Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, 30831-30868 [E8-11806]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 73, Number 104 (Thursday, May 29, 2008)]
[Proposed Rules]
[Pages 30831-30868]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-11806]


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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:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is proposing to amend 
its regulations concerning the format and content 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 agency is proposing to 
require that labeling include a summary of the risks of using a drug 
during pregnancy and lactation and a discussion of the data supporting 
that summary. The labeling would also include relevant clinical 
information to help health care providers make prescribing decisions 
and counsel women about the use of drugs during pregnancy and/or 
lactation. The proposal would eliminate the current pregnancy 
categories A, B, C, D, and X. The ``Labor and delivery'' subsection 
would be eliminated because information on labor and delivery is 
included in the proposed ``Pregnancy'' subsection. The proposed rule is 
intended to create a consistent format for providing information about 
the effects of a drug on pregnancy and lactation that will be useful 
for decisionmaking by women of childbearing age and their health care 
providers.

DATES:  Submit written or electronic comments on the proposed rule by 
August 27, 2008. Submit comments on information collection issues under 
the Paperwork Reduction Act of 1995 by June 30, 2008, (see the 
``Paperwork Reduction Act of 1995'' section of this document).

ADDRESSES:  You may submit comments, identified by Docket No. FDA-2006-
N-0515 and/or RIN number 0910-AF11, by any of the following methods, 
except that comments on information collection issues under the 
Paperwork Reduction Act of 1995 must be submitted to the Office of 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).
Electronic Submissions
Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal, as described previously, in the ADDRESSES portion 
of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to https://www.regulations.gov, including 
any personal information provided. For additional information on 
submitting comments, see the ``Comments'' heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts, and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT:

     Christine F. Rogers, Center for Drug Evaluation and Research (HFD-
7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-594-2041, or
     Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, suite 200N 
Rockville, MD 20856, 301-827-6210.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Current Pregnancy, Labor and Delivery, and Lactation Labeling

[[Page 30832]]

II. FDA's Examination of Pregnancy Labeling
    A. Part 15 Hearing on the Pregnancy Labeling Categories
    B. Development of a Model Pregnancy Labeling Format
    C. Focus Group Testing of Model Pregnancy Labeling Format
    D. Advisory Committee Assessment of Pregnancy Labeling Concepts
    E. Focus Group Testing of Pregnancy Risk Statements
III. FDA's Examination of Labeling on Lactation
    A. Recommendations on Lactation Labeling From Part 15 Hearing
    B. Advisory Committee on Lactation Labeling Issues
    C. The Need for Informative Lactation Labeling
IV. Description of the Proposed Rule
    A. General Description of the Format and Content of the Pregnancy 
and Lactation Subsections of Labeling
    B. Pregnancy Subsection
    C. Lactation Subsection
    D. Removing the Pregnancy Designation
V. Implementation Plan for the Proposed Rule
    A. General
    B. New Content (Proposed Sec.  201.57(c)(9)(i) and (c)(9)(ii))
    C. Removing the Pregnancy Category (Proposed Sec.  201.80(f)(6))
VI. Legal Authority
VII. Environmental Impact
VIII. Analysis of Impacts
    A. Need for the Proposed Rule
    B. Scope of the Proposed Rule
    C. Costs of the Proposed Rule
    D. Benefits of the Proposed Rule
    E. Impacts on Small Entities
    F. Alternatives Considered
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Request for Comments
XII. References
Appendix

I. Current Pregnancy, Labor and Delivery, and Lactation Labeling

    Under the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
352 and 355), FDA has responsibility for ensuring that prescription 
drug and biological products (both referred to as ``drugs'' in this 
proposed 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 for labeling for human prescription drugs (21 CFR part 201) (44 
FR 37434, June 26, 1979).\1\ The requirements on content and format of 
labeling for human prescription drug and biological products were 
revised on January 24, 2006 (71 FR 3922).\2\ As part of the 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 (21 CFR part 201) 
was not revised, but they were redesignated as Sec. Sec.  
201.57(c)(9)(i) through (c)(9)(iii). The previous labeling regulation 
(adopted in 1979) was redesignated Sec.  201.80, and this regulation 
applies to products not affected by the January 24, 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)).
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    \1\ Thus, the labeling for drugs originally approved before 1979 
may not contain the information required by these regulations 
regarding pregnancy, labor and delivery, and nursing mothers.
    \2\ FDA's regulations governing the content and format of 
labeling for human prescription drug products are contained in 
Sec. Sec.  201.56, 201.57, and 201.80. Although those regulations do 
not specifically mention the term ``biologics,'' under the act most 
biologics are drugs that require a prescription and, thus, are 
subject to these regulations.
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    The current regulations provide that, unless a drug is not absorbed 
systemically and is not known to have a potential for indirect harm to 
a fetus, a ``Pregnancy'' subsection must be included within the ``Use 
in Specific Populations'' section of the labeling. The ``Pregnancy'' 
subsection must contain information on the drug's teratogenic effects 
and other effects on reproduction and pregnancy. 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 must 
also be included. The regulations require 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.
    Currently, Sec. Sec.  201.57(c)(9)(i)(A)(1) through (c)(9)(i)(A)(5) 
and 201.80(f)(6)(i)(a) specify the following pregnancy category 
designations and language:
     Pregnancy Category A
    For pregnancy category A, if adequate and well-controlled studies 
in pregnant women have failed to demonstrate a risk to the fetus in the 
first trimester of pregnancy (and there is no evidence of a risk in 
later trimesters), the labeling must state:
    Pregnancy Category A. Studies in pregnant women have not shown 
that (name of drug) increases the risk of fetal abnormalities if 
administered during the first (second, third, or all) trimester(s) 
of pregnancy. If this drug is used during pregnancy, the possibility 
of fetal harm appears remote. Because studies cannot rule out the 
possibility of harm, however, (name of drug) should be used during 
pregnancy only if clearly needed.
    If animal reproduction studies are also available and they fail to 
demonstrate a risk to the fetus, the labeling must also state:
    Reproduction studies have been performed in (kinds of animal(s)) 
at doses up to (x) times the human dose and have revealed no 
evidence of impaired fertility or harm to the fetus due to (name of 
drug).
     Pregnancy Category B
    For pregnancy category B, if animal reproduction studies have 
failed to demonstrate a risk to the fetus and there are no adequate and 
well-controlled studies in pregnant women, the labeling must state:
    Pregnancy Category B. Reproduction studies have been performed 
in (kind(s) of animal(s)) at doses up to (x) times the human dose 
and have revealed no evidence of impaired fertility or harm to the 
fetus due to (name of drug). There are, however, no adequate and 
well-controlled studies in pregnant women. Because animal 
reproduction studies are not always predictive of human response, 
this drug should be used in pregnancy only if clearly needed.
If animal reproduction studies have shown an adverse effect (other than 
decrease in fertility), but adequate and well-controlled studies in 
pregnant women have failed to demonstrate a risk to the fetus during 
the first trimester of pregnancy (and there is no evidence of a risk in 
later trimesters), the labeling must state:
    Pregnancy Category B. Reproduction studies in (kind(s) of 
animal(s)) have shown (describe findings) at (x) times the human 
dose. Studies in pregnant women, however, have not shown that (name 
of drug) increases the risk of abnormalities when administered 
during the first (second, third, or all) trimester(s) of pregnancy. 
Despite the animal findings, it would appear that the possibility of 
fetal harm is remote, if the drug is used during pregnancy. 
Nevertheless, because the studies in humans cannot rule out the 
possibility of harm, (name of drug) should be used during pregnancy 
only if clearly needed.
     Pregnancy Category C
    For pregnancy category C, if animal reproduction studies have shown 
an adverse effect on the fetus, if there are no adequate and well-
controlled studies in humans, and if the benefits from the use of the 
drug in pregnant women may be acceptable despite its potential risks, 
the labeling must state:
    Pregnancy Category C. (Name of drug) has been shown to be 
teratogenic (or to have an

[[Page 30833]]

embryocidal effect or other adverse effect) in (name(s) of species) 
when given in doses (x) times the human dose. There are no adequate 
and well-controlled studies in pregnant women. (Name of drug) should 
be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.
    If there are no animal reproduction studies and no adequate and 
well-controlled studies in humans, the labeling must state:
    Pregnancy Category C. Animal reproduction studies have not been 
conducted with (name of drug). It is also not known whether (name of 
drug) can cause fetal harm when administered to a pregnant woman or 
can affect reproduction capacity. (Name of drug) should be given to 
a pregnant woman only if clearly needed.
     Pregnancy Category D
    For pregnancy category D, if there is positive evidence of human 
fetal risk based on adverse reaction data from investigational or 
marketing experience or studies in humans, but the potential benefits 
from the use of the drug in pregnant women may be acceptable despite 
its potential risks, the labeling must state: ``Pregnancy Category D. 
See `Warnings and Precautions' section'' (for Sec.  
201.57(c)(9)(i)(A)(4)) or ``Pregnancy Category D. See `Warnings' 
Section'' (for Sec.  201.80(f)(6)(i)(d)). Under the ``Warnings and 
Precautions'' or ``Warnings'' section, the labeling must state:
    (Name of drug) can cause fetal harm when administered to a 
pregnant woman. (Describe the human data and any pertinent animal 
data.) If this drug is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to a fetus.
     Pregnancy Category X
    For pregnancy category X, if studies in animals or humans have 
demonstrated fetal abnormalities or if there is positive evidence of 
fetal risk based on adverse reaction reports from investigational or 
marketing experience, or both, and the risk of the use of the drug in a 
pregnant woman clearly outweighs any possible benefit, the labeling 
must state: ``Pregnancy Category X. See `Contraindications' section.'' 
Under ``Contraindications,'' the labeling must state:
    (Name of drug) may (can) cause fetal harm when administered to a 
pregnant woman. (Describe the human data and any pertinent animal 
data.) (Name of drug) is contraindicated in women who are or may 
become pregnant. If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should 
be apprised of the potential hazard to a fetus.
    With regard to labor and delivery, the current regulations state at 
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, under current FDA 
regulations, a ``Nursing mothers'' subsection must be included in 
either the ``Use in Specific Populations'' section of the labeling 
(Sec.  201.57(c)(9)(iii)) or the ``Precautions'' section of the 
labeling (Sec.  201.80(f)(8)). The ``Nursing mothers'' subsections 
provide that if a drug is 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'' subsections require the use of certain standard statements.
    If the drug is known to be excreted in human milk and is associated 
with serious adverse reactions or has a known tumorigenic potential, 
the labeling must state: ``Because of the potential for serious adverse 
reactions in nursing infants from (name of drug) (or, ``Because of the 
potential for tumorigenicity shown for (name of drug) in (animal or 
human) studies), a decision should be made whether to discontinue 
nursing or to discontinue the drug, taking into account the importance 
of the drug to the mother.''
    If the drug is known to be excreted in human milk, but is not 
associated with serious adverse reactions and does not have a known 
tumorigenic potential, the labeling must state: ``Caution should be 
exercised when (name of drug) is administered to a nursing woman.''
    If information on excretion in human milk is unknown and the drug 
is associated with serious adverse reactions or has a known tumorigenic 
potential, the labeling must state: ``It is not known whether this drug 
is excreted in human milk. Because many drugs are excreted in human 
milk and because of the potential for serious adverse reactions in 
nursing infants from (name of drug) (or, ``Because of the potential for 
tumorigenicity shown for (name of drug) in (animal or human) studies), 
a decision should be made whether to discontinue nursing or to 
discontinue the drug, taking into account the importance of the drug to 
the mother.''
    If information on excretion in human milk is unknown, but the drug 
is not associated with serious adverse reactions and does not have a 
known tumorigenic potential, the labeling must state: ``It is not known 
whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk, caution should be exercised when (name of drug) 
is administered to a nursing woman.''

II. FDA's Examination of Pregnancy Labeling

A. Part 15 Hearing on the Pregnancy Labeling Categories

    In September 1997, the agency held a part 15 hearing (21 CFR part 
15) on the current category requirements for pregnancy labeling (62 FR 
41061, July 31, 1997). The agency sought comment on the practical 
utility and effects of the pregnancy categories as well as on problems 
associated with the categories. The agency also sought input on ways to 
address problems with the categories, including suggestions for 
possible alternatives to the categories for communicating information 
on reproductive and developmental toxicity. The following are the 
specific issues the agency sought comment and data on, followed by a 
summary of the comments received and the discussion related to those 
comments:
    (1) The agency requested comment on the extent to which the 
category designations are relied upon in making decisions about drug 
therapy in pregnant women and women of childbearing potential and 
decisions about inadvertent fetal exposure, the extent to which such 
reliance may be misplaced, and the extent to which such reliance may 
have untoward public health consequences.
    Participants stated that because the categories appear to provide a 
simple, convenient measure of risk, they are routinely relied upon by 
health care providers and others in making decisions about drug therapy 
in pregnant women and women of childbearing age. There was concern 
that, because these decisions are more complex than the category 
designations suggest, such reliance may often be misplaced and could 
result in poorly informed clinical decisionmaking.
    (2) The agency requested comment on the extent to which current 
pregnancy labeling (category designation and accompanying narrative 
text) is effective in communicating risk of reproductive and 
developmental toxicity.
    Participants stated that the current categories are confusing and 
overly simplistic and, therefore, not adequate to effectively 
communicate risk of reproductive and developmental toxicity. A major 
problem identified by the participants is that the categories convey 
the incorrect impression that developmental risk increases from 
category A to B to C to D to X when, in fact, the criteria for 
inclusion in the categories are not based solely on

[[Page 30834]]

increasing risk. Categories C, D, and X also consider risk weighed 
against benefit. Thus, drugs in categories C or D may pose risks 
similar to a drug in Category X based on animal or human data, but may 
be categorized differently based on different risk-benefit 
considerations.
    Participants stated that the categories also create the incorrect 
impression that drugs within a given category have similar potential to 
cause developmental toxicity. In fact, because the descriptive criteria 
for the individual categories focus largely on whether the available 
data have identified a potential hazard, they permit assignment of 
drugs to the same category when the severity, incidence, and types of 
risk may be quite different. The criteria also permit drugs with known 
risks and drugs with no known risks to be placed in the same category. 
Specifically, category C (which includes more than 60 percent of all 
products with a pregnancy category)\3\ includes both drugs with 
demonstrated adverse reproductive effects in animals and drugs for 
which no animal studies have been performed.
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    \3\ Based on searches of the 2001 and 2002 electronic version of 
the Physicians' Desk Reference (Ref. 39).
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    Participants also expressed concern that current labeling can be 
confusing because the way risk is characterized does not readily 
discriminate among potential developmental adverse effects on the basis 
of severity, incidence, or type of adverse effects, nor does it make a 
distinction between the nature of the data (e.g., possible effects in 
humans based on animal data versus known effects that have been 
observed in humans) and the quality of the data (e.g., statistical 
significance, study design) that identified the effects. In addition, 
current labeling often does not indicate whether there are degrees of 
risk based on the dose, duration, frequency, route of exposure, and 
gestational timing of exposure to a given product.
    (3) The agency requested comment on the extent to which current 
pregnancy labeling may not adequately address the range of issues that 
may bear on decisions about drug therapy in pregnant women and women of 
childbearing potential and decisions about inadvertent fetal exposure 
(e.g., indication-specific concerns, pregnancy status, magnitude of 
exposure, incidental exposure, chronic exposure, timing of exposure).
    Participants stated that current pregnancy labeling does not 
adequately address the range of clinical situations in which 
information about drug exposure in pregnancy is needed. Specifically, 
current pregnancy labeling focuses almost entirely on prospective 
considerations of whether to prescribe a drug for a pregnant woman and 
rarely addresses inadvertent exposure. However, because approximately 
50 percent of pregnancies are unplanned (Ref. 1), there is significant 
potential for inadvertent exposure to a drug before a pregnancy is 
detected. Participants expressed strong support for addressing 
inadvertent exposure issues in pregnancy labeling because clinical 
decisions about inadvertent exposures often involve deciding whether to 
terminate pregnancies due to the exposure. It was also pointed out that 
a statement about the risk associated with use of a drug during 
pregnancy should be put in the context of the background risk of 
adverse fetal outcomes.
    (4) The agency requested comment on additional information (data or 
interpretation of data) that could be included in pregnancy labeling to 
better address the range of issues that bear on decisions about drug 
therapy in pregnant women and women of childbearing potential and 
decisions about inadvertent fetal exposure.
    Participants stated that current pregnancy labeling does not 
adequately address the full range of potential developmental 
toxicities--fetal death, structural malformations, perturbations of 
fetal growth, and functional deficits. There were also concerns that 
current labeling does not present enough of the evidentiary basis for 
the category designation or adequately discuss the potential relevance 
of animal data to humans. Participants urged FDA to implement a 
mechanism to routinely update the ``Pregnancy'' subsection of labeling 
after a drug is marketed to include human exposure information as it 
becomes available. Several participants spoke favorably about the 
utility of pregnancy exposure registries. FDA was also encouraged to 
expand its assessment of the adequacy of pregnancy labeling to include 
what was then called the ``Nursing mothers'' subsection and to 
incorporate discussions of a product's effects on fertility, pregnancy, 
and lactation into a single labeling subsection. Some participants also 
expressed concern that current pregnancy labeling fails to discuss the 
risks, sometimes serious, of foregoing medically necessary medication 
during pregnancy.
    (5) The agency requested comment on options to improve 
communication of reproductive and developmental risk in labeling, which 
could include alternatives to the categories (both content and format 
options) or efforts to make the current category scheme and 
accompanying narrative text more consistent and informative.
    Most participants stated that the current letter categories should 
be replaced with a concise narrative summarizing a product's risks to 
pregnant women and women of childbearing age, and the clinical 
implications of such risks. To aid comprehension and facilitate 
evaluation of therapeutic options, it was recommended that the 
narratives contain common core elements. Some comments also supported 
providing a conclusive statement or recommendation about clinical use. 
FDA also was encouraged to take steps to better understand how language 
used in pregnancy labeling to communicate risk is perceived by health 
care providers.

B. Development of a Model Pregnancy Labeling Format

    After the part 15 hearing testimony and comments, FDA decided to 
revise its pregnancy labeling regulations and began to develop a model 
format to address the concerns raised about the existing format. The 
model format was designed to prominently display important information 
relevant to managing the risks of fetal and maternal adverse effects in 
the clinical setting, provide a summary of the risks that are the basis 
for the clinical care recommendations, and provide an overview of the 
data that are the basis for the risk conclusions. Accordingly, the 
model format divided the ``Pregnancy'' subsection into three 
components: (1) Clinical management statement, (2) summary risk 
assessment, and (3) discussion of data. The model format replaced the 
letter categories with concise conclusions about risk presented in 
narrative form, in large part to address concerns that users of the 
labeling might misinterpret the categories as presenting gradations of 
risk and as indicating that drugs in a given category pose similar 
risks. The model format also separated clinical management information 
from the risk assessment. This separation was intended to address 
concerns that the current categories (category X, in particular) appear 
to represent only risk assessments, but, in some cases, actually 
represent risk-benefit considerations. The three distinct labeling 
components were intended to clearly differentiate between the clinical 
management information, the risk conclusions, and the data that 
underpin the risk conclusions.

[[Page 30835]]

C. Focus Group Testing of Model Pregnancy Labeling Format

    FDA sought practical feedback on the model format the agency had 
developed for the ``Pregnancy'' subsection at the 15th Annual Clinical 
Update in Obstetrics and Gynecology Conference in February 1999 
(February 1999 Conference). At this conference, FDA conducted two focus 
groups that included obstetrician-gynecologists and family 
practitioners. One of the groups also included a reproductive 
endocrinologist.
    Participants were provided with sample ``Pregnancy'' subsections of 
labeling for three fictitious drugs. One sample used the current 
pregnancy labeling format and the other two used the model format that 
FDA had developed based on recommendations from the part 15 hearing. 
The feedback the agency sought and the responses it received from the 
participants were as follows:
    (1) What factors did they take into account when prescribing for a 
pregnant woman and what information did they rely on?
    Focus group members indicated that they rely on the pregnancy 
categories as a guide for prescribing and that they also rely on 
colleagues for advice.
    (2) What was the availability and quality of data they relied on in 
making prescribing decisions for pregnant women?
    The major concern of focus group members was the absence of human 
data. They indicated a willingness to rely on animal data in the 
absence of human data if the labeling provided some correlation to 
human dosing. They also recommended that if human data were available, 
they should take precedence over animal data in making risk 
conclusions.
    (3) What were their overall impressions of the sample labeling 
formats, including their thoughts about the formats generally and the 
clinical management section in particular?
    Focus group members preferred the model pregnancy labeling formats 
that had been developed based on recommendations from the part 15 
hearing. They agreed that the clinical recommendations should appear 
first in the labeling, followed by the details. They favored a clinical 
management section, but there was some difference of opinion as to how 
directive the management advice should be. While some members said they 
appreciated the directive nature of the new labeling formats, other 
participants were uncomfortable with the directive management advice. 
The overall consensus was that the participants wanted as much 
information as possible without specific instructions pertaining to 
clinical management.
    (4) What were their recommendations for what should be in labeling 
and how it should be presented?
    Focus group members recommended that animal data be arranged by 
species and that the data be organized by effect in trimester of 
pregnancy. They also preferred a uniform labeling format for all drug 
products. Finally, participants stated that more information was better 
and that the most important information should be presented first. 
Specifically, they encouraged FDA to include relevant information about 
human exposures even if such information was limited (e.g., from a very 
limited number of case reports of exposures).

D. Advisory Committee Assessment of Pregnancy Labeling Concepts

    Based on the part 15 hearing and the feedback from the focus groups 
at the February 1999 Conference, the agency further developed the model 
pregnancy labeling format and presented the revised version for 
discussion and comment at a meeting of the Pregnancy Labeling 
Subcommittee of the FDA Reproductive Health Drugs Advisory Committee in 
June 1999 (64 FR 23340, April 30, 1999). The model labeling format was 
presented as a Concept Paper on Pregnancy Labeling (https://www.fda.gov/
ohrms/dockets/ac/99/transcpt/3516r1.doc).
    The agency asked the advisory committee for input on the following 
issues:
    (1) The committee was asked to provide comment on the usefulness of 
the proposed reorganization of information on pregnancy, fertility, and 
lactation in the labeling that separates information into three 
components: Clinical management, summary risk assessment, and 
discussion of data, including their suggestions to refine or improve 
the model.
    In general, committee members thought the proposed model with its 
standardized format was an improvement over the current labeling and 
that separating information into three components (clinical management 
statement, risk summary, and discussion of data) under the fertility, 
pregnancy, and lactation subsections would be beneficial. However, they 
felt that the summary risk information was the most important 
information in the pregnancy subsection; therefore, the risk statement 
should precede the clinical management information. One advisory 
committee member recommended against including fertility, saying that 
fertility is a very different issue and should be considered 
separately.
    (2) How specific and detailed should the recommendations be in the 
clinical management statements (e.g., should they address types and 
frequency of testing and monitoring)? Were there circumstances under 
which specific recommendations should not be provided?
    Committee members agreed that it was important to have information 
relevant to clinical management of pregnant women in the labeling. 
However, they advised against providing directive advice or 
instructions (e.g., specific instructions about the type of monitoring 
that should be done and when to do it). They were concerned that 
directive advice could intrude on the practice of medicine and, if not 
kept current, could become outdated and contrary to the standard of 
care. They were also concerned about the liability implications for 
prescribers of failing to adhere to instructions in labeling that are 
no longer the standard of care for the relevant clinical situation.
    Committee members also objected to the heading ``Clinical 
Management Statement'' because it suggested that the information is 
intended to dictate to health care providers how to manage their 
patients. They recommended that the heading be changed to ``Clinical 
Considerations'' to clarify that the information is intended to assist 
health care providers and patients in making their own decisions.
    (3) In the risk summary, how could appropriate context for the 
reader be provided, such as risks to pregnancy associated with the 
maternal disease state or baseline population rates of the adverse 
outcomes in question?
    Committee members agreed that the risk summary should be expressed 
in terms of an increased risk due to drug exposure compared to a 
background risk--either a background risk for a disease state or 
general background risk for the occurrence of the hazard in pregnancy. 
Some members advocated including a general statement in this section to 
remind readers of the inherent risks of developmental adverse effects 
independent of drug therapy. The committee also recommended that 
standardized risk statements be used and that the risk statement 
indicate gestational periods of higher and lower fetal vulnerability if 
that information is available. They felt that any description of risk 
should be portrayed as either ``potential'' or ``known'' depending on 
whether the information is based on animal studies or human experience.
    (4) Could the committee provide guidance on the relative merits of

[[Page 30836]]

quantitative (e.g., risk ratios) vs. qualitative (e.g., high/low) 
descriptions of risk for this section of the label?
    There was general agreement among the committee members that 
quantitative description of risks is more informative and less 
problematic than qualitative description. Some members also expressed 
the view that stating the absolute or attributable risk is preferable 
to stating a risk ratio. Others stated they would like to see 
confidence intervals around numbers used because they convey 
information on the quantity of data.
    (5) What should the goals be for the discussion of data component? 
How should information be selected for inclusion?
    Committee members stated that the discussion of data component 
should include human data to the extent available. There was some 
discussion about the utility of animal data in the absence of human 
data. However, there was consensus among committee members that the 
labeling should address the relevance of animal data for the doses 
generally prescribed for humans.
    In the model format provided to the committee members, the 
discussion of data component included six subheadings: Structural 
alteration (or dysmorphogenesis), embryo-fetal death, growth 
retardation (irreversible and reversible), functional toxicities, 
maternal toxicity, and labor and delivery. The agency's purpose in 
proposing these subheadings was to address the full range of possible 
reproductive and developmental toxicities that might be appropriate for 
discussion in the data component. The committee's discussion focused on 
animal data because most of the data in current labeling is animal 
data. Committee members thought that the subheadings were too detailed. 
Instead, it was suggested that the presentation of animal studies 
should focus on describing the toxicities and include dose response 
information. Committee members also thought it was important, with 
regard to animal data, to compare the level of systemic exposure in 
animals to the human level.
    (6) In the setting where little is known about risk, how should 
this lack of information be communicated in a manner that is optimally 
informative?
    Committee members agreed that situations where there are ``no 
data'' should be distinguished from those where there are ``limited 
data.'' They agreed that the labeling should clearly state when there 
are no data available. When there are some data available, but the data 
are not sufficient to draw a conclusion about the risk of developmental 
abnormality, it was suggested that the labeling should qualify the risk 
by saying that the risk is undetermined. Committee members also 
cautioned against making the assumption that all drugs within a 
pharmaceutical class are teratogenic just because one member of the 
class is.
    (7) How could uncertainty associated with the predictive value of 
animal studies, particularly in the absence of human data, best be 
communicated?
    Some committee members stated that the uncertainty of predicting 
human risk based on animal data should be clearly expressed in the 
labeling. Other committee members suggested that in the absence of 
human data, instead of focusing on the uncertainty of the predictive 
value of the available animal data, the labeling should focus on the 
weight of evidence provided by the animal data.
    (8) Is there risk or other descriptive language that has acquired 
sufficient unintended connotation that it should be avoided in 
providing advice or in summary risk statements? Were there examples and 
could they suggest alternatives?
    There was general agreement among committee members that labeling 
should describe the facts. Committee members cautioned against the use 
of phrases or terms such as ``use with caution,'' ``crosses the 
placental barrier,'' and ``probability'' because the lay public and 
scientists define the terms very differently. One member also pointed 
out that all of the terms used to describe animal findings can be 
alarming to patients and providers.

E. Focus Group Testing of Pregnancy Risk Statements

    Based on the recommendations of the advisory committee, the agency 
further refined the model pregnancy labeling format. FDA also developed 
a number of standard statements to use in pregnancy labeling to 
characterize the risk of developmental abnormality associated with a 
drug. In May 2000, FDA conducted four focus groups to evaluate these 
standard statements being considered by the agency. Two focus groups 
consisted of nurse-midwives attending the annual meeting of the 
American College of Nurse-Midwives and two focus groups consisted of 
obstetrician/gynecologists attending the annual meeting of the American 
College of Obstetricians and Gynecologists (ACOG).
    Participants in all four focus groups were asked to review the 
following series of risk statements:
    Risk Statement 1
    Drug X does not appear to increase the risk of (type of 
developmental toxicity). Data on a limited number of exposed 
pregnancies indicate no adverse effects on the health of the (fetus/
newborn child). While animal studies did show (specific adverse effect 
seen in animals), such effects in humans are unlikely.
    Risk Statement 2
    Drug X is not expected to increase the risk of (type of 
developmental toxicity) attributable to Drug X. Data on a large number 
of exposed pregnancies indicate no adverse effects on the health of the 
(fetus/newborn child). Animal studies show (specific adverse effect 
seen in animals) but the implications for humans are uncertain.
    Risk Statement 3
    Drug X does not appear to increase the risk of (type of 
developmental toxicity). Data on a limited number of exposed 
pregnancies indicate no adverse effects on the health of the (fetus/
newborn child). Animal studies show (specific adverse effect seen in 
animals) but the implications for humans are uncertain.
    Risk Statement 4
    Drug X may increase the risk of (type of developmental toxicity or 
adverse effect) based on animal studies and data on a limited number of 
exposed pregnancies.
    Risk Statement 5
    Drug X does not appear to increase the risk of (type of 
developmental toxicity). Data on a large number of exposed pregnancies 
indicate no adverse effect on the health of the (fetus/newborn child), 
although animal studies did show (specific adverse effect seen in 
animals).
    Risk Statement 6
    Drug X may increase the risk of (type of developmental toxicity). 
Data on a limited number of exposed pregnancies indicate no adverse 
effects on the health of the (fetus/newborn child). However, animal 
studies did show (specific adverse effect seen in animals).
    The focus groups were asked to consider a number of phrases for 
possible use in risk statements, including phrases used in the six 
model risk statements above. These phrases included ``does not appear 
to increase the risk,'' ``there is no known risk attributable to,'' 
``is not expected to increase the risk,'' ``may not increase the 
risk,'' and ``may increase the risk.'' In general, the participants did 
not like the use of terms such as ``may increase,'' ``may not 
increase,'' ``is uncertain,'' ``although,'' or ``however,'' saying they 
felt the words were too vague and not useful to them. They preferred a 
factual statement that would allow them to

[[Page 30837]]

make a clinical judgment based on the circumstances of their patient. 
Participants also believed that the degree of risk that certain 
statements attempted to convey overlapped with that conveyed by other 
statements.
    The physicians participating in the focus groups at the ACOG 
meeting also were asked to review a general statement about the risks 
inherent in pregnancy independent of drug therapy, the difficulty in 
determining whether a drug poses any additional risk of developmental 
abnormality above the background incidence, and the uncertain 
predictive value of animal studies. The physicians agreed that it would 
be useful to include the general statement in labeling and said it 
would be particularly useful when explaining the concept of background 
risk to their patients.
    Based on feedback from the four focus groups, FDA revised the 
standard risk statements in the model format and incorporated the 
general statement reviewed by the physician groups.

III. FDA's Examination of Labeling on Lactation

A. Recommendations on Lactation Labeling From Part 15 Hearing

    Participants in the September 1997 part 15 hearing on pregnancy 
labeling also recommended that the agency revise the requirements for 
the ``Nursing mothers'' subsection of the labeling. They were concerned 
that current labeling on lactation is not informative for a number of 
reasons, including lack of data and a tendency for clinicians to 
conclude, based on the current format of the labeling, that they should 
recommend to their patients that they choose between breast-feeding and 
taking a drug. Based in part on these concerns, FDA developed a new 
format for the lactation subsection of labeling, using the draft 
pregnancy labeling model as a guide.

B. Advisory Committee on Lactation Labeling Issues

    In September 2000, the agency held a joint advisory committee 
meeting of the Pregnancy Labeling Subcommittee of the Advisory 
Committee for Reproductive Health Drugs and the Pediatric Subcommittee 
of the Anti-Infective Drugs Advisory Committee to consider lactation 
labeling (65 FR 50995, August 22, 2000) (advisory committee on 
lactation). Committee members heard presentations on what was then 
called the ``Nursing mothers'' subsection of the labeling, the need for 
research and information on drug therapy during lactation, and the 
draft format developed by FDA for the lactation portion of the 
labeling.
    The committee members were specifically asked to address the 
following questions:
    (1) Is maternal drug therapy during lactation an important health 
issue for infants? If yes, how should fundamental data be derived to 
determine if a drug is expressed in breast milk; whether a drug found 
in breast milk is available to the infant; and, when the drug is 
available, what the risk or lack of risk is to the nursing infant?
    The advisory committee members agreed that maternal drug therapy 
during lactation is an important health issue for infants. They 
believed that the only type of studies that could be ethically 
conducted involving nursing infants would be those in which the mother 
had already independently made the decision to breast-feed during drug 
therapy. The committee agreed that serum levels in the child would 
provide valuable information and that it is most important to assess 
clinical effects on the child from drug exposure. Committee members 
indicated that, as a practical matter, only short-term effects could be 
detected. They recommended that, if there is a known pediatric dose and 
safety profile, the dose received via breast milk should be put in 
perspective by reference to the recommended pediatric dose.
    (2) What products or types of therapies are most important to 
study: Those for conditions common in young women; those for chronic 
conditions; those for life-threatening conditions? Are there 
characteristics that are common across products or groups of products 
that make them a high priority?
    After lengthy discussion of the various issues and classes of 
drugs, the committee recommended that studies in the following 
categories of drugs should be of higher priority: Drugs predicted to 
have high levels in breast milk; drugs commonly used by women of 
childbearing age; and drugs used to treat chronic illnesses.
    (3) What kinds of information should be included in the labeling to 
allow informed decisions as to the safety of breast-feeding while 
taking a medication?
    The advisory committee members recommended that labeling include 
the following information:
     The amount of drug in breast milk,
     The anticipated daily dose for a nursing infant,
     The effect of the drug on the infant taking into account 
the infant's age,
     Drug pharmacokinetics during lactation,
     The presence of metabolites in breast milk and their half-
lives,
     The effect of the drug on displacement of bilirubin from 
protein-binding, and
     The effect of the drug on the quantity and quality of 
breast milk produced.
    Committee members recommended against a general statement that a 
drug enters the breast milk without information on the quantity of drug 
in breast milk. The committee advised that labeling discussions about 
the need to discontinue breast-feeding should be put in the context of 
a particular drug, its importance to the mother, and any risk to the 
infant. One member questioned the value of including animal data in 
lactation labeling, saying the data can be confusing and not 
necessarily helpful. Committee members urged FDA to provide a mechanism 
to ensure that labeling is updated as new data become available.

C. The Need for Informative Lactation Labeling

    Breast milk is the most complete form of nutrition for infants and 
offers a range of health benefits for breast-feeding women and infants. 
Research in developed and developing countries provides strong evidence 
that breast-feeding decreases the incidence and/or severity of a wide 
range of infectious diseases including bacterial meningitis, 
bacteremia, diarrhea, respiratory tract infection, necrotizing 
enterocolitis, otitis media, urinary tract infection, and late-onset 
sepsis in preterm infants. Studies suggest that breast-feeding 
significantly reduces postneonatal infant mortality and rates of sudden 
infant death syndrome in the first year of life. In addition, data 
suggest that older children who were breast-fed have slightly enhanced 
cognitive performance and decreased rates of asthma, obesity and 
overweight, diabetes mellitus (insulin and non-insulin dependent), 
lymphoma, leukemia, and Hodgkin's disease. Maternal benefits of breast-
feeding include reduction in postpartum bleeding, earlier return to 
pre-pregnancy weight, reduced risk of premenopausal breast cancer, and 
reduced risk of osteoporosis (Ref. 2).
    A survey conducted in 2001 found that 69.5 percent of women 
initiated breast-feeding and 32.5 percent had continued to breast-feed 
when surveyed at 6 months postpartum (Ref. 3). Given these numbers, FDA 
believes that it is highly likely that a woman will need and take 
medications while she is breast-feeding and thereby potentially will 
expose her child to the effects of

[[Page 30838]]

these medications. Surveys in various countries indicate that 90 to 99 
percent of nursing mothers receive a medication during the first week 
postpartum. At 4 months postpartum, the percentage of nursing mothers 
taking medication was 17 to 25 percent. Five percent of nursing mothers 
receive long-term drug therapy (Ref. 4).
    Because lactation studies, including studies of the transfer of 
drug into milk (animal or human), are not usually conducted during drug 
development, for most drugs there is little scientific information 
available on the effects on milk production, the extent of passage into 
breast milk, and the effects on the infant. Therefore, breast-feeding 
women and their health care providers must make decisions about 
treatment of maternal medical conditions in the absence of data. FDA is 
aware that a decision often is made to stop breast-feeding in order to 
take needed drug therapy.
    FDA encourages sponsors to conduct lactation studies so that women 
and their health care providers will have the information they need to 
make decisions about breast-feeding during maternal drug use. On 
February 8, 2005, the agency issued a draft guidance for industry 
entitled ``Clinical Lactation Studies--Study Design, Data Analysis, and 
Recommendations for Labeling'' (70 FR 6697). The draft guidance 
provides advice and recommendations on the design, conduct, and 
analysis of clinical lactation studies, including advice about when to 
perform such studies. It sets out in detail the types of information on 
lactation that the agency believes should be available to breast-
feeding women and their health care providers. In addition to the 
public comments received on the draft guidance, the agency requested 
input from the Pediatric Advisory Committee at its November 29, 2007, 
meeting. FDA is currently working to finalize its guidance on Clinical 
Lactation Studies.

IV. Description of the Proposed Rule

A. General Description of the Format and Content of the Pregnancy and 
Lactation Subsections of Labeling

    The agency is proposing to revise the format and content of Sec.  
201.57 to change the requirements for the current ``Pregnancy,'' 
``Labor and delivery,'' and ``Nursing mothers'' subsections. The 
proposed rule would merge the current ``Pregnancy'' and ``Labor and 
delivery'' subsections into a single ``Pregnancy'' subsection and would 
modify the requirements for the format and content of that subsection. 
The proposed rule would modify the format and content of the ``Nursing 
mothers'' subsection. The agency is proposing to rename the subsection 
``Lactation'' because the focus of the subsection is primarily on the 
breast-fed child rather than on the lactating woman. In labeling, the 
identifying numbers for the subsections under the section ``8 Use in 
Specific Populations'' would be 8.1 for ``Pregnancy'' and 8.2 for 
``Lactation.'' The identifying number 8.3 would be available for future 
use.

B. Pregnancy Subsection

    The proposed rule would amend Sec.  201.57(c)(9)(i) by entirely 
replacing the format and content of the ``Pregnancy'' subsection. As 
discussed in section II.A of this document, the pregnancy category 
system has been criticized as being confusing and overly simplistic. 
The standardized statements required by current regulations do not 
distinguish information about risk alone from judgments based on both 
risk and benefit. In addition, the statements associated with the 
pregnancy categories do not take into account that a woman may already 
have been exposed to a drug before learning she is pregnant, and thus 
considerations for her may differ from those for a women who has not 
yet been exposed to a drug during pregnancy. The agency believes that 
advice and cautions about drug use should be clear and should 
specifically relate to the particular clinical situation, which 
includes whether exposure has already occurred or is being 
contemplated. The clinical situation also includes the risks presented 
if the woman has a condition or disease that remains untreated during 
her pregnancy.
    FDA's process for developing this model for the pregnancy and 
lactation subsections of labeling included establishing an internal 
working group to obtain extensive input from experts from multiple 
disciplines across the Center for Drug Evaluation and Research and the 
Center for Biologics Evaluation and Research. The working group 
carefully explored a multitude of models to determine whether a 
different pregnancy category system could accurately and consistently 
communicate differences in degrees of maternal and fetal risk. The 
working group considered systems employed by other countries, including 
the European Union and Australia, but concluded that these approaches 
either did not address degrees of risk, or that these approaches simply 
provided statements that directed clinicians whether or not to use a 
product without describing risk information in a clinically meaningful 
way. The working group also explored developing a new model using 
alpha-numeric symbols or character/graphics to represent a continuum of 
risk. This approach included building tables and matrices of evidence-
based criteria that might underlie each category along the risk 
continuum. When the working group 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.
    FDA concluded that using a category system to characterize the 
risks of drug use during pregnancy would not be appropriate because of 
the complexity of medical decisionmaking about drug use during 
pregnancy. Various combinations of reproductive toxicology data, human 
pregnancy exposure data, and information about the mother's condition 
define a risk/benefit equation for each individual patient and her 
circumstances. As for any drug in any patient, prescribing and drug use 
decisions that affect both mother and fetus require consideration of 
various clinical and individual factors including the effects of the 
drug on the mother, the severity of the mother's condition, maternal 
tolerance of the drug, coexisting maternal conditions, the impact of 
maternal illness on the fetus, and the available alternative therapies. 
These conclusions mirror and support feedback FDA obtained from the 
public through the 1997 part 15 hearing and in Advisory Committee 
meetings and focus groups with experts and other clinicians who care 
for pregnant women. The feedback from the participants in these 
activities made it clear that the explanation of what is meant by any 
determination of ``risk'' or ``hazard'' is equally, if not more, 
important than the risk determination itself. 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 
much more complex constructs in clinical medicine than in other areas, 
such as environmental exposure or consumer product ratings. For similar 
reasons, FDA does not apply symbol or letter designations of risk to 
other potential toxicities or adverse effects expected with medical 
product use. Accordingly, FDA believes 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.
    One of FDA's primary objectives in developing the model labeling 
format in response to the part 15 hearing and

[[Page 30839]]

early focus group testing was to make a clear distinction between risk 
information and clinical management information. The model format 
originally contained three components in the following order: Clinical 
management, summary risk assessment, and discussion of data. Committee 
members at the June 1999 advisory committee stated that the summary 
risk assessment was the most important information in pregnancy 
labeling and therefore should precede the clinical considerations 
component. FDA agrees that the risks should be presented first, 
followed by clinical considerations. Accordingly, under the proposed 
rule, pregnancy labeling would contain a fetal risk summary, clinical 
considerations, and data discussion, in that order. Since developing 
the model format, the agency has concluded that pregnancy labeling 
should contain two additional components: Pregnancy exposure registry 
information (if applicable) and a general statement about the 
background risk of fetal developmental abnormalities. These two 
components, as well as the reasons for including them, are discussed in 
detail below. Thus, the proposed ``Pregnancy'' subsection would require 
prescription drug labeling to contain, under the subheading ``8.1 
Pregnancy,'' the following information: (1) Pregnancy exposure registry 
information (if applicable), (2) a general statement about the 
background risk of fetal developmental abnormalities, (3) a fetal risk 
summary, (4) clinical considerations, and (5) data. Information on 
labor and delivery would be included under clinical considerations of 
the pregnancy subsection because, from a medical perspective, labor and 
delivery is the end phase of pregnancy. FDA seeks comment on how these 
elements should be ordered to optimize the clinical usefulness of this 
labeling subsection. Specifically, FDA is interested in comments on 
whether the fetal risk summary should precede the pregnancy registry 
contact information and the information on background risk.
    FDA's current regulations permit omission of the ``Pregnancy'' 
subsection of labeling if the drug is not absorbed systemically and is 
not known to have a potential for indirect harm to the fetus. In 
contrast, the proposed rule would require that the labeling for all 
drugs contain a ``Pregnancy'' subsection. The agency believes that 
labeling that omits the ``Pregnancy'' subsection is confusing because 
the reader has no way of knowing why that subsection has been omitted. 
It is unlikely that most health care providers are aware that the 
``Pregnancy'' subsection may be omitted when the drug is not absorbed 
systemically. Thus, the lack of a ``Pregnancy'' subsection does not 
necessarily signal to the reader that the drug is not absorbed 
systemically. Furthermore, in some cases, particularly with older 
labeling, there may be no ``Pregnancy'' subsection even when the drug 
is systemically absorbed. To correct this potential source of 
confusion, the proposed rule would require that the labeling of all 
drugs contain a ``Pregnancy'' subsection. However, when the drug is not 
systemically absorbed, the fetal risk summary would 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.''
1. Pregnancy Exposure Registry Information (Proposed Sec.  
201.57(c)(9)(i)(A))
    FDA believes that appropriately conducted pregnancy exposure 
registries are an important mechanism for the collection of clinically 
relevant data concerning the effects of exposure to drugs during human 
pregnancy. Because of its belief in the value of pregnancy exposure 
registries, the agency has taken a number of steps to facilitate the 
establishment of well-designed pregnancy exposure registries and to 
encourage participation in such registries. In August 2002, the agency 
published a guidance for industry on ``Establishing Pregnancy Exposure 
Registries'' to provide sponsors with recommendations on the design of 
pregnancy exposure registries (67 FR 59528, September 23, 2002). FDA's 
Office of Women's Health maintains a Web site (https://www.fda.gov/
womens/registries/default.htm) that explains what a pregnancy registry 
is and lists pregnancy registries currently enrolling pregnant women 
with specific medical conditions and women using specific drugs. 
Providing information about pregnancy exposure registries in 
prescription drug labeling is an additional step to encourage 
participation in registries.
    Data from pregnancy registries have been used to support important 
labeling changes for certain drugs. The agency anticipates that, under 
the proposed labeling format, data from pregnancy registries, among 
other types of data, would be used to update labeling that, in most 
cases, would otherwise contain only animal data, and thus labeling 
would provide more clinically useful information for health care 
providers and their patients.
    The proposed rule states that, 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 stated at the beginning of the ``Pregnancy'' subsection of 
labeling. FDA believes that placing this information in a position of 
prominence in prescription drug labeling may encourage participation in 
pregnancy registries by making it easier for health care providers and 
their patients to learn of pregnancy registries and the means to 
contact them. This information may also be appropriate for inclusion in 
a Medication Guide (patient labeling) under 21 CFR part 208.
    If there is no pregnancy registry for the drug, the labeling is not 
required to contain any statement about pregnancy registries.
2. General Statement About Background Risk (Proposed Sec.  
201.57(c)(9)(i)(B))
    In all pregnancies, there is a risk that there will be an adverse 
outcome, even if the mother takes no medications during her pregnancy. 
This risk is usually referred to as the background risk. Rates of 
adverse pregnancy outcomes vary with maternal age and underlying 
maternal medical conditions (Ref. 5). Fifteen to twenty percent of 
recognized pregnancies result in spontaneous abortion or miscarriage 
(loss prior to 20 weeks) (Ref. 6), and 1 in 200 known pregnancies 
results in fetal death or stillbirth (loss after 20 weeks) (Ref. 7). 
One out of 28 infants is born with serious birth defects (i.e., those 
resulting in physical or mental disability or death) (Ref. 1). Except 
for genetic syndromes and chromosomal abnormalities, most birth defects 
have no known cause. Minor birth defects may be 10 to 20 times more 
common than major ones, and 20 percent of infants with one or more 
minor birth defects also have a major birth defect (Ref. 8).
    Because many women of reproductive age are not aware that there is 
a background risk in all pregnancies, physicians on the advisory 
committee and those who participated in focus testing of the model 
format suggested th