Toll-Free Number for Reporting Adverse Events on Labeling for Human Drug Products, 63886-63897 [E8-25670]
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Federal Register / Vol. 73, No. 209 / Tuesday, October 28, 2008 / Rules and Regulations
33°37′ N., longitude 86°45′ W.; thence to
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Issued in Washington, DC, on October 23,
2008.
Pamela Hamilton-Powell,
Director, Office of Rulemaking.
[FR Doc. E8–25692 Filed 10–27–08; 8:45 am]
BILLING CODE 4910–13–P
and the word ‘‘mailed’’ is removed, and
the word ‘‘posted’’ is added in its place.
§ 35.14
[Corrected]
2. On page 57532, in the third column,
in § 35.14, instruction 15a is revised to
read as follows: In paragraph (a),
introductory text, the phrase ‘‘(fuel
clause)’’ is added after the phrase ‘‘Fuel
adjustment clauses’’, and the phrase ‘‘,
tariffs or service agreements’’ is added
after the phrase ‘‘rate schedules’’
anywhere it appears in the paragraph’s
introductory text.
■
Kimberly D. Bose,
Secretary.
[FR Doc. E8–25611 Filed 10–27–08; 8:45 am]
BILLING CODE 6717–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
DEPARTMENT OF ENERGY
21 CFR Parts 201, 208, and 209
Federal Energy Regulatory
Commission
[Docket No. FDA–2003–N–0313] (formerly
Docket No. 2003N–0342)
18 CFR Part 35
RIN 0910–AC35
[Docket No. RM01–5–000, Order No. 714]
Toll-Free Number for Reporting
Adverse Events on Labeling for Human
Drug Products
Electronic Tariff Filings
October 22, 2008.
AGENCY:
Federal Energy Regulatory
Commission.
ACTION: Final rule; correction.
AGENCY:
ACTION:
The Federal Energy
Regulatory Commission published a
document in the Federal Register on
October 3, 2008 (73 FR 57515), revising
Commission rules. That document
inadvertently included two nonsubstantive errors in the instructions for
the amendatory language. This
document corrects those instructions.
DATES: Effective Date: Effective on
November 3, 2008.
FOR FURTHER INFORMATION CONTACT:
Andre Goodson, Office of the General
Counsel, Federal Energy Regulatory
Commission, 888 First Street, NE.,
Washington, DC 20426, (202) 502–8560,
Andre.Goodson@ferc.gov.
SUPPLEMENTARY INFORMATION: In FR Doc.
E8–22500 appearing on page 57515 in
the Federal Register of Friday, October
3, 2008, the following corrections are
made:
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SUMMARY:
§ 35.13
[Corrected]
1. On page 57532, in the second
column, in § 35.13, instruction 14g is
revised to read as follows: In paragraph
(b)(3), the word ‘‘schedule’’ is removed;
■
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Food and Drug Administration,
HHS.
Final rule.
SUMMARY: The Food and Drug
Administration (FDA) is issuing a final
rule that confirms the interim final rule
entitled ‘‘Toll-Free Number for
Reporting Adverse Events on Labeling
for Human Drug Products’’ (73 FR 402,
January 3, 2008) (interim final rule) and
responds to comments submitted in
response to the request for comments in
the proposed rule of the same title (69
FR 21778, April 22, 2004) (proposed
rule). This final rule affirms the interim
final rule’s requirement for the addition
of a statement to the labeling for certain
human drug products for which an
application is approved under section
505 of the Federal Food, Drug, and
Cosmetic Act (the act). The statement
includes a toll-free number and advises
that the number is to be used only for
reporting side effects and is not
intended for medical advice (the side
effects statement). This final rule also
affirms the interim final rule’s addition
of new part 209 to the regulations
requiring distribution of the side effects
statement. This final rule implements
provisions of the Best Pharmaceuticals
for Children Act (the BPCA) and the
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Food and Drug Administration
Amendments Act of 2007 (FDAAA).
DATES: Effective Date: This final rule is
effective November 28, 2008.
Compliance Date: The compliance
date for this final rule is July 1, 2009.
For more information on the compliance
date see section II of the SUPPLEMENTARY
INFORMATION section of this document.
FOR FURTHER INFORMATION CONTACT:
Carol Drew, Center for Drug Evaluation
and Research, Food and Drug
Administration, 10903 New Hampshire
Ave., Bldg. 51, rm. 6306, Silver Spring,
MD 20993–0002, 301–796–3601.
SUPPLEMENTARY INFORMATION:
I. Background
A. BPCA and Proposed Rule
The BPCA (Public Law 107–109)
directed FDA to issue a final rule
requiring the labeling of each human
drug product for which an application
is approved under section 505 of the act
(21 U.S.C. 355) to include: (1) A toll-free
number maintained by FDA for the
purpose of receiving reports of adverse
events regarding drugs and (2) a
statement that the number is to be used
for reporting purposes only, not to
receive medical advice. Collectively, we
refer to the toll-free number and
reporting statement as the ‘‘side effects
statement.’’ The BPCA stated that the
final rule must implement the labeling
requirement to reach the broadest
consumer audience and minimize the
cost to the pharmacy profession.
On April 22, 2004 (69 FR 21778), FDA
published a proposed rule entitled
‘‘Toll-Free Number for Reporting
Adverse Events on Labeling for Human
Drug Products.’’ FDA received 22
comments on the proposed rule.
B. FDAAA Requirements and Interim
Final Rule
On September 27, 2007, the President
signed into law FDAAA (Public Law
110–85). Among other things, FDAAA
reauthorized the BPCA. Section 502(f) of
FDAAA stated that ‘‘the proposed rule
* * * ‘Toll-Free Number for Reporting
Adverse Events on Labeling for Human
Drug Products’ * * * shall take effect
on January 1, 2008,’’ unless FDA issues
a final rule before that date. FDA was in
the process of analyzing the comments
on the proposed rule and conducting
research on consumer comprehension of
the proposed side effects statements
when FDAAA was enacted. FDA did not
issue a final rule prior to January 1,
2008. Therefore, by operation of law, the
proposed rule took effect on January 1,
2008.
FDAAA mandated one change to the
proposed rule. Section 502(f)(2) of
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FDAAA states that the proposed rule
shall not apply to over-the-counter
(OTC) drugs marketed with an
application approved under section 505
of the act (application OTC drug
products) if these application OTC drug
products meet certain labeling
requirements.
On January 3, 2008 (73 FR 402), FDA
published an interim final rule to: (1)
Codify the modifications made by
FDAAA to the proposed rule, (2) notify
the public that the agency planned to
complete the ongoing research testing
the proposed side effects statements for
consumer comprehension, and (3)
establish a compliance date of January
1, 2009. The interim final rule stated
that the agency did not intend to take
enforcement action prior to January 1,
2009, and that the agency would
complete the research on the side effects
statements and either finalize the
interim final rule as published or
publish a final rule that amends the
interim final rule.
II. Highlights of the Final Rule
The preamble to the proposed rule
described the provisions of this rule in
detail. In the preamble to the interim
final rule we described the changes to
the proposed rule required by FDAAA.
In this final rule we respond to
comments received on the proposed
rule and finalize the regulations. No
comments were received on the interim
final rule.
As described in the interim final rule,
one substantive change has been made
to the regulatory provisions published
in the proposed rule: Section
201.66(c)(5)(vii) (21 CFR
201.66(c)(5)(vii)) has been modified to
require that only approved application
OTC drug products whose packaging
does not include a toll-free number
through which consumers can report
complaints to the manufacturer or
distributor of the drug product are
required to include the side effects
statement in labeling. As discussed
previously in this document, this
modification was mandated by FDAAA.
In the interim final rule, FDA
established a compliance date of
January 1, 2009, and notified the public
that we intended to exercise
enforcement discretion and not take
enforcement actions with regard to the
effective regulations until January 1,
2009. In the interim final rule we stated
that the effective date and
implementation schedule for the final
rule would be designed to minimize the
burden of any additional regulatory
changes for affected entities who must
comply with the final rule. Since the
publication of the interim final rule, we
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have received several inquiries about
specific provisions of the interim final
rule. Given the short time interval
between the publication date of this
final rule and the original compliance
date of January 1, 2009, we are delaying
the compliance date by six months to
July 1, 2009. We believe this brief delay
is appropriate because we have made no
changes to the codified. All affected
entities are required to be in compliance
by July 1, 2009.
III. Comments and Agency Response
The agency received 22 comments on
the proposed rule. Comments were
received from prescription and
nonprescription drug manufacturers;
trade organizations representing drug
manufacturers; pharmacists,
pharmacies, and pharmacy-related
interests; consumer organizations;
professional associations and
organizations; one member of Congress;
one agency of a foreign government; and
others.
To make it easier to identify
comments and our responses, the word
‘‘Comment,’’ in parentheses, appears
before the comment’s description, and
the word ‘‘Response,’’ in parentheses,
appears before our response. We have
numbered each comment to help
distinguish between different
comments. Similar comments are
grouped together under the same
number. The number assigned to each
comment is purely for organizational
purposes and does not signify the
comment’s value or importance or the
order in which it was received. A
summary of the comments received and
our responses follow.
A. Scope of the Rule
(Comment 1) The agency received 7
comments opposing the proposed
requirement that the labeling for
application OTC drug products contain
the toll-free number and statement
mandated by the BPCA. These
comments argued that Congress did not
intend the BPCA requirements to apply
to application OTC drug products.
(Comment 2) Two comments
suggested that FDA limit the
applicability of the regulatory
provisions to new drugs that have been
approved for marketing within 5 years
of the date of the final rule, and that the
regulation’s requirements attach for only
5 years following a new drug’s approval.
These comments requested that FDA
limit the regulatory provisions to the
approximately 30 new molecular
entities (NMEs) that are approved each
year for the 5-year period after they are
approved and suggested that reporting
should be targeted to encourage
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consumer reporting of adverse reactions
from newer drugs.
(Response) Section 17 of the BPCA
required that the labeling of each drug
for which an application is approved
under section 505 of the act include the
toll-free number and statement. Because
OTC drug products may be approved
under section 505 of the act, we
proposed that the labeling for all
application OTC drug products contain
the BPCA mandated requirements.
However, in section 502(f)(2) of
FDAAA, Congress stated that the
proposed rule shall not apply to OTC
drugs marketed with an application
approved under section 505 of the act if
these application OTC drug products
meet certain labeling requirements.
Specifically, section 505(f)(2) of the act
states that the proposed rule shall not
apply to a drug: (1) For which an
application is approved under section
505 of the act; (2) that is not described
under section 503(b)(1) of the act (21
U.S.C. 353(b)(1)); and (3) the packaging
of which includes a toll-free number
through which consumers can report
complaints to the manufacturer or
distributor of the drug. In the interim
final rule, we stated that this provision
means that the proposed provisions do
not apply to application OTC drug
products if the product’s packaging
includes a manufacturer’s or
distributor’s toll-free number for
reporting complaints. Accordingly, this
final rule includes a modified
§ 201.66(c)(5)(vii) reflecting the changes
to the proposed rule required by
FDAAA.
As to the comments suggesting that
we limit the scope of the rule to a
specific subset of NMEs or for a specific
number of years for specific products,
we note that neither the BPCA nor
FDAAA gives FDA the legal authority to
limit the scope of the rule in this way.
The BPCA requires that the labeling of
each drug product approved under
section 505 of the act, regardless of the
date on which approved, include the
side effects statement.
B. Wording of the Side Effects Statement
As stated in the preamble to the
proposed rule, section 17 of the BPCA
requires that the labeling for each drug
approved under section 505 of the act
include: (1) A toll-free number
maintained by FDA for the purpose of
receiving reports of adverse events
regarding drug products and (2) a
statement that the number is to be used
for reporting purposes only, not to seek
medical advice. FDA considered these
requirements and proposed a
conforming statement for prescription
drug products: ‘‘Call your doctor for
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medical advice about side effects. You
may report side effects to FDA at 1–800–
FDA–1088.’’
As stated in the preamble to the
proposed rule, the drug facts labeling
format for OTC drug products required
us to modify the side effects statement
to correspond to the drug facts format
(§ 201.66). The OTC requirement was
included in the specific subheadings for
presenting warnings in the drug facts
format (§ 201.66(c)(5)(vii)). In
combination with the requirements of
§ 201.66(c)(5)(vii), the labeling provision
for the application OTC drug products
was proposed to read: ‘‘Stop use and ask
a doctor if • side effects occur. You may
report side effects to FDA at 1–800–
FDA–1088.’’
We solicited comments on the
proposed wording of the side effects
statements and on whether the term
‘‘side effects’’ should be further
qualified.
(Comment 3) We received several
comments suggesting that we test on
consumers the proposed language for
the side effects statements, as well as
alternatives, to evaluate consumer
comprehension and determine the best
and most precise terminology for the
statement.
(Comment 4) Among the comments
we received on the proposed wording of
the side effects statement, one comment
asserted that the proposed statement is
concise and makes it clear that the
number is not for medical advice.
Several comments suggested specific
additions to the wording of the
statements, including: Using the term
‘‘health care professional’’ instead of, or
in addition to, the term ‘‘doctor’’;
adding the term ‘‘pharmacist’’ to the
statement to suggest that consumers call
either their doctor or pharmacist for
medical advice about side effects;
adding wording to clarify that FDA does
not give medical advice and is not
offering medical consultation; and/or
adding wording to clarify that FDA
should not be called in case of medical
emergency and that FDA should only be
called once any medical emergency is
resolved.
(Comment 5) Of the six comments we
received on whether to use the term
‘‘side effects’’ or ‘‘adverse event,’’ five
supported use of the term ‘‘side effects’’
as more consumer friendly. Of those
comments, two suggested qualifying the
term with ‘‘serious’’ and one opposed
adding any qualifications to the term.
Those suggesting qualifying the term
were concerned about FDA receiving
numerous unnecessary reports about
side effects that are well-known and
expected, not serious; the comment
opposed to qualifying the term was
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concerned that qualifying the statement
would limit the types of events
reported, discourage consumers from
reporting, and hinder the agency’s
ability to identify trends from reporting.
One comment suggested that use of the
term ‘‘side effects’’ would have a
negative effect on drug marketing.
(Comment 6) Among the comments
we received on the wording of the side
effects statement for application OTC
drug products were comments opposing
the inclusion of the statement in the
‘‘warnings’’ section of the drug facts
format and the specific ‘‘stop use’’
language that section requires. One
comment suggested placing the side
effects statement under the ‘‘when using
this product’’ subheading as the last
bullet, so that the labeled adverse events
precede the side effects statement.
Comments opposed the ‘‘stop use’’
language on the grounds that stopping
use of an OTC drug product may be
inappropriate. Comments also stated
that the ‘‘stop use’’ language has a
greater impact on OTC drug products
than it does on prescription drug
products, i.e., there is no corresponding
requirement telling consumers using
prescription drug products to stop using
the product if they experience a side
effect. Several comments also stated that
because the drug facts format requires a
telephone number for consumers to call
to get answers to questions, there would
be confusion caused by having more
than one phone number in the labeling
for consumers to call.
(Response) After reviewing the
comments received on the proposed
rule, FDA initiated a two-part study to
test consumer comprehension of the
wording of the proposed side effects
statements. Part one of the study
consisted of focus groups held to narrow
the field of potential statement
alternatives. When describing the side
effects statement for prescription drug
products, participants in the focus
groups were asked whether they
preferred the use of ‘‘doctor’’ or ‘‘health
care provider,’’ ‘‘doctor’’ or ‘‘doctor or
pharmacist,’’ ‘‘serious side effects’’ or
‘‘side effects,’’ and ‘‘adverse events’’ or
‘‘side effects,’’ in the statement, as well
as other language variations. The focus
groups were completed in 2006 (OMB
Control No. 0910–0497).
The second part of this research was
a labeling comprehension experimental
study conducted over the Internet (OMB
Control No. 0910–0603). Nine
statements were tested as informed by
the prior focus group testing. A total of
1,674 men and women ranging in age
from 21 to 95 with varying levels of
education completed the study. Five
different versions of the side effects
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statement for prescription drug products
and four different versions of the side
effects statement proposed for
application OTC drug products were
tested. Approximately 40 percent of the
sample of consumers saw one of the
four OTC side effects statements and the
other 60 percent of the sample saw one
of the five prescription drug side effects
statements. FDA’s final report on the
study was completed in 2008 and is
available in the docket for this rule.
In answer to questions about the best
wording for the side effects statement,
only one of the statements tested was
significantly less clear than the others.
We eliminated this statement from
consideration. All other statements were
rated very similarly by participants.
Participants who responded to the side
effects statements for prescription drugs
responded nearly identically to
participants who responded to the side
effects statements for OTC drug
products. Given these results, FDA
concluded that in choosing among the
statements, considerations such as
length, readability, and other factors
could be used to select among the
remaining side effects statements.
Taking into account the results from the
labeling comprehension study and other
factors, we have chosen to finalize the
side effects statements as originally
proposed.
Additionally, to address comments
received indicating concern that
consumers would call FDA for medical
advice and suggested language changes
to prevent this, we queried participants
in the study about whether they would
choose to call FDA or their doctor in
certain circumstances. Participants did
not show an inclination to call FDA for
medical advice. Among those that
indicated a willingness to call FDA at
all, the majority appropriately indicated
that FDA was for reporting side effects
and their doctors were for personal
medical advice. Most individuals
indicated that they would contact their
doctor first regardless of the particular
side effect they experienced. We
conclude from this finding that the
language proposed for the side effects
statement is sufficient to convey the
intention of the BPCA requirement that
the statement is to be used for reporting
purposes only, not to receive medical
advice.
Similarly, with regard to concerns
that we should qualify the type of side
effect that should be reported to FDA by
adding the word ‘‘serious’’ to ‘‘side
effect’’ because FDA would receive
numerous unnecessary reports, our
research indicates that consumers are
able to distinguish between serious and
non-serious side effects and would
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contact their doctor or hospital
emergency room in the case of a
‘‘serious side effect.’’ A doctor who
determines that a patient has had a
serious side effect from a drug product
may then report the side effect to FDA.
Regarding the comments we received
on the specific language of the OTC side
effects statement and its placement in
the ‘‘warnings’’ section of the drug facts
format, we disagree that placement in
the ‘‘warnings’’ section is inappropriate
or that the ‘‘stop use’’ language is
inappropriate. The warnings section of
the drug facts format label for OTC drug
products may include several
statements about possible side effects,
telling consumers when to consult a
doctor, pharmacist, or other health care
professional in the use of the product.
Consumers using OTC drug products
most likely are not under the direct care
of a health care practitioner, whereas
consumers using prescription drug
products are under the care of a health
care practitioner. We believe it is
appropriate for the side effects
statement to instruct consumers using
an OTC drug product who believe they
are experiencing a side effect to stop
using the drug product and consult their
doctor before continuing use of the
product.
We do not agree that having more
than one phone number in the drug
facts format labeling would be confusing
to consumers. The agency’s toll-free
number clearly indicates it is an FDA
phone number for reporting side effects.
Our research indicates that the OTC side
effects statement is understood by
consumers. Moreover, section 502(f)(2)
of FDAAA states that application OTC
drug products that include a toll-free
number through which consumers can
report complaints to the manufacturer
or distributor of the drug product are
not required to include the side effects
statement. In all likelihood this means
that fewer application OTC drug
products will have FDA’s side effects
statement in their labeling. Therefore,
we anticipate that the majority of
application OTC drug products will not
have more than one phone number in
their labeling for reporting side effects,
reducing any potential for confusion.
C. Location of the Side Effects Statement
in FDA-Approved Labeling
We proposed to require the side
effects statement in two categories of
drug product labeling: (1) FDAapproved Medication Guides for drugs
approved under section 505 of the act,
and (2) the labeling for application OTC
drug products. We stated that
manufacturers voluntarily may include
the side effects statement in Medication
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Guides for products not approved under
section 505 of the act or in patient
package inserts (PPIs). For reasons
stated in the proposed rule, we did not
propose requiring the side effects
statement in physician labeling or PPIs,
but we solicited comments on those two
issues. In addition, we proposed that the
side effects statement be distributed
with each prescription drug product,
both new and refills, approved under
section 505 of the act and dispensed to
consumers by pharmacies and
authorized dispensers in an outpatient
setting.
(Comment 7) We received one
comment stating that the side effects
statement should be on all package
labeling, including refills, to ensure
maximum consumer exposure so that
when consumers experience a side
effect, they will find the side effects
statement wherever they turn first for
information.
(Comment 8) One comment suggested
that instead of putting the side effects
statement in drug product labeling,
FDA’s MedWatch telephone number
appear in public telephone books next
to the Poison Control phone number.
(Comment 9) Another comment
suggested that consumers be given small
magnets with FDA’s MedWatch phone
number obviating the need for repeated
dispensing of this information each time
a patient visits a pharmacy.
(Response) We believe that the
requirements of this final rule will
ensure that the side effects statement
reaches a broad consumer audience
while minimizing the burden on the
pharmacy profession, as required by the
BPCA. We require that the side effects
statement appear in Medication Guides
for drug products approved under
section 505 of the act and in the labeling
for certain application OTC drug
products, and that pharmacies distribute
the statement with all new prescriptions
and refills for drug products approved
under section 505 of the act. Under the
BPCA, Congress required that FDA
include the side effects statement in the
labeling of each drug product approved
under section 505 of the act. Placing the
number in public telephone books or on
magnets given to consumers would not
satisfy the legal requirements of the
BPCA.
(Comment 10) We received three
comments supporting the inclusion of
the side effects statement in approved
Medication Guides. One comment
suggested that this be the exclusive
place for the labeling requirement. We
do not agree that requiring the side
effects statement exclusively in
Medication Guides would satisfy the
requirements of the BPCA. FDA-
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approved Medication Guides are
prepared by manufacturers for a limited
number of drug products that FDA
determines pose a ‘‘serious and
significant public health concern’’ (21
CFR 208.1). Given the limited number of
drug products that have FDA-approved
Medication Guides, only requiring the
side effects statement in Medication
Guides would not satisfy the BPCA
requirement to reach the broadest
consumer audience.
(Response) We did not propose
including the side effects statement in
physician labeling. In the proposed rule
we stated that while consumers have
access to physician labeling reprinted in
the Physician Desk Reference (PDR),
physician labeling is not written for the
consumer audience. We solicited
comments on this issue.
(Comment 11) We received one
comment supporting our decision not to
include the side effects statement in
physician labeling. This comment
agreed that physician labeling is not
intended or written for a consumer
audience and that it is not necessary to
include both a manufacturer’s name and
telephone number and FDA’s telephone
number in physician labeling.
(Comment 12) We received three
comments suggesting we require the
side effect statement in physician
labeling. These comments argued that
some consumers may obtain physician
labeling either over the Internet or upon
request from their pharmacist and that
FDA’s toll-free number should be in all
FDA-approved prescription labeling to
ensure its widest exposure.
(Response) At the time the proposed
rule was written, the agency’s proposed
rule to revise the physician labeling
requirements in §§ 201.56 and 201.57
(21 CFR 201.56 and 201.57) was under
review (the physician labeling rule). On
January 24, 2006, the agency published
the final physician labeling rule (71 FR
3922). Section 201.57 of the physician
labeling rule requires that the following
verbatim statement appear in the
highlights section of the prescribing
information under ‘‘adverse reactions’’
(§ 201.57(a)(11)(ii)): ‘‘To report
SUSPECTED ADVERSE REACTIONS,
contact (insert name of manufacturer) at
(insert manufacturer’s phone number) or
FDA at (insert current FDA phone
number and Web address for voluntary
reporting of adverse reactions).’’ As
physician labeling is written for the
medical profession, the term ‘‘adverse
reactions’’ was selected for this
statement instead of the more consumerfriendly term ‘‘side effects.’’ While
placing this newly required statement in
the highlights section of physician
labeling will alert consumers who
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consult or refer to physician labeling
that they can report adverse reactions
directly to FDA at the MedWatch
telephone number or Web site, the
agency concludes that pharmacies’
distribution of only the physician
labeling containing this statement
would not be sufficient to satisfy the
requirement of the BPCA to reach the
broadest consumer audience. In
addition, the statement required under
the physician labeling rule does not
include the statement required by the
BPCA that the phone number be used
only for reporting side effects and not to
obtain medical advice. Therefore, while
the MedWatch phone number for
reporting side effects has been added to
physician labeling through the
physician labeling rule, distributing
physician labeling has not been added
to this rule as a means for pharmacies
to meet the requirements of distributing
the side effects statement.
The proposed rule did not include the
side effects statement in PPIs. PPIs are
required by FDA for certain drug
products, including oral contraceptives
and estrogen drug products (21 CFR
310.501 and 310.515) and, in addition,
some manufacturers also voluntarily
produce PPIs for drug products. PPIs are
based on physician labeling and are
often distributed to consumers when the
drug product is dispensed. In the
preamble to the proposed rule, we
stated that manufacturers may
voluntarily include the side effects
statement in PPIs. We solicited
comments on this issue.
(Comment 13) We received five
comments suggesting that we reconsider
our decision not to include the side
effects statement in PPIs. Of these four
comments, one suggested that the PPI
could be the first source of information
consumers turn to when they
experience a side effect; one suggested
that it may be beneficial for consumers
to see the statement more than once; one
stated that including the statement in
PPIs was a viable option; and two stated
that requiring the side effects statement
in PPIs would be a way to minimize the
impact of the rule on pharmacies.
(Response) We have considered these
comments and have concluded that, in
consideration of the other requirements
in this rule, requiring manufacturers to
include the side effects statement in
PPIs would have a minimal impact on
meeting the goals of the BPCA.
Furthermore, since drug products with
FDA-approved PPIs are a subset of all
prescription drug products, requiring
the side effects statement in PPIs would
most likely require pharmacies to
maintain a tracking system to identify
which drug products have a compliant
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PPI in order for pharmacies to know
whether they had distributed the side
effects statement through the PPI in
compliance with this rule. Therefore we
conclude that it is unlikely that adding
the statement to PPIs would minimize
the burden of this rule on pharmacies,
and it is more likely that pharmacies
would choose one of the other proposed
five methods of distributing the side
effects statement. As stated in the
preamble to the proposed rule,
manufacturers may voluntarily add the
side effects statement to PPIs, however
we are not adding the distribution of a
PPI to the list of options available to
authorized dispensers or pharmacies for
compliance with this rule.
(Comment 14) We did not require
manufacturers to provide the side
effects statement on labeling for unit-ofuse drug products. We received three
comments stating that FDA could
minimize the impact of the rule on
pharmacies by requiring manufacturers
of unit-of-use drug products to provide
the side effects statement on the labeling
of the exterior package.
(Response) We have considered these
comments and have concluded that the
proposed provisions are adequate to
address the goals of the BPCA to reach
a broad consumer audience; therefore
we are not requiring that manufacturers
add the side effects statement to unit-ofuse labeling. In addition, requiring the
side effects statement in the labeling for
unit-of-use drug products is unlikely to
decrease the burden of this rule on
pharmacies, since pharmacies would
most likely have to maintain a tracking
system to know whether they had
distributed the side effects statement
through dispensing a unit-of-use drug
product in compliance with this rule.
We believe it is more likely that
pharmacies would choose one of the
other five proposed methods of
distributing the side effects statement.
Consumers will receive the side effects
statement when the unit-of-use drug
product is dispensed by an authorized
dispenser or pharmacy using one of the
five distribution methods proposed.
(Comment 15) We did not require
health care practitioners who dispense
drug samples in the course of their
professional practice to distribute the
side effects statement. The proposed
rule stated that patients receiving drug
products in these circumstances will
rely on their health care practitioners to
monitor and report adverse events. We
received two comments asking us to
require distribution of the side effects
statement with drug samples.
(Response) Drug samples generally are
given to consumers in conjunction with
a new prescription. Patients who
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initially receive drug samples are under
the care of their doctor or health care
practitioner and generally use them in
the short term and followup by filling a
new prescription. For a drug product
approved under section 505 of the act,
consumers will receive the side effects
statement upon filling the new
prescription for the drug product for
which they initially received a sample.
We recognize that there may be
situations in which health care
practitioners provide drug samples to
patients on an ongoing basis, such as in
clinics for low-income patients.
However such patients should be
instructed by the health care
practitioner providing the drug sample
as to its directions for use and possible
side effects. We do not believe that the
benefit of requiring that the side effects
statement be distributed with drug
samples would be balanced by the
burden such a requirement would
impose on health care practitioners.
D. Distribution of Side Effects Statement
by Pharmacies and Authorized
Dispensers
We proposed that the side effects
statement be distributed with each
prescription drug product, both new
and refills, approved under section 505
of the act and dispensed to consumers
by pharmacies and authorized
dispensers in an outpatient setting. We
proposed five options through which
pharmacies and authorized dispensers
could distribute the side effects
statement, including the following: (1)
On a sticker attached to the package,
vial, or container of the drug product;
(2) on a preprinted pharmacy
prescription vial cap; (3) on a separate
sheet of paper; (4) in consumer
medication information (CMI); or (5) by
distributing the appropriate FDAapproved Medication Guide that
contains the side effects statement. We
solicited comments on other options
pharmacies might use for distribution.
(Comment 16) We received one
comment opposing a requirement to
place the side effects statement directly
on the label of the prescription vial or
container. This comment stated that in
many cases the vials or containers are
already too crowded, and requiring
another sticker on the container could
crowd out more important labels and
reduce the importance consumers
ascribe to these labels both because of
the number of stickers and because of
the placement of secondary information
in the stickers. We received one
comment supporting the placement of
the side effects statement on an
auxiliary label. We received another
comment stating that the most logical
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place for the side effects statement to
appear is in the CMI for the drug
product. Another comment suggested
that CMI not be the only means of
communicating the toll-free number, as
some pharmacies may not dispense CMI
for refill prescriptions.
(Comment 17) We received several
comments supporting our proposal to
provide multiple options for pharmacies
and authorized dispensers to distribute
the side effects statement. We received
two comments stating that while we
indicated we exercised discretion in
giving affected pharmacies flexibility in
complying with the law by providing
options, we failed to impose a
proportionate burden on manufacturers.
One comment stated that it is entirely
feasible for manufacturers to adhere
multiple copies of printed leaflets onto
bulk containers of drug products that
pharmacy personnel can then remove
from bulk containers and dispense with
each prescription filled.
(Comment 18) We received two
comments expressing concern about the
potential for consumers to lose or
dispose of paper messages (e.g., the
consumer medication information
option or the separate sheet of paper
option). One of these comments
requested that we require manufacturers
and pharmacists to work together to
include the side effects statement on
either the sticker or preprinted vial cap
with any separate printed materials
provided as a supplement. This
comment stated that if the package has
no cap, if there is no room on a package
for a sticker, or if the product already
requires a sticker for a different reason,
they would suggest that the sticker be
included inside the package so that
consumers can affix the sticker in a
place useful to them, such as a medicine
chest or pill caddy. Another comment
requested that we allow pharmacies the
option to distribute the side effects
statement by printing it directly on the
bag in which the pharmacy puts
prescription drugs before handing them
to consumers.
(Comment 19) Two comments
requested that pharmacies be allowed
the option to e-mail the side effects
statement to consumers along with
notice to these consumers that their
prescriptions are ready. These
comments stated that this would obviate
the need for the pharmacy to provide
the patient with a paper version of the
statement when the prescription is
picked up. We received two comments
requesting that we allow pharmacists to
exercise their judgment and discretion
in distributing the statement to a
consumer if a pharmacist is reasonably
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sure that a consumer already knows
about the agency’s toll-free number.
(Response) We have considered the
comments received and conclude that
the range of options provided to
pharmacies to distribute the side effects
statement is adequate to meet the
requirements of the BPCA. We disagree
that placing the side effects statement
on the pharmacy bag, sending the side
effects statement by e-mail when a
consumer is notified their prescription
is ready, or providing the side effects
statement on a separate sticker that
consumers could then affix to their
medicine chest or pill caddy would
effectively reach the broadest consumer
audience. While we recognize that a
consumer may throw away any
attachment a pharmacist provides when
dispensing a drug product, including
the CMI or a separate sheet of paper,
there is an even greater likelihood that
a consumer would throw away the
pharmacy bag that the prescription
came in or a small separate sticker, and
thus would not have the side effects
statement in proximity to the drug
product when needed. Similarly, e-mail
is easily deleted, and including the side
effects statement in an e-mail notifying
consumers when their prescription is
ready makes it likely that the consumers
will delete the e-mail before they even
pick up the prescription.
Pharmacies may provide voluntarily a
separate sticker to consumers with the
side effects statement for attachment in
the home as a public service if they
choose; however, distribution of such a
separate sticker would not meet the
distribution requirements of this rule.
Similarly, pharmacies may provide the
side effects statement voluntarily on
pharmacy bags or via e-mail, but
distribution of the side effects statement
using these methods likewise would not
meet the distribution requirements of
this rule. Also, we note that there is no
provision in the BPCA or FDAAA that
would allow us to grant pharmacists the
right to exercise their judgment or
discretion in deciding whether or not to
distribute the side effects statement to
an individual consumer.
E. Use of MedWatch System for
Consumer Reporting
As stated in the preamble to the
proposed rule, we proposed that FDA’s
existing MedWatch system be used to
fulfill the requirements of the BPCA for
providing a toll-free number for the
purpose of receiving adverse event
reports regarding drug products. While
we received comments supporting the
use of the MedWatch system to capture
consumer’s postmarket safety
information, we received several
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63891
comments suggesting changes to the
MedWatch system. These comments are
beyond the scope of this rule. This rule
does not make specific changes to the
MedWatch system.
F. Postmarketing Safety Reporting
While the proposed rule suggested no
changes to FDA’s postmarketing safety
reporting system, we received several
comments about our postmarketing
safety reporting system and how data
received from the side effects statement
would affect the system. These
comments are beyond the scope of this
rule. This rule does not make specific
changes to FDA’s postmarketing safety
reporting system.
G. Implementation of Regulation
(Comment 20) We received one
comment expressing dissatisfaction
with the agency for not implementing
the rule in a timelier manner. This
comment also stated that the
compliance date FDA proposed was too
long and suggested a bifurcated
compliance structure whereby
pharmacies would notify consumers
immediately of the toll-free number, and
manufacturers would have 1 year to
make any required labeling changes. We
also received comments supporting the
1-year compliance period from both
pharmacy interests and drug
manufacturing interests. These
comments noted that pharmacies and
drug manufacturers need time to
integrate any printing/labeling changes
into existing systems.
(Response) In implementing the
requirements of the BPCA and FDAAA,
we believe it is important to work with
stakeholders and provide time for
updating labels and systems so that we
reach the best possible outcome for
constituent groups, including
consumers, pharmacists and other
health care professionals, drug
manufacturers, and the agency. With the
publication of this final rule, we believe
we have implemented the provisions of
the BPCA and FDAAA effectively.
(Comment 21) Two comments
suggested that, after full implementation
of the laws and all necessary
modifications to the MedWatch system,
FDA undertake extensive consumer
outreach, educating the public about the
right to report under the new
provisions. One comment suggested that
FDA, in cooperation with the OTC drug
manufacturers, implement a public
relations program to raise consumer
awareness of the necessity of reporting
unexpected adverse events to the
product manufacturer. These comments
stated that FDA should work with
consumer educators and health
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professionals to provide clear
information and educational materials
on how, what, and when to report.
Another comment suggested the agency
add specific questions to the ongoing
National Survey of Prescription
Medicine Information Received by
Consumers (at the physician’s office and
pharmacy) to track awareness of the side
effects statement and to determine to
what extent consumers contact FDA to
report a side effect.
(Response) The agency is in the
process of implementing numerous
safety initiatives under FDAAA that will
benefit consumers. Section 906(a) of
FDAAA requires published direct-toconsumer advertisements to include a
statement encouraging reporting of
negative side effects to FDA and
providing the MedWatch Web site and
phone number. Given that section
502(f)(2) of FDAAA likely will reduce
the number of voluntary reports FDA
receives on application OTC drug
products as a result of this rule, we do
not believe it is necessary to undertake
an extensive educational campaign
targeted at voluntary reporting for
application OTC drug products at this
time. However, should our experience
with reporting under these new
provisions indicate otherwise, we will
consider whether educational efforts for
the general public would be beneficial.
In addition, we note that the National
Survey of Prescription Medicine
Information Received by Consumers is
not currently ongoing. If this survey is
reinstated at a future date, we will
consider adding specific questions
relevant to the side effects statement at
that time as suggested by the comment.
IV. Analysis of Impacts
FDA has examined the impacts of the
final rule under Executive Order 12866
and the Regulatory Flexibility Act (5
U.S.C. 601–612), and the Unfunded
Mandates Reform Act of 1995 (Public
Law 104–4). Executive Order 12866
directs 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 an
economically significant regulatory
action under the Executive order.
The Regulatory Flexibility Act
requires agencies to analyze regulatory
options that would minimize any
significant impact of a rule on small
entities. Because the impact of the final
rule will be proportional to sales
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volumes, the agency concludes that this
final rule will not 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 $127
million, using the most current (2006)
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.
In accordance with Executive Order
12866, FDA has previously analyzed the
potential economic effects of this final
rule. We estimated that annualized costs
of the proposed rule would be $9.3
million to $22.6 million (69 FR 21778 at
21783). For the final rule, we project
that one-time costs will range from
approximately $38.0 million to $49.6
million and annual costs will range
from $12.4 million to $46.3 million. The
total annualized impact of the final rule
will range from $16.9 million to $52.2
million with a 3-percent discount rate
and from $17.8 million to $53.4 million
with a 7-percent discount rate. We are
unable to quantify the benefits of the
final rule. Although the estimated costs
of this final rule are higher than the
estimated costs of the preliminary
regulatory impact analysis, the agency
has determined that the rule is not an
economically significant regulatory
action as defined by the order.
A. Need for Regulation
The BPCA required that the labeling
of each drug approved under section
505 of the act be accompanied by a tollfree number and statement that the
number is for reporting adverse events,
not to receive medical advice. Because
OTC drug products may be approved
under section 505 of the act, we
proposed that the labeling for all
application OTC drug products include
the side effects statement. Subsequently,
FDAAA exempted any application OTC
drug products whose packaging
includes a toll-free number that
consumers can call to report complaints
to the manufacturer or distributor of the
product. Consequently, to fulfill these
statutory requirements, the final rule
will require pharmacies and authorized
dispensers to provide patients with the
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side effects statement with each
dispensed prescription drug, and will
require drug manufacturers to include
the side effects statement in FDAapproved Medication Guides for drugs
approved under section 505 of the act
and in the labeling of application OTC
drug products not subject to the
exclusion in section 502(f)(2) of
FDAAA.
B. Costs of Regulation
(Comment 22) Most comments on the
costs of the proposed rule asserted that
we understated the number of affected
OTC drug products and the costs to
modify OTC drug product labeling.
(Response) In most cases, however,
changes under FDAAA made many of
these comments irrelevant. As noted in
this final analysis, we have updated the
initial analysis with current numbers
whenever possible.
1. Pharmacy Industry
a. Number of affected pharmacies. We
received no comments on our initial
estimate of the number of pharmacies
affected by the requirement to include
the side effects statement with each
dispensed prescription drug. For the
final analysis, we update the number of
affected outlets with data from the 2002
Economic Census on the number of
establishments that have merchandise
sales from prescription drugs (table 1 of
this document). Both retail and
nonretail pharmacies may dispense
prescription drugs to patients. Retail
channels include independent drug
stores, chain drug stores, mass
merchants, grocery stores with
pharmacies, and mail or Internet
services. Nonretail channels include
health maintenance organizations
(HMOs), hospital outpatient
pharmacies, offices of health care
practitioners, and ambulatory care
clinics.
The agency solicited comment on its
assumptions about the percentages of
affected dispensing locations currently
distributing some form of printed CMI
(69 FR 21783). Because no comments
were received and the agency has no
other information about pharmacy
practices, we continue to assume that
printed CMI accompanies: (1) 89
percent of the prescriptions dispensed
by retail pharmacies, (2) 89 percent of
prescriptions dispensed in ambulatory
outpatient settings, and (3) 0 percent of
prescriptions dispensed in other health
care settings. Table 1 of this document
shows the estimated number of affected
outlets distributing CMI.
b. Prescriptions dispensed. Although
information on the number of
prescriptions dispensed by retail
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channels is publicly available, it is
difficult to estimate the number of
prescriptions dispensed by nonretail
channels. For the initial analysis of
impacts, we used 2001 data from IMS
Health to approximate the volume of
prescriptions from nonretail channels.
Based on the IMS data, nonretail
channels dispensed from 6 percent to 18
percent of the prescription volume
dispensed from retail channels (69 FR
21778 at 21784). Although we solicited
comment on our estimate, we received
no additional information. Thus, we
assume that the percentage of
prescriptions dispensed by retail and
nonretail outlets remains similar to our
initial estimate. In 2007, IMS Health
estimated that retail channels dispensed
approximately 3.8 billion prescriptions
(https://imshealth.com/vgn/images/
portal/CIT_40000873/39/53/
834329692007%20Channel%
20Distribution%20by%20RXs.pdf). We
estimate that nonretail channels
dispensed from 228 million (6 percent
of 3.8 billion) to 671 million (18 percent
of 3.8 billion) prescriptions, for a total
volume of prescriptions in 2007 ranging
from 4.0 billion (= 3.8 billion + 0.2
billion) to 4.5 billion (= 3.8 billion + 0.7
billion).
c. Compliance costs for pharmacies.
For the initial analysis of impacts, we
assumed that pharmacies currently
distributing printed CMI would choose
to comply with the requirements of the
proposed rule by distributing the side
63893
effects statement in the CMI. We
anticipated that the side effects
statement could be added to existing
pharmaceutical information databases
used to produce CMI at a negligible onetime cost. Moreover, we assumed that
periodic updates of other drug labeling
information included in pharmaceutical
databases required pharmacies or their
computer system vendors to test the
printing of the CMI on a regular basis.
Because most pharmacies distribute
printed CMI, we assumed that only
pharmacies and authorized dispensers
not currently providing printed CMI
would incur incremental costs to
comply with the requirements of the
proposed rule.
TABLE 1—NUMBER OF PHARMACY OUTLETS WITH SALES OF PRESCRIPTION DRUGS AND DISTRIBUTING PRINTED
CONSUMER MEDICATION INFORMATION (CMI)
Number of Outlets
Distributing CMI
Number of
Outlets1
Type of Outlet
Retail outlets:
Pharmacy, drug, and health care stores
Food and beverage stores
Warehouse clubs and supercenters
Other general merchandise stores
Electronic shopping
Mail-order houses
Other direct selling establishments
39,159
20,227
2,553
5,469
88
365
26
7,424
5,506
3,117
162
Total outlets
0
0
2,774
144
84,096
Nonretail outlets:
Offices of health practitioners
Hospital outpatient services
Clinics
HMOs
34,711
18,002
2,502
4,867
78
325
23
63,427
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Sources: Retail outlets from table 1 of 2002 Economic Census, Retail Trade, Subject Series, publication number EC02–44SL–LS issued October 2005; Nonretail outlets from 2002 Economic Census, Health Care of Social Assistance, Subject Series, publication number EC02–62SL–LS
issued October 2005.
1 Includes establishments in the 2000 North American Industry Classification System (NAICS) industry codes 445, 446, 452, 454, 621, 622 that
had sales from product line code 20161 (Prescriptions).
(Comment 23) We received one
comment from a professional
organization representing pharmacists
that supported our assumption that
most pharmacies will adopt the CMI
option. One comment from a provider of
pharmaceutical databases stated that it
will not be difficult to include the side
effects statement in the CMI. Two
comments noted that in our initial
analysis we did not take into account
the one-time effort required to modify
and test computer programs controlling
the printing of the CMI and auxiliary
labels, but provided no detailed
information about these costs.
(Response) We agree that pharmacies
choosing to distribute revised CMI (i.e.,
CMI with the side effects statement) will
need to ensure proper printing of the
side effects statement if they choose this
option. Pharmacies that choose to print
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their own labels to affix on the
dispensing container will incur costs to
modify and test the computer programs
that control the printing of auxiliary
labels. However, we lack sufficient
information about the percentage of
pharmacies that would choose in-house
printing of auxiliary labels to modify
our initial estimate.
To illustrate the potential costs of the
proposed rule, we estimated the level of
effort required by a pharmacy to
manually affix a sticker preprinted with
the side effects statement on each
prescription container. Because this
option would cause a pharmacy to incur
additional costs for each prescription
drug dispensed, the agency believes that
this would be a higher cost option for
pharmacies and authorized dispensers
that currently distribute printed CMI
with prescription drugs.
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(Comment 24) Two comments on the
proposed rule stated that FDA failed to
understand the workflow in a modern
pharmacy and that manually affixing
stickers would be more costly than we
estimated.
(Response) We acknowledge that
manually affixing a sticker in a highly
automated system might cause
disruptions in workflow that were not
captured in our initial analysis.
However, we have no other information
that we could use to modify our
estimate. Nevertheless, we have
increased our cost estimate in the
proposed rule by 35 percent to account
for the following: (1) A 23-percent
increase in the number of prescriptions
and (2) a 12-percent increase in costs
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since 2003.1 For pharmacies, the
potential annual costs of the final rule
in 2007 dollars will range from $12.4
million to $27.3 million. Similar to the
range in the proposed rule, this range
reflects uncertainty about the costs to
affix the sticker to the prescription drug
container, and the average number of
prescriptions dispensed by affected
pharmacy outlets.
2. Drug Manufacturers
We proposed to require that the
labeling of application OTC drug
products not subject to the exclusion in
section 502(f)(2) of FDAAA include the
OTC side effects statement in the
warnings section of the drug facts
format labeling. For the analysis of the
proposed rule, we predicted that
manufacturers would spend $3,000 per
shelf-keeping unit (SKU) to modify the
labeling of a new drug application
(NDA) OTC drug product or $1,000 per
SKU to modify the labeling of an
abbreviated new drug application
(ANDA) OTC drug product. We
assumed that each affected OTC drug
product would have, on average, up to
3 SKUs. For the proposed rule, we
estimated that approximately 1,570 OTC
drug packages would need to be revised
to add the side effects statement.
Furthermore, we estimated
manufacturers would need to add the
side effects statement to about 18
Medication Guides.
a. Number of affected products.
Although we received no comments on
our estimate of the number of
Medication Guides that would be
revised, more prescription drugs have
added Medication Guides since our
initial estimate. Based on current agency
information, we have increased our
estimate from 18 to 370 Medication
Guides.
(Comment 25) Comments from the
drug industry and a member of Congress
stated that FDA should not have
included application OTC drug
products in the proposed rule. Some
comments expressed concern that
because the labeling of most NDA OTC
drug products includes a manufacturer’s
toll-free telephone number, addition of
the MedWatch telephone number could
confuse consumers. It was suggested
that FDA exempt from the requirements
of the proposed rule any OTC drug
product whose labeling contains a tollfree number for the manufacturer or
distributor.
(Response) The proposed rule would
have required the same side effects
statement on all application OTC drug
products. As discussed previously in
this preamble, the interim final rule
codified section 502(f)(2) of FDAAA,
which states that the requirement to
include the side effects statement does
not apply to any OTC drug product
approved under section 505 of the act if
the product’s packaging contains a tollfree telephone number through which
consumers can report complaints to the
manufacturer or distributor of the drug.
Section 502(f)(2) of FDAAA thus creates
a situation in which manufacturers and
distributors of affected application OTC
drug products will choose to either add
the side effects statement or their own
toll-free telephone number to OTC drug
product labeling. Therefore, under the
rule, the drug facts format labeling of
application OTC drug products could
vary depending on whether the affected
manufacturer or distributor uses the
side effects statement or its own toll-free
number.
The agency previously estimated that
certain retailers with more than 10
establishments would have some private
label OTC drug products (62 FR 9046,
February 27, 1997). Depending on the
size of the firm, each private label OTC
drug product could have numerous
SKUs. Agency records indicate that
there are about 60 unique application
OTC products (i.e., a unique
combination of active ingredient, dosage
form, and strength). An informal
convenience survey of stores in the
Washington, DC, area and in northern
New England looked at whether affected
private label OTC drug product labeling
contains a toll-free telephone number.
We found that the packaging of most
private label OTC drug products does
not include a toll-free number for
complaints.2 It appears that most private
label OTC drug product labeling will
need to be modified to comply with the
final rule. However, because most
national brand OTC drug products
affected by the rule already have a tollfree telephone number for complaints,
current packaging for most national
brand OTC drug products will conform
to the requirements of the final rule
without any further change.
For this final analysis, we assume that
distributors of private label OTC drug
products (i.e., the unique combination
of active ingredient, dosage form, and
strength) would not carry identical
SKUs from different manufacturers.
Although uncertain, the findings from
our informal survey give us an idea of
the number of private label OTC drug
product SKUs that might be affected by
the final rule. For the final analysis,
therefore, we anticipate that any firm
with 10 to 99 establishments will need
to change the packaging of between 40
to 55 affected private label OTC drug
products and any firm with 100 or more
establishments will need to change the
packaging of between 110 to 135 private
label OTC drug products. Table 2 of this
document illustrates the number of
possible firms that could have private
label OTC drug products.
TABLE 2—ESTIMATE OF THE NUMBER OF PRIVATE LABEL DISTRIBUTORS
Number of Firms With 10–99
Establishments
Kind of Business
Supermarket and other grocery
194
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1 U.S. Department of Labor, Bureau of Economic
Analysis, National Economic Accounts (https://
www.bea.gov/nationalnipaweb/SelectTable.asp?
Selected=Y).
2 FDA employees visited three mass merchants,
three chain grocery stores, and four chain drug
stores to roughly estimate the following: (1) The
number of SKUs per private label OTC product for
categories of products with high sales volumes and
(2) the proportion of the labeling of these products
including a toll-free telephone number. At each site,
14:54 Oct 27, 2008
Jkt 217001
at least one private label ANDA OTC drug product
from the following categories was examined to
determine the number of SKUs for the product and
the percentage of SKUs with a toll-free telephone
number—allergy and asthma, antifungal, feminine
hygiene, pain, stomach-diarrhea, and stomachdigestion. In addition, at some locations, employees
examined private label ANDA OTC drug products
for smoking cessation, lice control, hair restoration,
and cold and sinus. We examined over 300
packages and found that the labeling of smoking
cessation products and allergy and asthma eye
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37
59
Pharmacy, drug, and proprietary stores
VerDate Aug<31>2005
Number of Firms With 100 or
More Establishments
16
drops already appear to include a toll-free
telephone number. Excluding these products, only
about 20 percent of the labeling of private label
ANDA OTC products would conform to the
requirements of the final rule without change.
Finally, to estimate a range of products whose
labeling would need to be modified, we adjusted
the average number of SKUs for each product (i.e.,
active ingredient, dosage form, and strength) by the
proportion of SKUs with labeling including a tollfree telephone number.
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Federal Register / Vol. 73, No. 209 / Tuesday, October 28, 2008 / Rules and Regulations
63895
TABLE 2—ESTIMATE OF THE NUMBER OF PRIVATE LABEL DISTRIBUTORS—Continued
Number of Firms With 10–99
Establishments
Kind of Business
Warehouse clubs and supercenters
Number of Firms With 100 or
More Establishments
3
256
Total
6
59
Source: Data for NAICS numbers 445110, 4461101, 4461102, and 45291 from table 3 of 2002 Economic Census, Retail Trade, Subject Series, Establishment and Firm Size (Including Legal Form of Organization), publication number EC02–44SS–SZ issued November 2005.
ebenthall on PROD1PC60 with RULES
b. Cost to modify product labeling.
(Comment 26) We received three
detailed comments that included
alternative estimates of the cost to revise
NDA OTC drug product labeling. No
comments were submitted on our
estimate of the cost to revise ANDA or
private label OTC drug product labeling
or Medication Guides.
(Response) To account for inflation,
we updated our estimate of the cost to
revise a Medication Guide from $4,177
to $4,500 (2007 dollars) for an NDA
prescription drug and from $1,580 to
$1,800 (2007 dollars) for an ANDA
prescription drug. The total one-time
cost to add the side effects statement to
Medication Guides will be $990,000 (=
120 Medication Guides x $4,500 + 250
Medication Guides x $1,800).
In recent years some large retailers
have developed a single nationwide
private label brand for all of their
private label OTC drug products.3 When
comparing like OTC drug products,
consumers could perceive a difference
in the safety of the private label OTC
drug products if the private label OTC
drug product packaging displays the
side effects statement instead of a
manufacturer’s toll-free number, such as
is found on most innovators’ branded
products. Economic theory predicts that
any labeling change which signals a
decrease in product quality will be
balanced by a decrease in the demand
for the product. Large retailers will
weigh the additional costs associated
with the addition of their toll-free
number on their OTC drug product
packaging against the monetary value of
the perceived decrease in product
quality that could be signaled by the
addition of the side effects statement.
Private label retailers will choose to
include their own toll-free telephone
number instead of the side effects
statement if they believe that the side
effects statement will decrease the
perceived quality of their products more
than the cost to add the toll-free
telephone number.
We have increased our estimate of the
cost to modify the labeling of private
label OTC drug products from $1,000
per SKU to $2,140 per SKU. As shown
in table 3 of this document, private label
distributors might spend from $36.4
million to $47.9 million in one-time
costs to modify drug labeling to include
a telephone number or side effects
statement. In addition, each distributor
might spend up to 40 hours deciding
whether to include its own toll-free
telephone number at a one-time cost of
$640,000 (= 320 distributors x $50 per
hour x 40 hours), for total one-time costs
ranging from $37.0 million to $48.6
million.
We expect that there would be some
impact of the toll-free telephone number
on the workload of private label
distributors who choose to add their
own toll-free telephone number.
Although this impact is uncertain,
distributors may need to hire up to one
full-time employee (FTE) at a cost of
about $53,5004 to answer additional
telephone calls generated by the
addition of their toll-free telephone
number on private label OTC drug
product packaging. If the incremental
increase in telephone calls is minimal,
distributors will not incur these costs.
However, if all 320 distributors incurred
this incremental expense, it will cost the
pharmacy industry an additional $17.1
million dollars annually. In total, the
final rule will cost drug manufacturers
or private label distributors from $4.5
million to $22.9 million annualized at a
3-percent discount rate and from $5.4
million to $24.2 million annualized at a
7-percent discount rate.
3. Burden on FDA
3 ‘‘Consolidated Medicine,’’ January/February
2005, Private Label Magazine, at https://
www.privatelabelmag.com.
4 U.S. Department of Labor, Bureau of Labor
Statistics, Occupational Employment and Wages,
May 2007 (https://www.bls.gov/oes/current/
oes292052.htm).
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14:54 Oct 27, 2008
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(Comment 27) Several comments
stated that the side effects statement
would increase the volume of nonserious calls to MedWatch and
potentially dilute the value of direct
adverse event reports.
(Response) In our initial analysis, we
were uncertain about the burden this
rule would place on FDA. Although we
are still uncertain about the burden of
the final rule, the results of our Internet
study are encouraging. Most people
understood the meaning of the side
effects statement and understood that
the FDA toll-free number was intended
only to report serious side effects.
Participants in the study showed little
inclination to use the FDA toll-free
number and would be more likely to
expect their health care provider to
report side effects. Without other
information, we leave our initial
analysis of the FDA burden unchanged.
4. Summary of the Impacts of the Final
Rule
Table 4 of this document summarizes
the costs of the final rule. The total
annualized impact of the final rule will
range from $16.9 million to $52.2
million with a 3-percent discount rate
and from $17.8 million to $53.4 million
with a 7-percent discount rate. Most of
this cost will likely be passed on to
consumers. Even though the total
annualized costs are uncertain, they are
significantly below the threshold of an
economically significant rule. Moreover,
the final rule gives pharmacies
flexibility to select the option that is
least burdensome for their individual
business situation and fulfills the
statutory requirements of the BPCA and
FDAAA. Finally, these costs represent a
small proportion of affected product
sales.
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Federal Register / Vol. 73, No. 209 / Tuesday, October 28, 2008 / Rules and Regulations
TABLE 3—ESTIMATED COST TO MODIFY PRIVATE LABEL OTC LABELING
Type of Distributor
Estimate of the Number of
Private Label SKUs
Number of
Distributors
Low
Number of
Affected SKUs
High
Low
Cost to Revise OTC
Labeling ($ million)
High
Low
High
Small
260
40
55
10,400
14,300
22.3
30.6
Large
60
110
135
6,600
8,100
14.1
17.3
Total
320
17,000
22,400
36.4
47.9
TABLE 4—COST SUMMARY
One-Time Cost ($ mil)
Annual Costs ($ mil)
Annualized at 3% ($ mil)
Annualized at 7% ($ mil)
Affected Sector
low
high
low
Retail and nonretail pharmacies
high
low
high
12.4
38.0
49.6
FDA
Total
38.0
49.6
C. Benefits of Regulation
(Comment 28) One comment from an
organization representing drug
manufacturers stated that the proposed
rule had no obvious benefits and in
contrast could have a detrimental effect
on adverse event reporting and
detection.
(Response) The agency agrees that the
benefits of this rule are uncertain. As
described elsewhere in this preamble,
the results of our Internet labeling
comprehension study suggest that most
consumers understand the side effects
statement and would be unlikely to call
FDA. Even if they experienced a serious
side effect, most participants indicated
that they would contact their health care
provider and would assume that he or
she would report their side effect to
FDA. If the final rule increases reports
of serious side effects by health care
providers, it might aid the agency’s
efforts to monitor the postmarket safety
of drug products.
D. Final Regulatory Flexibility Analysis
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low
We received no comments that would
change our initial analysis of the
impacts on small entities. Most impacts
on small entities represent a small
proportion of sales and the rule would
probably have a minimal effect on even
the smallest entities. For our initial
analysis, we estimated that adding a
preprinted sticker to each prescription
container would cost about $.03 per
prescription and could reduce a retail
pharmacy’s average revenues by about
0.3 percent. For the final analysis, we
14:54 Oct 27, 2008
Jkt 217001
27.3
12.4
27.3
12.4
27.3
0.0
17.1
4.5
22.9
5.4
24.2
0.0
Drug manufacturers and
private label distributors
VerDate Aug<31>2005
high
1.9
0.0
1.9
0.0
1.9
12.4
46.3
16.9
52.2
17.8
53.4
adjust the per prescription cost of the
sticker option by 12 percent, increasing
the cost of this option to approximately
$0.04 per prescription. The National
Association of Chain Drug Stores
(NACDS) reports that in 2007 the
average cost of a retail prescription was
$69.91. Retail pharmacies received
about 17 percent or an average of $13.17
for each prescription.5 At current
revenue levels, the average cost for
small pharmacies to comply with the
final rule will still be about 0.3 percent
of the average per-prescription revenue.
The costs for private label distributors
were not included in the initial analysis.
However, all distributors large enough
to maintain private labels have annual
sales above the SBA size standards.
Because many of the impacts of the final
rule are uncertain, we are not able to
certify that the final rule will not have
a significant economic impact on a
substantial number of small entities.
VI. Paperwork Reduction Act of 1995
This regulation imposes no new
collection of information. Therefore,
clearance by the Office of Management
and Budget under the Paperwork
Reduction Act of 1995 is not required.
VII. 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,
5 https://www.nacds.org/wmspage.cfm?
parm1=507#pharmpricing.
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Fmt 4700
Sfmt 4700
neither an environmental assessment
nor an environmental impact statement
is required.
VIII. Federalism
FDA has analyzed this final rule in
accordance with the principles set forth
in Executive Order 13132. FDA has
determined that the rule will have a
preemptive effect on State law. Section
4(a) of the Executive order requires
agencies to ‘‘construe * * * a Federal
statute to preempt State law only where
the statute contains an express
preemption provision or there is some
other clear evidence that the Congress
intended preemption of State law, or
where the exercise of State authority
conflicts with the exercise of Federal
authority under the Federal statute.’’
Section 751 of the act (21 U.S.C. 379r)
is an express preemption provision.
Section 751(a) of the act provides that
‘‘* * * no State or political subdivision
of a State may establish or continue in
effect any requirement—(1) that relates
to the regulation of a drug that is not
subject to the requirements of section
503(b)(1) or 503(f)(1)(A); and (2) that is
different from or in addition to, or that
is otherwise not identical with, a
requirement under this act, the Poison
Prevention Packaging Act of 1970 (15
U.S.C. 1471 et seq.), or the Fair
Packaging and Labeling Act (15 U.S.C.
1451 et seq.).’’ Currently, this provision
operates to preempt States from
imposing requirements related to the
regulation of nonprescription drug
products. Section 751(b) through (e) of
the act outlines the scope of the express
E:\FR\FM\28OCR1.SGM
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Federal Register / Vol. 73, No. 209 / Tuesday, October 28, 2008 / Rules and Regulations
preemption provision, the exemption
procedures, and the exceptions to the
provision.
Even where the express preemption
provision is not applicable, implied
preemption may arise. See Geier v.
American Honda Co. 529 U.S. 861
(2000). Under the principles of implied
conflict preemption, courts have found
State law preempted where it is
impossible to comply with both Federal
and State law or where the State law
‘‘stands as an obstacle to the
accomplishment and execution of the
full purposes and objectives of
Congress.’’ See English v. General
Electric Co., 496 U.S. 72, 79 (1990);
Florida Lime & Avocado Growers, Inc.,
373 U.S. 132, 142–43 (1963); Hines v.
Davidowitz, 312 U.S. 52, 67 (1941).
This rule amends the labeling
requirements for certain application
OTC drug products to require the
addition of a side effects statement, and
to require pharmacies and authorized
dispensers to distribute the side effects
statement with each prescription drug
approved under section 505 of the act
and dispensed. This rule would have a
preemptive effect to the extent that a
State requires labeling that directly
conflicts with, is different from, or is in
addition to, the side effects statement
required by this rule for certain
application OTC drug products. This
preemptive effect is consistent with
what Congress set forth in section 751
of the act. Section 751(a) of the act
displaces both State legislative
requirements and State common law
duties. The rule would also have a
preemptive effect to the extent that a
State imposes requirements on
pharmacies or authorized dispensers
that conflict with the requirements of
this rule or frustrate the federal purpose
with respect to distribution of the side
effects statement. Preemption with
respect to these requirements is
consistent with the doctrine of implied
conflict preemption. FDA believes that
the preemptive effect of the final rule,
if finalized as proposed, would be
consistent with Executive Order 13132.
Section 4(e) of the Executive order
provides that ‘‘when an agency proposes
to act through adjudication or
rulemaking to preempt State law, the
agency shall provide all affected State
and local officials notice and an
opportunity for appropriate
participation in the proceedings.’’ FDA
provided the States with an opportunity
for appropriate participation in this
rulemaking when it sought input from
all stakeholders through publication of
the proposed rule (69 FR 21778). FDA
received no comments from any States
on the proposed rulemaking. On January
VerDate Aug<31>2005
14:54 Oct 27, 2008
Jkt 217001
3, 2008, FDA published an interim final
rule codifying the proposed rule which,
under FDAAA, became effective by
operation of law on January 1, 2008 (73
FR 402). FDA received no comments
from any State on the interim final rule.
In addition, on July 31, 2008, the FDA
Division of Federal and State Relations
provided notice via fax and e-mail
transmission to elected officials of State
governments and their representatives
of national organizations. The notice
provided the States with further
opportunity for comment on the rule. It
advised the States of the publication of
the proposed rule and interim final rule
and encouraged State and local
governments to review the notice and
interim final rule to provide any
comments to Docket No. FDA–2003–N–
0313 (formerly Docket No. 2003N–0342)
opened in the April 22, 2004, Federal
Register proposed rule, by a date 30
days from the date of the notice (i.e., by
August 31, 2008, or to contact certain
named individuals. FDA received no
comments in response to this notice.
The notice has been filed in Docket No.
FDA–2003–N–0313.
In conclusion, FDA believes that it
has complied with all of the applicable
requirements under the Executive order
and has determined that the preemptive
effects of this rule are consistent with
Executive Order 13132.
(FDA has verified all Web site
addresses, but FDA is not responsible
for any subsequent changes to the Web
sites after this document publishes in
the Federal Register.)
Therefore, under the Federal Food,
Drug, and Cosmetic Act and under
authority delegated to the Commissioner
of Food and Drugs, the interim final rule
amending 21 CFR parts 201 and 208 and
adding 21 CFR part 209, which was
published at 73 FR 402 (January 3,
2008), is adopted as a final rule without
change.
Dated: October 21, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and
Planning.
[FR Doc. E8–25670 Filed 10–27–08; 8:45 am]
BILLING CODE 4160–01–S
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63897
ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Part 272
[EPA–R06–RCRA–2008–0753; FRL–8729–6]
New Mexico: Incorporation by
Reference of Approved State
Hazardous Waste Management
Program
Environmental Protection
Agency (EPA).
ACTION: Immediate final rule.
AGENCY:
SUMMARY: The Solid Waste Disposal Act,
as amended, commonly referred to as
the Resource Conservation and
Recovery Act (RCRA), allows the
Environmental Protection Agency (EPA)
to authorize States to operate their
hazardous waste management programs
in lieu of the Federal program. The EPA
uses the regulations entitled ‘‘Approved
State Hazardous Waste Management
Programs’’ to provide notice of the
authorization status of State programs
and to incorporate by reference those
provisions of the State statutes and
regulations that will be subject to the
EPA’s inspection and enforcement. The
rule codifies in the regulations the prior
approval of New Mexico’s hazardous
waste management program and
incorporates by reference authorized
provisions of the State’s statutes and
regulations.
This regulation is effective
December 29, 2008, unless the EPA
receives adverse written comment on
this regulation by the close of business
November 28, 2008. If the EPA receives
such comments, it will publish a timely
withdrawal of this immediate final rule
in the Federal Register informing the
public that this rule will not take effect.
The Director of the Federal Register
approves this incorporation by reference
as of December 29, 2008 in accordance
with 5 U.S.C. 552(a) and 1 CFR part 51.
ADDRESSES: Submit your comments by
one of the following methods:
1. Federal eRulemaking Portal:
https://www.regulations.gov. Follow the
on-line instructions for submitting
comments.
2. E-mail: patterson.alima@epa.gov.
3. Mail: Alima Patterson, Region 6,
Regional Authorization Coordinator,
State/Tribal Oversight Section (6PD–O),
Multimedia Planning and Permitting
Division, EPA Region 6, 1445 Ross
Avenue, Dallas, Texas 75202–2733.
4. Hand Delivery or Courier: Deliver
your comments to Alima Patterson,
Region 6, Regional Authorization
Coordinator, State/Tribal Oversight
Section (6PD–O), Multimedia Planning
DATES:
E:\FR\FM\28OCR1.SGM
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Agencies
[Federal Register Volume 73, Number 209 (Tuesday, October 28, 2008)]
[Rules and Regulations]
[Pages 63886-63897]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-25670]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 201, 208, and 209
[Docket No. FDA-2003-N-0313] (formerly Docket No. 2003N-0342)
RIN 0910-AC35
Toll-Free Number for Reporting Adverse Events on Labeling for
Human Drug Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
that confirms the interim final rule entitled ``Toll-Free Number for
Reporting Adverse Events on Labeling for Human Drug Products'' (73 FR
402, January 3, 2008) (interim final rule) and responds to comments
submitted in response to the request for comments in the proposed rule
of the same title (69 FR 21778, April 22, 2004) (proposed rule). This
final rule affirms the interim final rule's requirement for the
addition of a statement to the labeling for certain human drug products
for which an application is approved under section 505 of the Federal
Food, Drug, and Cosmetic Act (the act). The statement includes a toll-
free number and advises that the number is to be used only for
reporting side effects and is not intended for medical advice (the side
effects statement). This final rule also affirms the interim final
rule's addition of new part 209 to the regulations requiring
distribution of the side effects statement. This final rule implements
provisions of the Best Pharmaceuticals for Children Act (the BPCA) and
the Food and Drug Administration Amendments Act of 2007 (FDAAA).
DATES: Effective Date: This final rule is effective November 28, 2008.
Compliance Date: The compliance date for this final rule is July 1,
2009. For more information on the compliance date see section II of the
SUPPLEMENTARY INFORMATION section of this document.
FOR FURTHER INFORMATION CONTACT: Carol Drew, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 51, rm. 6306, Silver Spring, MD 20993-0002, 301-796-3601.
SUPPLEMENTARY INFORMATION:
I. Background
A. BPCA and Proposed Rule
The BPCA (Public Law 107-109) directed FDA to issue a final rule
requiring the labeling of each human drug product for which an
application is approved under section 505 of the act (21 U.S.C. 355) to
include: (1) A toll-free number maintained by FDA for the purpose of
receiving reports of adverse events regarding drugs and (2) a statement
that the number is to be used for reporting purposes only, not to
receive medical advice. Collectively, we refer to the toll-free number
and reporting statement as the ``side effects statement.'' The BPCA
stated that the final rule must implement the labeling requirement to
reach the broadest consumer audience and minimize the cost to the
pharmacy profession.
On April 22, 2004 (69 FR 21778), FDA published a proposed rule
entitled ``Toll-Free Number for Reporting Adverse Events on Labeling
for Human Drug Products.'' FDA received 22 comments on the proposed
rule.
B. FDAAA Requirements and Interim Final Rule
On September 27, 2007, the President signed into law FDAAA (Public
Law 110-85). Among other things, FDAAA reauthorized the BPCA. Section
502(f) of FDAAA stated that ``the proposed rule * * * `Toll-Free Number
for Reporting Adverse Events on Labeling for Human Drug Products' * * *
shall take effect on January 1, 2008,'' unless FDA issues a final rule
before that date. FDA was in the process of analyzing the comments on
the proposed rule and conducting research on consumer comprehension of
the proposed side effects statements when FDAAA was enacted. FDA did
not issue a final rule prior to January 1, 2008. Therefore, by
operation of law, the proposed rule took effect on January 1, 2008.
FDAAA mandated one change to the proposed rule. Section 502(f)(2)
of
[[Page 63887]]
FDAAA states that the proposed rule shall not apply to over-the-counter
(OTC) drugs marketed with an application approved under section 505 of
the act (application OTC drug products) if these application OTC drug
products meet certain labeling requirements.
On January 3, 2008 (73 FR 402), FDA published an interim final rule
to: (1) Codify the modifications made by FDAAA to the proposed rule,
(2) notify the public that the agency planned to complete the ongoing
research testing the proposed side effects statements for consumer
comprehension, and (3) establish a compliance date of January 1, 2009.
The interim final rule stated that the agency did not intend to take
enforcement action prior to January 1, 2009, and that the agency would
complete the research on the side effects statements and either
finalize the interim final rule as published or publish a final rule
that amends the interim final rule.
II. Highlights of the Final Rule
The preamble to the proposed rule described the provisions of this
rule in detail. In the preamble to the interim final rule we described
the changes to the proposed rule required by FDAAA. In this final rule
we respond to comments received on the proposed rule and finalize the
regulations. No comments were received on the interim final rule.
As described in the interim final rule, one substantive change has
been made to the regulatory provisions published in the proposed rule:
Section 201.66(c)(5)(vii) (21 CFR 201.66(c)(5)(vii)) has been modified
to require that only approved application OTC drug products whose
packaging does not include a toll-free number through which consumers
can report complaints to the manufacturer or distributor of the drug
product are required to include the side effects statement in labeling.
As discussed previously in this document, this modification was
mandated by FDAAA.
In the interim final rule, FDA established a compliance date of
January 1, 2009, and notified the public that we intended to exercise
enforcement discretion and not take enforcement actions with regard to
the effective regulations until January 1, 2009. In the interim final
rule we stated that the effective date and implementation schedule for
the final rule would be designed to minimize the burden of any
additional regulatory changes for affected entities who must comply
with the final rule. Since the publication of the interim final rule,
we have received several inquiries about specific provisions of the
interim final rule. Given the short time interval between the
publication date of this final rule and the original compliance date of
January 1, 2009, we are delaying the compliance date by six months to
July 1, 2009. We believe this brief delay is appropriate because we
have made no changes to the codified. All affected entities are
required to be in compliance by July 1, 2009.
III. Comments and Agency Response
The agency received 22 comments on the proposed rule. Comments were
received from prescription and nonprescription drug manufacturers;
trade organizations representing drug manufacturers; pharmacists,
pharmacies, and pharmacy-related interests; consumer organizations;
professional associations and organizations; one member of Congress;
one agency of a foreign government; and others.
To make it easier to identify comments and our responses, the word
``Comment,'' in parentheses, appears before the comment's description,
and the word ``Response,'' in parentheses, appears before our response.
We have numbered each comment to help distinguish between different
comments. Similar comments are grouped together under the same number.
The number assigned to each comment is purely for organizational
purposes and does not signify the comment's value or importance or the
order in which it was received. A summary of the comments received and
our responses follow.
A. Scope of the Rule
(Comment 1) The agency received 7 comments opposing the proposed
requirement that the labeling for application OTC drug products contain
the toll-free number and statement mandated by the BPCA. These comments
argued that Congress did not intend the BPCA requirements to apply to
application OTC drug products.
(Comment 2) Two comments suggested that FDA limit the applicability
of the regulatory provisions to new drugs that have been approved for
marketing within 5 years of the date of the final rule, and that the
regulation's requirements attach for only 5 years following a new
drug's approval. These comments requested that FDA limit the regulatory
provisions to the approximately 30 new molecular entities (NMEs) that
are approved each year for the 5-year period after they are approved
and suggested that reporting should be targeted to encourage consumer
reporting of adverse reactions from newer drugs.
(Response) Section 17 of the BPCA required that the labeling of
each drug for which an application is approved under section 505 of the
act include the toll-free number and statement. Because OTC drug
products may be approved under section 505 of the act, we proposed that
the labeling for all application OTC drug products contain the BPCA
mandated requirements. However, in section 502(f)(2) of FDAAA, Congress
stated that the proposed rule shall not apply to OTC drugs marketed
with an application approved under section 505 of the act if these
application OTC drug products meet certain labeling requirements.
Specifically, section 505(f)(2) of the act states that the proposed
rule shall not apply to a drug: (1) For which an application is
approved under section 505 of the act; (2) that is not described under
section 503(b)(1) of the act (21 U.S.C. 353(b)(1)); and (3) the
packaging of which includes a toll-free number through which consumers
can report complaints to the manufacturer or distributor of the drug.
In the interim final rule, we stated that this provision means that the
proposed provisions do not apply to application OTC drug products if
the product's packaging includes a manufacturer's or distributor's
toll-free number for reporting complaints. Accordingly, this final rule
includes a modified Sec. 201.66(c)(5)(vii) reflecting the changes to
the proposed rule required by FDAAA.
As to the comments suggesting that we limit the scope of the rule
to a specific subset of NMEs or for a specific number of years for
specific products, we note that neither the BPCA nor FDAAA gives FDA
the legal authority to limit the scope of the rule in this way. The
BPCA requires that the labeling of each drug product approved under
section 505 of the act, regardless of the date on which approved,
include the side effects statement.
B. Wording of the Side Effects Statement
As stated in the preamble to the proposed rule, section 17 of the
BPCA requires that the labeling for each drug approved under section
505 of the act include: (1) A toll-free number maintained by FDA for
the purpose of receiving reports of adverse events regarding drug
products and (2) a statement that the number is to be used for
reporting purposes only, not to seek medical advice. FDA considered
these requirements and proposed a conforming statement for prescription
drug products: ``Call your doctor for
[[Page 63888]]
medical advice about side effects. You may report side effects to FDA
at 1-800-FDA-1088.''
As stated in the preamble to the proposed rule, the drug facts
labeling format for OTC drug products required us to modify the side
effects statement to correspond to the drug facts format (Sec.
201.66). The OTC requirement was included in the specific subheadings
for presenting warnings in the drug facts format (Sec.
201.66(c)(5)(vii)). In combination with the requirements of Sec.
201.66(c)(5)(vii), the labeling provision for the application OTC drug
products was proposed to read: ``Stop use and ask a doctor if
side effects occur. You may report side effects to FDA at 1-800-FDA-
1088.''
We solicited comments on the proposed wording of the side effects
statements and on whether the term ``side effects'' should be further
qualified.
(Comment 3) We received several comments suggesting that we test on
consumers the proposed language for the side effects statements, as
well as alternatives, to evaluate consumer comprehension and determine
the best and most precise terminology for the statement.
(Comment 4) Among the comments we received on the proposed wording
of the side effects statement, one comment asserted that the proposed
statement is concise and makes it clear that the number is not for
medical advice. Several comments suggested specific additions to the
wording of the statements, including: Using the term ``health care
professional'' instead of, or in addition to, the term ``doctor'';
adding the term ``pharmacist'' to the statement to suggest that
consumers call either their doctor or pharmacist for medical advice
about side effects; adding wording to clarify that FDA does not give
medical advice and is not offering medical consultation; and/or adding
wording to clarify that FDA should not be called in case of medical
emergency and that FDA should only be called once any medical emergency
is resolved.
(Comment 5) Of the six comments we received on whether to use the
term ``side effects'' or ``adverse event,'' five supported use of the
term ``side effects'' as more consumer friendly. Of those comments, two
suggested qualifying the term with ``serious'' and one opposed adding
any qualifications to the term. Those suggesting qualifying the term
were concerned about FDA receiving numerous unnecessary reports about
side effects that are well-known and expected, not serious; the comment
opposed to qualifying the term was concerned that qualifying the
statement would limit the types of events reported, discourage
consumers from reporting, and hinder the agency's ability to identify
trends from reporting. One comment suggested that use of the term
``side effects'' would have a negative effect on drug marketing.
(Comment 6) Among the comments we received on the wording of the
side effects statement for application OTC drug products were comments
opposing the inclusion of the statement in the ``warnings'' section of
the drug facts format and the specific ``stop use'' language that
section requires. One comment suggested placing the side effects
statement under the ``when using this product'' subheading as the last
bullet, so that the labeled adverse events precede the side effects
statement. Comments opposed the ``stop use'' language on the grounds
that stopping use of an OTC drug product may be inappropriate. Comments
also stated that the ``stop use'' language has a greater impact on OTC
drug products than it does on prescription drug products, i.e., there
is no corresponding requirement telling consumers using prescription
drug products to stop using the product if they experience a side
effect. Several comments also stated that because the drug facts format
requires a telephone number for consumers to call to get answers to
questions, there would be confusion caused by having more than one
phone number in the labeling for consumers to call.
(Response) After reviewing the comments received on the proposed
rule, FDA initiated a two-part study to test consumer comprehension of
the wording of the proposed side effects statements. Part one of the
study consisted of focus groups held to narrow the field of potential
statement alternatives. When describing the side effects statement for
prescription drug products, participants in the focus groups were asked
whether they preferred the use of ``doctor'' or ``health care
provider,'' ``doctor'' or ``doctor or pharmacist,'' ``serious side
effects'' or ``side effects,'' and ``adverse events'' or ``side
effects,'' in the statement, as well as other language variations. The
focus groups were completed in 2006 (OMB Control No. 0910-0497).
The second part of this research was a labeling comprehension
experimental study conducted over the Internet (OMB Control No. 0910-
0603). Nine statements were tested as informed by the prior focus group
testing. A total of 1,674 men and women ranging in age from 21 to 95
with varying levels of education completed the study. Five different
versions of the side effects statement for prescription drug products
and four different versions of the side effects statement proposed for
application OTC drug products were tested. Approximately 40 percent of
the sample of consumers saw one of the four OTC side effects statements
and the other 60 percent of the sample saw one of the five prescription
drug side effects statements. FDA's final report on the study was
completed in 2008 and is available in the docket for this rule.
In answer to questions about the best wording for the side effects
statement, only one of the statements tested was significantly less
clear than the others. We eliminated this statement from consideration.
All other statements were rated very similarly by participants.
Participants who responded to the side effects statements for
prescription drugs responded nearly identically to participants who
responded to the side effects statements for OTC drug products. Given
these results, FDA concluded that in choosing among the statements,
considerations such as length, readability, and other factors could be
used to select among the remaining side effects statements. Taking into
account the results from the labeling comprehension study and other
factors, we have chosen to finalize the side effects statements as
originally proposed.
Additionally, to address comments received indicating concern that
consumers would call FDA for medical advice and suggested language
changes to prevent this, we queried participants in the study about
whether they would choose to call FDA or their doctor in certain
circumstances. Participants did not show an inclination to call FDA for
medical advice. Among those that indicated a willingness to call FDA at
all, the majority appropriately indicated that FDA was for reporting
side effects and their doctors were for personal medical advice. Most
individuals indicated that they would contact their doctor first
regardless of the particular side effect they experienced. We conclude
from this finding that the language proposed for the side effects
statement is sufficient to convey the intention of the BPCA requirement
that the statement is to be used for reporting purposes only, not to
receive medical advice.
Similarly, with regard to concerns that we should qualify the type
of side effect that should be reported to FDA by adding the word
``serious'' to ``side effect'' because FDA would receive numerous
unnecessary reports, our research indicates that consumers are able to
distinguish between serious and non-serious side effects and would
[[Page 63889]]
contact their doctor or hospital emergency room in the case of a
``serious side effect.'' A doctor who determines that a patient has had
a serious side effect from a drug product may then report the side
effect to FDA.
Regarding the comments we received on the specific language of the
OTC side effects statement and its placement in the ``warnings''
section of the drug facts format, we disagree that placement in the
``warnings'' section is inappropriate or that the ``stop use'' language
is inappropriate. The warnings section of the drug facts format label
for OTC drug products may include several statements about possible
side effects, telling consumers when to consult a doctor, pharmacist,
or other health care professional in the use of the product. Consumers
using OTC drug products most likely are not under the direct care of a
health care practitioner, whereas consumers using prescription drug
products are under the care of a health care practitioner. We believe
it is appropriate for the side effects statement to instruct consumers
using an OTC drug product who believe they are experiencing a side
effect to stop using the drug product and consult their doctor before
continuing use of the product.
We do not agree that having more than one phone number in the drug
facts format labeling would be confusing to consumers. The agency's
toll-free number clearly indicates it is an FDA phone number for
reporting side effects. Our research indicates that the OTC side
effects statement is understood by consumers. Moreover, section
502(f)(2) of FDAAA states that application OTC drug products that
include a toll-free number through which consumers can report
complaints to the manufacturer or distributor of the drug product are
not required to include the side effects statement. In all likelihood
this means that fewer application OTC drug products will have FDA's
side effects statement in their labeling. Therefore, we anticipate that
the majority of application OTC drug products will not have more than
one phone number in their labeling for reporting side effects, reducing
any potential for confusion.
C. Location of the Side Effects Statement in FDA-Approved Labeling
We proposed to require the side effects statement in two categories
of drug product labeling: (1) FDA-approved Medication Guides for drugs
approved under section 505 of the act, and (2) the labeling for
application OTC drug products. We stated that manufacturers voluntarily
may include the side effects statement in Medication Guides for
products not approved under section 505 of the act or in patient
package inserts (PPIs). For reasons stated in the proposed rule, we did
not propose requiring the side effects statement in physician labeling
or PPIs, but we solicited comments on those two issues. In addition, we
proposed that the side effects statement be distributed with each
prescription drug product, both new and refills, approved under section
505 of the act and dispensed to consumers by pharmacies and authorized
dispensers in an outpatient setting.
(Comment 7) We received one comment stating that the side effects
statement should be on all package labeling, including refills, to
ensure maximum consumer exposure so that when consumers experience a
side effect, they will find the side effects statement wherever they
turn first for information.
(Comment 8) One comment suggested that instead of putting the side
effects statement in drug product labeling, FDA's MedWatch telephone
number appear in public telephone books next to the Poison Control
phone number.
(Comment 9) Another comment suggested that consumers be given small
magnets with FDA's MedWatch phone number obviating the need for
repeated dispensing of this information each time a patient visits a
pharmacy.
(Response) We believe that the requirements of this final rule will
ensure that the side effects statement reaches a broad consumer
audience while minimizing the burden on the pharmacy profession, as
required by the BPCA. We require that the side effects statement appear
in Medication Guides for drug products approved under section 505 of
the act and in the labeling for certain application OTC drug products,
and that pharmacies distribute the statement with all new prescriptions
and refills for drug products approved under section 505 of the act.
Under the BPCA, Congress required that FDA include the side effects
statement in the labeling of each drug product approved under section
505 of the act. Placing the number in public telephone books or on
magnets given to consumers would not satisfy the legal requirements of
the BPCA.
(Comment 10) We received three comments supporting the inclusion of
the side effects statement in approved Medication Guides. One comment
suggested that this be the exclusive place for the labeling
requirement. We do not agree that requiring the side effects statement
exclusively in Medication Guides would satisfy the requirements of the
BPCA. FDA-approved Medication Guides are prepared by manufacturers for
a limited number of drug products that FDA determines pose a ``serious
and significant public health concern'' (21 CFR 208.1). Given the
limited number of drug products that have FDA-approved Medication
Guides, only requiring the side effects statement in Medication Guides
would not satisfy the BPCA requirement to reach the broadest consumer
audience.
(Response) We did not propose including the side effects statement
in physician labeling. In the proposed rule we stated that while
consumers have access to physician labeling reprinted in the Physician
Desk Reference (PDR), physician labeling is not written for the
consumer audience. We solicited comments on this issue.
(Comment 11) We received one comment supporting our decision not to
include the side effects statement in physician labeling. This comment
agreed that physician labeling is not intended or written for a
consumer audience and that it is not necessary to include both a
manufacturer's name and telephone number and FDA's telephone number in
physician labeling.
(Comment 12) We received three comments suggesting we require the
side effect statement in physician labeling. These comments argued that
some consumers may obtain physician labeling either over the Internet
or upon request from their pharmacist and that FDA's toll-free number
should be in all FDA-approved prescription labeling to ensure its
widest exposure.
(Response) At the time the proposed rule was written, the agency's
proposed rule to revise the physician labeling requirements in
Sec. Sec. 201.56 and 201.57 (21 CFR 201.56 and 201.57) was under
review (the physician labeling rule). On January 24, 2006, the agency
published the final physician labeling rule (71 FR 3922). Section
201.57 of the physician labeling rule requires that the following
verbatim statement appear in the highlights section of the prescribing
information under ``adverse reactions'' (Sec. 201.57(a)(11)(ii)): ``To
report SUSPECTED ADVERSE REACTIONS, contact (insert name of
manufacturer) at (insert manufacturer's phone number) or FDA at (insert
current FDA phone number and Web address for voluntary reporting of
adverse reactions).'' As physician labeling is written for the medical
profession, the term ``adverse reactions'' was selected for this
statement instead of the more consumer-friendly term ``side effects.''
While placing this newly required statement in the highlights section
of physician labeling will alert consumers who
[[Page 63890]]
consult or refer to physician labeling that they can report adverse
reactions directly to FDA at the MedWatch telephone number or Web site,
the agency concludes that pharmacies' distribution of only the
physician labeling containing this statement would not be sufficient to
satisfy the requirement of the BPCA to reach the broadest consumer
audience. In addition, the statement required under the physician
labeling rule does not include the statement required by the BPCA that
the phone number be used only for reporting side effects and not to
obtain medical advice. Therefore, while the MedWatch phone number for
reporting side effects has been added to physician labeling through the
physician labeling rule, distributing physician labeling has not been
added to this rule as a means for pharmacies to meet the requirements
of distributing the side effects statement.
The proposed rule did not include the side effects statement in
PPIs. PPIs are required by FDA for certain drug products, including
oral contraceptives and estrogen drug products (21 CFR 310.501 and
310.515) and, in addition, some manufacturers also voluntarily produce
PPIs for drug products. PPIs are based on physician labeling and are
often distributed to consumers when the drug product is dispensed. In
the preamble to the proposed rule, we stated that manufacturers may
voluntarily include the side effects statement in PPIs. We solicited
comments on this issue.
(Comment 13) We received five comments suggesting that we
reconsider our decision not to include the side effects statement in
PPIs. Of these four comments, one suggested that the PPI could be the
first source of information consumers turn to when they experience a
side effect; one suggested that it may be beneficial for consumers to
see the statement more than once; one stated that including the
statement in PPIs was a viable option; and two stated that requiring
the side effects statement in PPIs would be a way to minimize the
impact of the rule on pharmacies.
(Response) We have considered these comments and have concluded
that, in consideration of the other requirements in this rule,
requiring manufacturers to include the side effects statement in PPIs
would have a minimal impact on meeting the goals of the BPCA.
Furthermore, since drug products with FDA-approved PPIs are a subset of
all prescription drug products, requiring the side effects statement in
PPIs would most likely require pharmacies to maintain a tracking system
to identify which drug products have a compliant PPI in order for
pharmacies to know whether they had distributed the side effects
statement through the PPI in compliance with this rule. Therefore we
conclude that it is unlikely that adding the statement to PPIs would
minimize the burden of this rule on pharmacies, and it is more likely
that pharmacies would choose one of the other proposed five methods of
distributing the side effects statement. As stated in the preamble to
the proposed rule, manufacturers may voluntarily add the side effects
statement to PPIs, however we are not adding the distribution of a PPI
to the list of options available to authorized dispensers or pharmacies
for compliance with this rule.
(Comment 14) We did not require manufacturers to provide the side
effects statement on labeling for unit-of-use drug products. We
received three comments stating that FDA could minimize the impact of
the rule on pharmacies by requiring manufacturers of unit-of-use drug
products to provide the side effects statement on the labeling of the
exterior package.
(Response) We have considered these comments and have concluded
that the proposed provisions are adequate to address the goals of the
BPCA to reach a broad consumer audience; therefore we are not requiring
that manufacturers add the side effects statement to unit-of-use
labeling. In addition, requiring the side effects statement in the
labeling for unit-of-use drug products is unlikely to decrease the
burden of this rule on pharmacies, since pharmacies would most likely
have to maintain a tracking system to know whether they had distributed
the side effects statement through dispensing a unit-of-use drug
product in compliance with this rule. We believe it is more likely that
pharmacies would choose one of the other five proposed methods of
distributing the side effects statement. Consumers will receive the
side effects statement when the unit-of-use drug product is dispensed
by an authorized dispenser or pharmacy using one of the five
distribution methods proposed.
(Comment 15) We did not require health care practitioners who
dispense drug samples in the course of their professional practice to
distribute the side effects statement. The proposed rule stated that
patients receiving drug products in these circumstances will rely on
their health care practitioners to monitor and report adverse events.
We received two comments asking us to require distribution of the side
effects statement with drug samples.
(Response) Drug samples generally are given to consumers in
conjunction with a new prescription. Patients who initially receive
drug samples are under the care of their doctor or health care
practitioner and generally use them in the short term and followup by
filling a new prescription. For a drug product approved under section
505 of the act, consumers will receive the side effects statement upon
filling the new prescription for the drug product for which they
initially received a sample. We recognize that there may be situations
in which health care practitioners provide drug samples to patients on
an ongoing basis, such as in clinics for low-income patients. However
such patients should be instructed by the health care practitioner
providing the drug sample as to its directions for use and possible
side effects. We do not believe that the benefit of requiring that the
side effects statement be distributed with drug samples would be
balanced by the burden such a requirement would impose on health care
practitioners.
D. Distribution of Side Effects Statement by Pharmacies and Authorized
Dispensers
We proposed that the side effects statement be distributed with
each prescription drug product, both new and refills, approved under
section 505 of the act and dispensed to consumers by pharmacies and
authorized dispensers in an outpatient setting. We proposed five
options through which pharmacies and authorized dispensers could
distribute the side effects statement, including the following: (1) On
a sticker attached to the package, vial, or container of the drug
product; (2) on a preprinted pharmacy prescription vial cap; (3) on a
separate sheet of paper; (4) in consumer medication information (CMI);
or (5) by distributing the appropriate FDA-approved Medication Guide
that contains the side effects statement. We solicited comments on
other options pharmacies might use for distribution.
(Comment 16) We received one comment opposing a requirement to
place the side effects statement directly on the label of the
prescription vial or container. This comment stated that in many cases
the vials or containers are already too crowded, and requiring another
sticker on the container could crowd out more important labels and
reduce the importance consumers ascribe to these labels both because of
the number of stickers and because of the placement of secondary
information in the stickers. We received one comment supporting the
placement of the side effects statement on an auxiliary label. We
received another comment stating that the most logical
[[Page 63891]]
place for the side effects statement to appear is in the CMI for the
drug product. Another comment suggested that CMI not be the only means
of communicating the toll-free number, as some pharmacies may not
dispense CMI for refill prescriptions.
(Comment 17) We received several comments supporting our proposal
to provide multiple options for pharmacies and authorized dispensers to
distribute the side effects statement. We received two comments stating
that while we indicated we exercised discretion in giving affected
pharmacies flexibility in complying with the law by providing options,
we failed to impose a proportionate burden on manufacturers. One
comment stated that it is entirely feasible for manufacturers to adhere
multiple copies of printed leaflets onto bulk containers of drug
products that pharmacy personnel can then remove from bulk containers
and dispense with each prescription filled.
(Comment 18) We received two comments expressing concern about the
potential for consumers to lose or dispose of paper messages (e.g., the
consumer medication information option or the separate sheet of paper
option). One of these comments requested that we require manufacturers
and pharmacists to work together to include the side effects statement
on either the sticker or preprinted vial cap with any separate printed
materials provided as a supplement. This comment stated that if the
package has no cap, if there is no room on a package for a sticker, or
if the product already requires a sticker for a different reason, they
would suggest that the sticker be included inside the package so that
consumers can affix the sticker in a place useful to them, such as a
medicine chest or pill caddy. Another comment requested that we allow
pharmacies the option to distribute the side effects statement by
printing it directly on the bag in which the pharmacy puts prescription
drugs before handing them to consumers.
(Comment 19) Two comments requested that pharmacies be allowed the
option to e-mail the side effects statement to consumers along with
notice to these consumers that their prescriptions are ready. These
comments stated that this would obviate the need for the pharmacy to
provide the patient with a paper version of the statement when the
prescription is picked up. We received two comments requesting that we
allow pharmacists to exercise their judgment and discretion in
distributing the statement to a consumer if a pharmacist is reasonably
sure that a consumer already knows about the agency's toll-free number.
(Response) We have considered the comments received and conclude
that the range of options provided to pharmacies to distribute the side
effects statement is adequate to meet the requirements of the BPCA. We
disagree that placing the side effects statement on the pharmacy bag,
sending the side effects statement by e-mail when a consumer is
notified their prescription is ready, or providing the side effects
statement on a separate sticker that consumers could then affix to
their medicine chest or pill caddy would effectively reach the broadest
consumer audience. While we recognize that a consumer may throw away
any attachment a pharmacist provides when dispensing a drug product,
including the CMI or a separate sheet of paper, there is an even
greater likelihood that a consumer would throw away the pharmacy bag
that the prescription came in or a small separate sticker, and thus
would not have the side effects statement in proximity to the drug
product when needed. Similarly, e-mail is easily deleted, and including
the side effects statement in an e-mail notifying consumers when their
prescription is ready makes it likely that the consumers will delete
the e-mail before they even pick up the prescription.
Pharmacies may provide voluntarily a separate sticker to consumers
with the side effects statement for attachment in the home as a public
service if they choose; however, distribution of such a separate
sticker would not meet the distribution requirements of this rule.
Similarly, pharmacies may provide the side effects statement
voluntarily on pharmacy bags or via e-mail, but distribution of the
side effects statement using these methods likewise would not meet the
distribution requirements of this rule. Also, we note that there is no
provision in the BPCA or FDAAA that would allow us to grant pharmacists
the right to exercise their judgment or discretion in deciding whether
or not to distribute the side effects statement to an individual
consumer.
E. Use of MedWatch System for Consumer Reporting
As stated in the preamble to the proposed rule, we proposed that
FDA's existing MedWatch system be used to fulfill the requirements of
the BPCA for providing a toll-free number for the purpose of receiving
adverse event reports regarding drug products. While we received
comments supporting the use of the MedWatch system to capture
consumer's postmarket safety information, we received several comments
suggesting changes to the MedWatch system. These comments are beyond
the scope of this rule. This rule does not make specific changes to the
MedWatch system.
F. Postmarketing Safety Reporting
While the proposed rule suggested no changes to FDA's postmarketing
safety reporting system, we received several comments about our
postmarketing safety reporting system and how data received from the
side effects statement would affect the system. These comments are
beyond the scope of this rule. This rule does not make specific changes
to FDA's postmarketing safety reporting system.
G. Implementation of Regulation
(Comment 20) We received one comment expressing dissatisfaction
with the agency for not implementing the rule in a timelier manner.
This comment also stated that the compliance date FDA proposed was too
long and suggested a bifurcated compliance structure whereby pharmacies
would notify consumers immediately of the toll-free number, and
manufacturers would have 1 year to make any required labeling changes.
We also received comments supporting the 1-year compliance period from
both pharmacy interests and drug manufacturing interests. These
comments noted that pharmacies and drug manufacturers need time to
integrate any printing/labeling changes into existing systems.
(Response) In implementing the requirements of the BPCA and FDAAA,
we believe it is important to work with stakeholders and provide time
for updating labels and systems so that we reach the best possible
outcome for constituent groups, including consumers, pharmacists and
other health care professionals, drug manufacturers, and the agency.
With the publication of this final rule, we believe we have implemented
the provisions of the BPCA and FDAAA effectively.
(Comment 21) Two comments suggested that, after full implementation
of the laws and all necessary modifications to the MedWatch system, FDA
undertake extensive consumer outreach, educating the public about the
right to report under the new provisions. One comment suggested that
FDA, in cooperation with the OTC drug manufacturers, implement a public
relations program to raise consumer awareness of the necessity of
reporting unexpected adverse events to the product manufacturer. These
comments stated that FDA should work with consumer educators and health
[[Page 63892]]
professionals to provide clear information and educational materials on
how, what, and when to report. Another comment suggested the agency add
specific questions to the ongoing National Survey of Prescription
Medicine Information Received by Consumers (at the physician's office
and pharmacy) to track awareness of the side effects statement and to
determine to what extent consumers contact FDA to report a side effect.
(Response) The agency is in the process of implementing numerous
safety initiatives under FDAAA that will benefit consumers. Section
906(a) of FDAAA requires published direct-to-consumer advertisements to
include a statement encouraging reporting of negative side effects to
FDA and providing the MedWatch Web site and phone number. Given that
section 502(f)(2) of FDAAA likely will reduce the number of voluntary
reports FDA receives on application OTC drug products as a result of
this rule, we do not believe it is necessary to undertake an extensive
educational campaign targeted at voluntary reporting for application
OTC drug products at this time. However, should our experience with
reporting under these new provisions indicate otherwise, we will
consider whether educational efforts for the general public would be
beneficial.
In addition, we note that the National Survey of Prescription
Medicine Information Received by Consumers is not currently ongoing. If
this survey is reinstated at a future date, we will consider adding
specific questions relevant to the side effects statement at that time
as suggested by the comment.
IV. Analysis of Impacts
FDA has examined the impacts of the final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs 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 an economically significant regulatory action
under the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the impact of the final rule will be
proportional to sales volumes, the agency concludes that this final
rule will not 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 $127 million, using the most current (2006) 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.
In accordance with Executive Order 12866, FDA has previously
analyzed the potential economic effects of this final rule. We
estimated that annualized costs of the proposed rule would be $9.3
million to $22.6 million (69 FR 21778 at 21783). For the final rule, we
project that one-time costs will range from approximately $38.0 million
to $49.6 million and annual costs will range from $12.4 million to
$46.3 million. The total annualized impact of the final rule will range
from $16.9 million to $52.2 million with a 3-percent discount rate and
from $17.8 million to $53.4 million with a 7-percent discount rate. We
are unable to quantify the benefits of the final rule. Although the
estimated costs of this final rule are higher than the estimated costs
of the preliminary regulatory impact analysis, the agency has
determined that the rule is not an economically significant regulatory
action as defined by the order.
A. Need for Regulation
The BPCA required that the labeling of each drug approved under
section 505 of the act be accompanied by a toll-free number and
statement that the number is for reporting adverse events, not to
receive medical advice. Because OTC drug products may be approved under
section 505 of the act, we proposed that the labeling for all
application OTC drug products include the side effects statement.
Subsequently, FDAAA exempted any application OTC drug products whose
packaging includes a toll-free number that consumers can call to report
complaints to the manufacturer or distributor of the product.
Consequently, to fulfill these statutory requirements, the final rule
will require pharmacies and authorized dispensers to provide patients
with the side effects statement with each dispensed prescription drug,
and will require drug manufacturers to include the side effects
statement in FDA-approved Medication Guides for drugs approved under
section 505 of the act and in the labeling of application OTC drug
products not subject to the exclusion in section 502(f)(2) of FDAAA.
B. Costs of Regulation
(Comment 22) Most comments on the costs of the proposed rule
asserted that we understated the number of affected OTC drug products
and the costs to modify OTC drug product labeling.
(Response) In most cases, however, changes under FDAAA made many of
these comments irrelevant. As noted in this final analysis, we have
updated the initial analysis with current numbers whenever possible.
1. Pharmacy Industry
a. Number of affected pharmacies. We received no comments on our
initial estimate of the number of pharmacies affected by the
requirement to include the side effects statement with each dispensed
prescription drug. For the final analysis, we update the number of
affected outlets with data from the 2002 Economic Census on the number
of establishments that have merchandise sales from prescription drugs
(table 1 of this document). Both retail and nonretail pharmacies may
dispense prescription drugs to patients. Retail channels include
independent drug stores, chain drug stores, mass merchants, grocery
stores with pharmacies, and mail or Internet services. Nonretail
channels include health maintenance organizations (HMOs), hospital
outpatient pharmacies, offices of health care practitioners, and
ambulatory care clinics.
The agency solicited comment on its assumptions about the
percentages of affected dispensing locations currently distributing
some form of printed CMI (69 FR 21783). Because no comments were
received and the agency has no other information about pharmacy
practices, we continue to assume that printed CMI accompanies: (1) 89
percent of the prescriptions dispensed by retail pharmacies, (2) 89
percent of prescriptions dispensed in ambulatory outpatient settings,
and (3) 0 percent of prescriptions dispensed in other health care
settings. Table 1 of this document shows the estimated number of
affected outlets distributing CMI.
b. Prescriptions dispensed. Although information on the number of
prescriptions dispensed by retail
[[Page 63893]]
channels is publicly available, it is difficult to estimate the number
of prescriptions dispensed by nonretail channels. For the initial
analysis of impacts, we used 2001 data from IMS Health to approximate
the volume of prescriptions from nonretail channels. Based on the IMS
data, nonretail channels dispensed from 6 percent to 18 percent of the
prescription volume dispensed from retail channels (69 FR 21778 at
21784). Although we solicited comment on our estimate, we received no
additional information. Thus, we assume that the percentage of
prescriptions dispensed by retail and nonretail outlets remains similar
to our initial estimate. In 2007, IMS Health estimated that retail
channels dispensed approximately 3.8 billion prescriptions (https://
imshealth.com/vgn/images/portal/CIT_40000873/39/53/
834329692007%20Channel%20Distribution%20by%20RXs.pdf). We estimate that
nonretail channels dispensed from 228 million (6 percent of 3.8
billion) to 671 million (18 percent of 3.8 billion) prescriptions, for
a total volume of prescriptions in 2007 ranging from 4.0 billion (= 3.8
billion + 0.2 billion) to 4.5 billion (= 3.8 billion + 0.7 billion).
c. Compliance costs for pharmacies. For the initial analysis of
impacts, we assumed that pharmacies currently distributing printed CMI
would choose to comply with the requirements of the proposed rule by
distributing the side effects statement in the CMI. We anticipated that
the side effects statement could be added to existing pharmaceutical
information databases used to produce CMI at a negligible one-time
cost. Moreover, we assumed that periodic updates of other drug labeling
information included in pharmaceutical databases required pharmacies or
their computer system vendors to test the printing of the CMI on a
regular basis. Because most pharmacies distribute printed CMI, we
assumed that only pharmacies and authorized dispensers not currently
providing printed CMI would incur incremental costs to comply with the
requirements of the proposed rule.
Table 1--Number of Pharmacy Outlets With Sales of Prescription Drugs and Distributing Printed Consumer
Medication Information (CMI)
----------------------------------------------------------------------------------------------------------------
Number of Outlets
Type of Outlet Number of Outlets\1\ Distributing CMI
----------------------------------------------------------------------------------------------------------------
Retail outlets: ....................... .......................
Pharmacy, drug, and health care stores 39,159 34,711
Food and beverage stores 20,227 18,002
Warehouse clubs and supercenters 2,553 2,502
Other general merchandise stores 5,469 4,867
Electronic shopping 88 78
Mail-order houses 365 325
Other direct selling establishments 26 23
----------------------------------------------------------------------------------------------------------------
Nonretail outlets: ....................... .......................
Offices of health practitioners 7,424 0
Hospital outpatient services 5,506 0
Clinics 3,117 2,774
HMOs 162 144
----------------------------------------------------------------------------------------------------------------
Total outlets 84,096 63,427
----------------------------------------------------------------------------------------------------------------
Sources: Retail outlets from table 1 of 2002 Economic Census, Retail Trade, Subject Series, publication number
EC02-44SL-LS issued October 2005; Nonretail outlets from 2002 Economic Census, Health Care of Social
Assistance, Subject Series, publication number EC02-62SL-LS issued October 2005.
\1\ Includes establishments in the 2000 North American Industry Classification System (NAICS) industry codes
445, 446, 452, 454, 621, 622 that had sales from product line code 20161 (Prescriptions).
(Comment 23) We received one comment from a professional
organization representing pharmacists that supported our assumption
that most pharmacies will adopt the CMI option. One comment from a
provider of pharmaceutical databases stated that it will not be
difficult to include the side effects statement in the CMI. Two
comments noted that in our initial analysis we did not take into
account the one-time effort required to modify and test computer
programs controlling the printing of the CMI and auxiliary labels, but
provided no detailed information about these costs.
(Response) We agree that pharmacies choosing to distribute revised
CMI (i.e., CMI with the side effects statement) will need to ensure
proper printing of the side effects statement if they choose this
option. Pharmacies that choose to print their own labels to affix on
the dispensing container will incur costs to modify and test the
computer programs that control the printing of auxiliary labels.
However, we lack sufficient information about the percentage of
pharmacies that would choose in-house printing of auxiliary labels to
modify our initial estimate.
To illustrate the potential costs of the proposed rule, we
estimated the level of effort required by a pharmacy to manually affix
a sticker preprinted with the side effects statement on each
prescription container. Because this option would cause a pharmacy to
incur additional costs for each prescription drug dispensed, the agency
believes that this would be a higher cost option for pharmacies and
authorized dispensers that currently distribute printed CMI with
prescription drugs.
(Comment 24) Two comments on the proposed rule stated that FDA
failed to understand the workflow in a modern pharmacy and that
manually affixing stickers would be more costly than we estimated.
(Response) We acknowledge that manually affixing a sticker in a
highly automated system might cause disruptions in workflow that were
not captured in our initial analysis. However, we have no other
information that we could use to modify our estimate. Nevertheless, we
have increased our cost estimate in the proposed rule by 35 percent to
account for the following: (1) A 23-percent increase in the number of
prescriptions and (2) a 12-percent increase in costs
[[Page 63894]]
since 2003.\1\ For pharmacies, the potential annual costs of the final
rule in 2007 dollars will range from $12.4 million to $27.3 million.
Similar to the range in the proposed rule, this range reflects
uncertainty about the costs to affix the sticker to the prescription
drug container, and the average number of prescriptions dispensed by
affected pharmacy outlets.
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\1\ U.S. Department of Labor, Bureau of Economic Analysis,
National Economic Accounts (https://www.bea.gov/nationalnipaweb/
SelectTable.asp?Selected=Y).
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2. Drug Manufacturers
We proposed to require that the labeling of application OTC drug
products not subject to the exclusion in section 502(f)(2) of FDAAA
include the OTC side effects statement in the warnings section of the
drug facts format labeling. For the analysis of the proposed rule, we
predicted that manufacturers would spend $3,000 per shelf-keeping unit
(SKU) to modify the labeling of a new drug application (NDA) OTC drug
product or $1,000 per SKU to modify the labeling of an abbreviated new
drug application (ANDA) OTC drug product. We assumed that each affected
OTC drug product would have, on average, up to 3 SKUs. For the proposed
rule, we estimated that approximately 1,570 OTC drug packages would
need to be revised to add the side effects statement. Furthermore, we
estimated manufacturers would need to add the side effects statement to
about 18 Medication Guides.
a. Number of affected products. Although we received no comments on
our estimate of the number of Medication Guides that would be revised,
more prescription drugs have added Medication Guides since our initial
estimate. Based on current agency information, we have increased our
estimate from 18 to 370 Medication Guides.
(Comment 25) Comments from the drug industry and a member of
Congress stated that FDA should not have included application OTC drug
products in the proposed rule. Some comments expressed concern that
because the labeling of most NDA OTC drug products includes a
manufacturer's toll-free telephone number, addition of the MedWatch
telephone number could confuse consumers. It was suggested that FDA
exempt from the requirements of the proposed rule any OTC drug product
whose labeling contains a toll-free number for the manufacturer or
distributor.
(Response) The proposed rule would have required the same side
effects statement on all application OTC drug products. As discussed
previously in this preamble, the interim final rule codified section
502(f)(2) of FDAAA, which states that the requirement to include the
side effects statement does not apply to any OTC drug product approved
under section 505 of the act if the product's packaging contains a
toll-free telephone number through which consumers can report
complaints to the manufacturer or distributor of the drug. Section
502(f)(2) of FDAAA thus creates a situation in which manufacturers and
distributors of affected application OTC drug products will choose to
either add the side effects statement or their own toll-free telephone
number to OTC drug product labeling. Therefore, under the rule, the
drug facts format labeling of application OTC drug products could vary
depending on whether the affected manufacturer or distributor uses the
side effects statement or its own toll-free number.
The agency previously estimated that certain retailers with more
than 10 establishments would have some private label OTC drug products
(62 FR 9046, February 27, 1997). Depending on the size of the firm,
each private label OTC drug product could have numerous SKUs. Agency
records indicate that there are about 60 unique application OTC
products (i.e., a unique combination of active ingredient, dosage form,
and strength). An informal convenience survey of stores in the
Washington, DC, area and in northern New England looked at whether
affected private label OTC drug product labeling contains a toll-free
telephone number. We found that the packaging of most private label OTC
drug products does not include a toll-free number for complaints.\2\ It
appears that most private label OTC drug product labeling will need to
be modified to comply with the final rule. However, because most
national brand OTC drug products affected by the rule already have a
toll-free telephone number for complaints, current packaging for most
national brand OTC drug products will conform to the requirements of
the final rule without any further change.
---------------------------------------------------------------------------
\2\ FDA employees visited three mass merchants, three chain
grocery stores, and four chain drug stores to roughly estimate the
following: (1) The number of SKUs per private label OTC product for
categories of products with high sales volumes and (2) the
proportion of the labeling of these products including a toll-free
telephone number. At each site, at least one private label ANDA OTC
drug product from the following categories was examined to determine
the number of SKUs for the product and the percentage of SKUs with a
toll-free telephone number--allergy and asthma, antifungal, feminine
hygiene, pain, stomach-diarrhea, and stomach-digestion. In addition,
at some locations, employees examined private label ANDA OTC drug
products for smoking cessation, lice control, hair restoration, and
cold and sinus. We examined over 300 packages and found that the
labeling of smoking cessation products and allergy and asthma eye
drops already appear to include a toll-free telephone number.
Excluding these products, only about 20 percent of the labeling of
private label ANDA OTC products would conform to the requirements of
the final rule without change. Finally, to estimate a range of
products whose labeling would need to be modified, we adjusted the
average number of SKUs for each product (i.e., active ingredient,
dosage form, and strength) by the proportion of SKUs with labeling
including a toll-free telephone number.
---------------------------------------------------------------------------
For this final analysis, we assume that distributors of private
label OTC drug products (i.e., the unique combination of active
ingredient, dosage form, and strength) would not carry identical SKUs
from different manufacturers. Although uncertain, the findings from our
informal survey give us an idea of the number of private label OTC drug
product SKUs that might be affected by the final rule. For the final
analysis, therefore, we anticipate that any firm with 10 to 99
establishments will need to change the packaging of between 40 to 55
affected private label OTC drug products and any firm with 100 or more
establishments will need to change the packaging of between 110 to 135
private label OTC drug products. Table 2 of this document illustrates
the number of possible firms that could have private label OTC drug
products.
Table 2--Estimate of the Number of Private Label Distributors
----------------------------------------------------------------------------------------------------------------
Number of Firms With 10-99 Number of Firms With 100 or
Kind of Business Establishments More Establishments
----------------------------------------------------------------------------------------------------------------
Supermarket and other grocery 194 37
----------------------------------------------------------------------------------------------------------------
Pharmacy, drug, and proprietary stores 59 16
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