[Federal Register Volume 79, Number 233 (Thursday, December 4, 2014)]
[Rules and Regulations]
[Pages 72063-72103]
[FR Doc No: 2014-28241]

Vol. 79

Thursday,

No. 233

December 4, 2014

Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 201

Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling;
Pregnancy, Lactation, and Reproductive Potential: Labeling for Human
Prescription Drug and Biological Products--Content and Format; Draft
Guidance for Industry; Availability; Final Rule and Notice

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 /
Rules and Regulations

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. FDA-2006-N-0515 (formerly Docket No. 2006N-0467)]
RIN 0910-AF11

Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations governing the content and format of the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Use in Specific Populations'' section of the labeling for human
prescription drug and biological products. The final rule requires the
removal of the pregnancy categories A, B, C, D, and X from all human
prescription drug and biological product labeling. For human
prescription drug and biological products subject to the Agency's 2006
Physician Labeling Rule, the final rule requires that the labeling
include a summary of the risks of using a drug during pregnancy and
lactation, a discussion of the data supporting that summary, and
relevant information to help health care providers make prescribing
decisions and counsel women about the use of drugs during pregnancy and
lactation. The final rule eliminates the ``Labor and delivery''
subsection because information about labor and delivery is included in
the ``Pregnancy'' subsection. The final rule requires that the labeling
include relevant information about pregnancy testing, contraception,
and infertility for health care providers prescribing for females and
males of reproductive potential. The final rule creates a consistent
format for providing information about the risks and benefits of
prescription drug and/or biological product use during pregnancy and
lactation and by females and males of reproductive potential. These
revisions will facilitate prescriber counseling for these populations.

DATES: This rule is effective June 30, 2015. See section IV of this
document for the implementation dates of this final rule.

FOR FURTHER INFORMATION CONTACT: Kathy Schreier, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, Rm. 6246, Silver Spring, MD 20993-0002, 301-
796-3432; or Stephen Ripley, Center for Biologics Evaluation and
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg.
71, Rm. 7301, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Table of Contents

Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the Regulatory Action in Question
Costs and Benefits
I. Background
    A. History of FDA-Approved Pregnancy and Lactation Labeling for
Prescription Drugs
    B. Development of the Proposed Rule
    C. The Proposed Rule
    D. Mental Models Research
II. Overview of the Final Rule Including Significant Changes to the
Proposed Rule
    A. Overview
    B. Significant Changes to the Proposed Rule
III. Comments on the Proposed Rule
    A. Proposed Rule as a Whole
    B. Specific Provisions of the Proposed Rule
IV. Implementation
V. Legal Authority
    A. Statutory Authority
    B. First Amendment
VI. Environmental Impact
VII. Summary of Final Regulatory Impact Analysis
    A. Introduction
    B. Summary of Costs and Benefits
VIII. Paperwork Reduction Act of 1995
IX. Federalism
X. References

Executive Summary

Purpose of the Regulatory Action

    FDA is amending its regulations governing the content and format of
the ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers''
subsections of the ``Use in Specific Populations'' section (under Sec.
201.57 (21 CFR 201.57)) and the ``Precautions'' section (under Sec.
201.80 (21 CFR 201.80)) of the labeling for human prescription drug and
biological products (both referred to as ``drugs'' or ``drug products''
in this final rule). In this rulemaking, the Agency is finalizing many
of the provisions in the proposed rule issued on May 29, 2008 (73 FR
30831).
    This rulemaking is part of a broad effort by the Agency to improve
the content and format of prescription drug labeling. The final rule
creates a consistent format for providing information about the risks
and benefits of drug use during pregnancy and lactation and by females
and males of reproductive potential. FDA's revisions to the content and
format requirements for prescription drug and biological product
labeling are authorized by the Federal Food, Drug, and Cosmetic Act
(the FD&C Act) and by the Public Health Service Act (PHS Act).
Summary of the Major Provisions of the Regulatory Action in Question
    The final rule requires that for the labeling of certain drug
products (as described in the ``Implementation'' section of this
document), the subsections ``Pregnancy,'' ``Nursing mothers,'' and
``Labor and delivery'' be replaced by three subsections entitled
``Pregnancy,'' ``Lactation,'' and ``Females and Males of Reproductive
Potential.'' The final rule also requires the removal of the pregnancy
categories A, B, C, D, and X from all drug product labeling.
``Pregnancy''
    The final rule merges the current ``Pregnancy'' and ``Labor and
delivery'' subsections into a single ``Pregnancy'' subsection of
labeling. If there is a scientifically acceptable pregnancy exposure
registry for the drug, the ``Pregnancy'' subsection must contain a
specified statement about the existence of the registry, followed by
contact information needed to enroll or to obtain information about the
registry. The Agency has concluded that including information about
pregnancy exposure registries in prescription drug labeling will
encourage participation in registries, thereby improving data
collection in pregnant women. Under ``Pregnancy,'' the final rule also
requires that the labeling include a summary of the risks of using a
drug during pregnancy. If data demonstrate that a drug is not absorbed
systemically, the ``Risk Summary'' must contain only a specified
statement regarding this fact. If data demonstrate that the drug is
absorbed systemically, the ``Risk Summary'' must include risk
statements based on data from all relevant sources (human, animal, and/
or pharmacologic), that describe, for the drug, the risk of adverse
developmental outcomes.
    The labeling must also contain relevant information, if it is
available, to help health care providers make prescribing decisions and
counsel women about the use of the drug during pregnancy; this could
include information on disease-associated maternal and/or embryo/fetal
risk, dose adjustments during pregnancy and the postpartum period,
maternal adverse reactions, fetal/neonatal adverse reactions, and/or
the effect of the drug on labor or delivery. FDA believes that
including such information supports

health care providers' understanding of drug product risks and benefits
and facilitates informed prescribing decisions and patient counseling.
The labeling must also describe the data that are the basis for the
risk statements and clinical information included in the ``Pregnancy''
subsection of labeling.
``Lactation''
    The final rule requires that the ``Lactation'' subsection of
labeling contain a summary of the risks of using a drug during
lactation. If data demonstrate that the drug is not absorbed
systemically, this summary must contain only a specified statement
regarding this fact. If data demonstrate that the drug is absorbed
systemically by the mother, this summary must include, to the extent it
is available, relevant information on the presence of the drug in human
milk, effects of the drug on the breast-fed child, and effects of the
drug on milk production. For drugs absorbed systemically, a risk and
benefit statement must appear at the end of the summary of risks,
unless breastfeeding is contraindicated during drug therapy. FDA has
determined that the inclusion of a risk and benefit statement will
provide a useful framework for health care providers to use when making
prescribing decisions for a lactating patient.
    The ``Lactation'' subsection must also include, to the extent
information is available, relevant information concerning ways to
minimize drug exposure in the breast-fed child in certain situations
and concerning available interventions for monitoring or mitigating the
adverse reactions presented elsewhere in the labeling. In addition, the
labeling must also include pertinent information about the data that
are the basis for the risk summary and clinical information included in
the ``Lactation'' subsection of labeling.
``Females and Males of Reproductive Potential''
    FDA determined that because there was no consistent placement in
the labeling of information about pregnancy testing, contraception, and
infertility, it was difficult for health care providers to find this
important information that can affect decisionmaking before or during
pregnancy. Thus, the final rule requires that the ``Females and Males
of Reproductive Potential'' subsection include relevant information
when pregnancy testing or contraception is required or recommended
before, during, or after drug therapy or when there are human or animal
data that suggest drug-associated fertility effects.
Removal of Pregnancy Categories
    Through experience and stakeholder feedback, FDA learned that the
pregnancy categories were confusing and did not accurately and
consistently communicate differences in degrees of fetal risk. In
addition, FDA learned that the pregnancy categories were heavily relied
upon by clinicians but were often misinterpreted and misused in that
prescribing decisions were being made based on the pregnancy category,
rather than an understanding of the underlying information that
informed the assignment of the pregnancy category. FDA believes that a
narrative structure for pregnancy labeling, rather than a category
system, is best able to capture and convey the potential risks of drug
exposure based on animal or human data, or both. FDA has determined
that retaining the pregnancy categories is inconsistent with the need
to accurately and consistently communicate differences in degrees of
fetal risk. Therefore, the final rule requires the removal of the
pregnancy categories A, B, C, D, and X from all drug product labeling.

Costs and Benefits

    We estimate that over 10 years with a 7 percent discount rate, the
present value of one-time costs of the rule equal $52.4 million and the
present value of the annual costs equal $14.4 million; with a 3 percent
discount rate, the present value of one-time costs equal $60.1 million
and the present value of the annual costs equal $18.2 million. The
present value of the total costs equal $66.8 million with a 7 percent
discount rate and $78.2 million with a 3 percent discount rate. The
annualized costs of the rule total $9.5 million with a 7 percent
discount rate and $9.2 million with a 3 percent discount rate. The
final rule will address issues raised by experts and stakeholders and
improve the quality of the affected sections of prescription drug
labeling. Better quality prescribing information will enhance the
usefulness of the labeling. The public health benefits of the final
rule would result from improved health outcomes. However, because we
have no information about how improved labeling will affect prescriber
behavior and patient outcomes, we are unable to quantify the benefits
of the final rule.

                                 Summary of Benefits and Costs of the Final Rule
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                                                                                Total            Total
                                               Present value    Present value      annualized       annualized
                                               of total costs   of total costs   costs over 10    costs over 10
               Total benefits                  with 3 percent   with 7 percent    years with 3     years with 7
                                               discount rate    discount rate       percent          percent
                                                  ($ mil)          ($ mil)       discount  rate   discount  rate
                                                                                ($ mil)          ($ mil)
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Not estimated...............................            78.2             66.8              9.2              9.5
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I. Background

    In the Federal Register of May 29, 2008 (73 FR 30831), FDA issued a
proposed rule to amend the content and format of the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Use in Specific Populations'' section of labeling for human
prescription drug and biological products, which appear in Sec.
201.57. The proposed rulemaking was part of a broad effort by the
Agency to improve the content and formatting of prescription drug
labeling.

A. History of FDA-Approved Pregnancy and Lactation Labeling for
Prescription Drugs

    Under sections 502 and 505 of the FD&C Act (21 U.S.C. 352 and 355),
FDA has responsibility for ensuring that prescription drug and
biological products (both referred to as ``drugs'' or ``drug products''
in this final rule) are accompanied by labeling (including prescribing
information) that summarizes scientific information concerning their
safe and effective use. FDA regulations on labeling for use during
pregnancy, during labor and delivery, and by nursing mothers were
originally issued in 1979 as part of a rule prescribing the content and
format

for labeling for human prescription drugs (part 201 (21 CFR part 201))
(44 FR 37434, June 26, 1979) (the 1979 regulations).\1\ The
requirements on content and format of labeling for drug products were
revised on January 24, 2006, in the final rule on ``Requirements on
Content and Format of Labeling for Human Prescription Drug and
Biological Products'' (71 FR 3922), commonly referred to as the
``Physician Labeling Rule'' (PLR).\2\ As part of the January 2006
revision, the subsections of the labeling on pregnancy, labor and
delivery, and nursing mothers were moved from the ``Precautions''
section under Sec.  201.57 to the ``Use in Specific Populations''
section. The content of these sections in part 201 was not revised, but
the sections were redesignated as Sec.  201.57(c)(9)(i) through
(c)(9)(iii). The previous labeling regulation (adopted in 1979) was
redesignated as Sec.  201.80, and applies to products not affected by
the January 2006, revisions. In redesignated Sec.  201.80, the
subsections on pregnancy, labor and delivery, and nursing mothers are
Sec.  201.80(f)(6) through (f)(8).
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    \1\ Thus, the labeling for drugs originally approved before 1979
may not contain the information required by those regulations
regarding pregnancy, labor and delivery, and nursing mothers.
    \2\ FDA's regulations governing the content and format of
labeling for human prescription drug and biological products are
contained in Sec. Sec.  201.56, 201.57, and 201.80.
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    The 1979 regulations provided, at what was redesignated in 2006 as
Sec.  201.57(c)(9)(i) and Sec.  201.80(f)(6)(i), that unless a drug was
not absorbed systemically and was not known to have a potential for
indirect harm to a fetus, a ``Pregnancy'' subsection must be included
within the ``Precautions'' section of the labeling. The 1979
regulations required that the ``Pregnancy'' subsection contain
information on the drug's teratogenic effects and other effects on
reproduction and pregnancy and, when available, a description of human
studies with the drug and data on its effects on later growth,
development, and functional maturation of the child. The 1979
regulations also required that each product be classified under one of
five pregnancy categories (A, B, C, D, or X) on the basis of risk of
reproductive and developmental adverse effects or, for certain
categories, on the basis of such risk weighed against potential
benefit.\3\
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    \3\ For further discussion of the pregnancy categories, see 73
FR 30831 at 30832 through 30833.
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    With regard to labor and delivery, the 1979 regulations stated, at
what was redesignated in 2006 as Sec.  201.57(c)(9)(ii) and Sec.
201.80(f)(7), that under certain circumstances, the labeling must
include information on the effects of the drug on, among other things,
the mother and the fetus, the duration of labor and delivery, and the
effect of the drug on the later growth, development, and functional
maturation of the child.
    With regard to labeling on lactation, the 1979 regulations
required, at what was redesignated in 2006 as Sec.  201.57(c)(9)(iii)
and Sec.  201.80(f)(8), that a ``Nursing mothers'' subsection be
included in the ``Precautions'' section of the labeling. The ``Nursing
mothers'' subsection provided that if a drug was absorbed systemically,
the labeling must contain information about excretion of the drug in
human milk and effects on the nursing infant, as well as a description
of any pertinent adverse effects observed in animal offspring. The
``Nursing mothers'' subsection required the use of certain standard
statements depending on whether the drug was known to be excreted in
human milk and whether it was associated with serious adverse
reactions.\4\
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    \4\ For further discussion of the history of both the
``Pregnancy'' and the ``Nursing mothers'' subsections of
prescription drug labeling, see 73 FR 30831 at 30833.
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B. Development of the Proposed Rule

    Over a number of years after the 1979 regulations were issued, FDA
received feedback on the issues and concerns with the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of
prescription drug labeling as defined by the 1979 regulations. In
response to this feedback, FDA held a part 15 public hearing, conducted
focus groups, and convened two advisory committees to provide expert
input. During this process, many stakeholders stated that these
subsections of prescription drug labeling lacked clarity, often failed
to provide meaningful clinical information about drug exposure during
pregnancy and lactation, and did not address the potential maternal and
fetal consequences of discontinuing needed maternal drug therapy during
pregnancy. Experts and other stakeholders noted that the pregnancy
categories, although highly relied upon by health care providers, were
often misinterpreted and misused. FDA also sought input on the
development of a model format for these subsections of labeling, and
the resulting model served as the basis for the May 29, 2008, proposed
rule (73 FR 30831). The preamble to the proposed rule contains a
detailed discussion about the background of the development of the
proposed rule and additional details regarding the 1979 regulations
governing labeling of drug products for use during pregnancy, during
labor and delivery, and while nursing (73 FR 30831 at 30832-30838).

C. The Proposed Rule

    FDA proposed to amend the content and format of the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Use in Specific Populations'' section of physician labeling for
prescription drug products subject to Sec.  201.57. The Agency's
proposed changes were intended to create a consistent format for
providing information about the effects of a drug on pregnancy and
lactation that would be useful for decisionmaking by health care
providers and their patients. With respect to the ``Pregnancy,''
``Labor and delivery,'' and ``Nursing mothers'' subsections of the
``Precautions'' section of prescription drug labeling for drug products
subject to Sec.  201.80, the Agency proposed only to remove the
pregnancy category from the ``Pregnancy'' subsection.
1. Proposed Provisions for New and Recently Approved Drugs
    FDA proposed the following format and content changes to the
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers''
subsections of prescription drug labeling for products subject to Sec.
201.57.
     Merge the current ``Pregnancy'' and ``Labor and delivery''
subsections into a single ``Pregnancy'' subsection designated 8.1 under
the section ``8 Use in Specific Populations.''
     Rename the ``Nursing mothers'' subsection as ``Lactation''
designated with the identifying number 8.2 under the section ``8 Use in
Specific Populations.''
     Reserve the identifying number 8.3 for future use.
     Replace the format and content of the ``Pregnancy''
subsection in its entirety with the following:
    [cir] If there is a pregnancy exposure registry for the drug, the
telephone number or other information needed to enroll in the registry
or to obtain information about the registry must be included at the
beginning of the ``Pregnancy'' subsection of labeling.
    [cir] Require the inclusion of a general statement about background
risk, specifically ``All pregnancies have a background risk of birth
defect, loss, or other adverse outcome regardless of drug exposure. The
fetal risk summary below describes (name of drug)'s potential to
increase the risk of developmental abnormalities above the background
risk.''

    [cir] Under the subheading ``Fetal Risk Summary,'' require the
labeling to contain a risk conclusion and a narrative description of
the risk(s) (if the risk conclusion is based on human data).
    [cir] Require the fetal risk summary to characterize the likelihood
that the drug increases the risk of developmental abnormalities and
other risks in humans.
    [cir] Require that if data demonstrate that a drug is not
systemically absorbed, the fetal risk summary contain only the
following statement: (Name of drug) is not absorbed systemically from
(part of body) and cannot be detected in the blood. Maternal use is not
expected to result in fetal exposure to the drug.
    [cir] When both human and animal data are available, require that
risk conclusions based on human data be presented before risk
conclusions based on animal data. Require that a risk conclusion based
on human data be followed by a narrative description of the risks.
    [cir] When human data are sufficient to reasonably determine the
likelihood that the drug increases the risk of fetal developmental
abnormalities or specific developmental abnormalities, require the
labeling to contain one of two risk conclusions: Human data do not
indicate that (name of drug) increases the risk of (type of
developmental abnormality or specific developmental abnormality) or
Human data indicate that (name of drug) increases the risk of (type of
developmental abnormality or specific developmental abnormality).
    [cir] When human data are available but not sufficient to
reasonably determine the drug's effects on fetal developmental
abnormalities, require the labeling to characterize the likelihood that
the drug increases the risk of developmental abnormalities as low,
moderate, or high.
    [cir] Require that when the data on which the risk conclusion is
based are animal data, the fetal risk summary characterize the
likelihood that the drug increases the risk of developmental
abnormalities using one of the following risk conclusions: Not
predicted to increase the risk, low likelihood of increased risk,
moderate likelihood of increased risk, high likelihood of increased
risk, or insufficient animal data on which to assess the likelihood of
increased risk.
    [cir] When human data are available, require that in addition to
the risk conclusion(s), the fetal risk summary be followed by a brief
narrative description of the risks of developmental abnormalities as
well as on other relevant risks associated with the drug.
    [cir] Require the fetal risk summary to refer to the
``Contraindications'' and/or ``Warnings and Precautions'' sections of
the labeling if there is any information in those sections on an
increased risk to the fetus from exposure to the drug.
    [cir] Require under the subheading ``Clinical Considerations'' the
inclusion of information about the known or predicted risks to the
fetus from inadvertent exposure to the drug, including human or animal
data on dose, timing, and duration of exposure. If there are no data to
assess the risk from inadvertent exposure, require the labeling to so
state.
    [cir] Require under the subheading ``Clinical Considerations'' the
inclusion of information related to prescribing decisions for pregnant
women, including the risk, if known, to the pregnant woman and the
fetus from the disease or condition the drug is indicated to treat and
the potential influence of drug treatment on that risk; information
about dosing adjustments during pregnancy; if use of the drug is
associated with any maternal adverse reactions that are unique to
pregnancy or if known adverse reactions occur with increased frequency
or severity in pregnant women, a description of such adverse reactions;
if it is known or anticipated that treatment of the pregnant woman will
cause a complication in the fetus or the neonate, a description of the
complication, the severity and reversibility of the complication, and
general types of interventions, if any, that may be needed.
    [cir] If the drug has a recognized use during labor or delivery,
whether or not that use is stated as an indication in the labeling, or
is expected to affect labor or delivery, require the inclusion of
available information about the effect of the drug on the mother; the
fetus/neonate; the duration of labor and delivery; the possibility of
complications, including interventions, if any, that may be needed; and
the later growth, development, and functional maturation of the child.
    [cir] Require the inclusion of a ``Data'' subheading that, for
human data, describes positive and negative experiences during
pregnancy, including developmental abnormalities, and, to the extent
applicable, the number of subjects and duration of the study. For
animal data, require under the subheading ``Data'' a description of the
relationship of the exposure and mechanism of action in the animal
species to the anticipated exposure and mechanism of action in humans.
     Replace the ``Nursing mothers'' subsection with
``Lactation'' and replace the content requirements of ``Nursing
mothers'' in its entirety with the following:
    [cir] Require that the labeling of all drugs contain a
``Lactation'' subsection.
    [cir] Under the subheading ``Risk Summary,'' if the data
demonstrate that the drug does not affect the quantity and/or quality
of human milk and there is reasonable certainty either that the drug is
not detectable in human milk or that the amount of drug consumed
through breast milk will not adversely affect the breast-fed child, the
labeling must state: The use of (name of drug) is compatible with
breastfeeding. After this statement (if applicable), the labeling must
summarize the drug's effect on milk production, what is known about the
presence of the drug in human milk, and the effects on the breast-fed
child.
    [cir] The source(s) of the data (e.g., human, animal, in vitro)
that are the basis for the ``Risk Summary'' must be stated. When there
are insufficient data or no data to assess the drug's effect on milk
production, the presence of the drug in human milk, and/or the effects
on the breast-fed child, the ``Risk Summary'' must so state.
    [cir] If the drug is not systemically absorbed, require that the
subheading ``Risk Summary'' contain only the following statement: (Name
of drug) is not absorbed systemically from (part of body) and cannot be
detected in the mother's blood. Therefore, detectable amounts of (name
of drug) will not be present in breast milk. Breastfeeding is not
expected to result in fetal exposure to the drug.
    [cir] If the drug is absorbed systemically, require the following
under the subheading ``Risk Summary'':
    [ssquf] A description of the effects of the drug's impact on milk
production, including the effect of the drug on the quality and
quantity of milk, including milk composition, and the implications of
these changes to the breast-fed child.
    [ssquf] A description of the presence of the drug in human milk in
one of the following ways: (1) The drug is not detectable in human
milk, (2) the drug has been detected in human milk, (3) the drug is
predicted to be present in human milk, (4) the drug is not predicted to
be present in human milk, or (5) the data are insufficient to know or
predict whether the drug is present in human milk.
    [ssquf] Require that if studies demonstrate that the drug is not
detectable in human milk, the ``Risk Summary'' state the limits of the
assay used.
    [ssquf] Require that if the drug has been detected in human milk,
the ``Risk Summary'' give the concentration

detected in milk in reference to a stated maternal dose (or, if the
drug has been labeled for pediatric use, in reference to the pediatric
dose), an estimate of the amount of the drug consumed daily by the
infant based on an average daily milk consumption of 150 milliliters
per kilogram of infant weight per day, and an estimate of the
percentage of the maternal dose excreted in human milk.
    [ssquf] Require the inclusion of information about the likelihood
and seriousness of known or predicted effects on the breast-fed child
from exposure to the drug in human milk based on the pharmacologic and
toxicologic profile of the drug, the amount of drug detected or
predicted to be found in human milk, and age-related differences in
absorption, distribution, metabolism, and elimination.
    [cir] Under the subheading ``Clinical Considerations,'' require the
labeling to provide the following information to the extent it is
available: Information concerning ways to minimize the exposure of the
breast-fed child to the drug, such as timing the dose relative to
breastfeeding or pumping and discarding milk for a specified period;
information about potential drug effects in the breast-fed child that
could be useful to caregivers, including recommendations for monitoring
or responding to these effects; information about dosing adjustments
during lactation.
    [cir] Require that the labeling include, under the subheading
``Data,'' an overview of the data that are the basis for the ``Risk
Summary'' and ``Clinical Considerations.''
2. Pregnancy Categories and Implementation
    FDA proposed to require the new content and format changes for
prescription drug labeling for all applications (including new drug
applications (NDAs), biologics license applications (BLAs), or efficacy
supplements) required to comply with the PLR, i.e., for drug products
for which an application was approved on or after June 30, 2001. FDA
proposed that holders of applications approved before June 30, 2001
(i.e., applications not subject to the PLR), would not be required to
implement the new content and format changes. Instead, if the labeling
for such applications contains a pregnancy category, the application
holders would be required to remove the pregnancy category designation
by 3 years after the effective date of the final rule.

D. Mental Models Research

    In a separate but related effort, FDA contracted with a third party
research firm to conduct a Mental Models Research study in 2009 to
better understand the decisionmaking processes of health care providers
prescribing drugs to pregnant and lactating women with chronic
conditions (Ref. 1). Mental Models Research is an established risk
analysis approach that evaluates, using a structured interview,
decisionmaking practices that require the synthesis of complex issues.
The specific objectives of this study, which involved interviews with
54 health care providers, were to understand how health care providers
used FDA-approved prescribing information (in the labeling format in
place at the time of the study in 2009), in order to determine the
factors that influence their treatment decisions for pregnant and
lactating women with chronic conditions, and to define measures that
could be used to quantify the value of prescribing information as a
tool for these decision makers.
    The findings from the Mental Models Research were consistent with
the feedback the Agency received during its work on the proposed and
final rules. For example, the research showed that the pregnancy
categories were relied upon by many health care providers almost to the
exclusion of other information found in the labeling. It also showed
that providers often relied on secondary sources to find the pregnancy
category for a particular product rather than using the product's
labeling. Interviewees made suggestions for improving prescribing
information, including simplifying the information presented,
centralizing the relevant information, and making the information
included in labeling clinically relevant.

II. Overview of the Final Rule, Including Significant Changes to the
Proposed Rule

A. Overview

    In this rulemaking, the Agency finalizes many of the provisions in
the May 2008 proposed rule. In addition, the final rule reflects
revisions the Agency made in response to comments on the May 2008
proposed rule. FDA has also made editorial and organizational changes
to clarify provisions. For the purposes of this rulemaking, the term
``drug'' or ``drug product'' is used to refer to human prescription
drugs and biological products that are regulated as drugs.
    The final rule requires that for the labeling of certain products
(as described in the ``Implementation'' section of this document), the
subsections ``Pregnancy,'' ``Nursing mothers,'' and ``Labor and
delivery'' be replaced by three subsections entitled ``Pregnancy,''
``Lactation,'' and ``Females and Males of Reproductive Potential.''
Information previously placed in ``Labor and delivery'' is required to
be included in the ``Pregnancy'' subsection of labeling. The final rule
requires ``Risk Summary'' subheadings in the ``Pregnancy'' and
``Lactation'' subsections of labeling. The ``Pregnancy Exposure
Registry'' subheading under ``Pregnancy'' is only required if there is
such a registry. The ``Clinical Considerations'' and ``Data''
subheadings are required under ``Pregnancy'' and under ``Lactation''
only to the extent relevant information is available. If data
demonstrate that the drug is systemically absorbed, the ``Risk
Summary'' in the ``Pregnancy'' subsection requires a statement
regarding the background risk, in addition to certain other
information, and the ``Risk Summary'' in the ``Lactation'' subsection
of labeling requires the inclusion of a risk and benefit statement,
unless breastfeeding is contraindicated. The ``Females and Males of
Reproductive Potential'' subsection is not required if none of the
subheadings are applicable. However, when pregnancy testing and/or
contraception is required or recommended before, during, or after drug
therapy and/or when there are human and/or animal data that suggest
drug-associated fertility effects, the ``Females and Males of
Reproductive Potential'' subsection requires the inclusion of such
information under the subheadings ``Pregnancy Testing,''
``Contraception,'' and ``Infertility,'' respectively. The final rule
also requires statements acknowledging when data on various labeling
elements either are not available or do not establish the presence or
absence of drug-associated risk In addition, the final rule requires
removal of pregnancy categories from all drug product labeling,
including those products for which an application was approved before
June 30, 2001.

B. Significant Changes to the Proposed Rule

    The final rule reflects revisions to the proposed rule in response
to comments received on the proposed rule, as discussed in detail in
section III of this document. FDA made the following organizational and
content-based changes to the proposed rule:

1. Pregnancy
     The final rule revises the proposed rule to clarify that
the ``Risk Summary'' subheading is always required in the ``Pregnancy''
subsection of labeling. The subheading ``Pregnancy Exposure Registry''
is only required when such a registry exists; the ``Clinical
Considerations'' and ``Data'' subheadings are required when relevant
information is available. If the ``Clinical Considerations'' subheading
is required, the following headings under it are also required to the
extent relevant information is available: ``Disease-associated maternal
and/or embryo/fetal risk,'' ``Dose adjustments during pregnancy and the
postpartum period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal
adverse reactions,'' and ``Labor or delivery.'' Similarly, if the
``Data'' subheading is required, the headings ``Human Data'' and
``Animal Data'' are required under it to the extent relevant
information is available.
     The final rule revises the proposed ``Pregnancy Exposure
Registry'' subheading as follows:
    [cir] Requires that contact information and a standard statement on
the pregnancy exposure registry will be included under its own
subheading ``Pregnancy Exposure Registry'' if there is a pregnancy
registry that is scientifically acceptable.
    [cir] Eliminates the phrase ``must be stated at the beginning of
the `Pregnancy' subsection of the labeling.''
    [cir] Revises the phrase ``telephone number or other information
needed to enroll'' to ``contact information needed to enroll.''
    [cir] Adds a requirement that the following statement be included
in labeling before the contact information for the pregnancy exposure
registry: There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to (name of drug) during pregnancy.
     The final rule revises the proposed ``Fetal Risk Summary''
as follows:
    [cir] Changes the title of the subheading ``Fetal Risk Summary'' to
``Risk Summary.''
    [cir] Eliminates the requirement that the following background risk
statement be included in the labeling before the fetal risk summary:
All pregnancies have a background risk of birth defect, loss, or other
adverse outcome regardless of drug exposure. The fetal risk summary
below describes (name of drug)'s potential to increase the risk of
developmental abnormalities above the background risk.
    [cir] Replaces the proposed standardized background risk statement
with the requirement that, if the drug is systemically absorbed, the
labeling state the percentage range of live births in the United States
with a major birth defect and the percentage range of pregnancies in
the United States that end in miscarriage, regardless of drug exposure.
The final rule also requires that if such information is available for
the population(s) for which the drug is labeled, it must also be
included.
    [cir] Replaces the term ``developmental abnormalities'' with the
term ``adverse developmental outcomes.'' The final rule defines
``adverse developmental outcomes'' as structural abnormalities, embryo-
fetal and/or infant mortality, functional impairment, and alterations
to growth.
    [cir] Clarifies that, when applicable, risk statements must include
a cross-reference to additional details located under the ``Data''
subheading of ``Pregnancy.''
    [cir] Revises the statement required when a drug is not
systemically absorbed as follows:
    [ssquf] Replaces the phrase ``from (part of the body)'' with
``following (route of administration)'' to describe how the drug enters
the body.
    [ssquf] Replaces the phrase ``cannot be detected in the blood''
with ``maternal use is not expected to result in fetal exposure to the
drug.''
    [cir] Adds a requirement that when use of the drug is
contraindicated during pregnancy, this must be stated first in the
``Risk Summary.''
    [cir] Requires that risk statements be presented in the following
order: Based on human data, based on animal data, based on
pharmacology.
     The ``Risk conclusions based on human data'' in the ``Risk
Summary'' is revised as follows:
    [cir] Replaces the term ``risk conclusions'' with ``risk
statement.''
    [cir] Eliminates the term ``sufficient human data'' and the
proposed rule's requirement that the labeling contain one of the
following standardized risk conclusions about sufficient human data:
Human data do not indicate that (name of drug) increases the risk of
(type of developmental abnormality or specific abnormality) and Human
data indicate that (name of drug) increases the risk of (type of
developmental abnormality or specific abnormality).
    [cir] Replaces the standardized risk conclusions based on human
data with the requirement that when human data are available that
establish the presence or absence of any adverse developmental
outcome(s) associated with maternal use of the drug, the Risk Summary
must summarize the specific developmental outcome, its incidence, and
the effects of dose, duration of exposure, and gestational timing of
exposure. The final rule also requires that if the human data indicate
that there is an increased risk for a specific adverse developmental
outcome in infants born to women exposed to the drug during pregnancy,
this risk must be quantitatively compared to the risk for the same
outcome in infants born to women who were not exposed to the drug but
who have the disease or condition for which the drug is indicated to be
used. When risk information is not available for women with these
condition(s), then the risk for the specific outcome must be compared
to the rate at which the outcome occurs in the general population.
    [cir] Requires that the ``Risk Summary'' must state when there are
no human data or when available human data do not establish the
presence or absence of drug-associated risk.
    [cir] Eliminates the term ``other human data'' and the requirement
that when there are other human data, the likelihood that the drug
increases the risk of developmental abnormalities must be characterized
as low, moderate, or high.
     The ``Risk conclusions based on animal data'' in the
``Risk Summary'' is revised as follows:
    [cir] Replaces the term ``risk conclusions'' with ``risk
statement.''
    [cir] Eliminates the requirement that animal data be characterized
as ``not predicted to increase the risk,'' ``low likelihood of
increased risk,'' ``moderate likelihood of increased risk,'' or ``high
likelihood of increased risk.''
    [cir] Requires that when animal data are available, the labeling
must summarize the findings in animals and based on these findings,
describe, for the drug, the potential risk of any adverse developmental
outcome(s) in humans. The final rule requires that the risk statement
include: The number and type(s) of species affected, the timing of
exposure, animal doses expressed in terms of human exposure or dose
equivalents, and outcomes for pregnant animals and offspring. When
animal studies do not meet current standards for nonclinical
developmental toxicity studies, the labeling must so state. The final
rule requires that when there are no animal data, the ``Risk Summary''
must so state.
     Adds a ``Risk statement based on pharmacology'' to the
``Risk Summary,'' requiring that when the drug has a well-understood
mechanism of action that may result in drug-associated adverse
developmental outcome(s), the ``Risk Summary'' must explain the
mechanism

of action and the potential associated risks.
     Eliminates the ``Narrative description of human data''
requirement from the ``Risk Summary.''
     Removes the requirement that the ``Risk Summary'' refer to
the ``Contraindications'' or ``Warnings and Precautions'' sections of
the labeling when those sections contain information on an increased
risk to the fetus from exposure to the drug.
     The final rule revises the ``Clinical Considerations''
component as follows:
    [cir] Requires headings, to the extent relevant information is
available, for ``Disease-associated maternal and/or embryo/fetal
risk,'' ``Dose adjustments during pregnancy and the postpartum
period,'' ``Maternal adverse reactions,'' ``Fetal/Neonatal adverse
reactions,'' and ``Labor or delivery''.
    [cir] Eliminates the ``Inadvertent exposure during pregnancy''
heading.
    [cir] Eliminates the ``Prescribing decisions for pregnant women''
heading.
    [cir] Revises ``risk, if known, to the pregnant woman and the fetus
from the disease or condition the drug is indicated to treat'' (which
was the language used in the proposed rule under the ``Prescribing
decisions for pregnant women'' heading) to ``serious known or potential
risk to the pregnant woman and/or the embryo/fetus associated with the
disease or condition for which the drug is indicated to be used'' and
places this information under the new heading ``Disease-associated
maternal and/or embryo/fetal risk.''
    [cir] Under ``Dose adjustments during pregnancy and the postpartum
period,'' requires the inclusion of information about dose adjustments
during pregnancy and the postpartum period if supported by
pharmacokinetic data.
    [cir] Under ``Dose adjustments during pregnancy and the postpartum
period,'' removes the requirement that, if there are no data on dosing
in pregnancy, the labeling must so state.
    [cir] Under ``Maternal adverse reactions,'' replaces the proposed
requirement that the ``labeling must describe any interventions that
may be needed (e.g., monitoring blood glucose for a drug that causes
hyperglycemia in pregnancy)'' with the requirement that the labeling
include a description of available intervention(s) for monitoring or
mitigating the reaction.
    [cir] Adds a requirement that the labeling include relevant
information about fetal/neonatal adverse reactions under the heading
``Fetal/Neonatal adverse reactions''.
    [cir] Under ``Fetal/Neonatal adverse reactions,'' replaces the
phrase ``will cause a complication in the neonate'' with ``increases or
may increase the risk of an adverse reaction in the fetus or neonate.''
    [cir] Under ``Fetal/Neonatal adverse reactions,'' replaces ``the
severity and reversibility of the complication'' with ``the potential
severity and reversibility of the adverse reaction,'' and replaces
``general types of interventions, if any, that may be needed'' with
``available intervention(s) for monitoring or mitigating the
reaction.''
    [cir] Under ``Fetal/Neonatal adverse reactions,'' adds a
requirement that the labeling must describe, if known, the effect of
dose, timing, and duration of exposure on the risk.
    [cir] Revises the heading ``Drug effects during labor or delivery''
to ``Labor or delivery.''
    [cir] Under ``Labor or delivery,'' revises ``[i]f the drug has a
recognized use during labor or delivery, whether or not the use is
stated as an indication in the labeling, or if the drug is expected to
affect labor or delivery'' to ``[i]f the drug is expected to affect
labor or delivery.''
    [cir] Under ``Labor or delivery,'' revises ``the possibility of
complications, including interventions, if any, that may be needed'' to
``the increased risk of adverse reactions, including their potential
severity and reversibility.''
    [cir] Under ``Labor or delivery,'' adds a requirement that the
labeling provide information about available intervention(s) that can
mitigate effects and/or adverse reactions.
    [cir] Under ``Labor or delivery,'' clarifies that the information
described under that heading is not required for drugs approved only
for use during labor and delivery.
    [cir] Under ``Labor or delivery,'' eliminates the requirement that
the labeling include information about the effect of the drug on the
later growth, development, and functional maturation of the child.
     The final rule revises the ``Data'' subheading of labeling
as follows:
    [cir] Replaces ``provide an overview of the data that were the
basis for the fetal risk summary'' with ``describe the data that are
the basis for the Risk Summary and Clinical Considerations.''
    [cir] Requires the inclusion of the subheading ``Data,'' and the
headings ``Human Data'' and ``Animal Data,'' to the extent available
information is relied on in the Risk Summary and Clinical
Considerations subheadings.
    [cir] Separates the requirements for human data from the
requirements for animal data.
    [cir] For human data, requires that the labeling describe adverse
developmental outcomes, adverse reactions, and other adverse effects
and, to the extent applicable, the types of studies or reports, number
of subjects and duration of each study, exposure information, and
limitations of the data. Requires that both positive and negative study
findings be included.
    [cir] For animal data, retains the requirement that the labeling
describe the types of studies, animal species, dose, duration and
timing of exposure, and adds the requirement that the labeling also
describe study findings, presence or absence of maternal toxicity, and
limitations of the data. Adds the requirement that the description of
maternal and offspring findings must include information on the dose-
response and severity of adverse developmental outcomes. Requires that
animal doses or exposures be described in terms of human dose or
exposure equivalents and that the basis for those calculations must be
included.
2. Lactation
     The final rule revises the ``Risk Summary'' as follows:
    [cir] Requires that when relevant human or animal lactation data
are available, the ``Risk Summary'' must include a cross-reference to
``Data'' in the ``Lactation'' subsection.
    [cir] Removes the proposed standardized statement ``The use of
(name of drug) is compatible with breastfeeding.''
    [cir] Requires that when human data are available, animal data must
not be included unless the animal model is specifically known to be
predictive for humans.
    [cir] Requires that when use of a drug is contraindicated during
breastfeeding, this information must be stated first in the ``Risk
Summary.''
    [cir] Revises the standardized statement required when the drug is
not absorbed systemically from (Name of drug) is not absorbed
systemically from (part of body) and cannot be detected in the mother's
blood. Therefore, detectable amounts of (name of drug) will not be
present in breast milk. Breastfeeding is not expected to result in
fetal exposure to the drug to (Name of drug) is not absorbed
systemically by the mother following (route of administration) and
breastfeeding is not expected to result in exposure of the child to
(name of drug).
    [cir] Revises the order of the types of information required if the
drug is systemically absorbed as follows: (1) Presence of drug in human
milk, (2) effects of drug on the breast-fed child, and (3) effects of
drug on milk production.
    [cir] Replaces proposed standardized statements regarding the
presence of the drug in human milk with a requirement

that the ``Risk Summary'' state whether the drug and/or its active
metabolites are present in human milk, and when there are no data to
assess this, the ``Risk Summary'' must so state.
    [cir] Under ``Presence of drug in human milk,'' requires that if
studies demonstrate the presence of the drug and/or its active
metabolites in human milk, the ``Risk Summary'' must state the
concentration of the drug and/or its active metabolites in human milk
and the actual or estimated daily dose for an infant fed exclusively
with human milk. The estimated amount of drug and/or its active
metabolites ingested by the infant must be compared to the labeled
infant or pediatric dose, if available, or to the maternal dose.
    [cir] Under ``Presence of drug in human milk,'' retains the
requirement that if studies demonstrate that the drug and/or its active
metabolite(s) are not detectable in human milk, the Risk Summary must
state the limits of the assay used.
    [cir] Under ``Presence of drug in human milk,'' adds the
requirement that if studies demonstrate the presence of the drug and/or
its active metabolite(s) in human milk but the drug and/or its active
metabolite(s) are not expected to be systemically bioavailable to the
breast-fed child, then the ``Risk Summary'' must describe the
disposition of the drug and/or its active metabolites.
    [cir] Adds a requirement that if only animal lactation data are
available, the ``Risk Summary'' must state only whether or not the drug
and/or its active metabolite(s) were detected in animal milk and
specify the animal species.
    [cir] Under ``Effects of drug on the breast-fed child,'' the final
rule:
    [ssquf] Adds a requirement that the ``Risk Summary'' include
available information on the known or predicted effects on the child
from exposure to the drug and/or its active metabolite(s) through human
milk or from contact with breast or nipple skin from a topical product.
    [ssquf] Requires the inclusion of information about systemic and/or
local adverse reactions.
    [ssquf] Requires that the ``Risk Summary'' state if there are no
data to assess the effects of the drug and/or its active metabolite(s)
on the breast-fed child.
    [cir] Under ``Effects of drug on milk production,'' the final rule:
    [ssquf] Replaces the proposed requirement that the ``Risk Summary''
describe the effect of the drug on the quality and quantity of milk,
including milk composition, and the implications of these changes to
the milk on the breast-fed child, with the requirement that the ``Risk
Summary'' must describe the effects of the drug and/or its active
metabolite(s) on milk production.
    [ssquf] Adds a requirement that when there are no data to assess
the effects of the drug and/or its active metabolite(s) on milk
production, the ``Risk Summary'' must so state.
    [cir] The final rule adds the requirement that for drugs absorbed
systemically, unless breastfeeding is contraindicated during drug
therapy, the following risk and benefit statement must appear at the
end of the ``Risk Summary'': The developmental and health benefits of
breastfeeding should be considered along with the mother's clinical
need for (name of drug) and any potential adverse effects on the
breast-fed child from the drug or from the underlying maternal
condition.
     Under ``Clinical Considerations,'' the final rule:
    [cir] Revises the provisions of the proposed rule to require that
the labeling include information concerning ways to minimize exposure
to the drug and/or its active metabolite(s) in the breast-fed child in
situations where the following conditions are present: The drug and/or
its active metabolite(s) are present in human milk in clinically
relevant concentrations; do not have an established safety profile in
infants; and are used either intermittently, in single doses, or for
short courses of therapy.
    [cir] Adds a requirement that, when applicable, the labeling must
describe ways to minimize a breast-fed child's oral intake of topical
drugs applied to the breast or nipple skin.
    [cir] Under ``Monitoring for adverse reactions,'' replaces the
proposed requirement that the labeling include information about
potential drug effects in the breast-fed child that could be useful to
caregivers, including recommendations for monitoring or responding to
those effects, with a requirement that the labeling must describe
available intervention(s) for monitoring or mitigating the adverse
reaction(s) presented in the ``Risk Summary.''
    [cir] Eliminates the proposed requirement that the labeling include
information about dosing adjustments during lactation.
     Under ``Data,'' the final rule replaces the phrase
``provide an overview of the data'' with the phrase ``describe the
data.''
3. Females and Males of Reproductive Potential
     Adds ``8.3 Females and Males of Reproductive Potential''
subsection requiring that when pregnancy testing and/or contraception
are required or recommended before, during, or after drug therapy and/
or when there are human and/or animal data that suggest drug-associated
fertility effects, this subsection of labeling must contain this
information under the subheadings ``Pregnancy Testing,''
``Contraception,'' and ``Infertility,'' in that order.

III. Comments on the Proposed Rule

    The Agency received 72 comments on the proposed rule. Comments were
received from prescription drug manufacturers, trade organizations
representing prescription drug manufacturers and other interested
parties, professional associations and organizations representing
health care providers, health care and consumer advocacy organizations,
individual physicians, pharmacists, consumers, and others.
    Most of the comments supported FDA's goal of improving the format
and content of the ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing
mothers'' subsections of prescription drug labeling, and several of
these comments stated that the proposed rule would address shortcomings
of the previous labeling regulations. Other comments noted that the
proposed rule would improve the accessibility of relevant information,
thereby enabling better informed medical decisions regarding the risks
and benefits of prescription drug use by pregnant and lactating women.
Although a number of comments supported all of FDA's proposed
revisions, many comments opposed particular aspects of the proposed
rule.
    To make it easier to identify comments and our responses, the word
``Comment'' and a comment number appear in parentheses before each
comment's description, and the word ``Response'' in parentheses
precedes each response. Similar comments are grouped together under the
same number. Specific issues raised by the comments and the Agency's
responses follow.

A. Proposed Rule as a Whole

1. Plain Language and Intended Audience
    (Comment 1) Several comments suggested that the language used in
the pregnancy and lactation subsections of prescription drug labeling
should be clear and accessible to a variety of audiences. One comment
stated that because the intended audience for prescription pregnancy
and lactation labeling is females of reproductive potential and their
health care providers, this portion of prescription

drug labeling should not include overly technical information. Another
comment suggested that to make the information more accessible to the
general public, FDA should include a plain language summary of the
pregnancy and lactation subsections. Two comments suggested that
because females of reproductive potential may read the ``Pregnancy''
and ``Lactation'' subsections of labeling, FDA should include a
statement that encourages patients to always consult a health care
provider before discontinuing medication. Another comment questioned
how patients would access the proposed information and asked whether it
would be included in patient-specific information that patients receive
at the pharmacy. Several other comments suggested that the final rule
should aim to create user-friendly labeling that contains a concise and
accurate presentation of information that is of clinical relevance.
    (Response) FDA acknowledges that some females of reproductive
potential may use prescribing information in the ``Pregnancy'' and
``Lactation'' subsections of prescription drug labeling. The intended
audience of prescription drug labeling, however, is health care
providers, and it is the responsibility of the prescribing health care
provider to communicate pertinent information regarding drug risks and
benefits and proper use to his or her patient. For this reason, we have
determined that it is not appropriate to require a summary of the
``Pregnancy'' and ``Lactation'' subsections of labeling as a mechanism
for all patients to readily access full prescribing information, or a
statement that encourages patients to always consult a health care
provider before discontinuing medication. We note that in addition to
the professional labeling that is the subject of this rulemaking, some
drugs also have FDA-approved patient labeling specifically written for
the consumer, such as Medication Guides (see 21 CFR part 208). Whether
the information required under the final rule will be included in FDA-
approved patient labeling for an individual drug will be decided on a
case-by-case basis in accordance with the applicable FDA regulations
and guidance.
2. Scope of the Rule
    (Comment 2) Several comments suggested that FDA expand the scope of
the rule in various ways. Two comments suggested that the rule be
expanded to include nonprescription products. Four comments suggested
that the proposed content changes also apply to drugs for which an
application was approved before June 30, 2001, although a separate
comment agreed with the proposal to limit the rule to drugs for which
an application was approved on or after June 30, 2001. One comment
suggested that the rule be expanded to include vaccine products (we
discuss this suggestion later in our response to Comment 8). Two other
comments suggested that the rule provide incentives to industry to
perform studies on the use of drugs and biological products during
pregnancy and lactation. One comment suggested that depression should
not be treated pharmacologically during pregnancy, whereas a separate
comment suggested that FDA ban the use of all drugs and vaccines during
pregnancy. Another comment suggested that the presentation of the
information required under the rule be standardized as much as possible
with applicable coding schema for ease of implementation in databases
or electronic health record systems.
    (Response) FDA has considered these comments and declines to expand
the scope of the final rule in any of the suggested ways. This final
rule amends our labeling regulations in Sec. Sec.  201.57 and 201.80,
which apply only to prescription drug and biological products. It is
therefore not within the scope of this rulemaking to address pregnancy
and lactation labeling for nonprescription drug products.
    The primary purpose of this final rule, and prescription drug
labeling in general, is to facilitate informed prescribing and safe and
effective product use. FDA recognizes the importance of use of labeling
information in electronic health records and other databases and agrees
that, if possible, the presentation of information in labeling should
facilitate its accessibility. However, this final rule is not designed
to standardize the required information with a coding schema for use in
databases or electronic health record systems. It is also beyond the
scope of this rule to address incentives for collecting data on the use
of drugs and biological products during pregnancy and lactation.
    FDA does not make recommendations about whether particular diseases
or conditions should or should not be treated pharmacologically, though
we specifically decline the suggestion to ban the use of all drugs
during pregnancy. We note that many diseases and conditions are
associated with adverse pregnancy outcomes when not appropriately
managed during pregnancy, and under-treating or not treating a pregnant
woman's medical condition may put the woman's health in danger, and is
often associated with greater risk to the developing fetus than the
risk of exposure to a maternal drug.
    FDA also declines the suggestion that the content changes required
by this final rule also apply to drugs for which an application was
approved before June 30, 2001. In developing this rule, FDA considered
the scientific, economic, and practical implications of alternative
approaches, including requiring implementation of the content and
format requirements for the ``Pregnancy,'' ``Lactation,'' and ``Females
and Males of Reproductive Potential'' subsections of labeling for all
drugs, regardless of approval date. FDA concluded that requiring the
content and format changes only for drugs for which an application was
approved on or after June 30, 2001, (as described in the
``Implementation'' section of this document) best balanced the public
health benefits and the economic and other costs of these labeling
changes. In addition, this approach provides conformity with the rest
of prescription drug labeling and the scope is consistent with the
scope of the PLR. FDA, however, encourages voluntary compliance with
these content and format changes for drugs for which an application was
approved before June 30, 2001.
3. Combining the ``Pregnancy'' and ``Lactation'' Subsections
    (Comment 3) One comment suggested that the ``Pregnancy'' and
``Lactation'' subsections should be combined for certain drugs. The
comment explained that combining these sections would be useful, for
example, in helping health care providers counsel women who take
selective serotonin reuptake inhibitors (SSRIs) for the treatment of
perinatal depression because clinicians have to consider the effects of
the medication during both pregnancy and the postpartum period.
    (Response) FDA disagrees. The risk and benefit considerations for
drug product use are different between pregnant and lactating patients,
and we have determined that the information is best presented in
separate but adjacent subsections of labeling. FDA believes that if the
sections were combined it would be more difficult for a health care
provider who has either a pregnant or a lactating patient to locate the
information relevant to the prescribing decision. For anticipatory
counseling, for which the health care provider is discussing the use of
the drug with a pregnant patient who in the future may be lactating, we
believe that having ``Lactation'' denoted in a separate, numbered,
indexed, and searchable

subsection of labeling will not make it harder for a prescriber to find
this information.
4. Updates
    In the preamble to the proposed rule, FDA stated that under Sec.
201.56(a) ``the labeling must be updated when new information becomes
available that causes the labeling to become inaccurate, false, or
misleading'' (73 FR 30831 at 30841). The Agency also explained that
``[w]hen new human data concerning the use of a drug during pregnancy
becomes available, if that information is clinically relevant, FDA
believes that it is necessary for the safe and effective use of the
drug and, therefore, the pregnancy subsection of the labeling must be
updated to include that information. Failure to include clinically
relevant new information about the use of a drug during pregnancy could
cause the drug's labeling to become inaccurate, false, or misleading''
(73 FR 30831 at 30841).
    (Comment 4) Several comments requested that FDA clarify its
expectations for the process and timing of updating the ``Pregnancy''
and ``Lactation'' subsections of labeling after new data become
available. Two of these comments stated that the data should be updated
regularly or continually. Another comment stated that the labeling
should be updated annually. Several other comments requested that FDA
define the quantity and quality of data that necessitates that the
labeling be updated. One of these comments suggested that FDA state in
the final rule that the labeling should be updated if the benefit-risk
profile changes because of new information, and that labeling changes
should be done according to ``current labeling regulations.'' Another
comment questioned whether health care providers will be informed of
changes to the ``Pregnancy'' and ``Lactation'' subsections of labeling.
One comment suggested that sponsors electronically post supplemental
information before updated printed labeling is available, and another
suggested using surveillance systems to facilitate obtaining updated
safety information.
    Two comments expressed specific concern that the ``Lactation''
subsection of drug labeling will not be updated frequently enough to be
useful for clinicians. One of these comments stated that it is critical
to routinely update labeling as human lactation data becomes available.
A separate comment suggested including references in labeling to online
resources regarding lactation data to provide prescribers and patients
with updated information.
    (Response) The requirements for labeling updates described in Sec.
201.56(a) apply to this final rule as follows: The labeling must be
informative and accurate and neither promotional in tone nor false or
misleading in any particular. In accordance with Sec. Sec.  314.70 and
601.12 of the chapter, the labeling must be updated when new
information becomes available that causes the labeling to become
inaccurate, false, or misleading (Sec.  201.56(a)(2)). With respect to
the comment about updating labeling as human lactation data becomes
available, although Sec.  201.56(a)(3) states that the labeling must be
based whenever possible on data derived from human experience, it also
requires that conclusions based on animal data but necessary for safe
and effective use of the drug in humans must be identified as such and
included with human data in the appropriate section of the labeling.
    Because studies are not usually conducted in pregnant women prior
to approval, most of the data regarding use in pregnancy and lactation
will be collected in the postmarketing setting. Accordingly, in order
that a drug product does not become misbranded, the labeling must be
updated when new information becomes available that causes the labeling
to become inaccurate, false, or misleading. Applicants are responsible
for following the medical literature and also for updating labeling as
new published and unpublished data become available. FDA declines the
suggestion to include references to online resources regarding drug use
during lactation because the information has not been reviewed by FDA.
5. Responsibility for Drafting and Reviewing Labeling
    (Comment 5) One comment requested that FDA clarify whether industry
or FDA would be responsible for writing and reviewing the new labeling.
The comment also questioned whether FDA would provide staff with the
training and expertise to make necessary judgments. Another comment
expressed concern about the potential for inconsistent implementation
of the new rule by FDA's review divisions. This comment suggested that
to increase labeling consistency, the Agency should establish a group
of FDA specialists that review pregnancy and lactation labeling.
    (Response) As with all prescription drug labeling, both the
manufacturer and FDA reviewers will play a shared role in determining
the new labeling content. The Division of Pediatrics and Maternal
Health (DPMH), within the Office of New Drugs at the Center for Drug
Evaluation and Research, includes staff with expertise in obstetrics,
lactation, pediatrics, clinical pharmacy, and regulatory science. The
DPMH is available for consultation by all FDA drug product review
divisions to whom the final rule applies for all issues related to
labeling content and for review of data on the use of drugs during
pregnancy and lactation. The DPMH, by working across review divisions,
helps to ensure consistent application of FDA pregnancy and lactation
labeling regulations to different drug products. The DPMH also provides
consultation services to and works collaboratively with other Offices
and Centers at FDA. FDA intends to provide staff with education and
training on the changes in the labeling regulations.
6. Process for Development of the Proposed Rule
    (Comment 6) One comment stated that FDA should have included
pharmacists in the focus tests used during development of the proposed
rule.
    (Response) FDA acknowledges the critical role that pharmacists play
in communicating drug information both to patients and health care
providers. However, during the development of the proposed rule, FDA's
priority was to understand the information health care providers need
to most effectively make prescribing decisions that consider both the
risk and benefit to the mother and her fetus or child. Therefore, the
focus testing was limited to health care providers who both care for
and prescribe for pregnant and lactating women.
7. Guidance on Formulating Labeling
    (Comment 7) FDA received one comment requesting that the Agency
provide clear guidance to manufacturers regarding how to formulate the
pregnancy and lactation labeling subsections.
    (Response) Concurrent with the publication of this final rule, FDA
is issuing a draft guidance for industry on ``Pregnancy, Lactation, and
Reproductive Potential: Labeling for Human Prescription Drug and
Biological Products--Content and Format'' (the draft guidance on
pregnancy and lactation labeling).\5\ The draft guidance is intended to
assist applicants in drafting the ``Pregnancy,'' ``Lactation,'' and
``Females and Males of Reproductive Potential'' subsections of

labeling for prescription drug products. It provides recommendations
for applicants revising labeling of already approved products and for
applicants drafting labeling for new products that will be submitted as
part of an NDA or BLA.
---------------------------------------------------------------------------

    \5\ This guidance, when finalized, will represent FDA's current
thinking on this topic.
---------------------------------------------------------------------------

8. Blood Products and Vaccines
    (Comment 8) FDA received two comments regarding the applicability
of the proposed rule to certain biological products. One comment
requested that the final rule be expanded to include vaccine products.
The other comment stated that blood products are not affected by the
rule and requested that this be noted when the final rule is published.
    (Response) This final rule applies to vaccine products. Vaccine
products are prophylactic biological products that are developed and
labeled to prevent specific diseases in specific populations. The types
of information that must be communicated about a vaccine, in general,
parallel the types of information that must be communicated about a
drug or therapeutic biologic through labeling to facilitate safe and
effective use, although there are some unique considerations for
vaccines addressed in the draft guidance on pregnancy and lactation
labeling, which is being published concurrently with this final rule.
    We disagree that blood products are not affected by the final rule.
The final rule applies to any biological products, including blood
products, that are subject to the PLR.
9. Numbering of ``Pregnancy'' and ``Lactation'' Subsections
    (Comment 9) FDA proposed that the identifying numbers and titles
for the new labeling content under the section ``8 Use in Specific
Populations'' would be 8.1 for ``Pregnancy'' and 8.2 for ``Lactation.''
FDA stated in the proposed rule that the identifying number 8.3 would
be available for future use (73 FR 30831 at 30838). Two comments
pointed out that under this proposal, the next subsections after ``8.2
Lactation'' will be ``8.4 Pediatric Use'' and ``8.5 Geriatric Use.''
These comments stated that the absence of subsection 8.3 may be
confusing and suggested that FDA renumber the subsections. One comment
requested that FDA clarify whether the Agency has a specific use in
mind for 8.3 and, if it does not, suggested that the Agency renumber
the subheadings to ``8.3 Pediatric Use'' and ``8.4 Geriatric Use.'' The
comment explained that if a future need for an additional subsection
arose, it could become 8.5.
    (Response) As discussed in further detail in section III.B of this
document, in this final rule, FDA designates 8.3 as ``Females and Males
of Reproductive Potential.'' Accordingly, we are no longer reserving
8.3 for future use.
10. International Harmonization
    (Comment 10) Two comments suggested that prescription drug labeling
should be consistent at an international level to reduce confusion
among health care providers, patients, and regulators interpreting the
risks and benefits associated with drug use during pregnancy and
lactation.
    (Response) FDA declines to adopt this suggestion because it is
beyond the scope of this rule to address the international
harmonization of prescription drug labeling. Although we acknowledge
the importance of working with our international regulatory colleagues
to harmonize drug development and drug regulatory science where
appropriate and beneficial, we also recognize that there is great
variation internationally in health care systems, access to care and
drugs, and the regulation and marketing of drugs. The final rule
reflects our judgment regarding the most useful pregnancy and lactation
prescription drug labeling for prescribers in the United States, which
may not be applicable to prescribers in all other countries.
11. Examples in an Appendix
    (Comment 11) The proposed rule included an appendix containing
examples, based on the proposed rule, of pregnancy and lactation
labeling for fictitious drugs.
    FDA received several comments suggesting that the examples be
revised or expanded. One comment requested that in the final rule, FDA
provide additional examples of sample labeling, including examples for
which extensive data exists. Another comment suggested that the
information included in the sample labeling for the fictitious drug
products did not reflect the amount of data that is typically
available. The comment explained that the examples would be more useful
if they presented situations where there is extensive data. Several
other comments pointed out that the terminology in the examples was not
consistent with the terminology in the proposed rule.
    (Response) FDA has not included sample drug labeling with the final
rule. The draft guidance on pregnancy and lactation labeling, which is
being published concurrently with this final rule, provides information
about how to interpret and apply the rule to labeling development.
Labeling development is a detailed and iterative process unique to each
prescription drug product, a process that is driven by the product's
characteristics and actions, the efficacy and safety data submitted to
the Agency, and the conditions and populations for and in which the
product is intended to be used. Accordingly, FDA has concluded that the
development of fictitious product labeling would not be useful to drug
developers or FDA reviewers who will be responsible for developing,
revising, and approving product labeling under this new final rule.
12. Cross-Referencing
    FDA proposed that when the risk conclusion in the fetal risk
summary is based solely on animal data, it must include a cross-
reference to the ``Data'' component of the ``Pregnancy'' subsection,
and the effects found in animals must be described in the ``Data''
component (73 FR 30831 at 30842).
    (Comment 12) One comment suggested that any cross-references to the
``Data'' or ``Clinical Considerations'' components made anywhere in
labeling specify whether the cross- reference is to the component in
the ``Pregnancy'' subsection or the component in the ``Lactation''
subsection. Another comment explained that the rule would benefit from
extensive use of cross-referencing within the text of each section to
ensure that the bases for the risk conclusions are thoroughly
understood, regardless of whether the risk conclusions are based on
human or animal data, for both the ``Pregnancy'' and ``Lactation''
subsections.
    (Response) FDA agrees that any cross-references to components of
``8.1 Pregnancy'' or ``8.2 Lactation'' must specify whether the cross-
reference is to the component in the ``Pregnancy'' subsection or the
component in the ``Lactation'' subsection. Accordingly, in the final
rule, when applicable, risk statements in the ``Pregnancy'' subsection
must include a cross-reference to additional details in the relevant
portion of the ``Data'' subheading in the ``Pregnancy'' subsection.
Also in the final rule, when relevant human and/or animal lactation
data are available, the ``Risk Summary'' must include a cross-reference
to the relevant portion of ``Data'' in the ``Lactation'' subsection.
13. Need for Educational Campaign
    (Comment 13) FDA received one comment suggesting that the Agency
develop educational campaigns for patients and health care providers
regarding the changes to pregnancy and

lactation drug labeling brought about by this rulemaking.
    (Response) FDA is developing educational materials for FDA staff,
health care providers, and patients to inform them about the changes in
these labeling regulations and how these changes will have a positive
impact on labeling regarding the use of drugs and biologics during
pregnancy and lactation. The draft guidance on pregnancy and lactation
labeling is being published concurrently with this final rule; however,
additional materials may be completed following this date.
14. Inventory
    (Comment 14) FDA received one comment requesting that the final
rule address how distributors should manage drug products in their
inventory that have outdated labeling. The comment suggested that
product inventory without the revised labeling should remain in the
supply chain until the labeled product's expiration date, regardless of
whether the product bears the new labeling.
    (Response) For previously approved products, the implementation
plan gives sponsors a minimum of 3 years after the effective date of
this final rule to submit labeling with the new content and format. As
we explained in the preamble to the proposed rule, FDA believes that
this 3-year period will allow industry sufficient time to use up any
existing labeling stock such that none will remain in the supply chain
after the product bears the new labeling (73 FR 30831 at 30846).
15. Highlights
    FDA's regulations require that all prescription drug labeling
described in Sec.  201.56(b)(1) contain ``Highlights of prescribing
information'' (Sec.  201.57(a)).
    (Comment 15) Two comments requested that FDA clarify which elements
of the ``Pregnancy'' and ``Lactation'' subsections are likely to be
included in the ``Highlights of prescribing information.'' One of the
comments expressed hope that adoption of the rule will promote
standardization with respect to which elements are elevated to the
``Highlights of prescribing information,'' thereby facilitating
consistent interpretation and implementation of the rule's requirements
among FDA reviewers and review divisions.
    (Response) The requirements for placement of information in the
``Highlights of prescribing information'' are specified in Sec.
201.57(a). This final rule does not revise or change the requirements
for the ``Highlights of prescribing information.'' Additional
discussion of FDA's recommendations on the content of the ``Highlights
of prescribing information'' may be found in FDA's guidance for
industry on ``Labeling for Human Prescription Drug and Biological
Products--Implementing the PLR Content and Format Requirements''
(February 2013).\6\
---------------------------------------------------------------------------

    \6\ U.S. Food and Drug Administration, ``Guidance for Industry,
Labeling for Human Prescription Drug and Biological Products--
Implementing the PLR Content and Format Requirements,'' (February
2013), available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM075082.pdf.
Many guidances are referenced throughout this document. The guidance
referred to in this footnote, as well as others referenced
throughout the remainder of the document, can be found on the FDA
Drugs guidance Web page at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We
update guidances periodically. To make sure you have the most recent
version of a guidance, check the FDA Drugs guidance Web page.
---------------------------------------------------------------------------

16. Preemption of State Law
    In the preamble to the proposed rule, FDA included a discussion in
the Federalism section that referred to a more extensive discussion and
analysis in the PLR regarding the preemption of product liability
lawsuits.
    (Comment 16) Comments expressed different views about this
discussion. One comment suggested that in the final rule FDA revise the
preamble to eliminate any reference to the preemption of product
liability lawsuits. Another comment expressed its appreciation of FDA's
view that the rule would preempt state laws that conflict with its
requirements. This comment also expressed its support for FDA's
intention to consult with State and local officials in an effort to
avoid conflict between State law and federally protected interests.
    (Response) FDA's statement regarding preemption in the proposed
rule relied on statements made in the preamble to the PLR (71 FR 3922).
In the preamble to the PLR, FDA discussed its views on the preemptive
effect of both that regulation's codified provisions and the FD&C Act.
Subsequent to the publication of the May 2008 proposed rule, the
Supreme Court, in Wyeth v. Levine (555 U.S. 555 (2009)), addressed the
preamble to the PLR and held that a State tort claim that an NDA-
approved drug should have had a stronger warning was not preempted by
the FD&C Act or FDA's labeling requirements. Following the Court's
decision in Wyeth, FDA concluded that the position on preemption we
articulated in the preamble to the PLR cannot be justified under legal
principles governing preemption (Preemption Review, 76 FR 61565,
October 5, 2011). Based on this analysis, to the extent that the
discussion in the proposed rule relied on the discussion about
preemption in the preamble to the PLR, we conclude that the statements
we made regarding preemption in the preamble to the proposed rule are
also not justified.

B. Specific Provisions of the Proposed Rule

1. 8.1 Pregnancy
    a. Comments related to the pregnancy subsection as a whole.
    i. Order of subsections--FDA proposed that information appear in
subsection ``8.1 Pregnancy'' in the following order: (1) Pregnancy
exposure registry (if applicable), (2) general statement about
background risk, (3) fetal risk summary, (4) clinical considerations,
and (5) data (proposed Sec.  201.57(c)(9)(i)). In the proposed rule,
FDA sought comment on how these elements should be ordered to optimize
the clinical usefulness of this labeling subsection (73 FR 30831 at
30839). Specifically, FDA asked whether the ``Fetal Risk Summary''
should precede the pregnancy exposure registry information and the
statement about background risk.
    (Comment 17) Comments expressed different opinions about the
proposed order of information in the ``Pregnancy'' subsection of
labeling. Three comments agreed with the proposed order. One of these
comments explained that the proposed order will maximize a physician's
ability to find and understand important pregnancy-related information
about a given drug product. Another comment explained that placing the
pregnancy exposure registry information first is preferable because if
this information were placed after the ``Risk Summary,'' it may be
interpreted to imply that the pregnancy exposure registry exists
because of the data in the fetal risk summary. One comment supported
placing the pregnancy exposure registry information first so that it
will appear more visible in labeling.
    Many comments disagreed with the proposed order and suggested a
variety of alternatives. Six comments suggested that the ``Fetal Risk
Summary'' subheading be placed first because it contains the most
important and useful information. One of these comments pointed out
that past FDA advisory committees have suggested that summary
information should be placed first. Two comments suggested that the
``Background Risk Statement'' should be first followed by the ``Fetal
Risk Summary.'' These comments explained

that the most important information should be placed first, as
recommended by FDA advisory committees. Three comments suggested that
the pregnancy exposure registry information be placed last. Another
comment suggested that the information be placed in the following
order: Pregnancy exposure registry information, clinical
considerations, fetal risk summary, data, and background risk
statement.
    (Response) FDA has determined that placing the pregnancy exposure
registry information first under ``8.1 Pregnancy'' best balances the
objectives of this rulemaking. Although we agree that the ``Risk
Summary'' information is most important to prescribers and we
acknowledge that the advisory committee expressed a preference for
placing the most important information first, it is also clear that
stakeholders desire greater quality and quantity of human data in
pregnancy labeling. FDA believes that the benefits of prominently
placing information about pregnancy registry availability at the
beginning of ``8.1 Pregnancy'' outweigh the downsides of a minor
decreased prominence of the ``Risk Summary'' information, which appears
immediately after the information under ``Pregnancy Exposure
Registry.'' Many health care providers are still learning about
pregnancy exposure registries and their purpose. We have concluded that
routinely placing this information first in pregnancy labeling may
increase pregnancy registry enrollment, the quality of human data that
emerge from these studies, and the quality of pregnancy labeling
(including the ``Risk Summary'') that follows. Because we agree that
the information under ``Risk Summary'' is most important to
prescribers, we also decline the suggestion to place the ``Risk
Summary'' after ``Clinical Considerations.'' The ``Pregnancy''
subsection will include, in this order, information under ``Pregnancy
Exposure Registry,'' as applicable, ``Risk Summary,'' ``Clinical
Considerations,'' as applicable, and ``Data,'' as applicable.
    ii. Removal of the pregnancy categories--FDA proposed to remove the
pregnancy categories from all prescription drug labeling. As discussed
in greater detail in section I of this document, in 1979 FDA adopted a
pregnancy category system that was used to convey risk and benefit
information related to potential or documented human teratogenic risk
and potential maternal/fetal benefits associated with drug treatment
during pregnancy. Under the 1979 regulations, each drug product was
identified with a pregnancy category: A, B, C, D, or X. Categories were
not used to characterize the risks and benefits associated with drug
treatment by lactating women. FDA proposed to remove pregnancy
categories from all prescription drug labeling because we determined
that the categories were confusing and did not accurately and
consistently communicate differences in degrees of fetal risk (73 FR
30831 at 30846).
    (Comment 18) Comments expressed different opinions about whether
the elimination of the pregnancy category system, in full or in part,
would improve or diminish the usefulness of the Pregnancy subsection of
prescription drug labeling. FDA received 11 comments from medical
associations, women's and reproductive health advocacy organizations,
toxicologists, individual health care practitioners, pharmacists, and
drug manufacturers specifically supporting our proposal to retire the
pregnancy category system. Several of these comments explained that the
categories were confusing or misleading. One of the comments stated
that although the use of pregnancy categories is easier for some
practitioners, it results in miscommunication and errors in
decisionmaking. Another comment explained that reliance on the
categories may result in poorly informed clinical decisionmaking.
    FDA received 16 comments from physicians, pharmacists, pharmacy
associations, nurses, manufacturers, drug safety consultants, and
individual consumers, requesting that FDA either retain the pregnancy
category system or replace the pregnancy category system with another
standardized schema. Many of these comments suggested that FDA add the
additional narrative information as proposed, but also retain the
category system. Two of these comments explained that the pregnancy
categories are simple and effective, and the new information may
confuse patients or prescribers. Another comment stated that without a
standardized schema, there will not be a consistent and useful format
for decisionmaking. Other comments agreed that the pregnancy categories
need to be revised but suggested that FDA develop new standardized
statements or categories or revise the bases for the current
categories. Two comments urged FDA to maintain an ``X''-like category
for drugs where the risks outweigh any benefit to a pregnant or nursing
patient, and one comment urged FDA to maintain an ``X''-like category
so that providers and patients could easily identify those drugs that
are contraindicated for the mother, fetus, and/or a breastfeeding
infant.
    A separate comment supported FDA's proposal to eliminate the
pregnancy categories but thought they should be retained until the
implementation of the final rule is complete.
    (Response) FDA has determined that retaining the pregnancy
categories is inconsistent with the need to accurately and consistently
communicate differences in degrees of fetal risk. As discussed in the
proposed rule, the current pregnancy category system has long been
criticized as being confusing and overly simplistic (73 FR 30831 at
30833-30834). Through experience and stakeholder feedback, FDA learned
that the pregnancy categories were heavily relied upon by clinicians
but misinterpreted, misunderstood, and erroneously used as a grading
system where fetal risk increased from A to X. The categories gave the
incorrect impression that drugs in the same category carried the same
risk or potential for human adverse developmental outcomes. In
addition, the categories did not discriminate among risk information
obtained from nonclinical animal studies and postmarketing human
studies and did not discriminate among drugs associated with adverse
outcomes of differing severity or incidence. Stakeholders also pointed
out that the pregnancy categories focused on structural abnormalities
and thus did not adequately address the full range of potential
developmental toxicities.
    As described in greater length in the preamble of the proposed
rule, FDA carefully explored a multitude of models to determine whether
the former pregnancy category system or a different pregnancy category
system could accurately and consistently communicate differences in
degrees of fetal risk (73 FR 30831 at 30833-30837). FDA found that when
it applied these criteria to actual animal and human data findings for
drugs with known risk profiles, none of the models produced clinically
informative and reliable differentiations of risk (73 FR 30831 at
30838). Prescribing and drug-use decisions during pregnancy require
consideration of not only fetal risk information, but also of various
clinical and individual factors, including maternal drug effects, the
severity of maternal disease, maternal tolerance of the drug,
coexisting maternal conditions, the impact of maternal disease on the
fetus, and available alternative therapies. FDA concluded that
continuing to use a category system to characterize the risks of drug
use during pregnancy would not be appropriate because of the complexity
of medical decisionmaking regarding

drug use during pregnancy (73 FR 30831 at 30838).
    FDA continues to believe that a narrative structure for pregnancy
labeling is best able to capture and convey the potential risks of drug
exposure based on animal or human data, or both. This perspective is
consistent with FDA's approach to other aspects of product labeling.
For example, numeric or letter or other categorical gradations of risk
have never been used for safety labeling because safety and risk are
complex constructs in clinical medicine. For similar reasons, FDA does
not apply symbol or letter designations of risk to other potential
toxicities or adverse effects expected with drug product use.
    For the reasons discussed previously, FDA declines the suggestion
to maintain pregnancy category X. We note, however, that labeling must
clearly identify populations in which use of a drug is contraindicated.
The labeling regulations in Sec.  201.57 clearly describe the
information that must be included in the ``Contraindications'' section
and all contraindications from the full prescribing information are
always listed in the ``Highlights of prescribing information'' (Sec.
201.57(c)(5)). Therefore, when use of a drug is contraindicated in
pregnancy, this information must be stated in the ``Contraindications''
section and listed in the ``Highlights of prescribing information,'' as
well as, per the previous discussion, stated first under the ``Risk
Summary'' subheading of the ``Pregnancy'' subsection of labeling.
    To the extent that the comment suggests that the pregnancy
categories should be retained for applications subject to Sec.  201.80
until the implementation of the new content and format requirements is
complete, we decline this suggestion; we believe it is more consistent
with the Agency's overall concerns with respect to removing the
pregnancy categories to implement that change within a shorter
timeframe that nevertheless provides sufficient time for compliance. We
would like to clarify that for applications required to implement the
new content and format requirements, the pregnancy categories are
required to be removed at the time the labeling is revised regardless
of whether this will result in the labeling including a pregnancy
category for more than 3 years after the effective date of the final
rule (as described in the ``Implementation'' section of this document
in response to Comment 92). Requiring that the labeling for some
applications be revised twice solely as part of the implementation of
this regulation would not be consistent with the Agency's goal to avoid
overburdening both the Agency and industry.
    b. Comments related to specific provisions of 8.1 Pregnancy.
    i. Pregnancy exposure registry--FDA proposed that if there is a
pregnancy exposure registry for a product described in Sec.
201.56(b)(1) (i.e., prescription drug products for which an application
was approved after June 30, 2001), the telephone number or other
information necessary to enroll in the registry or to obtain
information about the registry must be stated at the beginning of the
``Pregnancy'' subsection of prescription drug labeling (proposed Sec.
201.57(c)(9)(i)(A)). For drug products that do not have a pregnancy
exposure registry, the proposed rule did not require the ``Pregnancy''
subsection of prescription drug labeling to contain any statement about
pregnancy exposure registries.
    (Comment 19) Comments disagreed about the mandatory inclusion of
pregnancy exposure registry information. Many comments supported the
mandatory inclusion of pregnancy exposure registry information in the
``Pregnancy'' subsection of prescription drug labeling. These comments
explained, for example, that including pregnancy exposure registry
information in labeling may ``encourage patient involvement in
registries'' and ``pave the way for improved registry use by clinicians
leading to better documentation of drug effects and use during
pregnancy.''
    One comment stated that including a reference to an existing
pregnancy registry should not be mandatory.
    (Response) FDA believes that appropriately conducted pregnancy
registries are an important mechanism for the collection of clinically
relevant data concerning the effects of exposure to drugs during
pregnancy. The Agency believes that including information about
pregnancy exposure registries in prescription drug labeling will
encourage participation in registries, thereby improving their
usefulness. Thus, if there is a pregnancy registry that FDA has
reviewed and found scientifically acceptable, FDA is requiring that the
``Pregnancy'' subsection of prescription drug labeling include under
its own subheading, ``Pregnancy Exposure Registry,'' a standard
statement concerning the existence of the registry, as well as the
contact information necessary to enroll in the pregnancy exposure
registry or to obtain information about the registry. The Agency
generally considers a pregnancy exposure registry scientifically
acceptable when it is consistent with applicable FDA guidance,
including the guidance for industry on ``Establishing Pregnancy
Exposure Registries'' (August 2002). If there are changes to an
existing pregnancy registry or a new pregnancy registry is initiated
after drug approval, labeling will need to be updated to include this
new information.
    (Comment 20) Two comments sought clarification regarding the
standards for including contact information for a pregnancy exposure
registry. One comment stated that contact information should only be
included if the registry is scientifically acceptable to the sponsor
and FDA. Another comment asked whether contact information for non-U.S.
registries must be included.
    (Response) As stated previously, if there is a scientifically
acceptable pregnancy registry for a drug product, FDA is requiring a
standard statement concerning the registry as well as contact
information needed to enroll in the registry or obtain additional
information about it. For registries that include U.S. populations,
U.S. contact information should be included in the labeling, regardless
of whether the registry is maintained within the United States or
elsewhere.
    (Comment 21) Four comments suggested that the pregnancy exposure
registry information should have its own component header.
    (Response) FDA agrees with the suggestion that the pregnancy
exposure registry information should have its own component header. In
the final rule, contact information for an existing pregnancy exposure
registry and a standard statement on the registry will fall under the
subheading ``Pregnancy Exposure Registry'' in the ``Pregnancy''
subsection of prescription drug labeling. Because of this change, FDA
eliminated the phrase ``must be stated at the beginning of the
`Pregnancy' subsection of the labeling'' from the final rule.
    (Comment 22) Two comments stated that it should be easier to enroll
patients in pregnancy exposure registries.
    (Response) The importance of subject recruitment into pregnancy
exposure registries and the need to build awareness of pregnancy
exposure registries among health care providers are both factors in
FDA's decision to place information about existing pregnancy exposure
registries at the beginning of Sec.  201.57, ``8.1 Pregnancy.'' The
actual process of enrolling patients, however, is beyond the scope of
this rule.
    (Comment 23) Comments expressed disagreement about whether the
``Pregnancy Exposure Registry''

subheading should be omitted from the ``Pregnancy'' subsection of
prescription drug labeling when there is no existing registry for the
drug. One comment suggested that the ``Pregnancy Exposure Registry''
subheading should not be omitted even if there is no existing registry
for the drug, and that it should include a statement that there is no
specific pregnancy exposure registry for the drug. Another comment
requested that FDA consider incorporating a statement that the
subheading may be omitted if there is no pregnancy exposure registry.
    (Response) FDA concludes that the ``Pregnancy Exposure Registry''
subheading should be omitted when there is no pregnancy exposure
registry. We have determined that requiring the ``Pregnancy Exposure
Registry'' subheading in labeling when there is no pregnancy exposure
registry for the drug product, and the inclusion of a statement
indicating that no registry exists, would not further the goal of
improving the collection of data in pregnant women who are exposed to a
drug.
    (Comment 24) One comment suggested that the labeling should state
the purpose of the pregnancy exposure registry and provide the contact
information necessary for enrollment.
    (Response) FDA agrees that including a statement in the labeling
about the purpose of the pregnancy exposure registry would be useful.
In the final rule, FDA requires that if there is a scientifically
acceptable pregnancy exposure registry for the drug, the labeling must
include a statement that there is a pregnancy exposure registry that
monitors pregnancy outcomes in women exposed to the drug during
pregnancy, and include contact information needed to enroll in the
registry or to obtain information about the registry. Because the
purpose of all pregnancy registries is to collect clinically relevant
human data that can be used in a product's labeling to provide health
care providers with useful information for treating or counseling
patients who are pregnant or anticipating pregnancy, we do not believe
it is necessary to include a more specific statement in labeling about
their purpose.
    (Comment 25) Two comments suggested that pregnancy exposure
registry information be included in ``Highlights'' and in the ``Patient
Counseling Information'' section of labeling. One comment requested
that FDA clarify in guidance whether the Agency anticipates requesting
more pregnancy registries as a condition of marketing approval.
    (Response) FDA believes that including information about pregnancy
exposure registries in the ``Patient Counseling Information'' section
of labeling would be useful. If the drug product has a pregnancy
exposure registry, the availability of a pregnancy exposure registry
should be noted in the ``Patient Counseling Information'' section of
labeling, and a cross-reference should be included to ``8.1 Pregnancy''
for the contact information necessary to enroll. The preamble to the
PLR states that ``Highlights'' summarizes the information from the
``Full Prescribing Information'' that is most important for prescribing
the drug safely and effectively and organizes it into logical groups to
enhance accessibility, retention, and access to the more detailed
information (71 FR 3922 at 3931). Information about the availability of
and contact information for a pregnancy exposure registry are not
considered essential information for prescribing and should not appear
in ``Highlights'' (see FDA's guidance for industry on ``Labeling for
Human Prescription Drug and Biological Products--Implementing the PLR
Content and Format Requirements'' (February 2013)). The question of
whether FDA anticipates requesting more pregnancy exposure registries
as a condition of marketing approval is outside the scope of this rule.
    In the final rule, FDA revised the phrase ``telephone number or
other information needed to enroll'' to ``contact information needed to
enroll.'' FDA determined that this change would allow for more
flexibility in the type of contact information included under this
portion of the labeling.
    ii. Background risk statement--FDA proposed that a general
statement about the background risk of adverse pregnancy outcomes be
included in labeling. The proposed rule stated in Sec.
201.57(c)(9)(i)(B) that the following statement was required to be
included in the labeling: All pregnancies have a background risk of
birth defect, loss, or other adverse outcome regardless of drug
exposure. The fetal risk summary below describes (name of drug)'s
potential to increase the risk of developmental abnormalities above the
background risk.
    (Comment 26) Two comments expressed support for the inclusion of a
background risk statement. One of these comments noted that the
statement will be useful to clinicians when explaining the fetal risks
associated with drug use during pregnancy.
    Several comments suggested modifying the background risk statement.
One comment suggested that applicants be given the option to identify
in the background risk statement the specific risks described in the
fetal risk summary. The comment proposed that the second sentence of
the background statement be modified to state: ``The fetal risk summary
below describes the potential of (name of drug) to contribute to risk
of (`adverse outcomes, including developmental abnormalities' or
identify specific risks) above background risk.''
    Several comments requested clarification about whether the
background risk statement refers to the general population or the
population with the disease. Two other comments suggested that when the
background risk of adverse outcomes in the relevant disease population
is known to be higher than in the general population, this information
should be included in the background risk statement. One of these
comments suggested that relevant literature citations should also be
included as appropriate.
    One comment asked FDA to clarify how it will determine the
background rate of adverse pregnancy outcomes. Another comment
suggested that FDA and industry develop a standard definition of
background risk that would provide a common explanation for all
labeling, both for the general population and for any specific disease
states or conditions. This comment explained that different reviewers
may look at different criteria for assessing background risk (i.e.,
what constitutes a developmental abnormality or a congenital
malformation), and a standard definition would provide for consistency.
A separate comment stated that the background risks of pregnancy can
vary by demographics, location, ethnicity, and other variables. The
comment suggested that to maintain uniform and standardized
descriptions of background risk, FDA should provide industry with a
guidance document describing background risk.
    One comment recommended against requiring data in the background
risk statement. The comment explained that background statistics change
over time as new evidence is made available and accepted by the medical
community.
    Several comments suggested that FDA revise or omit the second
sentence of the background risk statement. One of the comments
explained that the sentence implies that the drug necessarily has the
potential to increase the risk of developmental abnormalities above the
background risk.
    (Response) In the final rule, FDA has eliminated the proposed
standardized background risk statement. In its place, the final rule
requires that the labeling

state the percentage range of live births in the general population of
the United States with a major birth defect and the percentage range of
pregnancies in the United States that end in miscarriage, regardless of
drug exposure. The final rule also requires that if such information is
available for the population(s) for which the drug is labeled, it must
also be included. The final rule requires that the background risk
information appear in labeling under the subheading ``Risk Summary,''
rather than as a standalone statement under its own subheading (as in
the proposed rule).
    The Agency has determined that rather than including a standardized
general statement about background risk, it is beneficial to include
the approximate background rates of major birth defects and
miscarriage. This will provide some context to the risk statement, and
a basis for comparison with risk estimates from studies in pregnant
women. Including the approximate background rates allows the prescriber
to inform patients of the risk of major birth defects and miscarriage,
regardless of drug exposure. Accordingly, the final rule requires that
the labeling include the approximate background rates of major birth
defects and miscarriage, regardless of drug exposure, in the United
States. FDA agrees, however, that it is possible that these numbers may
change over time. Therefore, the Agency did not include any specific
numbers in the final rule. Instead, the Agency has provided
information, including relevant literature citations, about current
background rates of major birth defects and miscarriage in the draft
guidance on pregnancy and lactation labeling, which is being published
concurrently with this final rule. Although the literature citations
are included in the draft guidance, the Agency does not believe it is
either necessary or appropriate to include them in the labeling.
    FDA agrees that the second sentence in the proposed background risk
statement, which states that the fetal risk summary describes the
drug's potential to increase the risk of developmental abnormalities
above the background risk, could have been misinterpreted as meaning
that the drug is associated with an increased risk. As discussed
previously, the Agency has removed the standardized background risk
statement, including the second sentence, from the final rule.
    iii. Fetal risk summary--FDA proposed that under ``Pregnancy,''
prescription drug labeling include a subheading ``Fetal Risk Summary''
(Sec.  201.57(c)(9)(i)(C)). FDA proposed that the section include a
risk conclusion, contain a narrative description of the risk(s) (if the
risk conclusion is based on human data), and refer to any
contraindications or warnings and precautions.
    (Comment 27) One comment expressed support for the proposed ``Fetal
Risk Summary,'' explaining that the proposed labeling requirements
increase the utility of the ``Pregnancy'' subsection by expanding the
teratology section to include information about specific developmental
abnormalities such as incidence, seriousness, reversibility, potential
for correction, and effect of dose, duration, and gestational timing of
exposure. Several other comments suggested that the proposed ``Fetal
Risk Summary'' be revised in various ways, discussed in detail as
follows.
    Sources of data. FDA proposed that all available data, including
human, animal, and pharmacologic data, that are relevant to assessing
the likelihood that a drug will increase the risk of developmental
abnormalities and other relevant risks must be considered (Proposed
Sec.  201.57(c)(9)(i)(C)(1)).
    (Comment 28) One comment recommended that rather than considering
``all available data,'' the data sources for the ``Fetal Risk Summary''
be limited to ``scientifically rigorous, organized data collection
schemes such as clinical or preclinical studies, and registries.''
    (Response) FDA declines this suggestion. For example, depending on
the safety signal, valuable information may come from epidemiological
studies that are not prospective pregnancy exposure registries. On
occasion, adverse event reporting or case series reporting may raise
enough concern about a potential increased risk for a specific
structural malformation or pattern of malformations, or a serious
adverse event, that the information should be included in labeling.
    (Comment 29) Maternal and neonatal risk. One comment suggested that
FDA include information regarding maternal and neonatal risks in the
``Pregnancy'' subsection of labeling. The comment suggested that FDA
add a ``maternal risk subsection,'' preferably before the ``Fetal Risk
Summary,'' which would address side effects and adverse reactions
associated with the use of a drug, including those unique to pregnancy.
The comment explained that placing this information higher on the label
and making it a separate subsection would underscore the importance of
the health of the mother. The comment also suggested that FDA include
neonatal outcomes as well as fetal outcomes in the ``Fetal Risk
Summary.''
    (Response) FDA agrees that information on drug-associated maternal
risk is important, and in the final rule has created a separate
heading, ``Maternal adverse reactions,'' under ``Clinical
Considerations,'' which requires relevant information, to the extent it
is available, about drug-associated maternal adverse reactions that are
unique to or more frequent or severe during pregnancy. FDA disagrees
that information on neonatal outcomes as well as fetal outcomes should
be included in the ``Risk Summary.'' Rather, if available, this
information is included under its own heading, ``Fetal/Neonatal adverse
reactions,'' under ``Clinical Considerations.'' FDA believes that
consistent placement of this information under a specified heading
under ``Clinical Considerations'' will allow health care providers to
easily locate this information. FDA also believes that this approach
ensures that maternal, fetal, and neonatal risks will be captured and
clearly conveyed in prescription drug labeling.
    Terms used to describe adverse fetal outcomes. FDA proposed that
the fetal risk summary must characterize the likelihood that the drug
increases the risk of developmental abnormalities in humans (i.e.,
structural anomalies, fetal and infant mortality, impaired physiologic
function, alterations to growth) and other relevant risks (e.g.,
transplacental carcinogenesis) (proposed Sec.  201.57(c)(9)(i)(C)(1)).
    (Comment 30) Several comments suggested that the term
``developmental abnormalities'' should be replaced with a broader and
more accurate term. One comment suggested FDA replace the term
``developmental abnormalities'' with the term ``adverse outcomes,
including developmental abnormalities.'' This comment explained that
the phrase ``developmental abnormalities'' does not include ``other
relevant risks (e.g., transplacental carcinogenesis)'' that are also
required to be described in the ``Fetal Risk Summary.'' Several
comments suggested replacing the term ``developmental abnormalities''
with the term ``developmental effects'' or ``adverse developmental
effects.'' These comments explained that in the field of developmental
toxicology, a developmental abnormality would imply, in general, a
dysmorphogenic effect (malformation or variation), rather than the
wider definition intended by the proposed rule. Several comments noted
the importance of using terminology consistently in labeling.

    (Response) FDA agrees that the terms used to describe various
developmental effects or outcomes should be accurate and
understandable, and that standard nomenclature in the field of
developmental toxicology should be used to the extent that it exists.
FDA also agrees that terminology should be used consistently in
labeling. FDA concludes that the term ``developmental abnormalities''
is widely recognizable as referring to structural defects
(malformations or variations), rather than the full range of possible
manifestations of developmental toxicity as FDA had intended.
Therefore, in the final rule, FDA has included the following terms that
describe various developmental toxicities, as explained in the
following list:
     ``Adverse developmental outcomes'' has replaced
``developmental abnormalities'' as the general term to encompass all
manifestations or types of developmental toxicity.
     ``Structural abnormalities'' is used to describe
dysmorphology, which includes malformations, variations, deformations,
and disruptions, rather than the proposed ``structural anomalies.''
     ``Embryo-fetal and/or infant mortality'' is used to
describe developmental mortality, which includes miscarriage,
stillbirth, and infant death (including neonatal death), instead of the
proposed ``fetal and infant mortality.''
     ``Functional impairment'' is used to describe functional
toxicity, which includes such outcomes as deafness, endocrinopathy,
neurodevelopmental effects, and impairment of reproduction, rather than
``impaired physiologic function.''
     ``Alterations to growth'' is used to describe such
outcomes as growth restriction, excessive growth, and delayed and early
maturations.
    These terms and descriptions are consistent with FDA's guidance for
industry on ``Reproductive and Developmental Toxicities--Integrating
Study Results to Assess Concerns'' (September 2011).
    Relationship between animal and human data. FDA proposed that when
both human and animal data are available, risk conclusions based on
human data must be presented before risk conclusions based on animal
data (proposed Sec.  201.57(c)(9)(i)(C)(2)).
    (Comment 31) A number of comments suggested that FDA reexamine the
emphasis that the ``Fetal Risk Summary'' places on human data as
compared to animal data.
    Several comments stated that because there will be frequent
conflicts between human and animal data, FDA should develop an overall
approach to characterize risk based on both human and animal data. One
of these comments suggested that FDA consider the European Medicines
Agency's (EMEA's) (now EMA's) Integration Table for Risk Assessment and
Recommendation for Use as an example of how to integrate risk
conclusions based on animal and human data.
    Two comments stated that the proposed rule gives primary emphasis
to human studies, if they exist, while downgrading the emphasis on
animal data. One of these comments explained that the quality and
statistical power of human data often fall well short of desirable, and
suggested that human data be accompanied by clear acknowledgement of
any deficiencies. The other comment explained that emphasizing minimal
human data over strong animal data can misrepresent the fetal risk of a
drug.
    Two comments suggested that if human data are ``insufficient''
(i.e., do not meet the standard for inclusion in proposed Sec.
201.57(c)(9)(i)(C)(2)(i)), a risk statement based on human data should
not precede a risk statement based on animal data. One of these
comments explained that the most robust and clinically relevant data
should always be presented first.
    Several comments stated that if risk conclusions are based on
sufficient human data, sponsors should not be required to include
animal data, even if such data are available. One comment also
suggested that if sufficient human data become available after the
labeling is approved, animal data should be removed when the human data
are added to the labeling. This comment explained that ``a risk
conclusion based on animal data might not support, or could flatly
contradict, a risk conclusion based on sufficient human data.''
    One comment suggested that FDA ban all animal studies because human
studies are more accurate.
    (Response) We continue to believe that the ``Risk Summary'' is
appropriately based on both human and animal data. Because of the
importance of human data, we also have determined that when human data
provide an incomplete assessment, this should be stated in the risk
statement based on human data. Specifically, the ``Risk Summary'' must
state when there are no human data or when available human data do not
establish the presence or absence of a drug-associated risk. FDA
believes that the use of narrative summaries of the data will avoid
conflicting characterizations of risk magnitude.
    FDA disagrees with the suggestion that animal data be presented
first in cases where the human data are insufficient. FDA also
disagrees that the most robust and clinically relevant data--whether
human data or animal data--should always be presented first. We have
determined that to promote consistency and to meet readers'
expectations that information will always be found in the same place, a
fixed order of presentation must be maintained. Moreover, we have
determined that human data should precede animal data because it is the
most clinically relevant.
    We note that the purpose of this rulemaking is to facilitate
informed prescribing and safe and effective drug product use; placing
restrictions on or encouraging any type of studies that may be used as
the basis for drug labeling is beyond the scope of this rule.
    Not systemically absorbed. FDA proposed that if the drug is not
systemically absorbed, the fetal risk statement must contain only the
following statement: (Name of drug) is not absorbed systemically from
(part of body) and cannot be detected in the blood. Maternal use is not
expected to result in fetal exposure to the drug (proposed Sec.
201.57(c)(9)(i)(C)(1)).
    (Comment 32) One comment suggested that this statement should focus
on the route of administration rather than the part of the body.
    (Response) FDA agrees that ``part of the body'' could be
misconstrued and we have determined that the use of ``route of
administration'' to describe how the drug enters the body is more
consistent with labeling language that addresses dosing and
administration. In the final rule, FDA has replaced ``part of the
body'' with ``route of administration.'' FDA has determined that
``cannot be detected in the blood'' is redundant and that the statement
is clear without this phrase. In the final rule, FDA has eliminated
that phrase.
    (Comment 33) Standard statement for certain drugs. FDA received one
comment suggesting that we develop a standard statement for drugs that