or its active
metabolite(s) ingested by the infant
must be compared to the labeled infant
or pediatric dose, if available, or to the
maternal dose. If studies demonstrate
the presence of the drug and/or its
active metabolite(s) in human milk but
the drug and/or its active metabolite(s)
are not expected to be systemically
bioavailable to the breast-fed child, the
Risk Summary must describe the
disposition of the drug and/or its active
metabolite(s). If only animal lactation
PO 00000
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Fmt 4701
Sfmt 4700
data are available, the Risk Summary
must state only whether or not the drug
and/or its active metabolite(s) were
detected in animal milk and specify the
animal species.
(ii) Effects of drug on the breast-fed
child. The Risk Summary must include
information, on the known or predicted
effects on the child from exposure to the
drug and/or its active metabolite(s)
through human milk or from contact
with breast or nipple skin (for topical
products). The Risk Summary also must
include information on systemic and/or
local adverse reactions. If there are no
data to assess the effects of the drug
and/or its active metabolite(s) on the
breast-fed child, the Risk Summary
must so state.
(iii) Effects of drug on milk
production. The Risk Summary must
describe the effects of the drug and/or
its active metabolite(s) on milk
production. If there are no data to assess
the effects of the drug and/or its active
metabolite(s) on milk production, the
Risk Summary must so state.
(3) Risk and benefit statement. For
drugs absorbed systemically, unless
breastfeeding is contraindicated during
drug therapy, the following risk and
benefit statement must appear at the end
of the Risk Summary: ‘‘The
developmental and health benefits of
breastfeeding should be considered
along with the mother’s clinical need for
(name of drug) and any potential
adverse effects on the breast-fed child
from (name of drug) or from the
underlying maternal condition.’’
(B) Clinical considerations. Under
‘‘Clinical Considerations,’’ the following
information must be provided to the
extent it is available and relevant:
(1) Minimizing exposure. The labeling
must describe ways to minimize
exposure in the breast-fed child if: The
drug and/or its active metabolite(s) are
present in human milk in clinically
relevant concentrations; the drug does
not have an established safety profile in
infants; and the drug is used either
intermittently, in single doses, or for
short courses of therapy. When
applicable, the labeling must also
describe ways to minimize a breast-fed
child’s oral intake of topical drugs
applied to the breast or nipple skin.
(2) Monitoring for adverse reactions.
The labeling must describe available
intervention(s) for monitoring or
mitigating the adverse reaction(s)
presented in the Risk Summary.
(C) Data. Under the subheading
‘‘Data,’’ the labeling must describe the
data that are the basis for the Risk
Summary and Clinical Considerations.
(iii) 8.3 Females and males of
reproductive potential. When pregnancy
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testing and/or contraception are
required or recommended before,
during, or after drug therapy and/or
when there are human and/or animal
data that suggest drug-associated
fertility effects, this subsection of
labeling must contain this information
under the subheadings ‘‘Pregnancy
Testing,’’ ‘‘Contraception,’’ and
‘‘Infertility,’’ in that order.
*
*
*
*
*
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§ 201.80
[Amended]
Frm 00041
Fmt 4701
d. Remove the paragraph heading
‘‘Pregnancy category D.’’ and the words
‘‘Pregnancy Category D.’’ from
paragraph (f)(6)(i)(d); and
■ e. Remove the paragraph heading
‘‘Pregnancy category X.’’ and the words
‘‘Pregnancy Category X.’’ from
paragraph (f)(6)(i)(e).
■
4. Amend § 201.80 as follows:
a. Remove the paragraph heading
‘‘Pregnancy category A.’’ and the words
‘‘Pregnancy Category A.’’ from
paragraph (f)(6)(i)(a);
■ b. Remove the paragraph heading
‘‘Pregnancy category B.’’ and the words
‘‘Pregnancy Category B.’’ both times
they appear from paragraph (f)(6)(i)(b);
■ c. Remove the paragraph heading
‘‘Pregnancy category C.’’ and the words
‘‘Pregnancy Category C.’’ both times
they appear from paragraph (f)(6)(i)(c);
■
■
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Sfmt 9990
Dated: November 25, 2014.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2014–28241 Filed 12–3–14; 8:45 am]
BILLING CODE 4164–01–P
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]]>Agencies
[Federal Register Volume 79, Number 233 (Thursday, December 4, 2014)]
[Rules and Regulations]
[Pages 72063-72103]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-28241]
[[Page 72063]]
Vol. 79
Thursday,
No. 233
December 4, 2014
Part II
Department of Health and Human Services
-----------------------------------------------------------------------
Food and Drug Administration
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21 CFR Part 201
Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling;
Pregnancy, Lactation, and Reproductive Potential: Labeling for Human
Prescription Drug and Biological Products--Content and Format; Draft
Guidance for Industry; Availability; Final Rule and Notice
Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 /
Rules and Regulations
[[Page 72064]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. FDA-2006-N-0515 (formerly Docket No. 2006N-0467)]
RIN 0910-AF11
Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations governing the content and format of the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Use in Specific Populations'' section of the labeling for human
prescription drug and biological products. The final rule requires the
removal of the pregnancy categories A, B, C, D, and X from all human
prescription drug and biological product labeling. For human
prescription drug and biological products subject to the Agency's 2006
Physician Labeling Rule, the final rule requires that the labeling
include a summary of the risks of using a drug during pregnancy and
lactation, a discussion of the data supporting that summary, and
relevant information to help health care providers make prescribing
decisions and counsel women about the use of drugs during pregnancy and
lactation. The final rule eliminates the ``Labor and delivery''
subsection because information about labor and delivery is included in
the ``Pregnancy'' subsection. The final rule requires that the labeling
include relevant information about pregnancy testing, contraception,
and infertility for health care providers prescribing for females and
males of reproductive potential. The final rule creates a consistent
format for providing information about the risks and benefits of
prescription drug and/or biological product use during pregnancy and
lactation and by females and males of reproductive potential. These
revisions will facilitate prescriber counseling for these populations.
DATES: This rule is effective June 30, 2015. See section IV of this
document for the implementation dates of this final rule.
FOR FURTHER INFORMATION CONTACT: Kathy Schreier, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6246, Silver Spring, MD 20993-0002, 301-
796-3432; or Stephen Ripley, Center for Biologics Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.
SUPPLEMENTARY INFORMATION:
Table of Contents
Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the Regulatory Action in Question
Costs and Benefits
I. Background
A. History of FDA-Approved Pregnancy and Lactation Labeling for
Prescription Drugs
B. Development of the Proposed Rule
C. The Proposed Rule
D. Mental Models Research
II. Overview of the Final Rule Including Significant Changes to the
Proposed Rule
A. Overview
B. Significant Changes to the Proposed Rule
III. Comments on the Proposed Rule
A. Proposed Rule as a Whole
B. Specific Provisions of the Proposed Rule
IV. Implementation
V. Legal Authority
A. Statutory Authority
B. First Amendment
VI. Environmental Impact
VII. Summary of Final Regulatory Impact Analysis
A. Introduction
B. Summary of Costs and Benefits
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. References
Executive Summary
Purpose of the Regulatory Action
FDA is amending its regulations governing the content and format of
the ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers''
subsections of the ``Use in Specific Populations'' section (under Sec.
201.57 (21 CFR 201.57)) and the ``Precautions'' section (under Sec.
201.80 (21 CFR 201.80)) of the labeling for human prescription drug and
biological products (both referred to as ``drugs'' or ``drug products''
in this final rule). In this rulemaking, the Agency is finalizing many
of the provisions in the proposed rule issued on May 29, 2008 (73 FR
30831).
This rulemaking is part of a broad effort by the Agency to improve
the content and format of prescription drug labeling. The final rule
creates a consistent format for providing information about the risks
and benefits of drug use during pregnancy and lactation and by females
and males of reproductive potential. FDA's revisions to the content and
format requirements for prescription drug and biological product
labeling are authorized by the Federal Food, Drug, and Cosmetic Act
(the FD&C Act) and by the Public Health Service Act (PHS Act).
Summary of the Major Provisions of the Regulatory Action in Question
The final rule requires that for the labeling of certain drug
products (as described in the ``Implementation'' section of this
document), the subsections ``Pregnancy,'' ``Nursing mothers,'' and
``Labor and delivery'' be replaced by three subsections entitled
``Pregnancy,'' ``Lactation,'' and ``Females and Males of Reproductive
Potential.'' The final rule also requires the removal of the pregnancy
categories A, B, C, D, and X from all drug product labeling.
``Pregnancy''
The final rule merges the current ``Pregnancy'' and ``Labor and
delivery'' subsections into a single ``Pregnancy'' subsection of
labeling. If there is a scientifically acceptable pregnancy exposure
registry for the drug, the ``Pregnancy'' subsection must contain a
specified statement about the existence of the registry, followed by
contact information needed to enroll or to obtain information about the
registry. The Agency has concluded that including information about
pregnancy exposure registries in prescription drug labeling will
encourage participation in registries, thereby improving data
collection in pregnant women. Under ``Pregnancy,'' the final rule also
requires that the labeling include a summary of the risks of using a
drug during pregnancy. If data demonstrate that a drug is not absorbed
systemically, the ``Risk Summary'' must contain only a specified
statement regarding this fact. If data demonstrate that the drug is
absorbed systemically, the ``Risk Summary'' must include risk
statements based on data from all relevant sources (human, animal, and/
or pharmacologic), that describe, for the drug, the risk of adverse
developmental outcomes.
The labeling must also contain relevant information, if it is
available, to help health care providers make prescribing decisions and
counsel women about the use of the drug during pregnancy; this could
include information on disease-associated maternal and/or embryo/fetal
risk, dose adjustments during pregnancy and the postpartum period,
maternal adverse reactions, fetal/neonatal adverse reactions, and/or
the effect of the drug on labor or delivery. FDA believes that
including such information supports
[[Page 72065]]
health care providers' understanding of drug product risks and benefits
and facilitates informed prescribing decisions and patient counseling.
The labeling must also describe the data that are the basis for the
risk statements and clinical information included in the ``Pregnancy''
subsection of labeling.
``Lactation''
The final rule requires that the ``Lactation'' subsection of
labeling contain a summary of the risks of using a drug during
lactation. If data demonstrate that the drug is not absorbed
systemically, this summary must contain only a specified statement
regarding this fact. If data demonstrate that the drug is absorbed
systemically by the mother, this summary must include, to the extent it
is available, relevant information on the presence of the drug in human
milk, effects of the drug on the breast-fed child, and effects of the
drug on milk production. For drugs absorbed systemically, a risk and
benefit statement must appear at the end of the summary of risks,
unless breastfeeding is contraindicated during drug therapy. FDA has
determined that the inclusion of a risk and benefit statement will
provide a useful framework for health care providers to use when making
prescribing decisions for a lactating patient.
The ``Lactation'' subsection must also include, to the extent
information is available, relevant information concerning ways to
minimize drug exposure in the breast-fed child in certain situations
and concerning available interventions for monitoring or mitigating the
adverse reactions presented elsewhere in the labeling. In addition, the
labeling must also include pertinent information about the data that
are the basis for the risk summary and clinical information included in
the ``Lactation'' subsection of labeling.
``Females and Males of Reproductive Potential''
FDA determined that because there was no consistent placement in
the labeling of information about pregnancy testing, contraception, and
infertility, it was difficult for health care providers to find this
important information that can affect decisionmaking before or during
pregnancy. Thus, the final rule requires that the ``Females and Males
of Reproductive Potential'' subsection include relevant information
when pregnancy testing or contraception is required or recommended
before, during, or after drug therapy or when there are human or animal
data that suggest drug-associated fertility effects.
Removal of Pregnancy Categories
Through experience and stakeholder feedback, FDA learned that the
pregnancy categories were confusing and did not accurately and
consistently communicate differences in degrees of fetal risk. In
addition, FDA learned that the pregnancy categories were heavily relied
upon by clinicians but were often misinterpreted and misused in that
prescribing decisions were being made based on the pregnancy category,
rather than an understanding of the underlying information that
informed the assignment of the pregnancy category. FDA believes that a
narrative structure for pregnancy labeling, rather than a category
system, is best able to capture and convey the potential risks of drug
exposure based on animal or human data, or both. FDA has determined
that retaining the pregnancy categories is inconsistent with the need
to accurately and consistently communicate differences in degrees of
fetal risk. Therefore, the final rule requires the removal of the
pregnancy categories A, B, C, D, and X from all drug product labeling.
Costs and Benefits
We estimate that over 10 years with a 7 percent discount rate, the
present value of one-time costs of the rule equal $52.4 million and the
present value of the annual costs equal $14.4 million; with a 3 percent
discount rate, the present value of one-time costs equal $60.1 million
and the present value of the annual costs equal $18.2 million. The
present value of the total costs equal $66.8 million with a 7 percent
discount rate and $78.2 million with a 3 percent discount rate. The
annualized costs of the rule total $9.5 million with a 7 percent
discount rate and $9.2 million with a 3 percent discount rate. The
final rule will address issues raised by experts and stakeholders and
improve the quality of the affected sections of prescription drug
labeling. Better quality prescribing information will enhance the
usefulness of the labeling. The public health benefits of the final
rule would result from improved health outcomes. However, because we
have no information about how improved labeling will affect prescriber
behavior and patient outcomes, we are unable to quantify the benefits
of the final rule.
Summary of Benefits and Costs of the Final Rule
----------------------------------------------------------------------------------------------------------------
Total Total
Present value Present value annualized annualized
of total costs of total costs costs over 10 costs over 10
Total benefits with 3 percent with 7 percent years with 3 years with 7
discount rate discount rate percent percent
($ mil) ($ mil) discount rate discount rate
($ mil) ($ mil)
----------------------------------------------------------------------------------------------------------------
Not estimated............................... 78.2 66.8 9.2 9.5
----------------------------------------------------------------------------------------------------------------
I. Background
In the Federal Register of May 29, 2008 (73 FR 30831), FDA issued a
proposed rule to amend the content and format of the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Use in Specific Populations'' section of labeling for human
prescription drug and biological products, which appear in Sec.
201.57. The proposed rulemaking was part of a broad effort by the
Agency to improve the content and formatting of prescription drug
labeling.
A. History of FDA-Approved Pregnancy and Lactation Labeling for
Prescription Drugs
Under sections 502 and 505 of the FD&C Act (21 U.S.C. 352 and 355),
FDA has responsibility for ensuring that prescription drug and
biological products (both referred to as ``drugs'' or ``drug products''
in this final rule) are accompanied by labeling (including prescribing
information) that summarizes scientific information concerning their
safe and effective use. FDA regulations on labeling for use during
pregnancy, during labor and delivery, and by nursing mothers were
originally issued in 1979 as part of a rule prescribing the content and
format
[[Page 72066]]
for labeling for human prescription drugs (part 201 (21 CFR part 201))
(44 FR 37434, June 26, 1979) (the 1979 regulations).\1\ The
requirements on content and format of labeling for drug products were
revised on January 24, 2006, in the final rule on ``Requirements on
Content and Format of Labeling for Human Prescription Drug and
Biological Products'' (71 FR 3922), commonly referred to as the
``Physician Labeling Rule'' (PLR).\2\ As part of the January 2006
revision, the subsections of the labeling on pregnancy, labor and
delivery, and nursing mothers were moved from the ``Precautions''
section under Sec. 201.57 to the ``Use in Specific Populations''
section. The content of these sections in part 201 was not revised, but
the sections were redesignated as Sec. 201.57(c)(9)(i) through
(c)(9)(iii). The previous labeling regulation (adopted in 1979) was
redesignated as Sec. 201.80, and applies to products not affected by
the January 2006, revisions. In redesignated Sec. 201.80, the
subsections on pregnancy, labor and delivery, and nursing mothers are
Sec. 201.80(f)(6) through (f)(8).
---------------------------------------------------------------------------
\1\ Thus, the labeling for drugs originally approved before 1979
may not contain the information required by those regulations
regarding pregnancy, labor and delivery, and nursing mothers.
\2\ FDA's regulations governing the content and format of
labeling for human prescription drug and biological products are
contained in Sec. Sec. 201.56, 201.57, and 201.80.
---------------------------------------------------------------------------
The 1979 regulations provided, at what was redesignated in 2006 as
Sec. 201.57(c)(9)(i) and Sec. 201.80(f)(6)(i), that unless a drug was
not absorbed systemically and was not known to have a potential for
indirect harm to a fetus, a ``Pregnancy'' subsection must be included
within the ``Precautions'' section of the labeling. The 1979
regulations required that the ``Pregnancy'' subsection contain
information on the drug's teratogenic effects and other effects on
reproduction and pregnancy and, when available, a description of human
studies with the drug and data on its effects on later growth,
development, and functional maturation of the child. The 1979
regulations also required that each product be classified under one of
five pregnancy categories (A, B, C, D, or X) on the basis of risk of
reproductive and developmental adverse effects or, for certain
categories, on the basis of such risk weighed against potential
benefit.\3\
---------------------------------------------------------------------------
\3\ For further discussion of the pregnancy categories, see 73
FR 30831 at 30832 through 30833.
---------------------------------------------------------------------------
With regard to labor and delivery, the 1979 regulations stated, at
what was redesignated in 2006 as Sec. 201.57(c)(9)(ii) and Sec.
201.80(f)(7), that under certain circumstances, the labeling must
include information on the effects of the drug on, among other things,
the mother and the fetus, the duration of labor and delivery, and the
effect of the drug on the later growth, development, and functional
maturation of the child.
With regard to labeling on lactation, the 1979 regulations
required, at what was redesignated in 2006 as Sec. 201.57(c)(9)(iii)
and Sec. 201.80(f)(8), that a ``Nursing mothers'' subsection be
included in the ``Precautions'' section of the labeling. The ``Nursing
mothers'' subsection provided that if a drug was absorbed systemically,
the labeling must contain information about excretion of the drug in
human milk and effects on the nursing infant, as well as a description
of any pertinent adverse effects observed in animal offspring. The
``Nursing mothers'' subsection required the use of certain standard
statements depending on whether the drug was known to be excreted in
human milk and whether it was associated with serious adverse
reactions.\4\
---------------------------------------------------------------------------
\4\ For further discussion of the history of both the
``Pregnancy'' and the ``Nursing mothers'' subsections of
prescription drug labeling, see 73 FR 30831 at 30833.
---------------------------------------------------------------------------
B. Development of the Proposed Rule
Over a number of years after the 1979 regulations were issued, FDA
received feedback on the issues and concerns with the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of
prescription drug labeling as defined by the 1979 regulations. In
response to this feedback, FDA held a part 15 public hearing, conducted
focus groups, and convened two advisory committees to provide expert
input. During this process, many stakeholders stated that these
subsections of prescription drug labeling lacked clarity, often failed
to provide meaningful clinical information about drug exposure during
pregnancy and lactation, and did not address the potential maternal and
fetal consequences of discontinuing needed maternal drug therapy during
pregnancy. Experts and other stakeholders noted that the pregnancy
categories, although highly relied upon by health care providers, were
often misinterpreted and misused. FDA also sought input on the
development of a model format for these subsections of labeling, and
the resulting model served as the basis for the May 29, 2008, proposed
rule (73 FR 30831). The preamble to the proposed rule contains a
detailed discussion about the background of the development of the
proposed rule and additional details regarding the 1979 regulations
governing labeling of drug products for use during pregnancy, during
labor and delivery, and while nursing (73 FR 30831 at 30832-30838).
C. The Proposed Rule
FDA proposed to amend the content and format of the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Use in Specific Populations'' section of physician labeling for
prescription drug products subject to Sec. 201.57. The Agency's
proposed changes were intended to create a consistent format for
providing information about the effects of a drug on pregnancy and
lactation that would be useful for decisionmaking by health care
providers and their patients. With respect to the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Precautions'' section of prescription drug labeling for drug products
subject to Sec. 201.80, the Agency proposed only to remove the
pregnancy category from the ``Pregnancy'' subsection.
1. Proposed Provisions for New and Recently Approved Drugs
FDA proposed the following format and content changes to the
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers''
subsections of prescription drug labeling for products subject to Sec.
201.57.
Merge the current ``Pregnancy'' and ``Labor and delivery''
subsections into a single ``Pregnancy'' subsection designated 8.1 under
the section ``8 Use in Specific Populations.''
Rename the ``Nursing mothers'' subsection as ``Lactation''
designated with the identifying number 8.2 under the section ``8 Use in
Specific Populations.''
Reserve the identifying number 8.3 for future use.
Replace the format and content of the ``Pregnancy''
subsection in its entirety with the following:
[cir] If there is a pregnancy exposure registry for the drug, the
telephone number or other information needed to enroll in the registry
or to obtain information about the registry must be included at the
beginning of the ``Pregnancy'' subsection of labeling.
[cir] Require the inclusion of a general statement about background
risk, specifically ``All pregnancies have a background risk of birth
defect, loss, or other adverse outcome regardless of drug exposure. The
fetal risk summary below describes (name of drug)'s potential to
increase the risk of developmental abnormalities above the background
risk.''
[[Page 72067]]
[cir] Under the subheading ``Fetal Risk Summary,'' require the
labeling to contain a risk conclusion and a narrative description of
the risk(s) (if the risk conclusion is based on human data).
[cir] Require the fetal risk summary to characterize the likelihood
that the drug increases the risk of developmental abnormalities and
other risks in humans.
[cir] Require that if data demonstrate that a drug is not
systemically absorbed, the fetal risk summary contain only the
following statement: (Name of drug) is not absorbed systemically from
(part of body) and cannot be detected in the blood. Maternal use is not
expected to result in fetal exposure to the drug.
[cir] When both human and animal data are available, require that
risk conclusions based on human data be presented before risk
conclusions based on animal data. Require that a risk conclusion based
on human data be followed by a narrative description of the risks.
[cir] When human data are sufficient to reasonably determine the
likelihood that the drug increases the risk of fetal developmental
abnormalities or specific developmental abnormalities, require the
labeling to contain one of two risk conclusions: Human data do not
indicate that (name of drug) increases the risk of (type of
developmental abnormality or specific developmental abnormality) or
Human data indicate that (name of drug) increases the risk of (type of
developmental abnormality or specific developmental abnormality).
[cir] When human data are available but not sufficient to
reasonably determine the drug's effects on fetal developmental
abnormalities, require the labeling to characterize the likelihood that
the drug increases the risk of developmental abnormalities as low,
moderate, or high.
[cir] Require that when the data on which the risk conclusion is
based are animal data, the fetal risk summary characterize the
likelihood that the drug increases the risk of developmental
abnormalities using one of the following risk conclusions: Not
predicted to increase the risk, low likelihood of increased risk,
moderate likelihood of increased risk, high likelihood of increased
risk, or insufficient animal data on which to assess the likelihood of
increased risk.
[cir] When human data are available, require that in addition to
the risk conclusion(s), the fetal risk summary be followed by a brief
narrative description of the risks of developmental abnormalities as
well as on other relevant risks associated with the drug.
[cir] Require the fetal risk summary to refer to the
``Contraindications'' and/or ``Warnings and Precautions'' sections of
the labeling if there is any information in those sections on an
increased risk to the fetus from exposure to the drug.
[cir] Require under the subheading ``Clinical Considerations'' the
inclusion of information about the known or predicted risks to the
fetus from inadvertent exposure to the drug, including human or animal
data on dose, timing, and duration of exposure. If there are no data to
assess the risk from inadvertent exposure, require the labeling to so
state.
[cir] Require under the subheading ``Clinical Considerations'' the
inclusion of information related to prescribing decisions for pregnant
women, including the risk, if known, to the pregnant woman and the
fetus from the disease or condition the drug is indicated to treat and
the potential influence of drug treatment on that risk; information
about dosing adjustments during pregnancy; if use of the drug is
associated with any maternal adverse reactions that are unique to
pregnancy or if known adverse reactions occur with increased frequency
or severity in pregnant women, a description of such adverse reactions;
if it is known or anticipated that treatment of the pregnant woman will
cause a complication in the fetus or the neonate, a description of the
complication, the severity and reversibility of the complication, and
general types of interventions, if any, that may be needed.
[cir] If the drug has a recognized use during labor or delivery,
whether or not that use is stated as an indication in the labeling, or
is expected to affect labor or delivery, require the inclusion of
available information about the effect of the drug on the mother; the
fetus/neonate; the duration of labor and delivery; the possibility of
complications, including interventions, if any, that may be needed; and
the later growth, development, and functional maturation of the child.
[cir] Require the inclusion of a ``Data'' subheading that, for
human data, describes positive and negative experiences during
pregnancy, including developmental abnormalities, and, to the extent
applicable, the number of subjects and duration of the study. For
animal data, require under the subheading ``Data'' a description of the
relationship of the exposure and mechanism of action in the animal
species to the anticipated exposure and mechanism of action in humans.
Replace the ``Nursing mothers'' subsection with
``Lactation'' and replace the content requirements of ``Nursing
mothers'' in its entirety with the following:
[cir] Require that the labeling of all drugs contain a
``Lactation'' subsection.
[cir] Under the subheading ``Risk Summary,'' if the data
demonstrate that the drug does not affect the quantity and/or quality
of human milk and there is reasonable certainty either that the drug is
not detectable in human milk or that the amount of drug consumed
through breast milk will not adversely affect the breast-fed child, the
labeling must state: The use of (name of drug) is compatible with
breastfeeding. After this statement (if applicable), the labeling must
summarize the drug's effect on milk production, what is known about the
presence of the drug in human milk, and the effects on the breast-fed
child.
[cir] The source(s) of the data (e.g., human, animal, in vitro)
that are the basis for the ``Risk Summary'' must be stated. When there
are insufficient data or no data to assess the drug's effect on milk
production, the presence of the drug in human milk, and/or the effects
on the breast-fed child, the ``Risk Summary'' must so state.
[cir] If the drug is not systemically absorbed, require that the
subheading ``Risk Summary'' contain only the following statement: (Name
of drug) is not absorbed systemically from (part of body) and cannot be
detected in the mother's blood. Therefore, detectable amounts of (name
of drug) will not be present in breast milk. Breastfeeding is not
expected to result in fetal exposure to the drug.
[cir] If the drug is absorbed systemically, require the following
under the subheading ``Risk Summary'':
[ssquf] A description of the effects of the drug's impact on milk
production, including the effect of the drug on the quality and
quantity of milk, including milk composition, and the implications of
these changes to the breast-fed child.
[ssquf] A description of the presence of the drug in human milk in
one of the following ways: (1) The drug is not detectable in human
milk, (2) the drug has been detected in human milk, (3) the drug is
predicted to be present in human milk, (4) the drug is not predicted to
be present in human milk, or (5) the data are insufficient to know or
predict whether the drug is present in human milk.
[ssquf] Require that if studies demonstrate that the drug is not
detectable in human milk, the ``Risk Summary'' state the limits of the
assay used.
[ssquf] Require that if the drug has been detected in human milk,
the ``Risk Summary'' give the concentration
[[Page 72068]]
detected in milk in reference to a stated maternal dose (or, if the
drug has been labeled for pediatric use, in reference to the pediatric
dose), an estimate of the amount of the drug consumed daily by the
infant based on an average daily milk consumption of 150 milliliters
per kilogram of infant weight per day, and an estimate of the
percentage of the maternal dose excreted in human milk.
[ssquf] Require the inclusion of information about the likelihood
and seriousness of known or predicted effects on the breast-fed child
from exposure to the drug in human milk based on the pharmacologic and
toxicologic profile of the drug, the amount of drug detected or
predicted to be found in human milk, and age-related differences in
absorption, distribution, metabolism, and elimination.
[cir] Under the subheading ``Clinical Considerations,'' require the
labeling to provide the following information to the extent it is
available: Information concerning ways to minimize the exposure of the
breast-fed child to the drug, such as timing the dose relative to
breastfeeding or pumping and discarding milk for a specified period;
information about potential drug effects in the breast-fed child that
could be useful to caregivers, including recommendations for monitoring
or responding to these effects; information about dosing adjustments
during lactation.
[cir] Require that the labeling include, under the subheading
``Data,'' an overview of the data that are the basis for the ``Risk
Summary'' and ``Clinical Considerations.''
2. Pregnancy Categories and Implementation
FDA proposed to require the new content and format changes for
prescription drug labeling for all applications (including new drug
applications (NDAs), biologics license applications (BLAs), or efficacy
supplements) required to comply with the PLR, i.e., for drug products
for which an application was approved on or after June 30, 2001. FDA
proposed that holders of applications approved before June 30, 2001
(i.e., applications not subject to the PLR), would not be required to
implement the new content and format changes. Instead, if the labeling
for such applications contains a pregnancy category, the application
holders would be required to remove the pregnancy category designation
by 3 years after the effective date of the final rule.
D. Mental Models Research
In a separate but related effort, FDA contracted with a third party
research firm to conduct a Mental Models Research study in 2009 to
better understand the decisionmaking processes of health care providers
prescribing drugs to pregnant and lactating women with chronic
conditions (Ref. 1). Mental Models Research is an established risk
analysis approach that evaluates, using a structured interview,
decisionmaking practices that require the synthesis of complex issues.
The specific objectives of this study, which involved interviews with
54 health care providers, were to understand how health care providers
used FDA-approved prescribing information (in the labeling format in
place at the time of the study in 2009), in order to determine the
factors that influence their treatment decisions for pregnant and
lactating women with chronic conditions, and to define measures that
could be used to quantify the value of prescribing information as a
tool for these decision makers.
The findings from the Mental Models Research were consistent with
the feedback the Agency received during its work on the proposed and
final rules. For example, the research showed that the pregnancy
categories were relied upon by many health care providers almost to the
exclusion of other information found in the labeling. It also showed
that providers often relied on secondary sources to find the pregnancy
category for a particular product rather than using the product's
labeling. Interviewees made suggestions for improving prescribing
information, including simplifying the information presented,
centralizing the relevant information, and making the information
included in labeling clinically relevant.
II. Overview of the Final Rule, Including Significant Changes to the
Proposed Rule
A. Overview
In this rulemaking, the Agency finalizes many of the provisions in
the May 2008 proposed rule. In addition, the final rule reflects
revisions the Agency made in response to comments on the May 2008
proposed rule. FDA has also made editorial and organizational changes
to clarify provisions. For the purposes of this rulemaking, the term
``drug'' or ``drug product'' is used to refer to human prescription
drugs and biological products that are regulated as drugs.
The final rule requires that for the labeling of certain products
(as described in the ``Implementation'' section of this document), the
subsections ``Pregnancy,'' ``Nursing mothers,'' and ``Labor and
delivery'' be replaced by three subsections entitled ``Pregnancy,''
``Lactation,'' and ``Females and Males of Reproductive Potential.''
Information previously placed in ``Labor and delivery'' is required to
be included in the ``Pregnancy'' subsection of labeling. The final rule
requires ``Risk Summary'' subheadings in the ``Pregnancy'' and
``Lactation'' subsections of labeling. The ``Pregnancy Exposure
Registry'' subheading under ``Pregnancy'' is only required if there is
such a registry. The ``Clinical Considerations'' and ``Data''
subheadings are required under ``Pregnancy'' and under ``Lactation''
only to the extent relevant information is available. If data
demonstrate that the drug is systemically absorbed, the ``Risk
Summary'' in the ``Pregnancy'' subsection requires a statement
regarding the background risk, in addition to certain other
information, and the ``Risk Summary'' in the ``Lactation'' subsection
of labeling requires the inclusion of a risk and benefit statement,
unless breastfeeding is contraindicated. The ``Females and Males of
Reproductive Potential'' subsection is not required if none of the
subheadings are applicable. However, when pregnancy testing and/or
contraception is required or recommended before, during, or after drug
therapy and/or when there are human and/or animal data that suggest
drug-associated fertility effects, the ``Females and Males of
Reproductive Potential'' subsection requires the inclusion of such
information under the subheadings ``Pregnancy Testing,''
``Contraception,'' and ``Infertility,'' respectively. The final rule
also requires statements acknowledging when data on various labeling
elements either are not available or do not establish the presence or
absence of drug-associated risk In addition, the final rule requires
removal of pregnancy categories from all drug product labeling,
including those products for which an application was approved before
June 30, 2001.
B. Significant Changes to the Proposed Rule
The final rule reflects revisions to the proposed rule in response
to comments received on the proposed rule, as discussed in detail in
section III of this document. FDA made the following organizational and
content-based changes to the proposed rule:
[[Page 72069]]
1. Pregnancy
The final rule revises the proposed rule to clarify that
the ``Risk Summary'' subheading is always required in the ``Pregnancy''
subsection of labeling. The subheading ``Pregnancy Exposure Registry''
is only required when such a registry exists; the ``Clinical
Considerations'' and ``Data'' subheadings are required when relevant
information is available. If the ``Clinical Considerations'' subheading
is required, the following headings under it are also required to the
extent relevant information is available: ``Disease-associated maternal
and/or embryo/fetal risk,'' ``Dose adjustments during pregnancy and the
postpartum period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal
adverse reactions,'' and ``Labor or delivery.'' Similarly, if the
``Data'' subheading is required, the headings ``Human Data'' and
``Animal Data'' are required under it to the extent relevant
information is available.
The final rule revises the proposed ``Pregnancy Exposure
Registry'' subheading as follows:
[cir] Requires that contact information and a standard statement on
the pregnancy exposure registry will be included under its own
subheading ``Pregnancy Exposure Registry'' if there is a pregnancy
registry that is scientifically acceptable.
[cir] Eliminates the phrase ``must be stated at the beginning of
the `Pregnancy' subsection of the labeling.''
[cir] Revises the phrase ``telephone number or other information
needed to enroll'' to ``contact information needed to enroll.''
[cir] Adds a requirement that the following statement be included
in labeling before the contact information for the pregnancy exposure
registry: There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to (name of drug) during pregnancy.
The final rule revises the proposed ``Fetal Risk Summary''
as follows:
[cir] Changes the title of the subheading ``Fetal Risk Summary'' to
``Risk Summary.''
[cir] Eliminates the requirement that the following background risk
statement be included in the labeling before the fetal risk summary:
All pregnancies have a background risk of birth defect, loss, or other
adverse outcome regardless of drug exposure. The fetal risk summary
below describes (name of drug)'s potential to increase the risk of
developmental abnormalities above the background risk.
[cir] Replaces the proposed standardized background risk statement
with the requirement that, if the drug is systemically absorbed, the
labeling state the percentage range of live births in the United States
with a major birth defect and the percentage range of pregnancies in
the United States that end in miscarriage, regardless of drug exposure.
The final rule also requires that if such information is available for
the population(s) for which the drug is labeled, it must also be
included.
[cir] Replaces the term ``developmental abnormalities'' with the
term ``adverse developmental outcomes.'' The final rule defines
``adverse developmental outcomes'' as structural abnormalities, embryo-
fetal and/or infant mortality, functional impairment, and alterations
to growth.
[cir] Clarifies that, when applicable, risk statements must include
a cross-reference to additional details located under the ``Data''
subheading of ``Pregnancy.''
[cir] Revises the statement required when a drug is not
systemically absorbed as follows:
[ssquf] Replaces the phrase ``from (part of the body)'' with
``following (route of administration)'' to describe how the drug enters
the body.
[ssquf] Replaces the phrase ``cannot be detected in the blood''
with ``maternal use is not expected to result in fetal exposure to the
drug.''
[cir] Adds a requirement that when use of the drug is
contraindicated during pregnancy, this must be stated first in the
``Risk Summary.''
[cir] Requires that risk statements be presented in the following
order: Based on human data, based on animal data, based on
pharmacology.
The ``Risk conclusions based on human data'' in the ``Risk
Summary'' is revised as follows:
[cir] Replaces the term ``risk conclusions'' with ``risk
statement.''
[cir] Eliminates the term ``sufficient human data'' and the
proposed rule's requirement that the labeling contain one of the
following standardized risk conclusions about sufficient human data:
Human data do not indicate that (name of drug) increases the risk of
(type of developmental abnormality or specific abnormality) and Human
data indicate that (name of drug) increases the risk of (type of
developmental abnormality or specific abnormality).
[cir] Replaces the standardized risk conclusions based on human
data with the requirement that when human data are available that
establish the presence or absence of any adverse developmental
outcome(s) associated with maternal use of the drug, the Risk Summary
must summarize the specific developmental outcome, its incidence, and
the effects of dose, duration of exposure, and gestational timing of
exposure. The final rule also requires that if the human data indicate
that there is an increased risk for a specific adverse developmental
outcome in infants born to women exposed to the drug during pregnancy,
this risk must be quantitatively compared to the risk for the same
outcome in infants born to women who were not exposed to the drug but
who have the disease or condition for which the drug is indicated to be
used. When risk information is not available for women with these
condition(s), then the risk for the specific outcome must be compared
to the rate at which the outcome occurs in the general population.
[cir] Requires that the ``Risk Summary'' must state when there are
no human data or when available human data do not establish the
presence or absence of drug-associated risk.
[cir] Eliminates the term ``other human data'' and the requirement
that when there are other human data, the likelihood that the drug
increases the risk of developmental abnormalities must be characterized
as low, moderate, or high.
The ``Risk conclusions based on animal data'' in the
``Risk Summary'' is revised as follows:
[cir] Replaces the term ``risk conclusions'' with ``risk
statement.''
[cir] Eliminates the requirement that animal data be characterized
as ``not predicted to increase the risk,'' ``low likelihood of
increased risk,'' ``moderate likelihood of increased risk,'' or ``high
likelihood of increased risk.''
[cir] Requires that when animal data are available, the labeling
must summarize the findings in animals and based on these findings,
describe, for the drug, the potential risk of any adverse developmental
outcome(s) in humans. The final rule requires that the risk statement
include: The number and type(s) of species affected, the timing of
exposure, animal doses expressed in terms of human exposure or dose
equivalents, and outcomes for pregnant animals and offspring. When
animal studies do not meet current standards for nonclinical
developmental toxicity studies, the labeling must so state. The final
rule requires that when there are no animal data, the ``Risk Summary''
must so state.
Adds a ``Risk statement based on pharmacology'' to the
``Risk Summary,'' requiring that when the drug has a well-understood
mechanism of action that may result in drug-associated adverse
developmental outcome(s), the ``Risk Summary'' must explain the
mechanism
[[Page 72070]]
of action and the potential associated risks.
Eliminates the ``Narrative description of human data''
requirement from the ``Risk Summary.''
Removes the requirement that the ``Risk Summary'' refer to
the ``Contraindications'' or ``Warnings and Precautions'' sections of
the labeling when those sections contain information on an increased
risk to the fetus from exposure to the drug.
The final rule revises the ``Clinical Considerations''
component as follows:
[cir] Requires headings, to the extent relevant information is
available, for ``Disease-associated maternal and/or embryo/fetal
risk,'' ``Dose adjustments during pregnancy and the postpartum
period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal adverse
reactions,'' and ``Labor or delivery''.
[cir] Eliminates the ``Inadvertent exposure during pregnancy''
heading.
[cir] Eliminates the ``Prescribing decisions for pregnant women''
heading.
[cir] Revises ``risk, if known, to the pregnant woman and the fetus
from the disease or condition the drug is indicated to treat'' (which
was the language used in the proposed rule under the ``Prescribing
decisions for pregnant women'' heading) to ``serious known or potential
risk to the pregnant woman and/or the embryo/fetus associated with the
disease or condition for which the drug is indicated to be used'' and
places this information under the new heading ``Disease-associated
maternal and/or embryo/fetal risk.''
[cir] Under ``Dose adjustments during pregnancy and the postpartum
period,'' requires the inclusion of information about dose adjustments
during pregnancy and the postpartum period if supported by
pharmacokinetic data.
[cir] Under ``Dose adjustments during pregnancy and the postpartum
period,'' removes the requirement that, if there are no data on dosing
in pregnancy, the labeling must so state.
[cir] Under ``Maternal adverse reactions,'' replaces the proposed
requirement that the ``labeling must describe any interventions that
may be needed (e.g., monitoring blood glucose for a drug that causes
hyperglycemia in pregnancy)'' with the requirement that the labeling
include a description of available intervention(s) for monitoring or
mitigating the reaction.
[cir] Adds a requirement that the labeling include relevant
information about fetal/neonatal adverse reactions under the heading
``Fetal/Neonatal adverse reactions''.
[cir] Under ``Fetal/Neonatal adverse reactions,'' replaces the
phrase ``will cause a complication in the neonate'' with ``increases or
may increase the risk of an adverse reaction in the fetus or neonate.''
[cir] Under ``Fetal/Neonatal adverse reactions,'' replaces ``the
severity and reversibility of the complication'' with ``the potential
severity and reversibility of the adverse reaction,'' and replaces
``general types of interventions, if any, that may be needed'' with
``available intervention(s) for monitoring or mitigating the
reaction.''
[cir] Under ``Fetal/Neonatal adverse reactions,'' adds a
requirement that the labeling must describe, if known, the effect of
dose, timing, and duration of exposure on the risk.
[cir] Revises the heading ``Drug effects during labor or delivery''
to ``Labor or delivery.''
[cir] Under ``Labor or delivery,'' revises ``[i]f the drug has a
recognized use during labor or delivery, whether or not the use is
stated as an indication in the labeling, or if the drug is expected to
affect labor or delivery'' to ``[i]f the drug is expected to affect
labor or delivery.''
[cir] Under ``Labor or delivery,'' revises ``the possibility of
complications, including interventions, if any, that may be needed'' to
``the increased risk of adverse reactions, including their potential
severity and reversibility.''
[cir] Under ``Labor or delivery,'' adds a requirement that the
labeling provide information about available intervention(s) that can
mitigate effects and/or adverse reactions.
[cir] Under ``Labor or delivery,'' clarifies that the information
described under that heading is not required for drugs approved only
for use during labor and delivery.
[cir] Under ``Labor or delivery,'' eliminates the requirement that
the labeling include information about the effect of the drug on the
later growth, development, and functional maturation of the child.
The final rule revises the ``Data'' subheading of labeling
as follows:
[cir] Replaces ``provide an overview of the data that were the
basis for the fetal risk summary'' with ``describe the data that are
the basis for the Risk Summary and Clinical Considerations.''
[cir] Requires the inclusion of the subheading ``Data,'' and the
headings ``Human Data'' and ``Animal Data,'' to the extent available
information is relied on in the Risk Summary and Clinical
Considerations subheadings.
[cir] Separates the requirements for human data from the
requirements for animal data.
[cir] For human data, requires that the labeling describe adverse
developmental outcomes, adverse reactions, and other adverse effects
and, to the extent applicable, the types of studies or reports, number
of subjects and duration of each study, exposure information, and
limitations of the data. Requires that both positive and negative study
findings be included.
[cir] For animal data, retains the requirement that the labeling
describe the types of studies, animal species, dose, duration and
timing of exposure, and adds the requirement that the labeling also
describe study findings, presence or absence of maternal toxicity, and
limitations of the data. Adds the requirement that the description of
maternal and offspring findings must include information on the dose-
response and severity of adverse developmental outcomes. Requires that
animal doses or exposures be described in terms of human dose or
exposure equivalents and that the basis for those calculations must be
included.
2. Lactation
The final rule revises the ``Risk Summary'' as follows:
[cir] Requires that when relevant human or animal lactation data
are available, the ``Risk Summary'' must include a cross-reference to
``Data'' in the ``Lactation'' subsection.
[cir] Removes the proposed standardized statement ``The use of
(name of drug) is compatible with breastfeeding.''
[cir] Requires that when human data are available, animal data must
not be included unless the animal model is specifically known to be
predictive for humans.
[cir] Requires that when use of a drug is contraindicated during
breastfeeding, this information must be stated first in the ``Risk
Summary.''
[cir] Revises the standardized statement required when the drug is
not absorbed systemically from (Name of drug) is not absorbed
systemically from (part of body) and cannot be detected in the mother's
blood. Therefore, detectable amounts of (name of drug) will not be
present in breast milk. Breastfeeding is not expected to result in
fetal exposure to the drug to (Name of drug) is not absorbed
systemically by the mother following (route of administration) and
breastfeeding is not expected to result in exposure of the child to
(name of drug).
[cir] Revises the order of the types of information required if the
drug is systemically absorbed as follows: (1) Presence of drug in human
milk, (2) effects of drug on the breast-fed child, and (3) effects of
drug on milk production.
[cir] Replaces proposed standardized statements regarding the
presence of the drug in human milk with a requirement
[[Page 72071]]
that the ``Risk Summary'' state whether the drug and/or its active
metabolites are present in human milk, and when there are no data to
assess this, the ``Risk Summary'' must so state.
[cir] Under ``Presence of drug in human milk,'' requires that if
studies demonstrate the presence of the drug and/or its active
metabolites in human milk, the ``Risk Summary'' must state the
concentration of the drug and/or its active metabolites in human milk
and the actual or estimated daily dose for an infant fed exclusively
with human milk. The estimated amount of drug and/or its active
metabolites ingested by the infant must be compared to the labeled
infant or pediatric dose, if available, or to the maternal dose.
[cir] Under ``Presence of drug in human milk,'' retains the
requirement that if studies demonstrate that the drug and/or its active
metabolite(s) are not detectable in human milk, the Risk Summary must
state the limits of the assay used.
[cir] Under ``Presence of drug in human milk,'' adds the
requirement that if studies demonstrate the presence of the drug and/or
its active metabolite(s) in human milk but the drug and/or its active
metabolite(s) are not expected to be systemically bioavailable to the
breast-fed child, then the ``Risk Summary'' must describe the
disposition of the drug and/or its active metabolites.
[cir] Adds a requirement that if only animal lactation data are
available, the ``Risk Summary'' must state only whether or not the drug
and/or its active metabolite(s) were detected in animal milk and
specify the animal species.
[cir] Under ``Effects of drug on the breast-fed child,'' the final
rule:
[ssquf] Adds a requirement that the ``Risk Summary'' include
available information on the known or predicted effects on the child
from exposure to the drug and/or its active metabolite(s) through human
milk or from contact with breast or nipple skin from a topical product.
[ssquf] Requires the inclusion of information about systemic and/or
local adverse reactions.
[ssquf] Requires that the ``Risk Summary'' state if there are no
data to assess the effects of the drug and/or its active metabolite(s)
on the breast-fed child.
[cir] Under ``Effects of drug on milk production,'' the final rule:
[ssquf] Replaces the proposed requirement that the ``Risk Summary''
describe the effect of the drug on the quality and quantity of milk,
including milk composition, and the implications of these changes to
the milk on the breast-fed child, with the requirement that the ``Risk
Summary'' must describe the effects of the drug and/or its active
metabolite(s) on milk production.
[ssquf] Adds a requirement that when there are no data to assess
the effects of the drug and/or its active metabolite(s) on milk
production, the ``Risk Summary'' must so state.
[cir] The final rule adds the requirement that for drugs absorbed
systemically, unless breastfeeding is contraindicated during drug
therapy, the following risk and benefit statement must appear at the
end of the ``Risk Summary'': The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical
need for (name of drug) and any potential adverse effects on the
breast-fed child from the drug or from the underlying maternal
condition.
Under ``Clinical Considerations,'' the final rule:
[cir] Revises the provisions of the proposed rule to require that
the labeling include information concerning ways to minimize exposure
to the drug and/or its active metabolite(s) in the breast-fed child in
situations where the following conditions are present: The drug and/or
its active metabolite(s) are present in human milk in clinically
relevant concentrations; do not have an established safety profile in
infants; and are used either intermittently, in single doses, or for
short courses of therapy.
[cir] Adds a requirement that, when applicable, the labeling must
describe ways to minimize a breast-fed child's oral intake of topical
drugs applied to the breast or nipple skin.
[cir] Under ``Monitoring for adverse reactions,'' replaces the
proposed requirement that the labeling include information about
potential drug effects in the breast-fed child that could be useful to
caregivers, including recommendations for monitoring or responding to
those effects, with a requirement that the labeling must describe
available intervention(s) for monitoring or mitigating the adverse
reaction(s) presented in the ``Risk Summary.''
[cir] Eliminates the proposed requirement that the labeling include
information about dosing adjustments during lactation.
Under ``Data,'' the final rule replaces the phrase
``provide an overview of the data'' with the phrase ``describe the
data.''
3. Females and Males of Reproductive Potential
Adds ``8.3 Females and Males of Reproductive Potential''
subsection requiring that when pregnancy testing and/or contraception
are required or recommended before, during, or after drug therapy and/
or when there are human and/or animal data that suggest drug-associated
fertility effects, this subsection of labeling must contain this
information under the subheadings ``Pregnancy Testing,''
``Contraception,'' and ``Infertility,'' in that order.
III. Comments on the Proposed Rule
The Agency received 72 comments on the proposed rule. Comments were
received from prescription drug manufacturers, trade organizations
representing prescription drug manufacturers and other interested
parties, professional associations and organizations representing
health care providers, health care and consumer advocacy organizations,
individual physicians, pharmacists, consumers, and others.
Most of the comments supported FDA's goal of improving the format
and content of the ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing
mothers'' subsections of prescription drug labeling, and several of
these comments stated that the proposed rule would address shortcomings
of the previous labeling regulations. Other comments noted that the
proposed rule would improve the accessibility of relevant information,
thereby enabling better informed medical decisions regarding the risks
and benefits of prescription drug use by pregnant and lactating women.
Although a number of comments supported all of FDA's proposed
revisions, many comments opposed particular aspects of the proposed
rule.
To make it easier to identify comments and our responses, the word
``Comment'' and a comment number appear in parentheses before each
comment's description, and the word ``Response'' in parentheses
precedes each response. Similar comments are grouped together under the
same number. Specific issues raised by the comments and the Agency's
responses follow.
A. Proposed Rule as a Whole
1. Plain Language and Intended Audience
(Comment 1) Several comments suggested that the language used in
the pregnancy and lactation subsections of prescription drug labeling
should be clear and accessible to a variety of audiences. One comment
stated that because the intended audience for prescription pregnancy
and lactation labeling is females of reproductive potential and their
health care providers, this portion of prescription
[[Page 72072]]
drug labeling should not include overly technical information. Another
comment suggested that to make the information more accessible to the
general public, FDA should include a plain language summary of the
pregnancy and lactation subsections. Two comments suggested that
because females of reproductive potential may read the ``Pregnancy''
and ``Lactation'' subsections of labeling, FDA should include a
statement that encourages patients to always consult a health care
provider before discontinuing medication. Another comment questioned
how patients would access the proposed information and asked whether it
would be included in patient-specific information that patients receive
at the pharmacy. Several other comments suggested that the final rule
should aim to create user-friendly labeling that contains a concise and
accurate presentation of information that is of clinical relevance.
(Response) FDA acknowledges that some females of reproductive
potential may use prescribing information in the ``Pregnancy'' and
``Lactation'' subsections of prescription drug labeling. The intended
audience of prescription drug labeling, however, is health care
providers, and it is the responsibility of the prescribing health care
provider to communicate pertinent information regarding drug risks and
benefits and proper use to his or her patient. For this reason, we have
determined that it is not appropriate to require a summary of the
``Pregnancy'' and ``Lactation'' subsections of labeling as a mechanism
for all patients to readily access full prescribing information, or a
statement that encourages patients to always consult a health care
provider before discontinuing medication. We note that in addition to
the professional labeling that is the subject of this rulemaking, some
drugs also have FDA-approved patient labeling specifically written for
the consumer, such as Medication Guides (see 21 CFR part 208). Whether
the information required under the final rule will be included in FDA-
approved patient labeling for an individual drug will be decided on a
case-by-case basis in accordance with the applicable FDA regulations
and guidance.
2. Scope of the Rule
(Comment 2) Several comments suggested that FDA expand the scope of
the rule in various ways. Two comments suggested that the rule be
expanded to include nonprescription products. Four comments suggested
that the proposed content changes also apply to drugs for which an
application was approved before June 30, 2001, although a separate
comment agreed with the proposal to limit the rule to drugs for which
an application was approved on or after June 30, 2001. One comment
suggested that the rule be expanded to include vaccine products (we
discuss this suggestion later in our response to Comment 8). Two other
comments suggested that the rule provide incentives to industry to
perform studies on the use of drugs and biological products during
pregnancy and lactation. One comment suggested that depression should
not be treated pharmacologically during pregnancy, whereas a separate
comment suggested that FDA ban the use of all drugs and vaccines during
pregnancy. Another comment suggested that the presentation of the
information required under the rule be standardized as much as possible
with applicable coding schema for ease of implementation in databases
or electronic health record systems.
(Response) FDA has considered these comments and declines to expand
the scope of the final rule in any of the suggested ways. This final
rule amends our labeling regulations in Sec. Sec. 201.57 and 201.80,
which apply only to prescription drug and biological products. It is
therefore not within the scope of this rulemaking to address pregnancy
and lactation labeling for nonprescription drug products.
The primary purpose of this final rule, and prescription drug
labeling in general, is to facilitate informed prescribing and safe and
effective product use. FDA recognizes the importance of use of labeling
information in electronic health records and other databases and agrees
that, if possible, the presentation of information in labeling should
facilitate its accessibility. However, this final rule is not designed
to standardize the required information with a coding schema for use in
databases or electronic health record systems. It is also beyond the
scope of this rule to address incentives for collecting data on the use
of drugs and biological products during pregnancy and lactation.
FDA does not make recommendations about whether particular diseases
or conditions should or should not be treated pharmacologically, though
we specifically decline the suggestion to ban the use of all drugs
during pregnancy. We note that many diseases and conditions are
associated with adverse pregnancy outcomes when not appropriately
managed during pregnancy, and under-treating or not treating a pregnant
woman's medical condition may put the woman's health in danger, and is
often associated with greater risk to the developing fetus than the
risk of exposure to a maternal drug.
FDA also declines the suggestion that the content changes required
by this final rule also apply to drugs for which an application was
approved before June 30, 2001. In developing this rule, FDA considered
the scientific, economic, and practical implications of alternative
approaches, including requiring implementation of the content and
format requirements for the ``Pregnancy,'' ``Lactation,'' and ``Females
and Males of Reproductive Potential'' subsections of labeling for all
drugs, regardless of approval date. FDA concluded that requiring the
content and format changes only for drugs for which an application was
approved on or after June 30, 2001, (as described in the
``Implementation'' section of this document) best balanced the public
health benefits and the economic and other costs of these labeling
changes. In addition, this approach provides conformity with the rest
of prescription drug labeling and the scope is consistent with the
scope of the PLR. FDA, however, encourages voluntary compliance with
these content and format changes for drugs for which an application was
approved before June 30, 2001.
3. Combining the ``Pregnancy'' and ``Lactation'' Subsections
(Comment 3) One comment suggested that the ``Pregnancy'' and
``Lactation'' subsections should be combined for certain drugs. The
comment explained that combining these sections would be useful, for
example, in helping health care providers counsel women who take
selective serotonin reuptake inhibitors (SSRIs) for the treatment of
perinatal depression because clinicians have to consider the effects of
the medication during both pregnancy and the postpartum period.
(Response) FDA disagrees. The risk and benefit considerations for
drug product use are different between pregnant and lactating patients,
and we have determined that the information is best presented in
separate but adjacent subsections of labeling. FDA believes that if the
sections were combined it would be more difficult for a health care
provider who has either a pregnant or a lactating patient to locate the
information relevant to the prescribing decision. For anticipatory
counseling, for which the health care provider is discussing the use of
the drug with a pregnant patient who in the future may be lactating, we
believe that having ``Lactation'' denoted in a separate, numbered,
indexed, and searchable
[[Page 72073]]
subsection of labeling will not make it harder for a prescriber to find
this information.
4. Updates
In the preamble to the proposed rule, FDA stated that under Sec.
201.56(a) ``the labeling must be updated when new information becomes
available that causes the labeling to become inaccurate, false, or
misleading'' (73 FR 30831 at 30841). The Agency also explained that
``[w]hen new human data concerning the use of a drug during pregnancy
becomes available, if that information is clinically relevant, FDA
believes that it is necessary for the safe and effective use of the
drug and, therefore, the pregnancy subsection of the labeling must be
updated to include that information. Failure to include clinically
relevant new information about the use of a drug during pregnancy could
cause the drug's labeling to become inaccurate, false, or misleading''
(73 FR 30831 at 30841).
(Comment 4) Several comments requested that FDA clarify its
expectations for the process and timing of updating the ``Pregnancy''
and ``Lactation'' subsections of labeling after new data become
available. Two of these comments stated that the data should be updated
regularly or continually. Another comment stated that the labeling
should be updated annually. Several other comments requested that FDA
define the quantity and quality of data that necessitates that the
labeling be updated. One of these comments suggested that FDA state in
the final rule that the labeling should be updated if the benefit-risk
profile changes because of new information, and that labeling changes
should be done according to ``current labeling regulations.'' Another
comment questioned whether health care providers will be informed of
changes to the ``Pregnancy'' and ``Lactation'' subsections of labeling.
One comment suggested that sponsors electronically post supplemental
information before updated printed labeling is available, and another
suggested using surveillance systems to facilitate obtaining updated
safety information.
Two comments expressed specific concern that the ``Lactation''
subsection of drug labeling will not be updated frequently enough to be
useful for clinicians. One of these comments stated that it is critical
to routinely update labeling as human lactation data becomes available.
A separate comment suggested including references in labeling to online
resources regarding lactation data to provide prescribers and patients
with updated information.
(Response) The requirements for labeling updates described in Sec.
201.56(a) apply to this final rule as follows: The labeling must be
informative and accurate and neither promotional in tone nor false or
misleading in any particular. In accordance with Sec. Sec. 314.70 and
601.12 of the chapter, the labeling must be updated when new
information becomes available that causes the labeling to become
inaccurate, false, or misleading (Sec. 201.56(a)(2)). With respect to
the comment about updating labeling as human lactation data becomes
available, although Sec. 201.56(a)(3) states that the labeling must be
based whenever possible on data derived from human experience, it also
requires that conclusions based on animal data but necessary for safe
and effective use of the drug in humans must be identified as such and
included with human data in the appropriate section of the labeling.
Because studies are not usually conducted in pregnant women prior
to approval, most of the data regarding use in pregnancy and lactation
will be collected in the postmarketing setting. Accordingly, in order
that a drug product does not become misbranded, the labeling must be
updated when new information becomes available that causes the labeling
to become inaccurate, false, or misleading. Applicants are responsible
for following the medical literature and also for updating labeling as
new published and unpublished data become available. FDA declines the
suggestion to include references to online resources regarding drug use
during lactation because the information has not been reviewed by FDA.
5. Responsibility for Drafting and Reviewing Labeling
(Comment 5) One comment requested that FDA clarify whether industry
or FDA would be responsible for writing and reviewing the new labeling.
The comment also questioned whether FDA would provide staff with the
training and expertise to make necessary judgments. Another comment
expressed concern about the potential for inconsistent implementation
of the new rule by FDA's review divisions. This comment suggested that
to increase labeling consistency, the Agency should establish a group
of FDA specialists that review pregnancy and lactation labeling.
(Response) As with all prescription drug labeling, both the
manufacturer and FDA reviewers will play a shared role in determining
the new labeling content. The Division of Pediatrics and Maternal
Health (DPMH), within the Office of New Drugs at the Center for Drug
Evaluation and Research, includes staff with expertise in obstetrics,
lactation, pediatrics, clinical pharmacy, and regulatory science. The
DPMH is available for consultation by all FDA drug product review
divisions to whom the final rule applies for all issues related to
labeling content and for review of data on the use of drugs during
pregnancy and lactation. The DPMH, by working across review divisions,
helps to ensure consistent application of FDA pregnancy and lactation
labeling regulations to different drug products. The DPMH also provides
consultation services to and works collaboratively with other Offices
and Centers at FDA. FDA intends to provide staff with education and
training on the changes in the labeling regulations.
6. Process for Development of the Proposed Rule
(Comment 6) One comment stated that FDA should have included
pharmacists in the focus tests used during development of the proposed
rule.
(Response) FDA acknowledges the critical role that pharmacists play
in communicating drug information both to patients and health care
providers. However, during the development of the proposed rule, FDA's
priority was to understand the information health care providers need
to most effectively make prescribing decisions that consider both the
risk and benefit to the mother and her fetus or child. Therefore, the
focus testing was limited to health care providers who both care for
and prescribe for pregnant and lactating women.
7. Guidance on Formulating Labeling
(Comment 7) FDA received one comment requesting that the Agency
provide clear guidance to manufacturers regarding how to formulate the
pregnancy and lactation labeling subsections.
(Response) Concurrent with the publication of this final rule, FDA
is issuing a draft guidance for industry on ``Pregnancy, Lactation, and
Reproductive Potential: Labeling for Human Prescription Drug and
Biological Products--Content and Format'' (the draft guidance on
pregnancy and lactation labeling).\5\ The draft guidance is intended to
assist applicants in drafting the ``Pregnancy,'' ``Lactation,'' and
``Females and Males of Reproductive Potential'' subsections of
[[Page 72074]]
labeling for prescription drug products. It provides recommendations
for applicants revising labeling of already approved products and for
applicants drafting labeling for new products that will be submitted as
part of an NDA or BLA.
---------------------------------------------------------------------------
\5\ This guidance, when finalized, will represent FDA's current
thinking on this topic.
---------------------------------------------------------------------------
8. Blood Products and Vaccines
(Comment 8) FDA received two comments regarding the applicability
of the proposed rule to certain biological products. One comment
requested that the final rule be expanded to include vaccine products.
The other comment stated that blood products are not affected by the
rule and requested that this be noted when the final rule is published.
(Response) This final rule applies to vaccine products. Vaccine
products are prophylactic biological products that are developed and
labeled to prevent specific diseases in specific populations. The types
of information that must be communicated about a vaccine, in general,
parallel the types of information that must be communicated about a
drug or therapeutic biologic through labeling to facilitate safe and
effective use, although there are some unique considerations for
vaccines addressed in the draft guidance on pregnancy and lactation
labeling, which is being published concurrently with this final rule.
We disagree that blood products are not affected by the final rule.
The final rule applies to any biological products, including blood
products, that are subject to the PLR.
9. Numbering of ``Pregnancy'' and ``Lactation'' Subsections
(Comment 9) FDA proposed that the identifying numbers and titles
for the new labeling content under the section ``8 Use in Specific
Populations'' would be 8.1 for ``Pregnancy'' and 8.2 for ``Lactation.''
FDA stated in the proposed rule that the identifying number 8.3 would
be available for future use (73 FR 30831 at 30838). Two comments
pointed out that under this proposal, the next subsections after ``8.2
Lactation'' will be ``8.4 Pediatric Use'' and ``8.5 Geriatric Use.''
These comments stated that the absence of subsection 8.3 may be
confusing and suggested that FDA renumber the subsections. One comment
requested that FDA clarify whether the Agency has a specific use in
mind for 8.3 and, if it does not, suggested that the Agency renumber
the subheadings to ``8.3 Pediatric Use'' and ``8.4 Geriatric Use.'' The
comment explained that if a future need for an additional subsection
arose, it could become 8.5.
(Response) As discussed in further detail in section III.B of this
document, in this final rule, FDA designates 8.3 as ``Females and Males
of Reproductive Potential.'' Accordingly, we are no longer reserving
8.3 for future use.
10. International Harmonization
(Comment 10) Two comments suggested that prescription drug labeling
should be consistent at an international level to reduce confusion
among health care providers, patients, and regulators interpreting the
risks and benefits associated with drug use during pregnancy and
lactation.
(Response) FDA declines to adopt this suggestion because it is
beyond the scope of this rule to address the international
harmonization of prescription drug labeling. Although we acknowledge
the importance of working with our international regulatory colleagues
to harmonize drug development and drug regulatory science where
appropriate and beneficial, we also recognize that there is great
variation internationally in health care systems, access to care and
drugs, and the regulation and marketing of drugs. The final rule
reflects our judgment regarding the most useful pregnancy and lactation
prescription drug labeling for prescribers in the United States, which
may not be applicable to prescribers in all other countries.
11. Examples in an Appendix
(Comment 11) The proposed rule included an appendix containing
examples, based on the proposed rule, of pregnancy and lactation
labeling for fictitious drugs.
FDA received several comments suggesting that the examples be
revised or expanded. One comment requested that in the final rule, FDA
provide additional examples of sample labeling, including examples for
which extensive data exists. Another comment suggested that the
information included in the sample labeling for the fictitious drug
products did not reflect the amount of data that is typically
available. The comment explained that the examples would be more useful
if they presented situations where there is extensive data. Several
other comments pointed out that the terminology in the examples was not
consistent with the terminology in the proposed rule.
(Response) FDA has not included sample drug labeling with the final
rule. The draft guidance on pregnancy and lactation labeling, which is
being published concurrently with this final rule, provides information
about how to interpret and apply the rule to labeling development.
Labeling development is a detailed and iterative process unique to each
prescription drug product, a process that is driven by the product's
characteristics and actions, the efficacy and safety data submitted to
the Agency, and the conditions and populations for and in which the
product is intended to be used. Accordingly, FDA has concluded that the
development of fictitious product labeling would not be useful to drug
developers or FDA reviewers who will be responsible for developing,
revising, and approving product labeling under this new final rule.
12. Cross-Referencing
FDA proposed that when the risk conclusion in the fetal risk
summary is based solely on animal data, it must include a cross-
reference to the ``Data'' component of the ``Pregnancy'' subsection,
and the effects found in animals must be described in the ``Data''
component (73 FR 30831 at 30842).
(Comment 12) One comment suggested that any cross-references to the
``Data'' or ``Clinical Considerations'' components made anywhere in
labeling specify whether the cross- reference is to the component in
the ``Pregnancy'' subsection or the component in the ``Lactation''
subsection. Another comment explained that the rule would benefit from
extensive use of cross-referencing within the text of each section to
ensure that the bases for the risk conclusions are thoroughly
understood, regardless of whether the risk conclusions are based on
human or animal data, for both the ``Pregnancy'' and ``Lactation''
subsections.
(Response) FDA agrees that any cross-references to components of
``8.1 Pregnancy'' or ``8.2 Lactation'' must specify whether the cross-
reference is to the component in the ``Pregnancy'' subsection or the
component in the ``Lactation'' subsection. Accordingly, in the final
rule, when applicable, risk statements in the ``Pregnancy'' subsection
must include a cross-reference to additional details in the relevant
portion of the ``Data'' subheading in the ``Pregnancy'' subsection.
Also in the final rule, when relevant human and/or animal lactation
data are available, the ``Risk Summary'' must include a cross-reference
to the relevant portion of ``Data'' in the ``Lactation'' subsection.
13. Need for Educational Campaign
(Comment 13) FDA received one comment suggesting that the Agency
develop educational campaigns for patients and health care providers
regarding the changes to pregnancy and
[[Page 72075]]
lactation drug labeling brought about by this rulemaking.
(Response) FDA is developing educational materials for FDA staff,
health care providers, and patients to inform them about the changes in
these labeling regulations and how these changes will have a positive
impact on labeling regarding the use of drugs and biologics during
pregnancy and lactation. The draft guidance on pregnancy and lactation
labeling is being published concurrently with this final rule; however,
additional materials may be completed following this date.
14. Inventory
(Comment 14) FDA received one comment requesting that the final
rule address how distributors should manage drug products in their
inventory that have outdated labeling. The comment suggested that
product inventory without the revised labeling should remain in the
supply chain until the labeled product's expiration date, regardless of
whether the product bears the new labeling.
(Response) For previously approved products, the implementation
plan gives sponsors a minimum of 3 years after the effective date of
this final rule to submit labeling with the new content and format. As
we explained in the preamble to the proposed rule, FDA believes that
this 3-year period will allow industry sufficient time to use up any
existing labeling stock such that none will remain in the supply chain
after the product bears the new labeling (73 FR 30831 at 30846).
15. Highlights
FDA's regulations require that all prescription drug labeling
described in Sec. 201.56(b)(1) contain ``Highlights of prescribing
information'' (Sec. 201.57(a)).
(Comment 15) Two comments requested that FDA clarify which elements
of the ``Pregnancy'' and ``Lactation'' subsections are likely to be
included in the ``Highlights of prescribing information.'' One of the
comments expressed hope that adoption of the rule will promote
standardization with respect to which elements are elevated to the
``Highlights of prescribing information,'' thereby facilitating
consistent interpretation and implementation of the rule's requirements
among FDA reviewers and review divisions.
(Response) The requirements for placement of information in the
``Highlights of prescribing information'' are specified in Sec.
201.57(a). This final rule does not revise or change the requirements
for the ``Highlights of prescribing information.'' Additional
discussion of FDA's recommendations on the content of the ``Highlights
of prescribing information'' may be found in FDA's guidance for
industry on ``Labeling for Human Prescription Drug and Biological
Products--Implementing the PLR Content and Format Requirements''
(February 2013).\6\
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\6\ U.S. Food and Drug Administration, ``Guidance for Industry,
Labeling for Human Prescription Drug and Biological Products--
Implementing the PLR Content and Format Requirements,'' (February
2013), available at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075082.pdf.
Many guidances are referenced throughout this document. The guidance
referred to in this footnote, as well as others referenced
throughout the remainder of the document, can be found on the FDA
Drugs guidance Web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We
update guidances periodically. To make sure you have the most recent
version of a guidance, check the FDA Drugs guidance Web page.
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16. Preemption of State Law
In the preamble to the proposed rule, FDA included a discussion in
the Federalism section that referred to a more extensive discussion and
analysis in the PLR regarding the preemption of product liability
lawsuits.
(Comment 16) Comments expressed different views about this
discussion. One comment suggested that in the final rule FDA revise the
preamble to eliminate any reference to the preemption of product
liability lawsuits. Another comment expressed its appreciation of FDA's
view that the rule would preempt state laws that conflict with its
requirements. This comment also expressed its support for FDA's
intention to consult with State and local officials in an effort to
avoid conflict between State law and federally protected interests.
(Response) FDA's statement regarding preemption in the proposed
rule relied on statements made in the preamble to the PLR (71 FR 3922).
In the preamble to the PLR, FDA discussed its views on the preemptive
effect of both that regulation's codified provisions and the FD&C Act.
Subsequent to the publication of the May 2008 proposed rule, the
Supreme Court, in Wyeth v. Levine (555 U.S. 555 (2009)), addressed the
preamble to the PLR and held that a State tort claim that an NDA-
approved drug should have had a stronger warning was not preempted by
the FD&C Act or FDA's labeling requirements. Following the Court's
decision in Wyeth, FDA concluded that the position on preemption we
articulated in the preamble to the PLR cannot be justified under legal
principles governing preemption (Preemption Review, 76 FR 61565,
October 5, 2011). Based on this analysis, to the extent that the
discussion in the proposed rule relied on the discussion about
preemption in the preamble to the PLR, we conclude that the statements
we made regarding preemption in the preamble to the proposed rule are
also not justified.
B. Specific Provisions of the Proposed Rule
1. 8.1 Pregnancy
a. Comments related to the pregnancy subsection as a whole.
i. Order of subsections--FDA proposed that information appear in
subsection ``8.1 Pregnancy'' in the following order: (1) Pregnancy
exposure registry (if applicable), (2) general statement about
background risk, (3) fetal risk summary, (4) clinical considerations,
and (5) data (proposed Sec. 201.57(c)(9)(i)). In the proposed rule,
FDA sought comment on how these elements should be ordered to optimize
the clinical usefulness of this labeling subsection (73 FR 30831 at
30839). Specifically, FDA asked whether the ``Fetal Risk Summary''
should precede the pregnancy exposure registry information and the
statement about background risk.
(Comment 17) Comments expressed different opinions about the
proposed order of information in the ``Pregnancy'' subsection of
labeling. Three comments agreed with the proposed order. One of these
comments explained that the proposed order will maximize a physician's
ability to find and understand important pregnancy-related information
about a given drug product. Another comment explained that placing the
pregnancy exposure registry information first is preferable because if
this information were placed after the ``Risk Summary,'' it may be
interpreted to imply that the pregnancy exposure registry exists
because of the data in the fetal risk summary. One comment supported
placing the pregnancy exposure registry information first so that it
will appear more visible in labeling.
Many comments disagreed with the proposed order and suggested a
variety of alternatives. Six comments suggested that the ``Fetal Risk
Summary'' subheading be placed first because it contains the most
important and useful information. One of these comments pointed out
that past FDA advisory committees have suggested that summary
information should be placed first. Two comments suggested that the
``Background Risk Statement'' should be first followed by the ``Fetal
Risk Summary.'' These comments explained
[[Page 72076]]
that the most important information should be placed first, as
recommended by FDA advisory committees. Three comments suggested that
the pregnancy exposure registry information be placed last. Another
comment suggested that the information be placed in the following
order: Pregnancy exposure registry information, clinical
considerations, fetal risk summary, data, and background risk
statement.
(Response) FDA has determined that placing the pregnancy exposure
registry information first under ``8.1 Pregnancy'' best balances the
objectives of this rulemaking. Although we agree that the ``Risk
Summary'' information is most important to prescribers and we
acknowledge that the advisory committee expressed a preference for
placing the most important information first, it is also clear that
stakeholders desire greater quality and quantity of human data in
pregnancy labeling. FDA believes that the benefits of prominently
placing information about pregnancy registry availability at the
beginning of ``8.1 Pregnancy'' outweigh the downsides of a minor
decreased prominence of the ``Risk Summary'' information, which appears
immediately after the information under ``Pregnancy Exposure
Registry.'' Many health care providers are still learning about
pregnancy exposure registries and their purpose. We have concluded that
routinely placing this information first in pregnancy labeling may
increase pregnancy registry enrollment, the quality of human data that
emerge from these studies, and the quality of pregnancy labeling
(including the ``Risk Summary'') that follows. Because we agree that
the information under ``Risk Summary'' is most important to
prescribers, we also decline the suggestion to place the ``Risk
Summary'' after ``Clinical Considerations.'' The ``Pregnancy''
subsection will include, in this order, information under ``Pregnancy
Exposure Registry,'' as applicable, ``Risk Summary,'' ``Clinical
Considerations,'' as applicable, and ``Data,'' as applicable.
ii. Removal of the pregnancy categories--FDA proposed to remove the
pregnancy categories from all prescription drug labeling. As discussed
in greater detail in section I of this document, in 1979 FDA adopted a
pregnancy category system that was used to convey risk and benefit
information related to potential or documented human teratogenic risk
and potential maternal/fetal benefits associated with drug treatment
during pregnancy. Under the 1979 regulations, each drug product was
identified with a pregnancy category: A, B, C, D, or X. Categories were
not used to characterize the risks and benefits associated with drug
treatment by lactating women. FDA proposed to remove pregnancy
categories from all prescription drug labeling because we determined
that the categories were confusing and did not accurately and
consistently communicate differences in degrees of fetal risk (73 FR
30831 at 30846).
(Comment 18) Comments expressed different opinions about whether
the elimination of the pregnancy category system, in full or in part,
would improve or diminish the usefulness of the Pregnancy subsection of
prescription drug labeling. FDA received 11 comments from medical
associations, women's and reproductive health advocacy organizations,
toxicologists, individual health care practitioners, pharmacists, and
drug manufacturers specifically supporting our proposal to retire the
pregnancy category system. Several of these comments explained that the
categories were confusing or misleading. One of the comments stated
that although the use of pregnancy categories is easier for some
practitioners, it results in miscommunication and errors in
decisionmaking. Another comment explained that reliance on the
categories may result in poorly informed clinical decisionmaking.
FDA received 16 comments from physicians, pharmacists, pharmacy
associations, nurses, manufacturers, drug safety consultants, and
individual consumers, requesting that FDA either retain the pregnancy
category system or replace the pregnancy category system with another
standardized schema. Many of these comments suggested that FDA add the
additional narrative information as proposed, but also retain the
category system. Two of these comments explained that the pregnancy
categories are simple and effective, and the new information may
confuse patients or prescribers. Another comment stated that without a
standardized schema, there will not be a consistent and useful format
for decisionmaking. Other comments agreed that the pregnancy categories
need to be revised but suggested that FDA develop new standardized
statements or categories or revise the bases for the current
categories. Two comments urged FDA to maintain an ``X''-like category
for drugs where the risks outweigh any benefit to a pregnant or nursing
patient, and one comment urged FDA to maintain an ``X''-like category
so that providers and patients could easily identify those drugs that
are contraindicated for the mother, fetus, and/or a breastfeeding
infant.
A separate comment supported FDA's proposal to eliminate the
pregnancy categories but thought they should be retained until the
implementation of the final rule is complete.
(Response) FDA has determined that retaining the pregnancy
categories is inconsistent with the need to accurately and consistently
communicate differences in degrees of fetal risk. As discussed in the
proposed rule, the current pregnancy category system has long been
criticized as being confusing and overly simplistic (73 FR 30831 at
30833-30834). Through experience and stakeholder feedback, FDA learned
that the pregnancy categories were heavily relied upon by clinicians
but misinterpreted, misunderstood, and erroneously used as a grading
system where fetal risk increased from A to X. The categories gave the
incorrect impression that drugs in the same category carried the same
risk or potential for human adverse developmental outcomes. In
addition, the categories did not discriminate among risk information
obtained from nonclinical animal studies and postmarketing human
studies and did not discriminate among drugs associated with adverse
outcomes of differing severity or incidence. Stakeholders also pointed
out that the pregnancy categories focused on structural abnormalities
and thus did not adequately address the full range of potential
developmental toxicities.
As described in greater length in the preamble of the proposed
rule, FDA carefully explored a multitude of models to determine whether
the former pregnancy category system or a different pregnancy category
system could accurately and consistently communicate differences in
degrees of fetal risk (73 FR 30831 at 30833-30837). FDA found that when
it applied these criteria to actual animal and human data findings for
drugs with known risk profiles, none of the models produced clinically
informative and reliable differentiations of risk (73 FR 30831 at
30838). Prescribing and drug-use decisions during pregnancy require
consideration of not only fetal risk information, but also of various
clinical and individual factors, including maternal drug effects, the
severity of maternal disease, maternal tolerance of the drug,
coexisting maternal conditions, the impact of maternal disease on the
fetus, and available alternative therapies. FDA concluded that
continuing to use a category system to characterize the risks of drug
use during pregnancy would not be appropriate because of the complexity
of medical decisionmaking regarding
[[Page 72077]]
drug use during pregnancy (73 FR 30831 at 30838).
FDA continues to believe that a narrative structure for pregnancy
labeling is best able to capture and convey the potential risks of drug
exposure based on animal or human data, or both. This perspective is
consistent with FDA's approach to other aspects of product labeling.
For example, numeric or letter or other categorical gradations of risk
have never been used for safety labeling because safety and risk are
complex constructs in clinical medicine. For similar reasons, FDA does
not apply symbol or letter designations of risk to other potential
toxicities or adverse effects expected with drug product use.
For the reasons discussed previously, FDA declines the suggestion
to maintain pregnancy category X. We note, however, that labeling must
clearly identify populations in which use of a drug is contraindicated.
The labeling regulations in Sec. 201.57 clearly describe the
information that must be included in the ``Contraindications'' section
and all contraindications from the full prescribing information are
always listed in the ``Highlights of prescribing information'' (Sec.
201.57(c)(5)). Therefore, when use of a drug is contraindicated in
pregnancy, this information must be stated in the ``Contraindications''
section and listed in the ``Highlights of prescribing information,'' as
well as, per the previous discussion, stated first under the ``Risk
Summary'' subheading of the ``Pregnancy'' subsection of labeling.
To the extent that the comment suggests that the pregnancy
categories should be retained for applications subject to Sec. 201.80
until the implementation of the new content and format requirements is
complete, we decline this suggestion; we believe it is more consistent
with the Agency's overall concerns with respect to removing the
pregnancy categories to implement that change within a shorter
timeframe that nevertheless provides sufficient time for compliance. We
would like to clarify that for applications required to implement the
new content and format requirements, the pregnancy categories are
required to be removed at the time the labeling is revised regardless
of whether this will result in the labeling including a pregnancy
category for more than 3 years after the effective date of the final
rule (as described in the ``Implementation'' section of this document
in response to Comment 92). Requiring that the labeling for some
applications be revised twice solely as part of the implementation of
this regulation would not be consistent with the Agency's goal to avoid
overburdening both the Agency and industry.
b. Comments related to specific provisions of 8.1 Pregnancy.
i. Pregnancy exposure registry--FDA proposed that if there is a
pregnancy exposure registry for a product described in Sec.
201.56(b)(1) (i.e., prescription drug products for which an application
was approved after June 30, 2001), the telephone number or other
information necessary to enroll in the registry or to obtain
information about the registry must be stated at the beginning of the
``Pregnancy'' subsection of prescription drug labeling (proposed Sec.
201.57(c)(9)(i)(A)). For drug products that do not have a pregnancy
exposure registry, the proposed rule did not require the ``Pregnancy''
subsection of prescription drug labeling to contain any statement about
pregnancy exposure registries.
(Comment 19) Comments disagreed about the mandatory inclusion of
pregnancy exposure registry information. Many comments supported the
mandatory inclusion of pregnancy exposure registry information in the
``Pregnancy'' subsection of prescription drug labeling. These comments
explained, for example, that including pregnancy exposure registry
information in labeling may ``encourage patient involvement in
registries'' and ``pave the way for improved registry use by clinicians
leading to better documentation of drug effects and use during
pregnancy.''
One comment stated that including a reference to an existing
pregnancy registry should not be mandatory.
(Response) FDA believes that appropriately conducted pregnancy
registries are an important mechanism for the collection of clinically
relevant data concerning the effects of exposure to drugs during
pregnancy. The Agency believes that including information about
pregnancy exposure registries in prescription drug labeling will
encourage participation in registries, thereby improving their
usefulness. Thus, if there is a pregnancy registry that FDA has
reviewed and found scientifically acceptable, FDA is requiring that the
``Pregnancy'' subsection of prescription drug labeling include under
its own subheading, ``Pregnancy Exposure Registry,'' a standard
statement concerning the existence of the registry, as well as the
contact information necessary to enroll in the pregnancy exposure
registry or to obtain information about the registry. The Agency
generally considers a pregnancy exposure registry scientifically
acceptable when it is consistent with applicable FDA guidance,
including the guidance for industry on ``Establishing Pregnancy
Exposure Registries'' (August 2002). If there are changes to an
existing pregnancy registry or a new pregnancy registry is initiated
after drug approval, labeling will need to be updated to include this
new information.
(Comment 20) Two comments sought clarification regarding the
standards for including contact information for a pregnancy exposure
registry. One comment stated that contact information should only be
included if the registry is scientifically acceptable to the sponsor
and FDA. Another comment asked whether contact information for non-U.S.
registries must be included.
(Response) As stated previously, if there is a scientifically
acceptable pregnancy registry for a drug product, FDA is requiring a
standard statement concerning the registry as well as contact
information needed to enroll in the registry or obtain additional
information about it. For registries that include U.S. populations,
U.S. contact information should be included in the labeling, regardless
of whether the registry is maintained within the United States or
elsewhere.
(Comment 21) Four comments suggested that the pregnancy exposure
registry information should have its own component header.
(Response) FDA agrees with the suggestion that the pregnancy
exposure registry information should have its own component header. In
the final rule, contact information for an existing pregnancy exposure
registry and a standard statement on the registry will fall under the
subheading ``Pregnancy Exposure Registry'' in the ``Pregnancy''
subsection of prescription drug labeling. Because of this change, FDA
eliminated the phrase ``must be stated at the beginning of the
`Pregnancy' subsection of the labeling'' from the final rule.
(Comment 22) Two comments stated that it should be easier to enroll
patients in pregnancy exposure registries.
(Response) The importance of subject recruitment into pregnancy
exposure registries and the need to build awareness of pregnancy
exposure registries among health care providers are both factors in
FDA's decision to place information about existing pregnancy exposure
registries at the beginning of Sec. 201.57, ``8.1 Pregnancy.'' The
actual process of enrolling patients, however, is beyond the scope of
this rule.
(Comment 23) Comments expressed disagreement about whether the
``Pregnancy Exposure Registry''
[[Page 72078]]
subheading should be omitted from the ``Pregnancy'' subsection of
prescription drug labeling when there is no existing registry for the
drug. One comment suggested that the ``Pregnancy Exposure Registry''
subheading should not be omitted even if there is no existing registry
for the drug, and that it should include a statement that there is no
specific pregnancy exposure registry for the drug. Another comment
requested that FDA consider incorporating a statement that the
subheading may be omitted if there is no pregnancy exposure registry.
(Response) FDA concludes that the ``Pregnancy Exposure Registry''
subheading should be omitted when there is no pregnancy exposure
registry. We have determined that requiring the ``Pregnancy Exposure
Registry'' subheading in labeling when there is no pregnancy exposure
registry for the drug product, and the inclusion of a statement
indicating that no registry exists, would not further the goal of
improving the collection of data in pregnant women who are exposed to a
drug.
(Comment 24) One comment suggested that the labeling should state
the purpose of the pregnancy exposure registry and provide the contact
information necessary for enrollment.
(Response) FDA agrees that including a statement in the labeling
about the purpose of the pregnancy exposure registry would be useful.
In the final rule, FDA requires that if there is a scientifically
acceptable pregnancy exposure registry for the drug, the labeling must
include a statement that there is a pregnancy exposure registry that
monitors pregnancy outcomes in women exposed to the drug during
pregnancy, and include contact information needed to enroll in the
registry or to obtain information about the registry. Because the
purpose of all pregnancy registries is to collect clinically relevant
human data that can be used in a product's labeling to provide health
care providers with useful information for treating or counseling
patients who are pregnant or anticipating pregnancy, we do not believe
it is necessary to include a more specific statement in labeling about
their purpose.
(Comment 25) Two comments suggested that pregnancy exposure
registry information be included in ``Highlights'' and in the ``Patient
Counseling Information'' section of labeling. One comment requested
that FDA clarify in guidance whether the Agency anticipates requesting
more pregnancy registries as a condition of marketing approval.
(Response) FDA believes that including information about pregnancy
exposure registries in the ``Patient Counseling Information'' section
of labeling would be useful. If the drug product has a pregnancy
exposure registry, the availability of a pregnancy exposure registry
should be noted in the ``Patient Counseling Information'' section of
labeling, and a cross-reference should be included to ``8.1 Pregnancy''
for the contact information necessary to enroll. The preamble to the
PLR states that ``Highlights'' summarizes the information from the
``Full Prescribing Information'' that is most important for prescribing
the drug safely and effectively and organizes it into logical groups to
enhance accessibility, retention, and access to the more detailed
information (71 FR 3922 at 3931). Information about the availability of
and contact information for a pregnancy exposure registry are not
considered essential information for prescribing and should not appear
in ``Highlights'' (see FDA's guidance for industry on ``Labeling for
Human Prescription Drug and Biological Products--Implementing the PLR
Content and Format Requirements'' (February 2013)). The question of
whether FDA anticipates requesting more pregnancy exposure registries
as a condition of marketing approval is outside the scope of this rule.
In the final rule, FDA revised the phrase ``telephone number or
other information needed to enroll'' to ``contact information needed to
enroll.'' FDA determined that this change would allow for more
flexibility in the type of contact information included under this
portion of the labeling.
ii. Background risk statement--FDA proposed that a general
statement about the background risk of adverse pregnancy outcomes be
included in labeling. The proposed rule stated in Sec.
201.57(c)(9)(i)(B) that the following statement was required to be
included in the labeling: All pregnancies have a background risk of
birth defect, loss, or other adverse outcome regardless of drug
exposure. The fetal risk summary below describes (name of drug)'s
potential to increase the risk of developmental abnormalities above the
background risk.
(Comment 26) Two comments expressed support for the inclusion of a
background risk statement. One of these comments noted that the
statement will be useful to clinicians when explaining the fetal risks
associated with drug use during pregnancy.
Several comments suggested modifying the background risk statement.
One comment suggested that applicants be given the option to identify
in the background risk statement the specific risks described in the
fetal risk summary. The comment proposed that the second sentence of
the background statement be modified to state: ``The fetal risk summary
below describes the potential of (name of drug) to contribute to risk
of (`adverse outcomes, including developmental abnormalities' or
identify specific risks) above background risk.''
Several comments requested clarification about whether the
background risk statement refers to the general population or the
population with the disease. Two other comments suggested that when the
background risk of adverse outcomes in the relevant disease population
is known to be higher than in the general population, this information
should be included in the background risk statement. One of these
comments suggested that relevant literature citations should also be
included as appropriate.
One comment asked FDA to clarify how it will determine the
background rate of adverse pregnancy outcomes. Another comment
suggested that FDA and industry develop a standard definition of
background risk that would provide a common explanation for all
labeling, both for the general population and for any specific disease
states or conditions. This comment explained that different reviewers
may look at different criteria for assessing background risk (i.e.,
what constitutes a developmental abnormality or a congenital
malformation), and a standard definition would provide for consistency.
A separate comment stated that the background risks of pregnancy can
vary by demographics, location, ethnicity, and other variables. The
comment suggested that to maintain uniform and standardized
descriptions of background risk, FDA should provide industry with a
guidance document describing background risk.
One comment recommended against requiring data in the background
risk statement. The comment explained that background statistics change
over time as new evidence is made available and accepted by the medical
community.
Several comments suggested that FDA revise or omit the second
sentence of the background risk statement. One of the comments
explained that the sentence implies that the drug necessarily has the
potential to increase the risk of developmental abnormalities above the
background risk.
(Response) In the final rule, FDA has eliminated the proposed
standardized background risk statement. In its place, the final rule
requires that the labeling
[[Page 72079]]
state the percentage range of live births in the general population of
the United States with a major birth defect and the percentage range of
pregnancies in the United States that end in miscarriage, regardless of
drug exposure. The final rule also requires that if such information is
available for the population(s) for which the drug is labeled, it must
also be included. The final rule requires that the background risk
information appear in labeling under the subheading ``Risk Summary,''
rather than as a standalone statement under its own subheading (as in
the proposed rule).
The Agency has determined that rather than including a standardized
general statement about background risk, it is beneficial to include
the approximate background rates of major birth defects and
miscarriage. This will provide some context to the risk statement, and
a basis for comparison with risk estimates from studies in pregnant
women. Including the approximate background rates allows the prescriber
to inform patients of the risk of major birth defects and miscarriage,
regardless of drug exposure. Accordingly, the final rule requires that
the labeling include the approximate background rates of major birth
defects and miscarriage, regardless of drug exposure, in the United
States. FDA agrees, however, that it is possible that these numbers may
change over time. Therefore, the Agency did not include any specific
numbers in the final rule. Instead, the Agency has provided
information, including relevant literature citations, about current
background rates of major birth defects and miscarriage in the draft
guidance on pregnancy and lactation labeling, which is being published
concurrently with this final rule. Although the literature citations
are included in the draft guidance, the Agency does not believe it is
either necessary or appropriate to include them in the labeling.
FDA agrees that the second sentence in the proposed background risk
statement, which states that the fetal risk summary describes the
drug's potential to increase the risk of developmental abnormalities
above the background risk, could have been misinterpreted as meaning
that the drug is associated with an increased risk. As discussed
previously, the Agency has removed the standardized background risk
statement, including the second sentence, from the final rule.
iii. Fetal risk summary--FDA proposed that under ``Pregnancy,''
prescription drug labeling include a subheading ``Fetal Risk Summary''
(Sec. 201.57(c)(9)(i)(C)). FDA proposed that the section include a
risk conclusion, contain a narrative description of the risk(s) (if the
risk conclusion is based on human data), and refer to any
contraindications or warnings and precautions.
(Comment 27) One comment expressed support for the proposed ``Fetal
Risk Summary,'' explaining that the proposed labeling requirements
increase the utility of the ``Pregnancy'' subsection by expanding the
teratology section to include information about specific developmental
abnormalities such as incidence, seriousness, reversibility, potential
for correction, and effect of dose, duration, and gestational timing of
exposure. Several other comments suggested that the proposed ``Fetal
Risk Summary'' be revised in various ways, discussed in detail as
follows.
Sources of data. FDA proposed that all available data, including
human, animal, and pharmacologic data, that are relevant to assessing
the likelihood that a drug will increase the risk of developmental
abnormalities and other relevant risks must be considered (Proposed
Sec. 201.57(c)(9)(i)(C)(1)).
(Comment 28) One comment recommended that rather than considering
``all available data,'' the data sources for the ``Fetal Risk Summary''
be limited to ``scientifically rigorous, organized data collection
schemes such as clinical or preclinical studies, and registries.''
(Response) FDA declines this suggestion. For example, depending on
the safety signal, valuable information may come from epidemiological
studies that are not prospective pregnancy exposure registries. On
occasion, adverse event reporting or case series reporting may raise
enough concern about a potential increased risk for a specific
structural malformation or pattern of malformations, or a serious
adverse event, that the information should be included in labeling.
(Comment 29) Maternal and neonatal risk. One comment suggested that
FDA include information regarding maternal and neonatal risks in the
``Pregnancy'' subsection of labeling. The comment suggested that FDA
add a ``maternal risk subsection,'' preferably before the ``Fetal Risk
Summary,'' which would address side effects and adverse reactions
associated with the use of a drug, including those unique to pregnancy.
The comment explained that placing this information higher on the label
and making it a separate subsection would underscore the importance of
the health of the mother. The comment also suggested that FDA include
neonatal outcomes as well as fetal outcomes in the ``Fetal Risk
Summary.''
(Response) FDA agrees that information on drug-associated maternal
risk is important, and in the final rule has created a separate
heading, ``Maternal adverse reactions,'' under ``Clinical
Considerations,'' which requires relevant information, to the extent it
is available, about drug-associated maternal adverse reactions that are
unique to or more frequent or severe during pregnancy. FDA disagrees
that information on neonatal outcomes as well as fetal outcomes should
be included in the ``Risk Summary.'' Rather, if available, this
information is included under its own heading, ``Fetal/Neonatal adverse
reactions,'' under ``Clinical Considerations.'' FDA believes that
consistent placement of this information under a specified heading
under ``Clinical Considerations'' will allow health care providers to
easily locate this information. FDA also believes that this approach
ensures that maternal, fetal, and neonatal risks will be captured and
clearly conveyed in prescription drug labeling.
Terms used to describe adverse fetal outcomes. FDA proposed that
the fetal risk summary must characterize the likelihood that the drug
increases the risk of developmental abnormalities in humans (i.e.,
structural anomalies, fetal and infant mortality, impaired physiologic
function, alterations to growth) and other relevant risks (e.g.,
transplacental carcinogenesis) (proposed Sec. 201.57(c)(9)(i)(C)(1)).
(Comment 30) Several comments suggested that the term
``developmental abnormalities'' should be replaced with a broader and
more accurate term. One comment suggested FDA replace the term
``developmental abnormalities'' with the term ``adverse outcomes,
including developmental abnormalities.'' This comment explained that
the phrase ``developmental abnormalities'' does not include ``other
relevant risks (e.g., transplacental carcinogenesis)'' that are also
required to be described in the ``Fetal Risk Summary.'' Several
comments suggested replacing the term ``developmental abnormalities''
with the term ``developmental effects'' or ``adverse developmental
effects.'' These comments explained that in the field of developmental
toxicology, a developmental abnormality would imply, in general, a
dysmorphogenic effect (malformation or variation), rather than the
wider definition intended by the proposed rule. Several comments noted
the importance of using terminology consistently in labeling.
[[Page 72080]]
(Response) FDA agrees that the terms used to describe various
developmental effects or outcomes should be accurate and
understandable, and that standard nomenclature in the field of
developmental toxicology should be used to the extent that it exists.
FDA also agrees that terminology should be used consistently in
labeling. FDA concludes that the term ``developmental abnormalities''
is widely recognizable as referring to structural defects
(malformations or variations), rather than the full range of possible
manifestations of developmental toxicity as FDA had intended.
Therefore, in the final rule, FDA has included the following terms that
describe various developmental toxicities, as explained in the
following list:
``Adverse developmental outcomes'' has replaced
``developmental abnormalities'' as the general term to encompass all
manifestations or types of developmental toxicity.
``Structural abnormalities'' is used to describe
dysmorphology, which includes malformations, variations, deformations,
and disruptions, rather than the proposed ``structural anomalies.''
``Embryo-fetal and/or infant mortality'' is used to
describe developmental mortality, which includes miscarriage,
stillbirth, and infant death (including neonatal death), instead of the
proposed ``fetal and infant mortality.''
``Functional impairment'' is used to describe functional
toxicity, which includes such outcomes as deafness, endocrinopathy,
neurodevelopmental effects, and impairment of reproduction, rather than
``impaired physiologic function.''
``Alterations to growth'' is used to describe such
outcomes as growth restriction, excessive growth, and delayed and early
maturations.
These terms and descriptions are consistent with FDA's guidance for
industry on ``Reproductive and Developmental Toxicities--Integrating
Study Results to Assess Concerns'' (September 2011).
Relationship between animal and human data. FDA proposed that when
both human and animal data are available, risk conclusions based on
human data must be presented before risk conclusions based on animal
data (proposed Sec. 201.57(c)(9)(i)(C)(2)).
(Comment 31) A number of comments suggested that FDA reexamine the
emphasis that the ``Fetal Risk Summary'' places on human data as
compared to animal data.
Several comments stated that because there will be frequent
conflicts between human and animal data, FDA should develop an overall
approach to characterize risk based on both human and animal data. One
of these comments suggested that FDA consider the European Medicines
Agency's (EMEA's) (now EMA's) Integration Table for Risk Assessment and
Recommendation for Use as an example of how to integrate risk
conclusions based on animal and human data.
Two comments stated that the proposed rule gives primary emphasis
to human studies, if they exist, while downgrading the emphasis on
animal data. One of these comments explained that the quality and
statistical power of human data often fall well short of desirable, and
suggested that human data be accompanied by clear acknowledgement of
any deficiencies. The other comment explained that emphasizing minimal
human data over strong animal data can misrepresent the fetal risk of a
drug.
Two comments suggested that if human data are ``insufficient''
(i.e., do not meet the standard for inclusion in proposed Sec.
201.57(c)(9)(i)(C)(2)(i)), a risk statement based on human data should
not precede a risk statement based on animal data. One of these
comments explained that the most robust and clinically relevant data
should always be presented first.
Several comments stated that if risk conclusions are based on
sufficient human data, sponsors should not be required to include
animal data, even if such data are available. One comment also
suggested that if sufficient human data become available after the
labeling is approved, animal data should be removed when the human data
are added to the labeling. This comment explained that ``a risk
conclusion based on animal data might not support, or could flatly
contradict, a risk conclusion based on sufficient human data.''
One comment suggested that FDA ban all animal studies because human
studies are more accurate.
(Response) We continue to believe that the ``Risk Summary'' is
appropriately based on both human and animal data. Because of the
importance of human data, we also have determined that when human data
provide an incomplete assessment, this should be stated in the risk
statement based on human data. Specifically, the ``Risk Summary'' must
state when there are no human data or when available human data do not
establish the presence or absence of a drug-associated risk. FDA
believes that the use of narrative summaries of the data will avoid
conflicting characterizations of risk magnitude.
FDA disagrees with the suggestion that animal data be presented
first in cases where the human data are insufficient. FDA also
disagrees that the most robust and clinically relevant data--whether
human data or animal data--should always be presented first. We have
determined that to promote consistency and to meet readers'
expectations that information will always be found in the same place, a
fixed order of presentation must be maintained. Moreover, we have
determined that human data should precede animal data because it is the
most clinically relevant.
We note that the purpose of this rulemaking is to facilitate
informed prescribing and safe and effective drug product use; placing
restrictions on or encouraging any type of studies that may be used as
the basis for drug labeling is beyond the scope of this rule.
Not systemically absorbed. FDA proposed that if the drug is not
systemically absorbed, the fetal risk statement must contain only the
following statement: (Name of drug) is not absorbed systemically from
(part of body) and cannot be detected in the blood. Maternal use is not
expected to result in fetal exposure to the drug (proposed Sec.
201.57(c)(9)(i)(C)(1)).
(Comment 32) One comment suggested that this statement should focus
on the route of administration rather than the part of the body.
(Response) FDA agrees that ``part of the body'' could be
misconstrued and we have determined that the use of ``route of
administration'' to describe how the drug enters the body is more
consistent with labeling language that addresses dosing and
administration. In the final rule, FDA has replaced ``part of the
body'' with ``route of administration.'' FDA has determined that
``cannot be detected in the blood'' is redundant and that the statement
is clear without this phrase. In the final rule, FDA has eliminated
that phrase.
(Comment 33) Standard statement for certain drugs. FDA received one
comment suggesting that we develop a standard statement for drugs that
are indicated for use only by males or by females who are not of
reproductive potential.
(Response) FDA disagrees. We have determined that a standard
statement is not needed. We believe it is appropriate that the ``Risk
Summary'' will be included in labeling for all drugs, regardless of
their indicated population. This will promote consistency in drug
labeling.
[[Page 72081]]
Risk conclusions based on human data. In the proposed rule, under
the subheading ``Fetal Risk Summary,'' FDA proposed that when human
data are sufficient to reasonably determine the likelihood that the
drug increases the risk of fetal developmental abnormalities or
specific developmental abnormalities, the likelihood of increased risk
must be characterized using one of the following risk conclusions:
Human data do not indicate that (name of drug) increases the risk of
(type of developmental abnormality or specific developmental
abnormality) or Human data indicate that (name of drug) increases the
risk of (type of developmental abnormality or specific abnormality)
(proposed Sec. 201.57(c)(9)(i)(C)(2)(i)). The proposed rule defined
the sources of ``sufficient human data'' as clinical trials, pregnancy
exposure registries or other large scale epidemiologic studies, or case
series reporting a rare event (proposed Sec.
201.57(c)(9)(i)(C)(2)(i)).
(Comment 34) Many comments requested that FDA more clearly define
the criteria for ``sufficient human data'' and provide further guidance
on the quantity and quality of evidence considered to be ``sufficient
human data'' rather than ``other human data.'' One comment requested
that FDA clarify the standards that constitute ``sufficient human
data,'' including how those standards were developed. Another comment
stated that there is no agreement among experts as to how much data are
needed to reach a risk conclusion and requested that FDA clarify what
is considered sufficient human data to reasonably determine the risk of
developmental abnormalities. Several comments questioned whether data
from an individual study could ever constitute ``sufficient human
data.'' These comments explained that although individual clinical
trials, pregnancy exposure registries, large-scale epidemiologic
studies, and case series can provide signals for potential adverse
pregnancy outcomes, an individual study is not statistically powered to
fully assess the incidence and form one of the proposed risk
conclusions. A separate comment stated that even if human data has
multiple sources, there is often not enough human data to make a risk
conclusion. This comment questioned how often the risk statements based
on sufficient human data would be used. One comment stated that the
proposed rule does not discuss who will determine whether the data are
sufficient or how such a determination will be made. The comment
suggested that to increase consistent implementation across review
divisions, a dedicated group of FDA specialists should review the
determination of whether the human data are sufficient or insufficient
for all labeling subject to the rule. This comment also requested that
FDA provide examples of sufficient and insufficient data and that FDA
caution prescribers that such classifications should not be considered
as scientific proof that a drug may or may not harm a particular
patient.
(Response) FDA agrees that the term ``sufficient human data'' is
ambiguous and has eliminated it from the final rule. FDA has also
eliminated from the final rule the distinction between ``sufficient
human data'' and ``other human data.'' In the final rule, FDA requires
that when human data are available that establish the presence or
absence of any adverse developmental outcome(s) associated with
maternal use of the drug, the labeling must summarize the specific
developmental outcome; its incidence; and the effects of dose, duration
of exposure, and gestational timing of exposure. As stated previously,
the final rule also requires that the ``Risk Summary'' state when there
are no human data or when available human data do not establish the
presence or absence of drug-associated risk.
FDA has also determined that the term ``risk conclusion'' is
inappropriate because the available data may not always lead to a
conclusion regarding the drug's risk to the fetus. Therefore, in the
final rule, FDA has replaced the term ``risk conclusion'' with the term
``risk statement.''
(Comment 35) Several comments suggested that the Agency revise the
proposed risk statements to make them more straightforward and
appropriately qualify the nature of the data and the inability to draw
definitive conclusions about an absence of risk based on them. Two of
these comments suggested that the term ``human data'' be replaced with
the term ``available human data.'' One comment suggested that the risk
conclusion ``Human data do not indicate that (name of drug) increases
the risk of (type of developmental abnormality or specific
developmental abnormality)'' be replaced with ``Available human data
indicate no additional risk of (type of developmental abnormality or
specific developmental abnormality) with (name of drug).'' One comment
suggested that the term ``indicate'' should be replaced with the term
``suggest.''
(Response) In the final rule, FDA has eliminated the requirement in
the proposed rule that standardized risk conclusions be used to
characterize the likelihood of increased risk. As discussed previously,
in the final rule, FDA requires instead, under ``Risk statement based
on human data,'' that when human data are available that establish the
presence or absence of any adverse developmental outcome(s) associated
with maternal use of the drug, the labeling must summarize the specific
developmental outcome; its incidence; and the effects of dose, duration
of exposure, and gestational timing of exposure. The final rule also
requires that if the data indicate that there is an increased risk for
a specific adverse developmental outcome in infants born to women
exposed to the drug during pregnancy, this risk must be quantitatively
compared to the risk for the same outcome in infants born to women who
were not exposed to the drug but who have the disease or condition for
which the drug is indicated to be used. The final rule requires that if
the data indicate that there is an increased risk for a specific
adverse developmental outcome in infants born to women exposed to the
drug during pregnancy, but risk information is not available for women
who were not exposed to the drug but who have the disease or condition
for which the drug is indicated to be used, then the risk for the
specific outcome must be compared to the rate at which the outcome
appears in the general population.
(Comment 36) FDA also received comments about the proposed sources
of sufficient human data. One comment stated that sufficient data must
be based on large-scale epidemiologic studies or clinical trials, and
cannot be based on pregnancy registries or case reports/series
requiring further evaluation. This comment explained that most
pregnancy registries can only serve to rule out a major teratogen and
to generally determine the similarity in array of effects seen in large
registries, and they cannot provide a quantitative estimate of
population rates of individual defects or abnormalities. Another
comment stated that a risk conclusion cannot always be reached based on
the types of human data described in the proposed rule, and questioned
whether there is a consistent approach to sufficient human data as it
relates to case series reporting of a rare event. This comment
explained that spontaneous reports should not be part of the basis for
this subsection. One comment questioned how the labeling will summarize
seemingly contradictory results of well-powered pregnancy exposure
registries or studies from
[[Page 72082]]
which a definitive clinical conclusion cannot be reached.
(Response) FDA recognizes that because retrospective voluntary
adverse event reporting may be biased and incomplete, spontaneous
reports cannot rule in or out a causal relationship between drug
exposure and clinical outcome. However, multiple spontaneous reports
(or case series) of rare events can be useful in suggesting possible
associations between adverse events and drug exposure during pregnancy
that warrant further investigation. Furthermore, FDA has determined
that data from studies with small numbers of pregnancy exposures may
provide valuable information about potential safety signals, especially
when corroborated by findings from other studies.
(Comment 37) One comment suggested that FDA eliminate the proposed
rule's requirement that sponsors specify all possible types of
developmental abnormalities or specific abnormalities for which human
data do not indicate that the drug increases the risk. The comment
explained that such a list could be lengthy and of little clinical
benefit to health care providers.
(Response) FDA did not intend to imply that every potential type of
developmental abnormality must be included in labeling when human data
are negative. We note that it is difficult to be certain that a lack of
findings equates to a lack of risk because the failure of a study to
detect an association between a drug exposure and an adverse outcome
may be related to many factors, including a true lack of an association
between exposure and outcome, a study of the wrong population, failure
to collect or analyze the right data endpoints, and/or inadequate
power. The intent of this final rule is to require accurate
descriptions of available data and facilitate the determination of
whether the data demonstrate potential associations between drug
exposure and an increased risk for developmental toxicities.
FDA proposed that when there are available human data that are not
sufficient to use one of the risk conclusions for sufficient human
data, the likelihood that the drug increases the risk of developmental
abnormalities must be characterized as low, moderate, or high (proposed
Sec. 201.57(c)(9)(i)(C)(2)(ii)). In the preamble to the proposed rule,
FDA sought comment on this subsection. Specifically, FDA sought
``comment on whether, in situations with human data that are not
sufficient, rather than classifying the risk as low, moderate, or high,
the risk should instead be characterized by specific statements
describing the findings, or whether the findings should be described at
all if they are not readily interpretable. Examples of specific
statements would be: `Limited data in humans show (describe outcomes),'
or `Limited data in humans show conflicting results (describe study
types, number of cases, outcomes, and limitations)''' (73 FR 30831 at
30842).
(Comment 38) FDA received 10 comments from a variety of sources
expressing strong disagreement with the proposal to use the terms
``low,'' ``moderate,'' and ``high'' to characterize the likelihood of
increased risk of adverse outcomes due to drug exposure based on less
than sufficient human data. FDA received only one comment supporting
the proposal.
Four comments stated that the proposal to classify risk as low,
moderate, or high based on insufficient human data might produce the
same confusion as the current pregnancy category system. These comments
explained that, as with the A, B, C, D, X category system, the use of
the categories low, moderate, and high to characterize the likelihood
of increased risk of adverse outcomes would oversimplify the data and
lump drugs with various types and amounts of data together without
describing the basis for the conclusions. Another comment suggested
that these characterizations are subjective and would be confusing to
health care providers.
One comment recommended that when the human data are insufficient,
FDA require the inclusion of the following risk conclusion:
``Insufficient data--risk conclusion not established.'' Another comment
recommended that FDA consider adopting something similar to the EMA's
system. One comment suggested that the ``Risk Summary'' should include
information about the findings, such as the gestational age of
exposure, the target organ or organ system, and the findings should be
characterized in terms of structural, developmental, growth, or
functional abnormality. Another comment recommended that when the human
data are not sufficient, the labeling contain statements specific to
the findings rather than classifying the risk as low, moderate, or
high. One comment suggested that when there are insufficient data, the
labeling should include a statement explaining that it is not possible
to draw conclusions based on insufficient human data. This comment also
expressed a preference for referring to the data portion of the
labeling rather than including a more detailed narrative discussion of
insufficient human data in the fetal risk summary.
(Response) As discussed previously, FDA agrees that the term
``sufficient human data'' is ambiguous and we have removed the term
from the final rule, as well as the distinction between ``sufficient
human data'' and ``other human data.'' FDA also agrees that the terms
``low,'' ``moderate,'' and ``high'' are subjective and should not be
used to describe human data that cannot support a statement about fetal
risk. The final rule requires instead that when human data are
available that establish the presence or absence of any adverse
developmental outcome(s) associated with maternal use of the drug, the
labeling must summarize the specific developmental outcome; its
incidence; and the effects of dose, duration of exposure, and
gestational timing of exposure. As discussed earlier, the final rule
also requires that if the human data indicate that there is an
increased risk for a specific adverse developmental outcome in infants
born to women exposed to the drug during pregnancy, this risk must be
quantitatively compared to the risk for the same outcome in infants
born to women who were not exposed to the drug but who have the disease
or condition for which the drug is indicated to be used. When risk
information is not available for women with the disease or condition
for which the drug is indicated, then the risk for the specific outcome
must be compared to the rate at which the outcome occurs in the general
population. The final rule also requires that the ``Risk Summary''
state when there are no human data or when available human data do not
establish the presence or absence of drug-associated risk.
Narrative description of risk(s) based on human data. FDA proposed
that when there are human data, the risk conclusion must be followed by
a brief description of the risks of developmental abnormalities as well
as other relevant risks associated with the drug. To the extent
possible, this description must include the specific developmental
abnormality (e.g., neural tube defects); the incidence, seriousness,
reversibility, and correctability of the abnormality; and the effect on
the risk of dose, duration of exposure, and gestational timing of
exposure. When appropriate, the description must include the risk above
the background risk attributed to drug exposure and confidence limits
and power calculations to establish the statistical power of the study
to identify
[[Page 72083]]
or rule out a specified level of risk (proposed Sec.
201.57(c)(9)(i)(C)(4)).
In the final rule, FDA has removed the ``Narrative description of
risk(s)'' heading from the ``Pregnancy'' subsection. FDA has determined
that much of the information required under that heading by the
proposed rule was duplicative of information now required in the ``Risk
Summary.'' As discussed previously, when human data are available that
establish the presence or absence of any adverse developmental
outcome(s) associated with maternal use of the drug, the ``Risk
Summary'' in the ``Pregnancy'' subsection must summarize the specific
developmental outcome; its incidence; and the effects of dose, duration
of exposure, and gestational timing of exposure. Because this
information is required to be included in a narrative form in the
``Risk Summary,'' we determined that including a separate ``Narrative
description of risk(s)'' heading in the labeling was unnecessary. In
addition, as explained in the following comments and our responses,
some of the information that was required by the proposed rule to
appear under ``Narrative description of risk(s)'' is required by the
final rule to appear instead under ``Clinical Considerations.''
(Comment 39) One comment suggested that FDA add a statement to the
``Narrative description of risk(s)'' portion of the ``Pregnancy''
subsection of labeling that explains that spontaneous abortions caused
by a drug could potentially mask the risk of developmental
abnormalities.
(Response) Although FDA acknowledges that embryo-fetal death (i.e.,
spontaneous abortion) does sometimes occur due to severe developmental
abnormalities, the Agency has determined that it is not necessary to
explicitly include such a statement in labeling. Any increase in
spontaneous abortions attributed to drug exposure above the background
risk is required to be described in the ``Risk Summary.''
(Comment 40) One comment stated that the term ``seriousness'' is
ambiguous and suggested replacing it with the phrase ``impact on
health.'' Two comments requested clarification of the terms
``reversibility'' and ``correctability.''
(Response) FDA agrees that the term ``seriousness'' is not clear,
and it is not used in the final rule; it has been replaced with a
requirement that the labeling describe the potential severity of the
adverse reaction. Information about the reversibility of adverse
reactions should be included under the heading, ``Fetal/Neonatal
adverse reactions,'' under ``Clinical Considerations.'' This portion of
the final rule requires that if it is known or anticipated that
maternal drug therapy increases or may increase the risk of an adverse
reaction in the fetus or neonate, the labeling must describe the
adverse reaction, the potential severity and reversibility of the
adverse reaction, and available interventions for monitoring or
mitigating the reaction.
In response to the comments requesting clarification of the terms
``reversibility'' and ``correctability,'' FDA considers a condition to
be reversible if it can self-correct with routine care and nurturing or
through an intervention such as discontinuing the drug. An example of a
potentially reversible drug effect in the neonate is provided in the
draft guidance on pregnancy and lactation labeling, which is being
published concurrently with the final rule. The term ``correctable''
has been removed from the final rule.
(Comment 41) One comment suggested that FDA include in the
``Narrative description of risk(s)'' information about precautionary
measures that can be taken to prevent an adverse outcome caused by the
drug.
(Response) FDA agrees that information about precautionary measures
to prevent an adverse drug effect should be included in labeling. In
the final rule, under ``8.1 Pregnancy,'' ``Clinical Considerations,''
``Maternal adverse reactions,'' FDA requires that if the use of the
drug is associated with a maternal adverse reaction that is unique to
pregnancy or if a known adverse reaction occurs with increased
frequency or severity in pregnant women, the labeling must describe the
adverse reaction and available intervention(s) for monitoring or
mitigating it. Also, in the final rule, FDA requires that under ``8.1
Pregnancy,'' ``Clinical Considerations,'' ``Fetal/Neonatal adverse
reactions,'' if it is known or anticipated that maternal drug therapy
increases or may increase the risk of an adverse reaction in the fetus
or neonate, the labeling must describe the adverse reaction, the
potential severity and reversibility of the adverse reaction, and
available intervention(s) for monitoring or mitigating the reaction.
For further discussion of these requirements, see Comment 61 and our
response.
(Comment 42) One comment suggested that FDA replace the phrase
``risk attributed to drug exposure'' in the ``Narrative description of
risk(s)'' with the phrase ``a drug's potential to contribute to the
risk of adverse outcomes.''
(Response) As discussed previously, the ``Narrative description of
risk(s)'' heading was removed from the final rule, and the phrase
``risk attributed to drug exposure'' is not used elsewhere in the final
rule.
(Comment 43) Two comments stated that confidence intervals and
power calculations should not be included in labeling because they are
too technical and not useful for most prescribers.
(Response) FDA does not agree. Under ``Data,'' the final rule
requires a description of the limitations of any data included in the
labeling. Confidence intervals and power calculations are important for
the review and interpretation of the data. As noted in the draft
guidance on pregnancy and lactation labeling, which is being published
concurrently with the final rule, the confidence intervals and power
calculation, when available, should be part of that description of
limitations.
(Comment 44) One comment suggested that the ``Narrative description
of risk(s)'' include a discussion about the uncertainties or
limitations of the ``Fetal Risk Summary'' when appropriate.
(Response) As discussed previously, FDA has removed the ``Narrative
description of risk(s)'' heading from the final rule. In the final
rule, any uncertainties or limitations of the data are required to be
stated in ``Data.''
(Comment 45) One comment suggested that the ``Narrative description
of risk(s)'' cross-reference ``Data'' to direct readers to the
information upon which the narrative is based.
(Response) As discussed previously, the ``Narrative description of
risk(s)'' was removed from the final rule.
Risk statement based on animal data. FDA proposed to require that
when the data on which the risk conclusion is based are animal data,
the ``Fetal Risk Summary'' must characterize the likelihood that the
drug increases the risk of developmental abnormalities using one of the
following risk conclusions: Not predicted to increase the risk, low
likelihood of increased risk, moderate likelihood of increased risk,
high likelihood of increased risk, or insufficient data (proposed Sec.
201.57(c)(9)(i)(C)(3)(i)-(c)(9)(i)(C)(3)(v)). In the preamble to the
proposed rule, the Agency sought comment on whether these standardized
statements can adequately communicate different levels of risk based on
animal data and their potential relevance to human fetal effects or
whether these statements are likely to generate
[[Page 72084]]
confusion among prescribers (73 FR 30831 at 30843).
(Comment 46) Comments expressed different opinions about the
proposal to use standardized statements to characterize animal data.
FDA received 11 comments, primarily from toxicologists, teratologists,
and organizations representing toxicologists and teratologists, as well
as a few comments from drug manufacturers, expressing strong
disagreement with the proposal to use risk statements to characterize
animal data. FDA received three comments that supported using
standardized statements to characterize the likelihood, based on animal
data, that a drug will increase the risk for a known developmental
abnormality. These comments explained, for example, that a standardized
statement indicating the possible correlation between animal and human
data would be helpful to clinicians.
Two comments stated that the proposed categories are confusing and
subject to variable interpretation. One of these comments explained
that it will be very difficult to categorize the results of multiple
studies conducted for a single drug into one of the proposed
categories, and there could be disagreement about whether to
characterize the risk based on the animal data as ``low,''
``moderate,'' or ``high.''
Several comments stated that the proposal to use category language
to describe animal data demonstrates a misunderstanding of the function
and meaning of experimental animal studies. These comments explained
that although animal data can identify the potential of a therapeutic
agent to cause developmental toxicity, it cannot give rise to an
estimate of the probability of human harm.
Two comments expressed concern that the use of standardized risk
statements would amount to a category system similar to the one that
FDA currently uses and would have all of its associated problems.
Several comments expressed particular concern with the proposal to
use these categories without an accompanying narrative description of
the animal studies. One comment suggested that the sample labels
provided in the Appendix of the proposed rule illustrate the difficulty
of trying to characterize the risk to humans based on animal data.
Another comment stated that ``the terms `risk,' `medium,' and `high'
are highly charged terms'' and expressed concern that the risk
statements will be over-interpreted by anxious consumers and their
clinicians.
One comment suggested that rather than using the proposed risk
statements, FDA should instead use the standardized statements
presented in the draft reviewer guidance on ``Integration of Study
Results to Assess Concerns about Human Reproductive and Developmental
Toxicities'' (October 2001).
Most of the comments that disagreed with the proposed standardized
risk statements suggested that the labeling instead contain narrative
statements describing the animal data and its potential relationship to
human pregnancy risk. One of these comments explained that ``succinct
narrative statements will promote a reasoned risk assessment,
facilitate comparisons among drugs, and enhance risk communication.''
Several of these comments suggested that the labeling should describe
animal data qualitatively, including the number of species with
positive findings, consistency of findings, and the type of findings.
(Response) The Agency has determined that the terms ``not predicted
to increase the risk,'' ``low likelihood of increased risk,''
``moderate likelihood of increased risk,'' and ``high likelihood of
increased risk'' are confusing and subject to different
interpretations. The Agency believes that using standardized risk
statements may give the false impression that animal data can provide a
semi-quantitative assessment of human risk. The Agency also agrees that
the use of standardized risk statements to characterize the risk of
developmental abnormalities based on animal data would potentially have
the same drawbacks as the current pregnancy category system. Therefore,
in the final rule, FDA removed the requirement that a standardized risk
statement be used to describe human risk based on animal data. Instead,
the ``Risk Summary'' requires that when animal data are available, the
labeling must summarize the findings in animals and, based on these
findings, describe, for the drug, the potential risk of adverse
developmental outcomes in humans. The final rule requires that the
statement include the number and type(s) of species affected, timing of
exposure, animal doses expressed in terms of human exposure or dose
equivalents, and outcomes for pregnant animals and offspring. The final
rule also requires that when animal studies do not meet current
standards for nonclinical developmental toxicity studies or when there
are no animal data, the labeling must so state.
(Comment 47) Two comments suggested that labeling should include
language explaining the limitations of using animal data to predict the
likelihood that the drug increases the risk of developmental
abnormalities.
(Response) FDA declines the suggestion to include language in
labeling explaining the limitations of using animal data to predict the
likelihood that the drug increases the risk of developmental
abnormalities, because this is beyond the scope of this rule, and is
discussed in guidance documents, such as FDA's guidance for industry on
``Reproductive and Developmental Toxicities--Integrating Study Results
to Assess Concerns'' (September 2011).
(Comment 48) FDA proposed that the ``Risk Summary'' contain ``risk
conclusions'' based on animal data. One comment suggested that the term
``risk conclusion'' be replaced with the term ``risk statement''
because it is difficult to reach any conclusions about fetal risk posed
by drugs based solely on animal data.
(Response) FDA agrees. As with human data, in the final rule, the
Agency has replaced the term ``risk conclusion'' with the term ``risk
statement'' when discussing risks based on animal data.
(Comment 49) Risk statement based on pharmacology. One comment
suggested that FDA consider whether a separate approach is appropriate
for a group of drugs, such as oncology products, for which the
pharmacological and toxicological mechanisms are similar. The comment
suggested that for cytotoxic drugs, FDA could use the following
standard risk statement: ``(Drug name) is indicated for (cancer type)
and is generally used in terminally ill patients. There are very
limited data on exposure in pregnant patients and, therefore, no
assessment of fetal or maternal risk is available. The mechanism of
action of this drug is to kill growing cells and it can be anticipated
that there is a risk to the fetus at all stages of development.''
(Response) FDA agrees that the ``Pregnancy'' subsection of labeling
should address situations in which a drug may result in an increased
risk of adverse developmental outcomes based on a well-understood
mechanism of action. The final rule requires that when the drug has a
well-understood mechanism of action that may result in adverse
developmental outcome(s), the ``Risk Summary'' must explain the
mechanism of action and the potential associated risks.
Contraindications, warnings, and precautions. FDA proposed that the
[[Page 72085]]
``Fetal Risk Summary'' refer to information that is included in the
``Contraindications'' or ``Warnings and Precautions'' section of
labeling regarding an increased risk to the fetus from exposure to the
drug (proposed Sec. 201.57(c)(9)(i)(C)(5)).
(Comment 50) One comment suggested that FDA specify that any
contraindications or warnings or precautions that must be included in
the ``Fetal Risk Summary'' are those that relate to risk to the fetus.
(Response) In the final rule, FDA removed the requirement that the
``Risk Summary'' refer to information that is included in the
``Contraindications'' or ``Warnings and Precautions'' section of
labeling regarding an increased risk to the fetus from exposure to the
drug. As described in FDA's draft guidance for industry implementing
the PLR, when a topic is discussed in more than one section of
labeling, the section containing the most important information
relevant to prescribing should typically include a succinct description
and should cross-reference sections that contain additional detail
(FDA's guidance for industry on ``Labeling for Human Prescription Drug
and Biological Products--Implementing the PLR Content and Format
Requirements'' (February 2013)). Consistent with that principle, cross-
referencing of information required under the final rule will typically
appear in the section where the topic is briefly summarized, e.g.,
``Warnings and Precautions,'' and will refer the reader to the place in
labeling where it will be presented in greater detail, i.e.,
``Pregnancy.'' We note that because a contraindication is important
information that needs to be communicated to the health care provider,
the final rule requires that when use of a drug is contraindicated
during pregnancy, this information must be stated first in the ``Risk
Summary.''
iv. Clinical considerations.
FDA proposed that the ``Pregnancy'' subsection of prescription drug
labeling include a ``Clinical Considerations'' component to provide
guidance and information to health care providers about the use of the
drug in three distinct clinical situations: (1) Counseling women who
were inadvertently exposed to the drug during pregnancy, (2) making
prescribing decisions for pregnant women, and (3) making prescribing
decisions during labor and delivery (proposed Sec.
201.57(c)(9)(i)(D)).
We received many comments on this proposal. Based on those
comments, FDA has made some changes to the final rule. A description of
each comment we received and our responses follow.
(Comment 51) General comments. Comments expressed different
opinions about the utility and appropriateness of the proposed
``Clinical Considerations'' component. Many comments expressed general
support for including this information. One comment stated that
``Clinical Considerations'' will help clinicians and patients to
consider all aspects of the patient's care when deciding when and how
to prescribe drugs during pregnancy and in women of childbearing
potential. Another comment stated that the title ``Clinical
Considerations'' encourages professionals to make their own medical
judgments. A separate comment noted that FDA refrained from interfering
with the physician's discretion by framing ``Clinical Considerations''
as a practical guide that assists the provider in decisionmaking.
Some comments cautioned that ``Clinical Considerations'' was too
directive in its advice and requiring this information intruded on the
practice of medicine and could increase physician liability for failure
to adhere to labeling instructions. One comment stated that ``Clinical
Considerations'' should not dictate prescribing by a physician for
pregnant women. The comment requested that FDA revisit this provision
to see whether the content can be made more useful without advising
physicians how to practice medicine. In particular, the comment
suggested that information about known alternative therapies should be
included. Alternatively, the comment suggested that FDA consider the
use of a general statement about clinical considerations rather than an
extensive, clinically based discussion that may be unable to
incorporate risk and benefit information. Another comment stated that
it is the health care provider's responsibility to keep abreast of the
latest information about the disease state and its effect on pregnant
women and to apply that knowledge to treatment of each individual
patient, and the professional labeling is not the appropriate place for
this information.
(Response) FDA disagrees both that ``Clinical Considerations'' is
too directive and that professional labeling is not the appropriate
place for this information. As a Public Health Agency with expertise in
drug regulation and safety, FDA has a responsibility to issue
regulations that facilitate the development of drug labeling that
communicates how to safely and effectively prescribe drugs in the
clinical setting. The Agency does not regard ``Clinical
Considerations'' as dictating prescribing decisions. Rather, FDA views
the ``Clinical Considerations'' component of ``Pregnancy'' as providing
information that supports health care providers' understanding of drug
product risks and benefits and facilitates informed prescribing
decisions and patient counseling.
Inadvertent exposure. FDA proposed that under the subheading
``Clinical Considerations,'' the ``Pregnancy'' subsection of labeling
include information regarding known or predicted risks to the fetus
from inadvertent exposure to the drug during pregnancy (proposed Sec.
201.57(c)(9)(i)(D)(1)). The proposed rule would have required that: The
labeling must discuss the known or predicted risks to the fetus from
inadvertent exposure to the drug (exposure in early pregnancy before a
woman knows she is pregnant), including human or animal data on dose,
timing, and duration of exposure. If there are no human or animal data
to assess the risk from inadvertent exposure, the labeling must so
state.
(Comment 52) Comments expressed different opinions about the
necessity and utility of including this information.
Two comments supported including information about inadvertent
exposure. One of these comments explained that the proposed section
improves a physician's ability to manage such cases.
Two comments, however, suggested that FDA consider removing this
requirement because it will be duplicative of the information contained
in the ``Fetal Risk Summary.'' One of these comments explained that
assuming equal exposure to the drug, the known or predicted risks to
the fetus would be the same regardless of whether the exposure was
intentional or not. This comment explained that because fetal risks are
already fully described in the ``Fetal Risk Summary,'' including the
same information under ``inadvertent exposure during pregnancy'' would
be redundant. The comment suggested that the ``inadvertent exposure
during pregnancy'' component instead include a cross-reference to the
``Fetal Risk Summary'' and describe only information not already
described in the ``Fetal Risk Summary,'' in particular, any information
about ways to manage or mitigate the effects of inadvertent drug
exposure. The other comment explained that the risk of drug exposure to
the fetus early in pregnancy should not be different between women who
[[Page 72086]]
choose to become pregnant and those whose pregnancies were unplanned.
Another comment suggested that FDA either delete the statement
``exposure in early pregnancy before a woman knows that she is
pregnant'' or retain it as an example. This comment explained that
although inadvertent exposure is more likely in early pregnancy, it may
occur at any time during pregnancy.
One comment asked for clarification as to what is expected to be
included in this section. Specifically, this comment questioned how the
risk conclusions from animal data in the ``Fetal Risk Summary'' will be
used to counsel clinicians on the risk of inadvertent exposure, and
requested that FDA provide examples of this section in an Appendix.
(Response) The Agency agrees that the proposed ``inadvertent
exposure during pregnancy'' component would have required information
about drug effects on the fetus that is largely redundant of the
information that is required to be included in the ``Risk Summary'' in
the ``Pregnancy'' subsection of prescription drug labeling. FDA has
removed the ``inadvertent exposure during pregnancy'' component from
the final rule.
Prescribing decisions for pregnant women. FDA proposed that the
``Clinical Considerations'' portion of the ``Pregnancy'' subsection of
prescription drug labeling contain information about prescribing
decisions for pregnant women, including the following: (1) The risk, if
known, to the pregnant woman and the fetus from the disease or
condition the drug is indicated to treat; (2) information about dosing
adjustments during pregnancy; (3) information about maternal adverse
reactions associated with use of the drug; and (4) information about
any known or anticipated complications in the neonate from treatment of
the pregnant woman (proposed Sec. 201.57(c)(9)(i)(D)(2)).
In the final rule, FDA removed the heading ``Prescribing decisions
for pregnant women.'' FDA determined that because the ``inadvertent
exposure'' component was removed from the final rule, the ``Clinical
Considerations'' portion of the ``Pregnancy'' subsection was shortened
such that having a separate heading for ``Prescribing decisions for
pregnant women'' was unnecessary.
FDA received comments about the information required in the
proposed rule under the heading ``Prescribing decisions for pregnant
women.'' A description of each comment and our responses follow.
FDA proposed that the ``Prescribing decisions for pregnant women''
component under ``Clinical Considerations'' include information about
the risk, if known, to the pregnant woman and the fetus from the
disease or condition the drug is indicated to treat (proposed Sec.
201.57(c)(9)(i)(D)(2)(i)).
(Comment 53) Comments disagreed about whether the ``Pregnancy''
subsection of labeling should include information about the effects of
not treating the woman's underlying disease or condition.
Two comments supported requiring the inclusion of information about
the short- and long-term effects of not taking a necessary drug to
treat a chronic disease or condition for the duration of a pregnancy,
as well as information about the severity of the condition for which
the drug might be prescribed.
Two other comments, however, disagreed with including information
in ``Clinical Considerations'' about the risks of not treating the
mother's underlying disease or condition during pregnancy. These
comments stated that prescription drug labeling is not the appropriate
place for health care providers to learn about the risks of diseases
that drugs are indicated to treat.
(Response) FDA has determined that when relevant information is
available about the serious effects of not treating conditions or
diseases during pregnancy, it must be included in this section of
labeling. In the final rule, this requirement appears first under
``Clinical Considerations'' under the heading ``Disease-associated
maternal and/or embryo/fetal risk.'' The wording of this portion of the
final rule was revised to require that when there is a serious known or
potential risk to the pregnant woman and/or the embryo/fetus associated
with the disease or condition for which the drug is indicated to be
used, the labeling must describe the risk.
(Comment 54) Other comments suggested that the ``Clinical
Considerations'' component of the proposed rule be altered in various
ways.
Two comments expressed concern that descriptions of risks to the
pregnant patient or fetus posed by diseases or conditions would vary
among drugs that are indicated to treat the same disease or condition,
thereby promoting confusion. One of these comments suggested that FDA
develop disease-specific text for developmental risks of major disease
classes, such as asthma, hypertension, diabetes, and epilepsy, which
sponsors can use in their prescription drug labeling. This comment also
requested that the information be updated on a timely basis.
(Response) FDA agrees that it is important that information
provided in labeling is consistent and up-to-date, and we address this
issue in our response to Comment 4. FDA is not mandating that labeling
contain consistent disease-specific text, as knowledge of disease-
associated risk may change over time as more data become available.
(Comment 55) One comment suggested that FDA add a statement under
``Clinical Considerations'' explicitly stating that untreated or
inadequately treated health conditions (such as infections; chronic
diseases such as diabetes, hypertension, renal and thyroid diseases;
and psychiatric disorders such as depression) can adversely affect the
health of the woman and the outcomes of the pregnancy, and that
decisions about medication usage must be balanced with the risks of
untreated and/or poorly managed health conditions.
(Response) FDA disagrees with this suggestion. We have determined
that requiring a general standardized statement is less effective than
providing drug-specific information about the risks of not treating the
condition or disease for which the drug is indicated to be used.
(Comment 56) One comment suggested that ``Clinical Considerations''
should provide information about how to discontinue or switch
medications during pregnancy when necessary.
(Response) FDA agrees that when such information is available, it
may be appropriate to include it in ``Clinical Considerations.'' We
note that this does not require a change to the final rule, because
this is consistent with current labeling practices.
(Comment 57) One comment suggested that ``Clinical Considerations''
take into account the severity of the disease, disorder, or condition
to the mother, and the availability and the benefits and risks of
alternative therapies for which greater or lesser knowledge may be
known about their use in pregnant women.
(Response) FDA disagrees with the suggestion that the labeling
address the availability and the benefits and risks of alternative
therapies during pregnancy. Because the comparative risks and benefits
for different therapies may vary by patient, this determination must be
made by the prescribing health care provider. FDA acknowledges,
however, that under certain circumstances it may be appropriate to
include a statement in the labeling that pregnant women
[[Page 72087]]
should consider alternative drug therapies, and the appropriateness of
this would be evaluated on a case-by-case basis during the labeling
review process for a specific application.
Dosing adjustments during pregnancy. FDA proposed that ``Clinical
Considerations'' provide information about dosing adjustments during
pregnancy (proposed Sec. 201.57(c)(9)(i)(D)(2)(ii)). The proposed rule
stated that this information must also be included in the ``Dosage and
Administration'' and ``Clinical Pharmacology'' sections of the
labeling, and that if there are no data on dosing during pregnancy, the
labeling must so state.
(Comment 58) One comment suggested that dosing information should
be restricted to the ``Dosage and Administration'' section of labeling
and that ``Clinical Considerations'' should cross-reference the
``Dosage and Administration'' and ``Clinical Pharmacology'' sections of
the labeling rather than repeat dosing adjustment information in the
``Pregnancy'' subsection of labeling. The comment also suggested
replacing the phrase ``no data'' because it could become outdated and
because, in some instances, there may be data but it might not be
sufficient to support recommendations for dosing adjustments.
(Response) We disagree with the suggestion that all information
about dosing should be restricted to the ``Dosage and Administration''
section of labeling. FDA has determined that it is important that
labeling information relevant to the use of the drug during pregnancy
be included in the ``Pregnancy'' subsection. These issues are discussed
in the draft guidance on pregnancy and lactation labeling, which is
being published concurrently with the final rule. If there are
pharmacokinetic data that support dose adjustment(s) during pregnancy
and the postpartum period, this information must be provided under the
heading, ``Dose adjustments during pregnancy and the postpartum
period'' in ``Clinical Considerations,'' and there should be a cross-
reference to other sections of labeling that include more details
(e.g., ``Dosage and Administration'' or ``Clinical Pharmacology'').
Although in the proposed rule FDA had required a cross-reference to
``Dosage and Administration'' and ``Clinical Pharmacology,'' we have
removed that requirement. We believe, however, that when appropriate, a
cross-reference should be included. This approach is consistent with
the regulations and guidance applicable to the ``Dosage and
Administration'' section of labeling (Sec. 201.57(c)(3)) and FDA's
guidance for industry on ``Dosage and Administration Section of
Labeling for Human Prescription Drug and Biological Products--Content
and Format'' (March 2012), which require that the labeling provide
details on how to adjust or modify the dosage in the ``Dosage and
Administration'' section of labeling, including for specific patient
populations.
FDA agrees with the suggestion to remove the phrase ``no data''
from the final rule. In the final rule, we have removed the requirement
to state if there are no data available on dose adjustments during
pregnancy and the postpartum period. In addition, as noted in the draft
guidance on pregnancy and lactation labeling, which is being published
concurrently with the final rule, headings under ``Clinical
Considerations'' (including ''Dose adjustments during pregnancy and the
postpartum period'') should be omitted if there are no data available
or the available data are not relevant.
Maternal adverse reactions. FDA proposed that ``Clinical
Considerations'' contain information about maternal adverse reactions
that are unique to pregnancy or adverse reactions that occur with
increased frequency or severity in pregnant women. The proposed rule
required that the labeling also describe any interventions that may be
needed, such as monitoring blood glucose for a drug that causes
hyperglycemia in pregnancy (proposed Sec. 201.57(c)(9)(i)(D)(2)(iii)).
(Comment 59) One comment suggested that a cross-reference, ``see
Pregnancy,'' be added to the ``Adverse Reactions'' section of labeling
to ensure that health care providers refer to this section.
(Response) FDA disagrees with this comment. The conventions for
cross-referencing are explained in FDA's guidance for industry on
``Labeling for Human Prescription Drug and Biological Products--
Implementing the PLR Content and Format Requirements'' (February 2013).
The suggestion that this rule require a cross-reference from the
``Adverse Reactions'' section to the ``Pregnancy'' subsection of
labeling is not consistent with the conventions set forth in that
guidance. In addition, not every drug product will have pregnancy-
related adverse reactions; thus, a required cross-reference is
unnecessary.
(Comment 60) One comment suggested that ``Clinical Considerations''
refer to ``available'' interventions rather than ``needed''
interventions to avoid interfering with the practice of medicine.
(Response) FDA agrees with the suggestion to replace the phrase
``interventions that may be needed'' with the phrase ``available
interventions.'' In the final rule, FDA requires that if use of the
drug is associated with a maternal adverse reaction that is unique to
pregnancy or if a known adverse reaction occurs with increased
frequency or severity in pregnant women, the labeling must describe the
adverse reaction and available intervention(s) for monitoring or
mitigating the reaction. This change also allows for differences that
may exist in community standards of care and available services across
the United States. We note that in the final rule we removed the
following language from the codified: ``e.g., monitoring blood glucose
for a drug that causes hyperglycemia in pregnancy.''
Fetal/Neonatal adverse reactions. FDA proposed that ``Clinical
Considerations'' contain information about any known or anticipated
complications in the neonate, including any interventions that might be
needed (proposed Sec. 201.57(c)(9)(i)(D)(2)(iv)).
(Comment 61) Two comments asked FDA to clarify the meaning of the
term ``complication.'' One comment suggested that if FDA intended the
term ``complication'' to mean adverse reaction in the neonate, the
Agency should use the term ``adverse reaction.'' This comment also
suggested that if an adverse reaction/complication has been described
in the ``Fetal Risk Summary,'' only a cross-reference to Sec.
201.57(c)(9)(i)(C) should be required to appear in Sec.
201.57(c)(9)(i)(D)(2)(iv). Another comment suggested that FDA state
that a ``complication'' could be an ``adverse drug reaction,'' and
suggested that FDA state that the term ``adverse drug reaction'' may be
used when appropriate.
(Response) FDA agrees that ``adverse reaction'' is a more
appropriate term and that it is more consistent with the other portions
of the final rule. In the final rule, the term ``adverse reaction'' (as
defined in Sec. 201.57(b)(7)) has replaced ``complication.''
Additionally, in the final rule FDA is requiring the inclusion of
information regarding fetal adverse reactions in this section of
labeling. Although the proposed rule only addressed adverse reactions
(referred to there as ``complications'') in the neonate under what in
the final rule is required in Sec. 201.57(c)(9)(i)(C), FDA concludes
that information intended to inform prescribing decisions for pregnant
women appropriately includes information on fetal adverse reactions as
well as neonatal adverse reactions. FDA does not believe that there is
a
[[Page 72088]]
principled distinction between the importance of such information with
respect to the fetus and with respect to the neonate. The consistent
location under ``Clinical Considerations'' of information about
potential adverse reactions in the fetus as well as in the pregnant
woman and the neonate, and about available interventions, will make the
information in that subsection more useful, as well as easier to
identify for prescribers and other health care providers. Accordingly,
the final rule requires that if it is known or anticipated that
maternal drug therapy increases the risk of an adverse reaction in the
fetus or the neonate, the labeling must describe the adverse reaction,
the potential severity and reversibility of the adverse reaction, and
available intervention(s) for monitoring or mitigating the reaction.
FDA disagrees with the suggestion that if an adverse reaction/
complication has been described in the ``Fetal Risk Summary,'' only a
cross-reference to Sec. 201.57(c)(9)(i)(C) should be required to
appear in Sec. 201.57(c)(9)(i)(D)(2)(iv). As discussed in the draft
guidance on pregnancy and lactation labeling, which is being published
concurrently with the final rule, the ``Clinical Considerations''
portion of the labeling is intended to describe fetal/neonatal adverse
reactions that are not adverse developmental outcomes. Therefore,
because the two portions of the labeling address different potential
reactions/outcomes, a cross-reference would not be appropriate.
Additionally, in the final rule, FDA added the requirement that the
labeling must describe, if known, the effect of dose, timing, and
duration of exposure on the risk of an adverse reaction in the fetus or
neonate as FDA has concluded that this information is important for
informing prescribing decisions.
Drug effects during labor or delivery. FDA proposed that the
``Clinical Considerations'' portion of pregnancy labeling contain
information about drug effects during labor or delivery for drugs that
have a recognized use during labor or delivery, whether or not the use
is stated as an indication in the labeling, or are expected to affect
labor or delivery (proposed Sec. 201.57(c)(9)(i)(D)(3)).
(Comment 62) One comment supported the proposal to merge
information about labor and delivery into the ``Pregnancy'' subsection
of labeling.
Another comment expressed concern that including information about
drugs used during labor or delivery, including drugs that are used off-
label during labor or delivery, conflicts with FDA's long-standing
position that off-label information is not to be included in labeling.
(Response) We note that, as stated in the proposed rule (73 FR
30831 at 30844), the language proposed for this heading contained only
slight modifications from that in existing Sec. 201.57(c)(9)(ii).
However, because important safety information, whether for an approved
or unapproved use, may be required to be included in labeling (see,
e.g., Sec. 201.57(c)(6)(i)), we concluded that it is not necessary to
include specific language regarding this issue. Therefore, FDA has
removed the language regarding ``drugs that have a recognized use
during labor or delivery, whether or not the use is stated as an
indication in the labeling.'' In the final rule, FDA revised the
heading ``Drug effects during labor or delivery'' to ``Labor or
delivery,'' which is consistent with the level of specificity used in
the other headings under ``Clinical Considerations.''
v. Data.
FDA proposed that the following information be included in the
``Pregnancy'' subsection of labeling under the subheading ``Data'':
(1) Under the subheading ``Data,'' the ``Pregnancy'' subsection of
the labeling must provide an overview of the data that were the basis
for the fetal risk summary.
(2) Human and animal data must be presented separately, and human
data must be presented first.
(3) The labeling must describe the studies, including study type(s)
(e.g., controlled clinical or nonclinical, ongoing or completed
pregnancy exposure registries, other epidemiological or surveillance
studies), animal species used, exposure information (e.g., dose,
duration, timing), if known, and the nature of any identified fetal
developmental abnormalities or other adverse effect(s). Animal doses
must be described in terms of human dose equivalents and the basis for
those calculations must be included.
(4) For human data, positive and negative experiences during
pregnancy, including developmental abnormalities, must be described. To
the extent applicable, the description must include the number of
subjects and the duration of the study.
(5) For animal data, the relationship of the exposure and mechanism
of action in the animal species to the anticipated exposure and
mechanism of action in humans must be described. If this relationship
is not known, that should be stated (proposed Sec.
201.57(c)(9)(i)(E)).
FDA received comments about the information required under ``Data''
in the proposed rule and made some changes to the final rule. The
following discussion addresses these comments, our responses, and the
changes to the final rule.
(Comment 63) References. One comment suggested that under ``Data,''
the labeling should include references for the cited data. The comment
explained that including references for the data would allow clinicians
and other health care workers to further research pregnancy issues.
(Response) We decline this suggestion. FDA has determined that
prescription drug labeling is intended to facilitate prescribing
decisions and is not intended as a research tool. We also note that
this final rule is a part of labeling regulations, found at Sec.
201.57, which address the inclusion of references in prescription drug
labeling (see Sec. 201.57(c)(16)).
(Comment 64) Postmarketing reporting of adverse reactions. One
comment stated that if specific numbers of adverse event reports are
included in drug labeling, the labeling will need to be constantly
updated. The comment suggested that the Agency instead consider using
quantitative measures of frequency to produce a more stable label.
(Response) FDA acknowledges that the inclusion in labeling of
actual numbers of postmarketing reports for particular adverse
reactions is often not appropriate. We agree that the number of
postmarketing reports of adverse reactions changes over time and
labeling may become rapidly outdated. In addition, postmarketing
reports of adverse reactions generally do not establish an incidence or
prevalence of a particular outcome or definitively demonstrate an
association between prenatal exposure to the drug in question and the
adverse developmental outcome. However, FDA also recognizes that there
may be isolated situations in which reporting of adverse reactions
corroborates other human data and, in these situations, it may be
appropriate to list a specific number of cases with the date when the
reporting was collected. FDA will consider whether the labeling for a
drug product should include specific numbers of reports of adverse
reactions on a case-by-case basis based on evaluating all available
data and principles of epidemiology and data interpretation.
In the final rule, FDA replaced the phrase ``provide an overview of
the data'' with ``describe the data.'' FDA made this change to clarify
our intention that under the subheading
[[Page 72089]]
``Data,'' the labeling must include a more detailed description of the
data than might be understood from use of the term ``overview.'' In the
final rule, FDA also added the requirement that under ``Data,'' the
labeling describe the data that are the basis for the ``Clinical
Considerations.'' The proposed rule stated that ``Data'' must describe
the data that were the basis for the fetal risk summary, and did not
address the data that were the basis for ``Clinical Considerations.''
FDA has determined that there is no principled reason to distinguish
between the data under the fetal risk summary and that underlying
``Clinical Considerations.'' Accordingly, the final rule requires that
under the subheading ``Data,'' the labeling describe the data that are
the basis for both the ``Risk Summary'' and ``Clinical
Considerations.'' This subheading, therefore, is only required to the
extent that there are data that are the basis for these two subheadings
and the headings under them.
FDA has also determined that the information in labeling would be
clearer if human data and animal data appeared separately under
applicable headings. In the final rule, FDA requires that human and
animal data be presented separately under the headings ``Human Data''
and ``Animal Data.''
In the final rule, FDA requires that for human data, the labeling
must describe adverse developmental outcomes, adverse reactions, and
other adverse effects. To the extent applicable, the labeling must
describe the types of studies or reports, number of subjects and the
duration of each study, exposure information, and limitations of the
data. The final rule requires that both positive and negative study
findings be included. The proposed rule listed various types of
studies. These were removed from the final rule because we determined
that it is more appropriate to discuss these elements in guidance.
Animal data. FDA proposed that human and animal data must be
presented separately, and human data must be presented first.
(Comment 65) One comment suggested that FDA omit the requirement
that human data must be presented first. The comment explained that the
most robust data should be presented first regardless of whether it is
animal or human data.
(Response) FDA declines this suggestion. We have determined that to
promote consistency and to meet readers' expectations that information
will always be found in the same place, a fixed order of presentation
must be maintained. Additionally, as discussed in the preamble to the
proposed rule, the importance of human data in labeling was stressed by
physicians who participated in focus group testing of the model
labeling format and also by the FDA advisory committee that provided
input on the proposed format (73 FR 30831 at 30841). FDA has determined
that human data should always be presented first because human data are
often the most relevant to prescribers, and animal data may not always
be applicable to humans.
FDA also proposed that animal doses must be described in terms of
human dose equivalents and the basis for those calculations must be
included.
(Comment 66) Two comments suggested that the final rule remove the
requirement to use ``administered dose'' as a comparator between animal
and human data and to replace it with comparisons based on systemic
exposure, if available. One of these comments explained that basing the
comparison on systemic exposure will provide greater consistency within
the labeling and will also provide a way to more easily make
comparisons between drugs.
(Response) FDA declines this suggestion to restrict the comparison
to only those based on systemic exposure. We agree that comparisons
based on systemic exposure could provide consistency within labeling
and therefore the final rule requires that they must be included when
data are available, but the data are not always available for such a
comparison. FDA believes that including the human dose equivalent may
be more meaningful information for health care providers, particularly
in the absence of data to make comparisons based on systemic exposure,
and as such, in the final rule, a comparison of the animal to human
doses must be included using the data available.
The proposed rule required that for animal data under the ``Data''
component the relationship of the exposure and mechanism of action in
the animal species to the anticipated exposure and mechanism of action
in humans be described. In the final rule, we removed this requirement
because often this relationship is not known. The final rule requires
that animal doses or exposures be described in terms of human dose or
exposure equivalents, and that the basis for those calculations be
included.
2. 8.2 Lactation
FDA proposed that the ``Nursing mothers'' subsection of
prescription drug labeling be replaced with the subsection
``Lactation'' (proposed Sec. Sec. 201.56(d)(1) and 201.57(c)(9)(ii)).
FDA proposed that the ``Lactation'' subsection of prescription drug
labeling contain the following subheadings: ``Risk Summary,''
``Clinical Considerations,'' and ``Data'' (proposed Sec.
201.57(c)(9)(ii)). FDA received many comments about the proposed
``Lactation'' subsection and made changes to the final rule based on
these comments. The discussion that follows addresses these comments,
our responses, and the changes FDA made to the final rule.
a. General comments.
i. Support for ``Lactation'' subsection
(Comment 67) FDA received many comments expressing support for the
proposed ``Lactation'' subsection. One of these comments explained that
it is essential for drug labeling ``to carry 'best science' information
that enables clinicians to efficiently and thoroughly review what is
known about the drug and any reported health effects to the breast-fed
infant.'' The comment stated that the proposed rule would facilitate
more efficient consideration of the data.
(Response) We agree with these comments, and our final rule
requires labeling to include a subsection on lactation with risk and
benefit information related to breastfeeding and the breast-fed infant.
ii. Drug alternatives
(Comment 68) One comment suggested that a statement should be
included that many drugs for which we may not have lactation data have
a suitable alternative for which we do have data.
(Response) We decline to adopt this comment. We do not believe it
would be appropriate to include this type of statement in labeling.
Because the comparative risks and benefits will vary among individual
patients, a health care provider, in consultation with his or her
patient, is in the best position to determine whether there is a
``suitable alternative'' for a particular drug.
iii. Validating data
(Comment 69) One comment expressed concern about the potential for
bias or omissions with respect to which data the sponsor includes and
the risk statements the sponsor uses to characterize such data. The
comment encouraged FDA to employ all reasonable means to validate the
sponsor's collection, evaluation, and subsequent conclusions regarding
lactation data.
(Response) FDA agrees. FDA will review data available in literature
and sponsor-submitted data used for developing the ``Lactation''
subsection of drug labeling. We note that this does not require a
change to the final rule
[[Page 72090]]
because FDA's normal review process for prescription drug labeling
includes validating the applicant's collection, evaluation, and
subsequent conclusions regarding data.
b. Risk summary
i. ``Active metabolites''
(Comment 70) Two comments suggested that FDA revise the ``Risk
Summary'' so that it explicitly refers to active metabolites of the
drug, in addition to the drug itself.
(Response) FDA agrees with this comment. We also have determined
that it is appropriate to include information about the effects of a
drug and/or its active metabolite(s) not only in the ``Risk Summary,''
but under other subheadings in the ``Lactation'' subsection of
labeling. Therefore, the final rule has been revised to refer
explicitly to drugs and/or their active metabolites.
ii. ``Compatible with breastfeeding''
FDA proposed that under the subheading ``Risk Summary,'' if, as
described under Sec. 201.57(c)(9)(ii)(A)(1) through (c)(9)(ii)(A)(3)
of the section, the data demonstrate that the drug does not affect the
quantity and/or quality of human milk and there is reasonable certainty
either that the drug is not detectable in human milk or that the amount
of drug consumed via breast milk will not adversely affect the breast-
fed child, the labeling must state: The use of (name of drug) is
compatible with breastfeeding. After this statement (if applicable),
the risk summary must summarize the drug's effect on milk production,
what is known about the presence of the drug in human milk, and the
effects on the breast-fed child (proposed Sec. 201.57(c)(9)(ii)(A)).
(Comment 71) Two comments suggested that FDA eliminate the
statement, ``The use of (name of drug) is compatible with
breastfeeding'' from the ``Lactation'' subsection of the final rule.
One of the comments explained that it will be difficult to determine
whether a drug is compatible with breastfeeding with such definitive
certainty, especially since the term ``compatible'' implies safety.
Another comment suggested that in the final rule FDA should replace the
statement ``compatible with breastfeeding'' with a standardized
statement that ``sufficient'' human data exist to indicate that the
drug does or does not adversely affect the breast-fed child, followed
by a supportive narrative.
(Response) FDA agrees that the term ``compatible'' is not clearly
defined and implies that the use of a drug during lactation is
``safe.'' No drug is completely safe even in a person who is not
pregnant or breastfeeding. In addition to offering potential
therapeutic benefit(s), all drugs have potential side effects and risks
involved with their use. The balance between those benefits and risks
is taken into account not just at the approval stage, but also helps
direct diagnostic and treatment recommendations for a particular
patient in a particular clinical scenario. Accordingly, in the final
rule FDA removed the statement ``The use of (name of drug) is
compatible with breastfeeding.''
Breastfeeding offers significant health benefits to both the child
and mother. Different drugs and/or their active metabolites pass into
breast milk in different concentrations; they may or may not be orally
bioavailable in the infant, and they may or may not result in
significant adverse reactions in the short term or adverse outcomes in
the long term. Often, all of the potential risks related to drug
treatment during lactation are not known even though the benefits of
breastfeeding are known and substantial.
FDA declines the suggestion to include a standardized statement
that ``sufficient'' human data exist to indicate that the drug does or
does not adversely affect the breast-fed child, followed by a
supportive narrative. However, the final rule requires that if the drug
is absorbed systemically, the labeling must include, under ``Risk
Summary,'' available information, if relevant, on the known or
predicted effects on the breast-fed child from exposure to the drug
and/or its active metabolite(s), including systemic and/or local
adverse reactions. If the available information is sufficient to
determine that use of the drug is contraindicated during breastfeeding,
this significant information is required at the beginning of the ``Risk
Summary.'' The ``Risk Summary'' must state when there are no data to
assess the effects of the drug on the child.
FDA also revised the final rule to require that if studies
demonstrate the presence of the drug and/or its active metabolite(s) in
human milk but the drug and/or its active metabolite(s) are not
expected to be systemically bioavailable to the breast-fed child, then
the ``Risk Summary'' must describe the disposition of the drug and/or
its active metabolite(s). FDA added this requirement to the final rule
to identify situations in which a drug and/or its active metabolite(s)
are present in human milk but the breast-fed child does not have any
systemic exposure because of degradation in the gastrointestinal tract.
iii. Not systemically absorbed
FDA proposed that if data demonstrate that a drug is not
systemically absorbed, the fetal risk summary must contain only the
following statement: (Name of drug) is not absorbed systemically from
(part of body) and cannot be detected in the mother's blood. Therefore,
detectable amounts of (name of drug) will not be present in milk.
Breastfeeding is not expected to result in fetal exposure to the drug
(proposed Sec. 201.57(c)(9)(ii)(A)).
(Comment 72) One comment suggested that the statement be revised to
focus on the route of administration rather than on the part of the
body where the drug is administered. The comment also suggested that
the language ``cannot be detected in blood'' could be omitted because
it is redundant with ``not systemically absorbed.''
(Response) FDA agrees with this comment and we removed the phrase
``cannot be detected in blood'' from the final rule.
We also agree with the suggestion to focus on the route of
administration. FDA agrees that ``part of the body'' could be
misconstrued and we have determined that the use of ``route of
administration'' to describe how the drug enters the body is more
consistent with labeling language that addresses dosing and
administration. In the final rule, FDA has replaced ``part of the
body'' with ``route of administration.''
(Comment 73) Another comment suggested revising the language
``systemically absorbed'' to ``has a systemic effect'' to include the
action of biological products (vaccines) that are immune stimulants
rather than chemicals that are absorbed.
(Response) FDA declines the suggestion to change the language
``systemically absorbed'' to ``has a systemic effect.'' The terms
``systemically absorbed'' and ``absorbed systemically'' refer to the
absorption of the drug or biological product from its site of
administration into serum and/or other body tissues where the drug or
biological product, including a vaccine, can reach its receptor or
target cell and exert its pharmacological or immunological effect. A
drug or biological product that is not systemically absorbed will not
be excreted into human milk and, therefore, breastfeeding should not
result in the child's exposure to the drug. In the final rule, FDA has
deleted the sentence, ``Therefore, detectable amounts of (name of drug)
will not be present in breast milk.'' The final rule also replaces the
sentence, ``Breastfeeding is not expected to result in fetal exposure
to the drug'' with
[[Page 72091]]
``breastfeeding is not expected to result in exposure of the child to
(name of drug).''
(Comment 74) Two comments noted that the term ``fetal'' was used
improperly in this section of the proposed rule.
(Response) FDA agrees and has removed the term ``fetal'' from the
``Lactation'' subsection and replaced it with the term ``child.''
iv. Presence of drug in human milk
FDA proposed that under the heading ``Presence of drug in human
milk'':
(1) The risk summary must describe the presence of the drug in
human milk in one of the following ways: The drug is not detectable in
human milk; the drug has been detected in human milk; the drug is
predicted to be present in human milk; the drug is not predicted to be
present in human milk; or the data are insufficient to know or predict
whether the drug is present in human milk;
(2) If studies demonstrate that the drug is not detectable in human
milk, the risk summary must state the limits of the assay used; and
(3) If the drug has been detected in human milk, the risk summary
must give the concentration detected in milk in reference to a stated
maternal dose (or, if the drug has been labeled for pediatric use, in
reference to the labeled pediatric dose), an estimate of the amount of
the drug consumed daily by the infant based on an average daily milk
consumption of 150 milliliters per kilogram of infant weight per day,
and an estimate of the [percentage] of the maternal dose excreted in
human milk (proposed Sec. 201.57(c)(9)(ii)(A)(2)(i)-
(c)(9)(ii)(A)(2)(iii)). We received comments about this portion of the
``Lactation'' subsection of the proposed rule. The discussion that
follows addresses these comments, our responses, and the changes FDA
made to this portion of the ``Lactation'' subsection of the final rule.
(Comment 75) Predicting whether drug is present in human milk.
Several comments objected to the proposal that the ``Risk Summary''
state that the drug is ``predicted'' or ``not predicted'' to be present
in human milk. One of these comments stated that avoiding predictions
and relying instead on clinical data would better assist providers. Two
comments suggested that the statements about whether the drug is
predicted or not predicted to be present in human milk should be
omitted because the other proposed descriptions effectively cover the
range of potential options.
(Response) FDA agrees that the terms ``predicted'' and ``not
predicted'' should not be used in the ``Risk Summary,'' and that a
description of available data, if relevant, on the presence of the drug
and/or its active metabolite(s) in human milk should be used instead.
In addition, FDA has determined that, in order to provide clarity in
the ``Risk Summary,'' in situations where there are no data to assess
whether the drug and/or its active metabolite(s) are present in human
milk, the ``Risk Summary'' must so state.
(Comment 76) Limits of the assay used. Two comments suggested
omitting assay information if the presence of drug in milk is not
detectable. The comments stated that assay information is overly
technical and unfamiliar for many health care providers. In addition,
the comments explained that it would be presumed that during its review
of the data, the review division at FDA would consider the validity of
studies, including the assay's reliability and sensitivity, before
approving the inclusion in labeling of a statement that the drug is not
detectable in human milk.
(Response) FDA declines this comment. We have determined that the
limit of the assay is critical to understanding the amount of the drug
and/or its active metabolite(s) that may or may not be present in human
milk. We also believe that most health care providers are capable of
interpreting this data when presented in labeling and that health care
providers are familiar with the importance of assay limits for all
types of laboratory testing. In the final rule, FDA has retained the
requirement from the proposed rule that if studies demonstrate that the
drug and/or its active metabolite(s) are not detectable in human milk,
the ``Risk Summary'' must state the limits of the assay used.
(Comment 77) Concentration of the drug detected in human milk. Two
comments expressed support for FDA's proposal that the ``Lactation''
subsection of prescription drug labeling provide the concentration of
the drug detected in human milk in reference to a stated adult or
labeled pediatric dose. One of these comments suggested that the
labeling should also include the milligrams per kilogram received per
day and the percentage of the weight-equivalent therapeutic dose
administered to the mother. This comment requested that the doses be
presented according to infant age ranges when possible. A separate
comment suggested providing a calculation of the estimated infant daily
dose consumed as compared to available pediatric dosing rather than to
maternal dosing, but added that clinicians may have difficulty
interpreting the calculations.
One comment stated that the concentration of the drug detected in
milk should not be made in reference to the maternal dose or the
labeled pediatric dose. The comment explained that the concentration of
a drug in milk may vary widely depending upon whether it reflects
steady-state or a single dose, and could vary based on the timing
between the ingestion of the drug and taking the sample. The comment
suggested that an estimate of the amount of the drug consumed daily by
the infant could be made in reference to the maximum maternal daily
dose or the maximum labeled pediatric dose and that ``an estimate of
the [percentage] of the maternal dose excreted in human milk'' could be
omitted.
One comment suggested that FDA standardize the approach to
presenting drug concentrations in breast milk and stated that this
would ensure that uniform data are presented by all manufacturers,
allowing for easy comparisons between prescription products. The
comment also suggested that FDA provide a guidance document
highlighting the value of breast milk area under the curve (AUC)
concentrations, explaining that providing standardized ways of
calculating weight-normalized drug doses and average breast milk
consumption could better guide manufacturers and help create a unified
approach to describing drug concentrations in breast milk.
(Response) FDA addresses these issues in the draft guidance for
industry on ``Clinical Lactation Studies--Study Design, Data Analysis,
and Recommendations for Labeling'' (February 2005) (the draft guidance
on clinical lactation studies).
FDA agrees that it would be helpful to clinicians to provide infant
drug exposure dosing in milligrams per kilograms received per day so
that a clinician may compare it to a labeled infant or pediatric dose
if available. However, because of the technical considerations for
calculating drug and/or active metabolite levels in milk, FDA is not
requiring this in the final rule.
FDA has determined that the actual or calculated infant daily dose
must be compared to the labeled infant or pediatric dose, when
available, and to the maternal dose when pediatric dosing is not
available. When infant or pediatric dosing is available for a drug and
pediatric pharmacokinetic data are available for a drug and/or its
active metabolite(s), these data provide an effective way to estimate
comparative exposure (and potentially comparative
[[Page 72092]]
safety) of a breast-fed child versus a child receiving a drug
therapeutically.
Although not required by the final rule, FDA agrees that data
presented according to infant age groups could be useful given the
changes in infant hepatic and renal function during the first few
months of life, and infants' increasing ability with age to metabolize
and clear drugs and/or their active metabolites. These data may not
always be available, but when they are, their presentation stratified
by age would be clinically relevant and should be included in labeling.
(Comment 78) ``No data.'' One comment suggested removing the phrase
``no data'' from the ``Risk Summary'' in the ``Lactation'' subsection,
because there are rarely no data for a drug.
(Response) FDA disagrees with the suggestion to remove the phrase
``no data'' from the ``Risk Summary.'' Often, there are no lactation
data (either human or animal) at the time of approval of NDAs and BLAs.
v. Effects on milk production and quality
FDA proposed that if the drug is absorbed systemically, the risk
summary must describe the effect of the drug on the quality and
quantity of milk, including milk composition, and the implications of
these changes to the milk on the breast-fed child (proposed Sec.
201.57(c)(9)(ii)(A)(1)).
(Comment 79) Several comments stated that it is seldom feasible to
adequately study the effects of a drug on the quality and quantity of
breast milk, and this information should only be provided when
available. One comment explained that to be scientifically valid, such
evaluation requires a study before, during, and after drug exposure.
This comment explained that further complicating factors are
substantial inter- and intra-individual variation and small study
sample size.
One comment requested that FDA include information about the
effects of the drug on the woman's milk supply and other issues that
affect the process of breastfeeding. The comment stated that many women
are advised against taking medications that affect milk supply while
lactating but are not informed that this is the reason they should
avoid these medications.
(Response) Although FDA agrees that it is not always possible to
determine the effects of a drug and/or its active metabolite(s) on milk
production, we have determined that when the relevant data are
available, this information must be included in the labeling. In the
final rule, FDA requires that the ``Risk Summary'' describe the effects
of the drug and/or its active metabolite(s) on milk production, and if
there are no data to assess the effects of the drug and/or its active
metabolite(s) on milk production, the ``Risk Summary'' must so state.
With respect to milk quality and composition, there are currently
no established standards or documented population variability for milk
content. It is also not known how much change in various milk
components would reduce the known benefits of breastfeeding relative to
the risks of exposure to a drug and/or its active metabolite(s) through
breast milk combined with any potential effects on milk composition and
quality. Accordingly, in the final rule, FDA has removed the
requirement that the ``Risk Summary'' describe the effect of the drug
on the quality and composition of milk, and the implications of these
changes to the milk on the breast-fed child.
vi. Sufficient Data
(Comment 80) One comment noted that the proposed rule does not
require sufficient data to reach conclusions in the ``Risk Summary'' in
the ``Lactation'' subsection, and suggested that FDA discuss what
constitutes sufficient data, as it does in the ``Pregnancy''
subsection.
(Response) As discussed previously, many comments disagreed with
FDA's proposed use of the term ``sufficient'' in the ``Pregnancy''
subsection of labeling. The comments stated that the term was not
clearly defined in the proposed rule, and suggested that it would be
difficult to apply the term consistently across drug labeling. Based on
FDA's consideration of these comments, the final rule does not refer to
``sufficient'' data in either the ``Pregnancy'' or the ``Lactation''
subsection.
vii. Risk and Benefit Statement
(Comment 81) FDA received seven comments noting that the proposed
``Lactation'' subsection did not require the inclusion in labeling of
any information about the benefits of breastfeeding. Some of these
comments recommended that FDA add such a statement to the final rule to
prevent patients from unnecessarily foregoing or discontinuing
breastfeeding.
(Response) FDA acknowledges that the proposed rule did not require
the inclusion of information about the benefits of breastfeeding. The
Agency has determined that the inclusion in the ``Lactation''
subsection of labeling of a risk and benefit statement will provide a
useful framework for health care providers to use when making
prescribing decisions for lactating patients. In the final rule, FDA
requires that for drugs absorbed systemically, unless breastfeeding is
contraindicated during drug therapy, a statement that the developmental
and health benefits of breastfeeding should be considered along with
the mother's clinical need for the drug and any potential adverse
effects on the breast-fed child from the drug or from the underlying
maternal condition, must be included at the end of the ``Risk Summary''
in the ``Lactation'' subsection of labeling.
c. Clinical Considerations
FDA proposed that under the subheading ``Clinical Considerations,''
the labeling must provide the following information to the extent it is
available: (1) Information concerning ways to minimize the exposure of
the breast-fed child to the drug, such as timing the dose relative to
breastfeeding or pumping and discarding milk for a specified period;
(2) information about potential drug effects in the breast-fed child
that could be useful to caregivers, including recommendations for
monitoring or responding to these effects; and (3) information about
dosing adjustments during lactation. This information must also be
included in the `Dosage and Administration' and `Clinical Pharmacology'
sections (proposed Sec. 201.57(c)(9)(ii)(B)(1)-(c)(9)(ii)(B)(3)). FDA
received comments about the proposed ``Clinical Considerations''
subheading. The discussion that follows addresses these comments, our
responses, and FDA's changes to the final rule.
i. Other Therapies
In the Proposed rule, FDA included sample labeling for several
fictitious drugs. In the ``Clinical Considerations'' portion of the
``Lactation'' subsection, the ALPHAZINE sample stated that ``Other
medical therapies are available for treatment of maternal
hypertension.''
(Comment 82) Two comments disagreed with the inclusion of this
statement. The comments explained that the statement is confusing
because although no comparator data are presented, clinicians may infer
that other drugs in the class are safe and effective.
(Response) We note that the language to which these comments refer
was included in sample labeling included with the proposed rule, and
not in the proposed rule itself. FDA included sample labeling with the
proposed rule to serve as examples of how to apply the requirements of
the proposed rule in different scenarios. We note that the final rule
does not include sample labeling. FDA agrees, however, that
[[Page 72093]]
statements such as, ``Other medical therapies are available for
treatment of maternal hypertension,'' may be confusing, and should not
be included in the ``Pregnancy'' or ``Lactation'' subsections of
labeling.
ii. Minimizing Exposure to the Breast-Fed Child
(Comment 83) General comments. Four comments disagreed with the
proposal to include information regarding minimizing exposure of the
breast-fed child in the ``Clinical Considerations'' portion of the
``Lactation'' subsection. These comments explained that inclusion of
this information could discourage women from breastfeeding even when
there is no reason for concern. One comment noted that this information
should only be included when there is information that breastfeeding
should be withheld during drug therapy and the timing of pumping and
discarding of breast milk can be provided. Alternatively, the comment
suggested stating when information regarding the timing of pumping and
discarding breast milk cannot be provided. Another comment noted that
this information should not be obligatory when data suggest that there
is not sufficient excretion of the drug in milk to cause concern for
the infant. The comment explained that including this information when
the ``Risk Summary'' and ``Data'' components have already stated that
the drug is compatible with breastfeeding could give the false
impression that the drug is unsafe for the child and may encourage
women to discontinue breastfeeding. One comment noted that in cases
when the drug disappears from breast milk with a known half-life, it is
possible to minimize infant exposure by recommending dosing occur at
certain times related to feeding.
(Response) FDA notes that information concerning minimizing
exposure to the breast-fed child must be provided only to the extent it
is available and relevant. In addition, the final rule was revised to
clarify that information concerning minimizing drug exposure in the
breast-fed child must be included only if the drug and/or its active
metabolite(s) are present in human milk in clinically relevant
concentrations; the drug does not have an established safety profile in
infants; and the drug is used either intermittently, in single doses,
or for short courses of therapy. As discussed further in our response
to Comment 84, the final rule also requires that, when applicable, the
labeling describe ways to minimize a breast-fed child's oral intake of
topical drugs applied to the breast or nipple skin.
(Comment 84) Topical products. In the proposed rule, FDA did not
provide for inclusion of data regarding topical drugs that are not
absorbed systemically by the mother but that may transfer to infants
during breastfeeding. One comment requested that FDA include a
standardized statement in the ``Risk Summary'' about such drug
products.
(Response) Situations in which a topical pharmaceutical product can
result in infant exposure without systemic absorption of the product
into maternal serum are limited to topicals applied to the skin of the
breast, especially that of the nipple and areola. For prescription drug
products, these topicals would most likely include corticosteroids and
anti-infectives. FDA acknowledges that the proposed rule did not
accommodate a situation in which a drug product does not result in
maternal systemic exposure but could result in infant systemic
exposure. In response to this comment, FDA revised the ``Minimizing
exposure'' portion of ``Clinical Considerations'' to accommodate the
inclusion of information about such products. In the final rule, FDA
added a requirement that, when applicable, the labeling must also
describe ways to minimize a breast-fed child's oral intake of topical
drugs applied to the breast or nipple skin.
iii. Drug Effects in the Breast-Fed Child and Monitoring for Adverse
Reactions
FDA proposed that the ``Clinical Considerations'' portion of the
``Lactation'' subsection of prescription drug labeling include
information about potential drug effects in the breast-fed child that
could be useful to caregivers, including recommendations for monitoring
or responding to these effects (proposed Sec. 201.57(c)(9)(ii)(B)(2)).
(Comment 85) FDA received one comment about this portion of the
proposed ``Clinical Considerations.'' The comment suggested that FDA
omit the first part of this provision--''information about potential
drug effects in the breast-fed child''--because this information
duplicates the information required to appear in the ``Risk Summary''
under proposed Sec. 201.57(c)(9)(ii)(A)(3), ``Effects of drug on the
breast-fed child.'' The comment also stated that the term
``recommendations'' in the second part of this provision could
interfere with the practice of medicine. The comment suggested the
following language: ``Information about ways to monitor for, or respond
to, potential drug effects in the breast-fed child that could be useful
to caregivers.''
(Response) FDA acknowledges that this portion of the proposed rule
appeared to require information duplicative of information in the
``Risk Summary.'' We removed the language, ``information about
potential drug effects in the breast-fed child,'' from the ``Clinical
Considerations'' portion of the ``Lactation'' subsection of the final
rule. In the final rule, when relevant information is available about
potential adverse effects in an infant due to exposure to the maternal
drug and/or its active metabolite(s) through human milk, this
information must be included in the ``Risk Summary.'' FDA also
concluded that it was not necessary to characterize information about
the potential effects of a drug and/or its active metabolite(s) on a
breast-fed child as being useful to caregivers because, although
caregivers sometimes read prescription drug labeling, it is not
directed at them, and individual health care providers are in the best
position to discuss with their patients information that may be useful
for the patients to share with other caregivers. Therefore, the
reference to information that may be useful to caregivers also has been
removed.
FDA acknowledges the comment concerning the use of the term
``recommendations'' in the second part of this provision, and in the
final rule has removed the term ``recommendations for monitoring'' and
replaced it with ``available interventions for monitoring or
mitigating.'' The final rule requires that under ``Clinical
Considerations'' the labeling describe information about available
interventions for monitoring or mitigating the adverse reactions
described in the ``Risk Summary.'' We note that this language is
consistent with the language in the ``Pregnancy'' subsection.
iv. Dose Adjustments
(Comment 86) One comment stated that dose adjustment information
should not be included in the ``Lactation'' subsection. The comment
suggested that dosing information generally should be restricted to the
``Dosage and Administration'' section of labeling.
(Response) FDA agrees with the suggestion that we omit information
about dose adjustments from the ``Lactation'' subsection of
prescription drug labeling, although this decision is not based on a
conclusion (as suggested in the comment) that dosing information
generally should be restricted to the ``Dosage and Administration''
section of
[[Page 72094]]
labeling. FDA has determined that other than during the immediate
postpartum period when a woman's physiology is reverting from a
pregnant to a nonpregnant state, a lactating woman is unlikely to
require dose adjustments for drugs. The physiological changes
associated with lactation are unlikely to result in pharmacokinetic
changes significant enough to warrant maternal dose adjustments.
Therefore, FDA has determined that all available and relevant
information about dose adjustments during pregnancy and the postpartum
period must be included in the ``Pregnancy'' subsection of labeling. In
the final rule, FDA has removed the requirement that information about
dosing adjustments during lactation be included in the ``Lactation''
subsection of labeling.
d. Data
FDA proposed that under the subheading `Data,' the `Lactation'
subsection of the labeling must provide an overview of the data that
are the basis for the risk summary and clinical considerations
(proposed Sec. 201.57(c)(9)(ii)(C)). FDA received comments about this
portion of the rule. One comment expressed support for presenting
lactation data under ``Data'' when available. The other comments and
changes we made in response to those comments are explained in this
section of the document.
(Comment 87) FDA received comments requesting that the Agency
clarify when animal lactation data should be included in labeling.
Several comments questioned the usefulness of animal lactation data in
the absence of clinical data. One comment stated that extrapolation of
animal data to humans may not be helpful without stating what is known
about the correlation to humans.
Several comments stated that only human data should be presented
when it is available. Two comments requested that if, in cases where
both human and animal data are available, FDA decides to retain the
requirement that both kinds of data be presented, the ``Lactation''
subsection be revised to state that clinical data are to be presented
before preclinical data.
One comment requested additional clarification regarding the
quantity and quality of animal data that would support inclusion of the
data in labeling, and asked that FDA provide sample labeling for a drug
for which only animal lactation data are available. Another comment
suggested that the labeling state when there is an absence of available
or sufficient human and/or animal data in the ``Lactation'' subsection.
(Response) The preamble to the proposed rule did not include a
discussion of animal lactation data, and the inclusion of animal
lactation data was not addressed in the codified section of the
proposed rule. In the final rule, under ``Risk Summary,'' FDA defines
situations for which animal lactation data must and must not be
included in the ``Lactation'' subsection. Animal lactation data can be
helpful in predicting whether a drug and/or its active metabolite(s)
will be present in human milk; however, because of species-specific
differences in lactation physiology, animal lactation data typically do
not reliably predict drug levels in human milk. FDA added a requirement
to the final rule that when relevant human lactation data are
available, animal data must not be included unless the animal model is
specifically known to be predictive for humans. In addition, under
``Risk Summary,'' ``Presence of drug in human milk,'' FDA clarified
that if only animal lactation data are available, the ``Risk Summary''
must state only whether or not the drug and/or its active metabolite(s)
were detected in animal milk and specify the animal species. Although
animal data do not reliably predict whether a drug and/or its active
metabolite(s) will be present in human milk, in the absence of human
data, FDA determined that the fact that a drug and/or its active
metabolite(s) were or were not detected in animal milk may nevertheless
be useful in informing prescribing decisions.
In the final rule, FDA revised the ``Data'' portion of the
``Lactation'' subsection to require that the labeling ``describe the
data that are the basis for the Risk Summary and Clinical
Considerations'' and removed the requirement that the labeling
``provide an overview of the data.'' FDA made this change to clarify
that under ``Data,'' the labeling must include a more detailed
description of the data than might be understood from use of the term
``overview,'' as well as to maintain consistency between the ``Data''
portions of the ``Lactation'' and ``Pregnancy'' subsections.
Furthermore, this subheading is only required to the extent that there
are data that are the basis for the Risk Summary and Clinical
Considerations subheadings, and the headings under them.
3. 8.3 Females and Males of Reproductive Potential
In the final rule, FDA is adding a requirement that information
regarding pregnancy testing, contraception, and infertility be
relocated in labeling under subsection ``8.3 Females and Males of
Reproductive Potential.'' FDA is adding this requirement to the final
rule based on public comments regarding these issues, and based on the
Agency's conclusion that this information should be presented in
labeling in a consistent location. Subsection ``8.3 Females and Males
of Reproductive Potential'' includes three subheadings, ``Pregnancy
Testing,'' ``Contraception,'' and ``Infertility.'' Each subheading
should only be included if it is applicable or if relevant information
is available, and Section 8.3 should be omitted in its entirety if none
of the subheadings are applicable. The comments are discussed in detail
in our responses to Comments 88, 89, and 90.
Information concerning pregnancy testing, contraception, and
infertility is important for informing decisions made by patients, in
consultation with their health care providers, regarding the use of
prescription drugs before or during pregnancy. This information is in
many ways inherently linked to the scientific and medical rationale
underpinning the Pregnancy subsection of prescription drug labeling.
However, in the course of developing this final rule, and in particular
in evaluating comments 88, 89, and 90, FDA concluded that because there
was no consistent placement in the labeling of information about
pregnancy testing, contraception, and infertility, it was difficult for
health care providers to find this important information. For example,
clinical advice on infertility might be found with the discussion of
animal data in the ``Nonclinical Toxicology'' section, in the ``Adverse
Reactions'' section, or in the ``Warnings and Precautions'' section.
Contraception and pregnancy testing recommendations for known or
suspected teratogens might be found in the ``Pregnancy'' subsection or
in the ``Warnings and Precautions'' section.
(Comment 88) FDA received one comment suggesting that the new
labeling explicitly state that a woman taking drugs with potential or
known adverse effects on pregnancy outcomes should (1) consider using
reliable contraception if she does not intend to become pregnant or (2)
if she does intend to become pregnant, seek consultation with her
health care provider to discuss medical management of her health
condition before becoming pregnant, if possible.
(Response) FDA agrees that when a drug has a potential or known
adverse effect on pregnancy outcomes (e.g., is a known or suspected
human teratogen), information regarding recommendations or requirements
regarding contraception
[[Page 72095]]
use must be included in prescription drug labeling. In the final rule,
FDA requires that when contraception is required or recommended before,
during, or after drug therapy, this information must be included under
the subheading ``Contraception'' in subsection ``8.3 Females and Males
of Reproductive Potential.'' In addition, it may be appropriate to
include in this subsection information concerning counseling females of
reproductive potential about pregnancy planning.
Furthermore, the concerns expressed in the comment regarding the
inclusion of information about contraception use when taking a drug
with potential or known adverse effects on pregnancy outcomes apply
equally to information about pregnancy testing, particularly when a
drug is a known or suspected human teratogen. Therefore, FDA has
determined that information regarding recommendations or requirements
concerning pregnancy testing before, during, or after drug therapy must
also be included in prescription drug labeling. In the final rule, FDA
requires that this information be included under the subheading
``Pregnancy Testing'' in subsection ``8.3 Females and Males of
Reproductive Potential.''
(Comment 89) FDA received three comments noting that the
``Pregnancy'' subsection of the proposed rule only addresses risks to
the fetus when the drug is administered to a pregnant woman, and it
does not address the potential for manifestations of developmental
toxicity associated with fetal drug exposure from transfer of drug
through semen to the maternal and fetal circulations. One of the three
comments noted that the proposed rule does not address the potential
for manifestations of developmental toxicity associated with exposure
resulting from transfer through the semen or the need for male
contraception when a compound is determined to have a predicted risk of
developmental toxicity and the transfer of semen is unknown. This
comment suggested that statements addressing this issue be added when
the information is required for the product. One of the comments
suggested that FDA add a section to the final rule that addresses
prescribing information for male patients with a partner of
reproductive potential or a pregnant partner. Another comment suggested
that the risk conclusion statement specify whether it is based on
maternal or paternal exposure when that information is available.
(Response) FDA agrees that when relevant information is available,
this information should be included in labeling. In the final rule, FDA
requires that information about recommended or required use of
contraception by men be included under the subheading ``Contraception''
in subsection ``8.3 Females and Males of Reproductive Potential.''
(Comment 90) FDA received one comment requesting that the Agency
clarify how and when animal data described in subsection 13.1 of
labeling (``Carcinogenesis, Mutagenesis, Impairment of Fertility'')
that raises concerns about mutagenesis, impairment of fertility, or
pre-implantation loss should be included in subsection ``8.1
Pregnancy.'' The comment also requested that FDA clarify when it would
be appropriate to move information from subsection 13.1 to subsection
8.1 or to cross-reference subsection 13.1 in subsection 8.1.
(Response) As stated previously, FDA concluded that it is important
to include information about drug-associated fertility effects in
labeling in a consistent location and manner. In the final rule, animal
data that raise concerns about drug-associated impairment of fertility
and/or pre-implantation loss effects must be included under
``Infertility'' in subsection ``8.3. Females and Males of Reproductive
Potential.'' In addition, when there are contraception recommendations
based on animal mutagenesis data, this information must be included in
subsection 8.3 under the Contraception subheading. Because the same
concerns about drug-associated fertility effects apply to human data,
FDA has determined that human data that raise such concerns also must
be included in the ``Infertility'' subsection. With respect to the
question about cross-referencing, subsection 8.3 should cross-reference
the applicable animal data included in subsection 13.1, consistent with
FDA's cross-referencing regulations (e.g., Sec. 201.57(c)(1),
(c)(6)(iv), and (c)(15)(ii)). The draft guidance on pregnancy and
lactation labeling, which is being published concurrently with this
final rule, addresses these issues.
IV. Implementation
FDA proposed that holders of applications (including an NDA, BLA,
or efficacy supplement) approved before June 30, 2001, would be
required to remove the pregnancy category from their labeling within 3
years after the effective date of this rule. These applications are
those that are not subject to the requirements of the PLR. For drugs
with applications (including an NDA, BLA, or efficacy supplement)
approved on or after June 30, 2001, FDA proposed a phased-in
implementation plan that would stagger the required dates these
products would be required to replace the content and formatting of the
pregnancy and lactation subsections of their labeling with the new
content and formatting required by this rule. These applications are
those that are subject to the requirements of the PLR.
Table 1 contains the implementation plan that was included in the
proposed rule. In table 1, ``Applications'' includes NDAs, BLAs, and
efficacy supplements.
Table 1--Implementation Plan
------------------------------------------------------------------------
Time by which labeling with new
Applications required to conform to new pregnancy/lactation content
pregnancy/lactation content must be submitted to FDA for
requirements approval
------------------------------------------------------------------------
New or Pending Applications
------------------------------------------------------------------------
Applications submitted on or after the Time of submission.
effective date of the pregnancy final
rule.
Applications pending on the effective 4 years after the effective
date of the pregnancy final rule. date of pregnancy final rule
or at time of approval,
whichever is later.
------------------------------------------------------------------------
Approved Applications Subject to the Physician Labeling Rule
------------------------------------------------------------------------
Applications approved any time from 3 years after the effective
June 30, 2001, up to and including date of pregnancy final rule.
June 29, 2002, and from June 30, 2005,
up to and including June 29, 2007.
Applications approved any time from 4 years after the effective
June 30, 2007, up to and including the date of pregnancy final rule.
effective date of the pregnancy final
rule.
[[Page 72096]]
Applications approved from June 30, 5 years after the effective
2002, up to and including June 29, date of pregnancy final rule.
2005.
------------------------------------------------------------------------
(Comment 91) Two comments stated that the proposed implementation
plan was confusing. One of these comments requested that FDA explain
the rationale supporting the implementation schedule. Another comment
stated the proposed phased-in approach for previously approved drugs
may generate confusion. The comment explained that if drug labeling
information and drug reference materials contain pregnancy information
that is inconsistent between newly approved and previously approved
drugs through a 3- to 5-year period, confusion may limit the
understanding of the new labeling.
Comments disagreed about whether the length of the implementation
schedule was reasonable. One comment stated that the long
implementation timeline will delay the delivery of complete
information. Another comment stated that FDA should expedite the
implementation schedule for licensed drugs that are necessary to
maintain the health status of the mother and could harm the fetus if
the mother is left untreated. This comment also suggested that the
Agency should make supplemental information available in advance of the
printed label. Another comment, however, expressed support for the
proposal to give sponsors 3 years after the effective date of the rule
to remove the pregnancy categories.
(Response) The Agency has taken all of these comments into
consideration, and has decided to maintain the implementation schedule
that was published in the proposed rule. The implementation schedule
follows the timetable used for implementation of the PLR and works to
balance the anticipated workload for the review of labels. The purpose
of having a staggered approach is to avoid overburdening both the
Agency and industry. The implementation plan for the final rule (also
referred to as the Pregnancy and Lactation Labeling Rule (PLLR)) is
modeled from the implementation plan for the PLR and experience
acquired from that plan. The PLLR implementation timeline also depends
on the PLR implementation and the extent to which applications are
subject to the PLR.
(Comment 92) One comment expressed concern that under the proposed
implementation schedule, the pregnancy categories will be removed from
the labeling for some drugs before the new content required by the rule
will be added to the labeling, and this could cause confusion among
doctors and patients.
(Response) We would like to clarify that a holder of an application
that is not subject to the PLR, and thus, not subject to the new
content and format requirements of this final rule, must remove the
pregnancy category from its labeling within 3 years after the effective
date of this rule. A holder of an application that is subject to the
PLR and thus, subject to the new content and format requirements of
this rule, is not required to remove the pregnancy category until such
time that it is required to submit revised labeling with the new
content and format, even if that occurs more than 3 years after the
effective date of the final rule. FDA did not intend to suggest that
application holders of previously approved applications subject to the
PLR might, in some circumstances, be required to revise labeling twice
as a part of implementation. Therefore, if a holder of an application
is subject to the PLR, FDA does not anticipate that the pregnancy
category will be removed from the labeling prior to submitting the
revised labeling with the new content and format for that product under
the PLLR implementation schedule. In conjunction with the publication
of the final rule, the Agency is planning to launch an education
campaign for all stakeholders, including health care providers and
professional organizations, to ensure that they are well informed about
the changes.
V. Legal Authority
A. Statutory Authority
FDA is revising its regulations on the format and content of the
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers''
subsections of the ``Use in Specific Populations'' section (under Sec.
201.57) and the ``Precautions'' section (under Sec. 201.80) of the
labeling for human prescription drugs (in addition to the list of
headings and subheadings under Sec. 201.56(d)(1)).
FDA's revisions to the content and format requirements for
prescription drug labeling are authorized by the FD&C Act and by the
PHS Act. Section 502(a) of the FD&C Act deems a drug to be misbranded
if its labeling is false or misleading ``in any particular.'' Under
section 201(n) of the FD&C Act (21 U.S.C. 321(n)), labeling is
misleading if it fails to reveal facts that are material with respect
to consequences that may result from the use of the drug under the
conditions of use prescribed in the labeling or under customary or
usual conditions of use. Section 502(f) of the FD&C Act deems a drug to
be misbranded if its labeling lacks adequate directions for use and
adequate warnings against use in those pathological conditions where
its use may be dangerous to health, as well as adequate warnings
against unsafe dosage or methods or duration of administration or
application, in such manner and form, as are necessary for the
protection of users. Section 502(j) of the FD&C Act deems a drug to be
misbranded if it is dangerous to health when used in the dosage or
manner, or with the frequency or duration, prescribed, recommended, or
suggested in its labeling.
In addition, the premarket approval provisions of the FD&C Act
authorize FDA to require that prescription drug labeling provide the
practitioner with adequate information to permit safe and effective use
of the drug product. Under section 505 of the FD&C Act, FDA will
approve an NDA only if the drug is shown to be both safe and effective
for use under the conditions set forth in the drug's labeling. Section
701(a) of the FD&C Act (21 U.S.C. 371(a)) authorizes FDA to issue
regulations for the efficient enforcement of the FD&C Act.
Under 21 CFR 314.125, FDA will not approve an NDA unless, among
other things, there is adequate safety and effectiveness information
for the labeled uses and the product labeling complies with the
requirements of part 201. Under Sec. 201.100(d) of FDA's regulations,
a prescription drug product must bear labeling that contains adequate
information under which licensed practitioners can use the drug safely
for their intended uses. This final rule amends the regulations
specifying the format and content for such labeling.
Section 351 of the PHS Act (42 U.S.C. 262) provides legal authority
for the Agency to regulate the labeling and
[[Page 72097]]
shipment of biological products. Licenses for biological products are
to be issued only upon a showing that they meet standards ``designed to
insure the continued safety, purity, and potency of such products''
prescribed in regulations (section 351(d) of the PHS Act). The
``potency'' of a biological product includes its effectiveness (21 CFR
600.3(s)). Section 351(b) of the PHS Act prohibits false labeling of a
biological product. FDA's regulations in part 201 apply to all
prescription drug products, including biological products.
B. First Amendment
FDA's requirements for the content and format of the ``Pregnancy''
and ``Lactation'' subsections of labeling for prescription drug
products are constitutionally permissible because they are reasonably
related to the government's interest in ensuring the safe and effective
use of prescription drug products and because they do not impose
unjustified or unduly burdensome disclosure requirements. In the PLR,
FDA explained in greater depth why that rule passes muster under the
First Amendment (see 71 FR 3922 at 3964, January 24, 2006). That
analysis is equally applicable to this final rule, and we hereby adopt
that discussion by reference.
VI. Environmental Impact
The Agency has determined under 21 CFR 25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VII. Summary of Final Regulatory Impact Analysis
A. Introduction
FDA has examined the impacts of the final rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Public
Law 104-4). Executive Orders 12866 and 13563 direct Agencies to assess
all costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The Agency believes that this final rule is not a significant
regulatory action under Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because our analysis suggests that some small
prescription drug manufacturers and prescription drug repackagers and
relabelers will incur costs that total more than 1 percent of their
annual income in some years, the Agency finds that the final rule will
have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $141 million, using the most current (2013) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
The first regulations on the content and format of prescription
drug labeling were established in 1979, including the requirement to
assign drugs to one of five pregnancy categories. Over time, however,
labeling became long, repetitive, and difficult to use. With the PLR in
2006, the Agency began to apply modern principles of effective
communication to improve the quality of prescription drug labeling.
However, the PLR left the content of the ``Pregnancy,'' ``Labor and
delivery,'' and ``Nursing mothers'' subsections of the ``Use in
Specific Populations'' section untouched. This decision gave the Agency
sufficient time to meet with experts and stakeholders to develop a
regulatory framework that encourages applicants to prepare content that
clearly communicates available information about prescription drug use
during pregnancy and lactation, and in females and males of
reproductive potential. With this final rule, the Agency specifically
addresses the content and format of these subsections.
B. Summary of Costs and Benefits
The final regulatory impact analysis of the final rule (Ref. 2) is
available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm. Table 2 presents a summary of the
annualized costs and benefits of the final rule over 10 years. With a 7
percent discount rate, annualized costs equal about $9.5 million; with
a 3 percent discount rate, annualized costs equal about $9.2 million.
The final rule will require that applicants comply with new
labeling content and format requirements for affected subsections for
prescription drug and biological product labeling subject to the PLR
under Sec. 201.57(c)(9) (PLR labeling) and will require that
applicants remove the pregnancy category from all prescription drug and
biological product labeling subject to Sec. 201.80(f)(6)(i) (non-PLR
labeling). The ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing
mothers'' subsections of the ``Use in Specific Populations'' section
will be replaced by the ``Pregnancy,'' ``Lactation,'' and ``Females and
Males of Reproductive Potential'' subsections. New information will be
required to summarize the key information needed by health care
providers treating females and males of reproductive potential. The
information in these subsections will be presented in a narrative,
following a standardized order and format with clear subheadings.
The primary objectives of the final rule are to improve labeling by
updating the content and format of these subsections of prescription
drug product labeling, and to remove the pregnancy category system. The
Agency concluded that following a standardized structure is essential
for effective communication. The final rule is needed to ensure that
these subsections contain the most up-to-date information available and
provide prescribers with clinically relevant data that they can use in
their decisionmaking processes. Consistent with the approach taken by
the PLR, the Agency intends to provide applicants with clear guidance
about the required content and format. Concurrent with the publication
of this final rule, FDA is issuing a draft guidance for industry on
``Pregnancy, Lactation, and Reproductive Potential: Labeling for Human
Prescription Drug and Biological Products--Content and Format.''
The level of effort needed to comply with the requirements of the
final rule will depend on the type of labeling (PLR or non-PLR
labeling) and the length of time the product has been marketed.
Applicants and persons responsible for existing prescription drug and
biological product labeling will incur one-time costs to revise
existing labeling in years 3, 4, and 5. Applicants submitting new BLAs,
NDAs, and certain efficacy supplements will incur one-time costs to
gather and organize new content required by the final rule at the time
they prepare labeling for the application or supplement. In addition,
we estimate the additional annual printing costs for
[[Page 72098]]
longer PLR labeling that will include new content.
We estimate that the total cost of the rule over 10 years will
equal about $88.7 million. The present value of the total costs will
equal $78.2 million with a 3 percent discount rate and $66.8 million
with a 7 percent discount rate. Over 10 years, the annualized present
value will equal $9.2 million with a 3 percent discount rate and $9.5
million with a 7 percent discount rate.
Table 2--Economic Data: Costs and Benefits Accounting Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------------------
Category Primary Low estimate High estimate Period Notes
estimate Year dollars Discount rate covered
(percent) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized.......................... .............. .............. .............. .............. 7 .............. ..............
Monetized $millions/year............ .............. .............. .............. .............. 3 .............. ..............
Annualized.......................... .............. .............. .............. .............. 7 .............. ..............
Quantified.......................... .............. .............. .............. .............. 3 .............. ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qualitative......................... Improved quality of prescription drug labeling
for health care providers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
Annualized.......................... $9.5 .............. .............. 2011 7 10 ..............
Monetized $millions/year............ 9.2 .............. .............. 2011 3 10 ..............
Annualized.......................... .............. .............. .............. .............. 7 .............. ..............
Quantified.......................... .............. .............. .............. .............. 3 .............. ..............
Qualitative......................... .............. .............. .............. .............. .............. .............. ..............
Transfers:
Federal Annualized.................. .............. .............. .............. .............. 7 .............. ..............
Monetized $millions/year............ .............. .............. .............. .............. 3 .............. ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To: From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Other Annualized.................... .............. .............. .............. .............. 7 .............. ..............
Monetized $millions/year............ .............. .............. .............. .............. 3 .............. ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To: From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
--------------------------------------------------------------------------------------------------------------------------------------------------------
State, Local or Tribal Government: No effect
--------------------------------------------------------------------------------------------------------------------------------------------------------
Small Business: The final rule will have significant impacts on some small pharmaceutical manufacturers and prescription drug
repackagers and relabelers.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Wages: No effect
--------------------------------------------------------------------------------------------------------------------------------------------------------
Growth: No effect
--------------------------------------------------------------------------------------------------------------------------------------------------------
VIII. Paperwork Reduction Act of 1995
This final rule contains information collection requirements that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the
information collection provisions are shown in the following paragraphs
with an estimate of the total reporting and disclosure burdens.
Included in the estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
Title: Content and Format of Labeling for Human Prescription Drug
and Biological Products; Requirements for Pregnancy and Lactation
Labeling
Description: The final rule amends FDA regulations concerning the
content and format of the ``Pregnancy,'' ``Labor and delivery,'' and
``Nursing mothers'' subsections of the ``Use in Specific Populations''
section of the labeling for human prescription drugs. The final rule
requires that labeling include, among other things, a summary of the
risks of using a drug during pregnancy and lactation and a discussion
of the data supporting that summary. The labeling also includes
relevant information to help health care providers make prescribing
decisions and counsel women about the use of drugs during pregnancy and
lactation. The final rule eliminates the current pregnancy categories
A, B, C, D, and X. In addition, the ``Labor and delivery'' subsection
has been eliminated because information on labor and delivery is
included in the ``Pregnancy'' subsection. The final rule also requires
that the labeling include relevant information about pregnancy testing,
contraception, and infertility for health care providers prescribing
for females and males of reproductive potential. The final rule is
intended to create a consistent format for providing information about
the risks and benefits of prescription drug and/or biological product
use during
[[Page 72099]]
pregnancy and lactation and by females and males of reproductive
potential.
Under Sec. 201.57(c)(9)(i) and (c)(9)(ii), holders of approved
applications are required to provide new labeling content in a new
format--that is, to rewrite the pregnancy and lactation portions of
each drug's labeling. Under Sec. 201.57(c)(9)(iii), these application
holders are also required to include a new subsection 8.3, ``Females
and Males of Reproductive Potential,'' which requires that when
pregnancy testing or contraception is required or recommended before,
during, or after drug therapy or when there are human or animal data
that suggest drug-associated fertility effects, this subsection must
contain this information. These application holders are required to
submit supplements requiring prior approval by FDA before distribution
of the new labeling, as required in Sec. 314.70(b) or Sec.
601.12(f)(1).
Under Sec. 201.80(f)(6)(i), holders of approved applications are
required to remove the pregnancy category designation (e.g.,
``Pregnancy Category C'') from the ``Pregnancy'' subsection of the
``Precautions'' section of the labeling. These application holders must
report the labeling change in their annual reports, as required in
Sec. 314.70(d) or Sec. 601.12(f)(3).
The new content and format requirements of the final rule apply to
all applications that are required to comply with the PLR, including:
(1) Applications submitted on or after the effective date of the final
rule; (2) applications pending on the effective date of the final rule;
and (3) applications approved from June 30, 2001, to the effective date
of the final rule.
The following submissions under the final rule are subject to the
PRA:
Applications submitted on or after the effective date of
the final rule (Sec. Sec. 314.50, 314.70(b), 601.2, 601.12(f)(1));
Amendments to applications pending on the effective date
of the final rule (Sec. Sec. 314.60, 601.2, 601.12(f)(1));
Supplements to applications approved from June 30, 2001,
to the effective date of the final rule (Sec. Sec. 314.70(b),
601.12(f)(1));
Annual reports for applications approved before June 30,
2001, that contain a pregnancy category, to report removal of the
pregnancy category letter in their labeling (Sec. Sec. 314.70(d),
601.12(f)(3)).
The information collection requirements and burden estimates are
summarized in tables 3 and 4 of this document. The burden estimates are
based on data and timeframes used for section VII of this document
(Summary of Final Regulatory Impact Analysis) and for the final
regulatory impact analysis of the final rule (available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm). FDA estimates that approximately 4,000 applications
containing labeling consistent with this rulemaking will be submitted
to FDA during the 10-year period on or after the effective date of the
final rule by approximately 390 applicants and repackagers and
relabelers. The estimate of 4,000 applications includes labeling for
approximately 800 applications submitted under section 505(b) of the
FD&C Act or section 351 of the PHS Act, and 1,200 applications
submitted under section 505(j) of the FD&C Act, and revised labeling
from repackagers and relabelers for approximately 2,000 drug products.
This estimate also includes labeling amendments submitted to FDA for
applications pending on the effective date of the final rule. Based on
data provided in section VII of this document and in the final
regulatory impact analysis of the final rule, FDA estimates that for
future approvals it will take applicants approximately 40 hours to
prepare and submit labeling consistent with this rulemaking. The
estimate of 40 hours applies only to the requirements of this
rulemaking and does not indicate the total hours required to prepare
and submit complete labeling for these applications. The information
collection burden to prepare and submit labeling in accordance with
Sec. Sec. 201.56, 201.57, and 201.80 is approved by OMB under control
numbers 0910-0572 and 0910-0001.
In addition, FDA estimates that approximately 10,150 supplements to
applications approved from June 30, 2001, to the effective date of the
final rule, or pending on the effective date, will be submitted to FDA
during the third, fourth, and fifth years after the effective date to
update labeling in accordance with this final rule. This estimate
includes approximately 1,080 NDA, BLA, and efficacy supplements,
approximately 1,320 ANDA supplements, and labeling supplements from
repackagers and relabelers for approximately 7,750 drug products. FDA
estimates that approximately 390 application holders and repackagers
and relabelers will submit these supplements, and that it will take
approximately 120 hours to prepare and submit each supplement.
FDA also estimates that approximately 5,500 annual reports will be
submitted to FDA during the third year after the effective date for
applications approved before June 30, 2001, that contain a pregnancy
category (5,500 includes annual reports for approximately 1,340 NDAs
and BLAs and approximately 4,160 ANDAs containing labeling changes
resulting from this rulemaking). FDA estimates that approximately 320
application holders will submit these annual reports, and that it will
take approximately 40 hours for each submission.
As indicated in tables 3 and 4 of this document, we estimate that
the total hours resulting from the information collection in this
rulemaking will be approximately 1,598,000 hours. The costs associated
with this rulemaking, including labor costs, are discussed in section
VII of this document and in the final regulatory impact analysis of the
final rule.
Description of Respondents: Persons and businesses, including small
businesses and manufacturers.
Table 3--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
Type of submission (21 CFR Number of responses per Total annual burden per Total hours
section) respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
Supplements to applications 390 26 10,150 120 1,218,000
approved 6/30/01 to effective (Submitted 3rd,
date (Sec. Sec. 314.70(b), 4th, and 5th
601.12(f)(1)). years after
effective date).
Annual report submission of 320 17 5,500 (Submitted 40 220,000
revised labeling for 3rd year after
applications approved before effective date).
6/30/01 that contain a
pregnancy category (Sec.
Sec. 314.70(d),
601.12(f)(3)).
---------------------------------------------------------------------------------
[[Page 72100]]
Total..................... .............. .............. ................ .............. 1,438,000
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.
Table 4--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of
Type of submission (21 CFR section) Number of disclosures per Total annual disclosures Average burden Total hours
respondents respondent per disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
New NDAs/ANDAs/BLAs/efficacy supplements 390 10 4,000 (Submitted during 10-year 40 160,000
submitted on or after effective date, including period after effective date).
amendments to applications pending on effective
date (Sec. Sec. 314.50, 314.60, 314.70(b),
601.2, 601.12(f)(1)).
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.
The information collection provisions of this final rule have been
submitted to OMB for review, as required by section 3507(d) of the PRA.
Prior to the effective date of this final rule, FDA will publish a
notice in the Federal Register announcing OMB's decision to approve,
modify, or disapprove the information collection provisions in this
final rule. An Agency may not conduct or sponsor, and a person is not
required to respond to, a collection of information unless it displays
a currently valid OMB control number.
IX. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that this final
rule does not contain policies that have substantial direct effects on
the States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the Agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
X. References
In addition to the references placed on display in the Division of
Dockets Management for the proposed rule under Docket No. FDA-2006-N-
0515 (formerly Docket No. 2006N-0467), the following references are on
display in the Division of Dockets Management under Docket No. FDA-
2006-N-0515 (formerly Docket No. 2006N-0467) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday,
and are available electronically at https://www.regulations.gov. (FDA
has verified all Web site addresses in this reference section, but we
are not responsible for any subsequent changes to the Web sites after
this document publishes in the Federal Register.)
1. Decision Partners, LLC, ``Evaluation of How Best to Communicate
to Healthcare Providers about the Risks and Benefits of Prescription
Drug Use for Pregnant and Nursing Women: A Mental Models Research
Report,'' September 2009 (available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm).
2. Final Regulatory Impact Analysis for Docket No. FDA-2006-N-0515
(formerly Docket No. 2006N-0467) (available at https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm
and at https://www.regulations.gov).
3. U.S. Food and Drug Administration, ``Guidance for Industry,
Warnings and Precautions, Contraindications, and Boxed Warning
Sections of Labeling for Human Prescription Drug and Biological
Products--Content and Format,'' 2011.
4. Kweder, S.L., ``Drugs and Biologics in Pregnancy and
Breastfeeding: FDA in the 21st Century.'' Birth Defects Research
Part A: Clinical and Molecular Teratology. 82(9):605-609, September
2008.
5. Adam, M.P., J.E. Polifka, and J.M. Friedman, ``Evolving Knowledge
of the Teratogenicity of Medications in Human Pregnancy.'' American
Journal of Medical Genetics Part C: Seminars in Medical Genetics.
157C(3):175-182, August 15, 2011.
6. Law, R., P. Bozzo, G. Koren, et al. ``FDA Pregnancy Risk
Categories and the CPS. Do They Help or Are They a Hindrance?''
Canadian Family Physician. 56:239-241, March 2010.
7. U.S. Food and Drug Administration ``Guidance for industry,
Establishing Pregnancy Exposure Registries,'' 2002.
8. U.S. Food and Drug Administration ``Guidance for Industry,
Reproductive and Developmental Toxicities--Integrating Study Results
to Assess Concerns,'' 2011.
9. Rynn, L., J. Cragan, and A. Correa, ``Update on Overall
Prevalence of Major Birth Defects--Atlanta, Georgia, 1978-2005.''
Centers for Disease Control and Prevention Morbidity and Mortality
Weekly Report. 57(01):1-5, January 11, 2008.
10. American College of Obstetricians and Gynecologists Frequently
Asked Questions: Miscarriage and Molar Pregnancy, 2011 (available at
https://www.acog.org/~/media/For%20Patients/
faq090.pdf?dmc=1&ts=20140130T1655496642).
11. U.S. Food and Drug Administration, ``Reviewer Guidance,
Evaluating the Risks of Drug Exposure in Human Pregnancies,'' 2005.
12. U.S. Food and Drug Administration, ``Guidance for industry,
Considerations for Developmental Toxicity Studies for Preventive and
Therapeutic Vaccines for Infectious Disease Indications,'' 2006.
13. U.S. Food and Drug Administration, ``Guidance for industry, M3
(R2) Nonclinical Safety Studies for the Conduct of Human Clinical
Trials and Marketing Authorization for Pharmaceuticals and the
International Conference on Harmonisation S5 (R2) Guideline:
Detection of Toxicity to Reproduction for Medicinal Products and
Toxicity to Male Fertility,'' 2010.
14. Tracy, T.S., et al. ``Temporal Changes in Drug Metabolism
(CYP1A2, CYP2D6 and CYP3A Activity) During Pregnancy.'' American
Journal of Obstetrics and Gynecology. 192(2):633-639, February 2005.
15. Anderson, G.D., ``Pregnancy-Induced Changes in
Pharmacokinetics.'' Clinical Pharmacokinetics. 44(10):989-1008,
2005.
[[Page 72101]]
16. American Academy of Pediatrics Policy Statement. ``Breastfeeding
and the Use of Human Milk.'' Pediatrics. 129(3):e827-841, 2012.
17. Sachs, H.C. and Committee on Drugs. ``The Transfer of Drugs and
Therapeutics Into Human Breast Milk: An Update on Selected Topics.''
Pediatrics. 132(3):e796-809, September 2013.
18. U.S. Food and Drug Administration, ``Draft Guidance for industry
Clinical Lactation Studies--Study Design, Data Analysis, and
Recommendations for Labeling,'' 2005.
19. Proposed Pregnancy and Lactation Labeling Rule (available at
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).
20. Public Comments on Proposed Pregnancy and Lactation Labeling
Rule (available at https://www.regulations.gov/#!docketDetail;D=FDA-
2006-N-0515).
List of Subjects in 21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
201 is amended as follows:
PART 201--LABELING
0
1. The authority citation for 21 CFR part 201 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360,
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.
Sec. 201.56 [Amended]
0
2. Amend Sec. 201.56 in paragraph (d)(1) by removing from the list of
headings and subheadings the subheadings ``8.2 Labor and delivery'' and
``8.3 Nursing mothers'' and adding in their places the subheadings
``8.2 Lactation'' and ``8.3 Females and Males of Reproductive
Potential'', respectively.
0
3. Amend Sec. 201.57 by revising paragraphs (c)(9)(i), (ii), and (iii)
to read as follows:
Sec. 201.57 Specific requirements on content and format of labeling
for human prescription drug and biological products described in Sec.
201.56(b)(1).
* * * * *
(c) * * *
(9) * * *
(i) 8.1 Pregnancy. This subsection of the labeling must contain the
following information in the following order under the subheadings
``Pregnancy Exposure Registry,'' ``Risk Summary,'' ``Clinical
Considerations,'' and ``Data'':
(A) Pregnancy exposure registry. If there is a scientifically
acceptable pregnancy exposure registry for the drug, contact
information needed to enroll in the registry or to obtain information
about the registry must be provided following the statement: ``There is
a pregnancy exposure registry that monitors pregnancy outcomes in women
exposed to (name of drug) during pregnancy.''
(B) Risk summary. The Risk Summary must contain risk statement(s)
based on data from all relevant sources (human, animal, and/or
pharmacologic) that describe, for the drug, the risk of adverse
developmental outcomes (i.e., structural abnormalities, embryo-fetal
and/or infant mortality, functional impairment, alterations to growth).
When multiple data sources are available, the statements must be
presented in the following order: Human, animal, pharmacologic. The
source(s) of the data must be stated. The labeling must state the
percentage range of live births in the United States with a major birth
defect and the percentage range of pregnancies in the United States
that end in miscarriage, regardless of drug exposure. If such
information is available for the population(s) for which the drug is
labeled, it must also be included. When use of a drug is
contraindicated during pregnancy, this information must be stated first
in the Risk Summary. When applicable, risk statements as described in
paragraphs (c)(9)(i)(B)(1) and (2) of this section must include a
cross-reference to additional details in the relevant portion of the
``Data'' subheading in the ``Pregnancy'' subsection of the labeling. If
data demonstrate that a drug is not systemically absorbed following a
particular route of administration, the Risk Summary must contain only
the following statement: ``(Name of drug) is not absorbed systemically
following (route of administration), and maternal use is not expected
to result in fetal exposure to the drug.''
(1) Risk statement based on human data. When human data are
available that establish the presence or absence of any adverse
developmental outcome(s) associated with maternal use of the drug, the
Risk Summary must summarize the specific developmental outcome(s);
their incidence; and the effects of dose, duration of exposure, and
gestational timing of exposure. If human data indicate that there is an
increased risk for a specific adverse developmental outcome in infants
born to women exposed to the drug during pregnancy, this risk must be
quantitatively compared to the risk for the same outcome in infants
born to women who were not exposed to the drug but who have the disease
or condition for which the drug is indicated to be used. When risk
information is not available for women with the disease or condition
for which the drug is indicated, the risk for the specific outcome must
be compared to the rate at which the outcome occurs in the general
population. The Risk Summary must state when there are no human data or
when available human data do not establish the presence or absence of
drug-associated risk.
(2) Risk statement based on animal data. When animal data are
available, the Risk Summary must summarize the findings in animals and
based on these findings, describe, for the drug, the potential risk of
any adverse developmental outcome(s) in humans. This statement must
include: The number and type(s) of species affected, timing of
exposure, animal doses expressed in terms of human dose or exposure
equivalents, and outcomes for pregnant animals and offspring. When
animal studies do not meet current standards for nonclinical
developmental toxicity studies, the Risk Summary must so state. When
there are no animal data, the Risk Summary must so state.
(3) Risk statement based on pharmacology. When the drug has a well-
understood mechanism of action that may result in adverse developmental
outcome(s), the Risk Summary must explain the mechanism of action and
the potential associated risks.
(C) Clinical considerations. Under the subheading ``Clinical
Considerations,'' the labeling must provide relevant information, to
the extent it is available, under the headings ``Disease-associated
maternal and/or embryo/fetal risk,'' ``Dose adjustments during
pregnancy and the postpartum period,'' ``Maternal adverse reactions,''
``Fetal/Neonatal adverse reactions,'' and ``Labor or delivery'':
(1) Disease-associated maternal and/or embryo/fetal risk. If there
is a serious known or potential risk to the pregnant woman and/or the
embryo/fetus associated with the disease or condition for which the
drug is indicated to be used, the labeling must describe the risk.
(2) Dose adjustments during pregnancy and the postpartum period. If
there are pharmacokinetic data that support dose adjustment(s) during
pregnancy and the postpartum period, a summary of this information must
be provided.
(3) Maternal adverse reactions. If use of the drug is associated
with a maternal adverse reaction that is unique to pregnancy or if a
known adverse reaction occurs with increased frequency or severity in
pregnant
[[Page 72102]]
women, the labeling must describe the adverse reaction and available
intervention(s) for monitoring or mitigating the reaction. The labeling
must describe, if known, the effect of dose, timing, and duration of
exposure on the risk to the pregnant woman of experiencing the adverse
reaction.
(4) Fetal/Neonatal adverse reactions. If it is known or anticipated
that treatment of the pregnant woman increases or may increase the risk
of an adverse reaction in the fetus or neonate, the labeling must
describe the adverse reaction, the potential severity and reversibility
of the adverse reaction, and available intervention(s) for monitoring
or mitigating the reaction. The labeling must describe, if known, the
effect of dose, timing, and duration of exposure on the risk.
(5) Labor or delivery. If the drug is expected to affect labor or
delivery, the labeling must provide information about the effect of the
drug on the pregnant woman and the fetus or neonate; the effect of the
drug on the duration of labor and delivery; any increased risk of
adverse reactions, including their potential severity and
reversibility; and must provide information about available
intervention(s) that can mitigate these effects and/or adverse
reactions. The information described under this heading is not required
for drugs approved for use only during labor and delivery.
(D) Data--(1) ``Data'' subheading. Under the subheading ``Data,''
the labeling must describe the data that are the basis for the Risk
Summary and Clinical Considerations.
(2) Human and animal data headings. Human and animal data must be
presented separately, beneath the headings ``Human Data'' and ``Animal
Data,'' and human data must be presented first.
(3) Description of human data. For human data, the labeling must
describe adverse developmental outcomes, adverse reactions, and other
adverse effects. To the extent applicable, the labeling must describe
the types of studies or reports, number of subjects and the duration of
each study, exposure information, and limitations of the data. Both
positive and negative study findings must be included.
(4) Description of animal data. For animal data, the labeling must
describe the following: Types of studies, animal species, dose,
duration and timing of exposure, study findings, presence or absence of
maternal toxicity, and limitations of the data. Description of maternal
and offspring findings must include dose-response and severity of
adverse developmental outcomes. Animal doses or exposures must be
described in terms of human dose or exposure equivalents and the basis
for those calculations must be included.
(ii) 8.2 Lactation. This subsection of the labeling must contain
the following information in the following order under the subheadings
``Risk Summary,'' ``Clinical Considerations,'' and ``Data'':
(A) Risk summary. When relevant human and/or animal lactation data
are available, the Risk Summary must include a cross-reference to the
``Data'' subheading in the ``Lactation'' subsection of the labeling.
When human data are available, animal data must not be included unless
the animal model is specifically known to be predictive for humans.
When use of a drug is contraindicated during breastfeeding, this
information must be stated first in the Risk Summary.
(1) Drug not absorbed systemically. If data demonstrate that the
drug is not systemically absorbed by the mother, the Risk Summary must
contain only the following statement: ``(Name of drug) is not absorbed
systemically by the mother following (route of administration), and
breastfeeding is not expected to result in exposure of the child to
(name of drug).''
(2) Drug absorbed systemically. If the drug is absorbed
systemically, the Risk Summary must describe the following to the
extent relevant information is available:
(i) Presence of drug in human milk. The Risk Summary must state
whether the drug and/or its active metabolite(s) are present in human
milk. If there are no data to assess this, the Risk Summary must so
state. If studies demonstrate that the drug and/or its active
metabolite(s) are not detectable in human milk, the Risk Summary must
state the limits of the assay used. If studies demonstrate the presence
of the drug and/or its active metabolite(s) in human milk, the Risk
Summary must state the concentration of the drug and/or its active
metabolite(s) in human milk and the actual or estimated daily dose for
an infant fed exclusively with human milk. The actual or estimated
amount of the drug and/or its active metabolite(s) ingested by the
infant must be compared to the labeled infant or pediatric dose, if
available, or to the maternal dose. If studies demonstrate the presence
of the drug and/or its active metabolite(s) in human milk but the drug
and/or its active metabolite(s) are not expected to be systemically
bioavailable to the breast-fed child, the Risk Summary must describe
the disposition of the drug and/or its active metabolite(s). If only
animal lactation data are available, the Risk Summary must state only
whether or not the drug and/or its active metabolite(s) were detected
in animal milk and specify the animal species.
(ii) Effects of drug on the breast-fed child. The Risk Summary must
include information, on the known or predicted effects on the child
from exposure to the drug and/or its active metabolite(s) through human
milk or from contact with breast or nipple skin (for topical products).
The Risk Summary also must include information on systemic and/or local
adverse reactions. If there are no data to assess the effects of the
drug and/or its active metabolite(s) on the breast-fed child, the Risk
Summary must so state.
(iii) Effects of drug on milk production. The Risk Summary must
describe the effects of the drug and/or its active metabolite(s) on
milk production. If there are no data to assess the effects of the drug
and/or its active metabolite(s) on milk production, the Risk Summary
must so state.
(3) Risk and benefit statement. For drugs absorbed systemically,
unless breastfeeding is contraindicated during drug therapy, the
following risk and benefit statement must appear at the end of the Risk
Summary: ``The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for (name of
drug) and any potential adverse effects on the breast-fed child from
(name of drug) or from the underlying maternal condition.''
(B) Clinical considerations. Under ``Clinical Considerations,'' the
following information must be provided to the extent it is available
and relevant:
(1) Minimizing exposure. The labeling must describe ways to
minimize exposure in the breast-fed child if: The drug and/or its
active metabolite(s) are present in human milk in clinically relevant
concentrations; the drug does not have an established safety profile in
infants; and the drug is used either intermittently, in single doses,
or for short courses of therapy. When applicable, the labeling must
also describe ways to minimize a breast-fed child's oral intake of
topical drugs applied to the breast or nipple skin.
(2) Monitoring for adverse reactions. The labeling must describe
available intervention(s) for monitoring or mitigating the adverse
reaction(s) presented in the Risk Summary.
(C) Data. Under the subheading ``Data,'' the labeling must describe
the data that are the basis for the Risk Summary and Clinical
Considerations.
(iii) 8.3 Females and males of reproductive potential. When
pregnancy
[[Page 72103]]
testing and/or contraception are required or recommended before,
during, or after drug therapy and/or when there are human and/or animal
data that suggest drug-associated fertility effects, this subsection of
labeling must contain this information under the subheadings
``Pregnancy Testing,'' ``Contraception,'' and ``Infertility,'' in that
order.
* * * * *
Sec. 201.80 [Amended]
0
4. Amend Sec. 201.80 as follows:
0
a. Remove the paragraph heading ``Pregnancy category A.'' and the words
``Pregnancy Category A.'' from paragraph (f)(6)(i)(a);
0
b. Remove the paragraph heading ``Pregnancy category B.'' and the words
``Pregnancy Category B.'' both times they appear from paragraph
(f)(6)(i)(b);
0
c. Remove the paragraph heading ``Pregnancy category C.'' and the words
``Pregnancy Category C.'' both times they appear from paragraph
(f)(6)(i)(c);
0
d. Remove the paragraph heading ``Pregnancy category D.'' and the words
``Pregnancy Category D.'' from paragraph (f)(6)(i)(d); and
0
e. Remove the paragraph heading ``Pregnancy category X.'' and the words
``Pregnancy Category X.'' from paragraph (f)(6)(i)(e).
Dated: November 25, 2014.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2014-28241 Filed 12-3-14; 8:45 am]
BILLING CODE 4164-01-P
