
[Federal Register Volume 79, Number 233 (Thursday, December 4, 2014)]
[Rules and Regulations]
[Pages 72063-72103]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-28241]



[[Page 72063]]

Vol. 79

Thursday,

No. 233

December 4, 2014

Part II





Department of Health and Human Services





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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Prescription Drug and Biological Products--Content and Format; Draft 
Guidance for Industry; Availability; Final Rule and Notice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  

[[Page 72064]]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

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


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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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, 240-402-7911.

SUPPLEMENTARY INFORMATION:

Table of Contents

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

Executive Summary

Purpose of the Regulatory Action

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

[[Page 72065]]

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

Costs and Benefits

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

                                 Summary of Benefits and Costs of the Final Rule
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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)
----------------------------------------------------------------------------------------------------------------
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

[[Page 72066]]

for labeling for human prescription drugs (part 201 (21 CFR part 201)) 
(44 FR 37434, June 26, 1979) (the 1979 regulations).\1\ The 
requirements on content and format of labeling for drug products were 
revised on January 24, 2006, in the final rule on ``Requirements on 
Content and Format of Labeling for Human Prescription Drug and 
Biological Products'' (71 FR 3922), commonly referred to as the 
``Physician Labeling Rule'' (PLR).\2\ As part of the January 2006 
revision, the subsections of the labeling on pregnancy, labor and 
delivery, and nursing mothers were moved from the ``Precautions'' 
section under Sec.  201.57 to the ``Use in Specific Populations'' 
section. The content of these sections in part 201 was not revised, but 
the sections were redesignated as Sec.  201.57(c)(9)(i) through 
(c)(9)(iii). The previous labeling regulation (adopted in 1979) was 
redesignated as Sec.  201.80, and applies to products not affected by 
the January 2006, revisions. In redesignated Sec.  201.80, the 
subsections on pregnancy, labor and delivery, and nursing mothers are 
Sec.  201.80(f)(6) through (f)(8).
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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.''

[[Page 72067]]

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

[[Page 72068]]

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

D. Mental Models Research

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

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

A. Overview

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

B. Significant Changes to the Proposed Rule

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

[[Page 72069]]

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

[[Page 72070]]

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

[[Page 72071]]

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

III. Comments on the Proposed Rule

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

A. Proposed Rule as a Whole

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

[[Page 72072]]

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

[[Page 72073]]

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

[[Page 72074]]

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

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

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

[[Page 72075]]

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

    \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

[[Page 72076]]

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

[[Page 72077]]

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

[[Page 72078]]

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

[[Page 72079]]

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

[[Page 72080]]

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

[[Page 72081]]

    Risk conclusions based on human data. In the proposed rule, under 
the subheading ``Fetal Risk Summary,'' FDA proposed that when human 
data are sufficient to reasonably determine the likelihood that the 
drug increases the risk of fetal developmental abnormalities or 
specific developmental abnormalities, the likelihood of increased risk 
must be characterized using one of the following risk conclusions: 
Human data do not indicate that (name of drug) increases the risk of 
(type of developmental abnormality or specific developmental 
abnormality) or Human data indicate that (name of drug) increases the 
risk of (type of developmental abnormality or specific abnormality) 
(proposed Sec.  201.57(c)(9)(i)(C)(2)(i)). The proposed rule defined 
the sources of ``sufficient human data'' as clinical trials, pregnancy 
exposure registries or other large scale epidemiologic studies, or case 
series reporting a rare event (proposed Sec.  
201.57(c)(9)(i)(C)(2)(i)).
    (Comment 34) Many comments requested that FDA more clearly define 
the criteria for ``sufficient human data'' and provide further guidance 
on the quantity and quality of evidence considered to be ``sufficient 
human data'' rather than ``other human data.'' One comment requested 
that FDA clarify the standards that constitute ``sufficient human 
data,'' including how those standards were developed. Another comment 
stated that there is no agreement among experts as to how much data are 
needed to reach a risk conclusion and requested that FDA clarify what 
is considered sufficient human data to reasonably determine the risk of 
developmental abnormalities. Several comments questioned whether data 
from an individual study could ever constitute ``sufficient human 
data.'' These comments explained that although individual clinical 
trials, pregnancy exposure registries, large-scale epidemiologic 
studies, and case series can provide signals for potential adverse 
pregnancy outcomes, an individual study is not statistically powered to 
fully assess the incidence and form one of the proposed risk 
conclusions. A separate comment stated that even if human data has 
multiple sources, there is often not enough human data to make a risk 
conclusion. This comment questioned how often the risk statements based 
on sufficient human data would be used. One comment stated that the 
proposed rule does not discuss who will determine whether the data are 
sufficient or how such a determination will be made. The comment 
suggested that to increase consistent implementation across review 
divisions, a dedicated group of FDA specialists should review the 
determination of whether the human data are sufficient or insufficient 
for all labeling subject to the rule. This comment also requested that 
FDA provide examples of sufficient and insufficient data and that FDA 
caution prescribers that such classifications should not be considered 
as scientific proof that a drug may or may not harm a particular 
patient.
    (Response) FDA agrees that the term ``sufficient human data'' is 
ambiguous and has eliminated it from the final rule. FDA has also 
eliminated from the final rule the distinction between ``sufficient 
human data'' and ``other human data.'' In the final rule, FDA requires 
that when human data are available that establish the presence or 
absence of any adverse developmental outcome(s) associated with 
maternal use of the drug, the labeling must summarize the specific 
developmental outcome; its incidence; and the effects of dose, duration 
of exposure, and gestational timing of exposure. As stated previously, 
the final rule also requires that the ``Risk Summary'' state when there 
are no human data or when available human data do not establish the 
presence or absence of drug-associated risk.
    FDA has also determined that the term ``risk conclusion'' is 
inappropriate because the available data may not always lead to a 
conclusion regarding the drug's risk to the fetus. Therefore, in the 
final rule, FDA has replaced the term ``risk conclusion'' with the term 
``risk statement.''
    (Comment 35) Several comments suggested that the Agency revise the 
proposed risk statements to make them more straightforward and 
appropriately qualify the nature of the data and the inability to draw 
definitive conclusions about an absence of risk based on them. Two of 
these comments suggested that the term ``human data'' be replaced with 
the term ``available human data.'' One comment suggested that the risk 
conclusion ``Human data do not indicate that (name of drug) increases 
the risk of (type of developmental abnormality or specific 
developmental abnormality)'' be replaced with ``Available human data 
indicate no additional risk of (type of developmental abnormality or 
specific developmental abnormality) with (name of drug).'' One comment 
suggested that the term ``indicate'' should be replaced with the term 
``suggest.''
    (Response) In the final rule, FDA has eliminated the requirement in 
the proposed rule that standardized risk conclusions be used to 
characterize the likelihood of increased risk. As discussed previously, 
in the final rule, FDA requires instead, under ``Risk statement based 
on human data,'' that when human data are available that establish the 
presence or absence of any adverse developmental outcome(s) associated 
with maternal use of the drug, the labeling must summarize the specific 
developmental outcome; its incidence; and the effects of dose, duration 
of exposure, and gestational timing of exposure. The final rule also 
requires that if the data indicate that there is an increased risk for 
a specific adverse developmental outcome in infants born to women 
exposed to the drug during pregnancy, this risk must be quantitatively 
compared to the risk for the same outcome in infants born to women who 
were not exposed to the drug but who have the disease or condition for 
which the drug is indicated to be used. The final rule requires that if 
the data indicate that there is an increased risk for a specific 
adverse developmental outcome in infants born to women exposed to the 
drug during pregnancy, but risk information is not available for women 
who were not exposed to the drug but who have the disease or condition 
for which the drug is indicated to be used, then the risk for the 
specific outcome must be compared to the rate at which the outcome 
appears in the general population.
    (Comment 36) FDA also received comments about the proposed sources 
of sufficient human data. One comment stated that sufficient data must 
be based on large-scale epidemiologic studies or clinical trials, and 
cannot be based on pregnancy registries or case reports/series 
requiring further evaluation. This comment explained that most 
pregnancy registries can only serve to rule out a major teratogen and 
to generally determine the similarity in array of effects seen in large 
registries, and they cannot provide a quantitative estimate of 
population rates of individual defects or abnormalities. Another 
comment stated that a risk conclusion cannot always be reached based on 
the types of human data described in the proposed rule, and questioned 
whether there is a consistent approach to sufficient human data as it 
relates to case series reporting of a rare event. This comment 
explained that spontaneous reports should not be part of the basis for 
this subsection. One comment questioned how the labeling will summarize 
seemingly contradictory results of well-powered pregnancy exposure 
registries or studies from

[[Page 72082]]

which a definitive clinical conclusion cannot be reached.
    (Response) FDA recognizes that because retrospective voluntary 
adverse event reporting may be biased and incomplete, spontaneous 
reports cannot rule in or out a causal relationship between drug 
exposure and clinical outcome. However, multiple spontaneous reports 
(or case series) of rare events can be useful in suggesting possible 
associations between adverse events and drug exposure during pregnancy 
that warrant further investigation. Furthermore, FDA has determined 
that data from studies with small numbers of pregnancy exposures may 
provide valuable information about potential safety signals, especially 
when corroborated by findings from other studies.
    (Comment 37) One comment suggested that FDA eliminate the proposed 
rule's requirement that sponsors specify all possible types of 
developmental abnormalities or specific abnormalities for which human 
data do not indicate that the drug increases the risk. The comment 
explained that such a list could be lengthy and of little clinical 
benefit to health care providers.
    (Response) FDA did not intend to imply that every potential type of 
developmental abnormality must be included in labeling when human data 
are negative. We note that it is difficult to be certain that a lack of 
findings equates to a lack of risk because the failure of a study to 
detect an association between a drug exposure and an adverse outcome 
may be related to many factors, including a true lack of an association 
between exposure and outcome, a study of the wrong population, failure 
to collect or analyze the right data endpoints, and/or inadequate 
power. The intent of this final rule is to require accurate 
descriptions of available data and facilitate the determination of 
whether the data demonstrate potential associations between drug 
exposure and an increased risk for developmental toxicities.
    FDA proposed that when there are available human data that are not 
sufficient to use one of the risk conclusions for sufficient human 
data, the likelihood that the drug increases the risk of developmental 
abnormalities must be characterized as low, moderate, or high (proposed 
Sec.  201.57(c)(9)(i)(C)(2)(ii)). In the preamble to the proposed rule, 
FDA sought comment on this subsection. Specifically, FDA sought 
``comment on whether, in situations with human data that are not 
sufficient, rather than classifying the risk as low, moderate, or high, 
the risk should instead be characterized by specific statements 
describing the findings, or whether the findings should be described at 
all if they are not readily interpretable. Examples of specific 
statements would be: `Limited data in humans show (describe outcomes),' 
or `Limited data in humans show conflicting results (describe study 
types, number of cases, outcomes, and limitations)''' (73 FR 30831 at 
30842).
    (Comment 38) FDA received 10 comments from a variety of sources 
expressing strong disagreement with the proposal to use the terms 
``low,'' ``moderate,'' and ``high'' to characterize the likelihood of 
increased risk of adverse outcomes due to drug exposure based on less 
than sufficient human data. FDA received only one comment supporting 
the proposal.
    Four comments stated that the proposal to classify risk as low, 
moderate, or high based on insufficient human data might produce the 
same confusion as the current pregnancy category system. These comments 
explained that, as with the A, B, C, D, X category system, the use of 
the categories low, moderate, and high to characterize the likelihood 
of increased risk of adverse outcomes would oversimplify the data and 
lump drugs with various types and amounts of data together without 
describing the basis for the conclusions. Another comment suggested 
that these characterizations are subjective and would be confusing to 
health care providers.
    One comment recommended that when the human data are insufficient, 
FDA require the inclusion of the following risk conclusion: 
``Insufficient data--risk conclusion not established.'' Another comment 
recommended that FDA consider adopting something similar to the EMA's 
system. One comment suggested that the ``Risk Summary'' should include 
information about the findings, such as the gestational age of 
exposure, the target organ or organ system, and the findings should be 
characterized in terms of structural, developmental, growth, or 
functional abnormality. Another comment recommended that when the human 
data are not sufficient, the labeling contain statements specific to 
the findings rather than classifying the risk as low, moderate, or 
high. One comment suggested that when there are insufficient data, the 
labeling should include a statement explaining that it is not possible 
to draw conclusions based on insufficient human data. This comment also 
expressed a preference for referring to the data portion of the 
labeling rather than including a more detailed narrative discussion of 
insufficient human data in the fetal risk summary.
    (Response) As discussed previously, FDA agrees that the term 
``sufficient human data'' is ambiguous and we have removed the term 
from the final rule, as well as the distinction between ``sufficient 
human data'' and ``other human data.'' FDA also agrees that the terms 
``low,'' ``moderate,'' and ``high'' are subjective and should not be 
used to describe human data that cannot support a statement about fetal 
risk. The final rule requires instead that when human data are 
available that establish the presence or absence of any adverse 
developmental outcome(s) associated with maternal use of the drug, the 
labeling must summarize the specific developmental outcome; its 
incidence; and the effects of dose, duration of exposure, and 
gestational timing of exposure. As discussed earlier, the final rule 
also requires that if the human data indicate that there is an 
increased risk for a specific adverse developmental outcome in infants 
born to women exposed to the drug during pregnancy, this risk must be 
quantitatively compared to the risk for the same outcome in infants 
born to women who were not exposed to the drug but who have the disease 
or condition for which the drug is indicated to be used. When risk 
information is not available for women with the disease or condition 
for which the drug is indicated, then the risk for the specific outcome 
must be compared to the rate at which the outcome occurs in the general 
population. The final rule also requires that the ``Risk Summary'' 
state when there are no human data or when available human data do not 
establish the presence or absence of drug-associated risk.
    Narrative description of risk(s) based on human data. FDA proposed 
that when there are human data, the risk conclusion must be followed by 
a brief description of the risks of developmental abnormalities as well 
as other relevant risks associated with the drug. To the extent 
possible, this description must include the specific developmental 
abnormality (e.g., neural tube defects); the incidence, seriousness, 
reversibility, and correctability of the abnormality; and the effect on 
the risk of dose, duration of exposure, and gestational timing of 
exposure. When appropriate, the description must include the risk above 
the background risk attributed to drug exposure and confidence limits 
and power calculations to establish the statistical power of the study 
to identify

[[Page 72083]]

or rule out a specified level of risk (proposed Sec.  
201.57(c)(9)(i)(C)(4)).
    In the final rule, FDA has removed the ``Narrative description of 
risk(s)'' heading from the ``Pregnancy'' subsection. FDA has determined 
that much of the information required under that heading by the 
proposed rule was duplicative of information now required in the ``Risk 
Summary.'' As discussed previously, when human data are available that 
establish the presence or absence of any adverse developmental 
outcome(s) associated with maternal use of the drug, the ``Risk 
Summary'' in the ``Pregnancy'' subsection must summarize the specific 
developmental outcome; its incidence; and the effects of dose, duration 
of exposure, and gestational timing of exposure. Because this 
information is required to be included in a narrative form in the 
``Risk Summary,'' we determined that including a separate ``Narrative 
description of risk(s)'' heading in the labeling was unnecessary. In 
addition, as explained in the following comments and our responses, 
some of the information that was required by the proposed rule to 
appear under ``Narrative description of risk(s)'' is required by the 
final rule to appear instead under ``Clinical Considerations.''
    (Comment 39) One comment suggested that FDA add a statement to the 
``Narrative description of risk(s)'' portion of the ``Pregnancy'' 
subsection of labeling that explains that spontaneous abortions caused 
by a drug could potentially mask the risk of developmental 
abnormalities.
    (Response) Although FDA acknowledges that embryo-fetal death (i.e., 
spontaneous abortion) does sometimes occur due to severe developmental 
abnormalities, the Agency has determined that it is not necessary to 
explicitly include such a statement in labeling. Any increase in 
spontaneous abortions attributed to drug exposure above the background 
risk is required to be described in the ``Risk Summary.''
    (Comment 40) One comment stated that the term ``seriousness'' is 
ambiguous and suggested replacing it with the phrase ``impact on 
health.'' Two comments requested clarification of the terms 
``reversibility'' and ``correctability.''
    (Response) FDA agrees that the term ``seriousness'' is not clear, 
and it is not used in the final rule; it has been replaced with a 
requirement that the labeling describe the potential severity of the 
adverse reaction. Information about the reversibility of adverse 
reactions should be included under the heading, ``Fetal/Neonatal 
adverse reactions,'' under ``Clinical Considerations.'' This portion of 
the final rule requires that if it is known or anticipated that 
maternal drug therapy increases or may increase the risk of an adverse 
reaction in the fetus or neonate, the labeling must describe the 
adverse reaction, the potential severity and reversibility of the 
adverse reaction, and available interventions for monitoring or 
mitigating the reaction.
    In response to the comments requesting clarification of the terms 
``reversibility'' and ``correctability,'' FDA considers a condition to 
be reversible if it can self-correct with routine care and nurturing or 
through an intervention such as discontinuing the drug. An example of a 
potentially reversible drug effect in the neonate is provided in the 
draft guidance on pregnancy and lactation labeling, which is being 
published concurrently with the final rule. The term ``correctable'' 
has been removed from the final rule.
    (Comment 41) One comment suggested that FDA include in the 
``Narrative description of risk(s)'' information about precautionary 
measures that can be taken to prevent an adverse outcome caused by the 
drug.
    (Response) FDA agrees that information about precautionary measures 
to prevent an adverse drug effect should be included in labeling. In 
the final rule, under ``8.1 Pregnancy,'' ``Clinical Considerations,'' 
``Maternal adverse reactions,'' FDA requires that if the use of the 
drug is associated with a maternal adverse reaction that is unique to 
pregnancy or if a known adverse reaction occurs with increased 
frequency or severity in pregnant women, the labeling must describe the 
adverse reaction and available intervention(s) for monitoring or 
mitigating it. Also, in the final rule, FDA requires that under ``8.1 
Pregnancy,'' ``Clinical Considerations,'' ``Fetal/Neonatal adverse 
reactions,'' if it is known or anticipated that maternal drug therapy 
increases or may increase the risk of an adverse reaction in the fetus 
or neonate, the labeling must describe the adverse reaction, the 
potential severity and reversibility of the adverse reaction, and 
available intervention(s) for monitoring or mitigating the reaction. 
For further discussion of these requirements, see Comment 61 and our 
response.
    (Comment 42) One comment suggested that FDA replace the phrase 
``risk attributed to drug exposure'' in the ``Narrative description of 
risk(s)'' with the phrase ``a drug's potential to contribute to the 
risk of adverse outcomes.''
    (Response) As discussed previously, the ``Narrative description of 
risk(s)'' heading was removed from the final rule, and the phrase 
``risk attributed to drug exposure'' is not used elsewhere in the final 
rule.
    (Comment 43) Two comments stated that confidence intervals and 
power calculations should not be included in labeling because they are 
too technical and not useful for most prescribers.
    (Response) FDA does not agree. Under ``Data,'' the final rule 
requires a description of the limitations of any data included in the 
labeling. Confidence intervals and power calculations are important for 
the review and interpretation of the data. As noted in the draft 
guidance on pregnancy and lactation labeling, which is being published 
concurrently with the final rule, the confidence intervals and power 
calculation, when available, should be part of that description of 
limitations.
    (Comment 44) One comment suggested that the ``Narrative description 
of risk(s)'' include a discussion about the uncertainties or 
limitations of the ``Fetal Risk Summary'' when appropriate.
    (Response) As discussed previously, FDA has removed the ``Narrative 
description of risk(s)'' heading from the final rule. In the final 
rule, any uncertainties or limitations of the data are required to be 
stated in ``Data.''
    (Comment 45) One comment suggested that the ``Narrative description 
of risk(s)'' cross-reference ``Data'' to direct readers to the 
information upon which the narrative is based.
    (Response) As discussed previously, the ``Narrative description of 
risk(s)'' was removed from the final rule.
    Risk statement based on animal data. FDA proposed to require that 
when the data on which the risk conclusion is based are animal data, 
the ``Fetal Risk Summary'' must characterize the likelihood that the 
drug increases the risk of developmental abnormalities using one of the 
following risk conclusions: Not predicted to increase the risk, low 
likelihood of increased risk, moderate likelihood of increased risk, 
high likelihood of increased risk, or insufficient data (proposed Sec.  
201.57(c)(9)(i)(C)(3)(i)-(c)(9)(i)(C)(3)(v)). In the preamble to the 
proposed rule, the Agency sought comment on whether these standardized 
statements can adequately communicate different levels of risk based on 
animal data and their potential relevance to human fetal effects or 
whether these statements are likely to generate

[[Page 72084]]

confusion among prescribers (73 FR 30831 at 30843).
    (Comment 46) Comments expressed different opinions about the 
proposal to use standardized statements to characterize animal data. 
FDA received 11 comments, primarily from toxicologists, teratologists, 
and organizations representing toxicologists and teratologists, as well 
as a few comments from drug manufacturers, expressing strong 
disagreement with the proposal to use risk statements to characterize 
animal data. FDA received three comments that supported using 
standardized statements to characterize the likelihood, based on animal 
data, that a drug will increase the risk for a known developmental 
abnormality. These comments explained, for example, that a standardized 
statement indicating the possible correlation between animal and human 
data would be helpful to clinicians.
    Two comments stated that the proposed categories are confusing and 
subject to variable interpretation. One of these comments explained 
that it will be very difficult to categorize the results of multiple 
studies conducted for a single drug into one of the proposed 
categories, and there could be disagreement about whether to 
characterize the risk based on the animal data as ``low,'' 
``moderate,'' or ``high.''
    Several comments stated that the proposal to use category language 
to describe animal data demonstrates a misunderstanding of the function 
and meaning of experimental animal studies. These comments explained 
that although animal data can identify the potential of a therapeutic 
agent to cause developmental toxicity, it cannot give rise to an 
estimate of the probability of human harm.
    Two comments expressed concern that the use of standardized risk 
statements would amount to a category system similar to the one that 
FDA currently uses and would have all of its associated problems.
    Several comments expressed particular concern with the proposal to 
use these categories without an accompanying narrative description of 
the animal studies. One comment suggested that the sample labels 
provided in the Appendix of the proposed rule illustrate the difficulty 
of trying to characterize the risk to humans based on animal data. 
Another comment stated that ``the terms `risk,' `medium,' and `high' 
are highly charged terms'' and expressed concern that the risk 
statements will be over-interpreted by anxious consumers and their 
clinicians.
    One comment suggested that rather than using the proposed risk 
statements, FDA should instead use the standardized statements 
presented in the draft reviewer guidance on ``Integration of Study 
Results to Assess Concerns about Human Reproductive and Developmental 
Toxicities'' (October 2001).
    Most of the comments that disagreed with the proposed standardized 
risk statements suggested that the labeling instead contain narrative 
statements describing the animal data and its potential relationship to 
human pregnancy risk. One of these comments explained that ``succinct 
narrative statements will promote a reasoned risk assessment, 
facilitate comparisons among drugs, and enhance risk communication.'' 
Several of these comments suggested that the labeling should describe 
animal data qualitatively, including the number of species with 
positive findings, consistency of findings, and the type of findings.
    (Response) The Agency has determined that the terms ``not predicted 
to increase the risk,'' ``low likelihood of increased risk,'' 
``moderate likelihood of increased risk,'' and ``high likelihood of 
increased risk'' are confusing and subject to different 
interpretations. The Agency believes that using standardized risk 
statements may give the false impression that animal data can provide a 
semi-quantitative assessment of human risk. The Agency also agrees that 
the use of standardized risk statements to characterize the risk of 
developmental abnormalities based on animal data would potentially have 
the same drawbacks as the current pregnancy category system. Therefore, 
in the final rule, FDA removed the requirement that a standardized risk 
statement be used to describe human risk based on animal data. Instead, 
the ``Risk Summary'' requires that when animal data are available, the 
labeling must summarize the findings in animals and, based on these 
findings, describe, for the drug, the potential risk of adverse 
developmental outcomes in humans. The final rule requires that the 
statement include the number and type(s) of species affected, timing of 
exposure, animal doses expressed in terms of human exposure or dose 
equivalents, and outcomes for pregnant animals and offspring. The final 
rule also requires that when animal studies do not meet current 
standards for nonclinical developmental toxicity studies or when there 
are no animal data, the labeling must so state.
    (Comment 47) Two comments suggested that labeling should include 
language explaining the limitations of using animal data to predict the 
likelihood that the drug increases the risk of developmental 
abnormalities.
    (Response) FDA declines the suggestion to include language in 
labeling explaining the limitations of using animal data to predict the 
likelihood that the drug increases the risk of developmental 
abnormalities, because this is beyond the scope of this rule, and is 
discussed in guidance documents, such as FDA's guidance for industry on 
``Reproductive and Developmental Toxicities--Integrating Study Results 
to Assess Concerns'' (September 2011).
    (Comment 48) FDA proposed that the ``Risk Summary'' contain ``risk 
conclusions'' based on animal data. One comment suggested that the term 
``risk conclusion'' be replaced with the term ``risk statement'' 
because it is difficult to reach any conclusions about fetal risk posed 
by drugs based solely on animal data.
    (Response) FDA agrees. As with human data, in the final rule, the 
Agency has replaced the term ``risk conclusion'' with the term ``risk 
statement'' when discussing risks based on animal data.
    (Comment 49) Risk statement based on pharmacology. One comment 
suggested that FDA consider whether a separate approach is appropriate 
for a group of drugs, such as oncology products, for which the 
pharmacological and toxicological mechanisms are similar. The comment 
suggested that for cytotoxic drugs, FDA could use the following 
standard risk statement: ``(Drug name) is indicated for (cancer type) 
and is generally used in terminally ill patients. There are very 
limited data on exposure in pregnant patients and, therefore, no 
assessment of fetal or maternal risk is available. The mechanism of 
action of this drug is to kill growing cells and it can be anticipated 
that there is a risk to the fetus at all stages of development.''
    (Response) FDA agrees that the ``Pregnancy'' subsection of labeling 
should address situations in which a drug may result in an increased 
risk of adverse developmental outcomes based on a well-understood 
mechanism of action. The final rule requires that when the drug has a 
well-understood mechanism of action that may result in adverse 
developmental outcome(s), the ``Risk Summary'' must explain the 
mechanism of action and the potential associated risks.
    Contraindications, warnings, and precautions. FDA proposed that the

[[Page 72085]]

``Fetal Risk Summary'' refer to information that is included in the 
``Contraindications'' or ``Warnings and Precautions'' section of 
labeling regarding an increased risk to the fetus from exposure to the 
drug (proposed Sec.  201.57(c)(9)(i)(C)(5)).
    (Comment 50) One comment suggested that FDA specify that any 
contraindications or warnings or precautions that must be included in 
the ``Fetal Risk Summary'' are those that relate to risk to the fetus.
    (Response) In the final rule, FDA removed the requirement that the 
``Risk Summary'' refer to information that is included in the 
``Contraindications'' or ``Warnings and Precautions'' section of 
labeling regarding an increased risk to the fetus from exposure to the 
drug. As described in FDA's draft guidance for industry implementing 
the PLR, when a topic is discussed in more than one section of 
labeling, the section containing the most important information 
relevant to prescribing should typically include a succinct description 
and should cross-reference sections that contain additional detail 
(FDA's guidance for industry on ``Labeling for Human Prescription Drug 
and Biological Products--Implementing the PLR Content and Format 
Requirements'' (February 2013)). Consistent with that principle, cross-
referencing of information required under the final rule will typically 
appear in the section where the topic is briefly summarized, e.g., 
``Warnings and Precautions,'' and will refer the reader to the place in 
labeling where it will be presented in greater detail, i.e., 
``Pregnancy.'' We note that because a contraindication is important 
information that needs to be communicated to the health care provider, 
the final rule requires that when use of a drug is contraindicated 
during pregnancy, this information must be stated first in the ``Risk 
Summary.''
    iv. Clinical considerations.
    FDA proposed that the ``Pregnancy'' subsection of prescription drug 
labeling include a ``Clinical Considerations'' component to provide 
guidance and information to health care providers about the use of the 
drug in three distinct clinical situations: (1) Counseling women who 
were inadvertently exposed to the drug during pregnancy, (2) making 
prescribing decisions for pregnant women, and (3) making prescribing 
decisions during labor and delivery (proposed Sec.  
201.57(c)(9)(i)(D)).
    We received many comments on this proposal. Based on those 
comments, FDA has made some changes to the final rule. A description of 
each comment we received and our responses follow.
    (Comment 51) General comments. Comments expressed different 
opinions about the utility and appropriateness of the proposed 
``Clinical Considerations'' component. Many comments expressed general 
support for including this information. One comment stated that 
``Clinical Considerations'' will help clinicians and patients to 
consider all aspects of the patient's care when deciding when and how 
to prescribe drugs during pregnancy and in women of childbearing 
potential. Another comment stated that the title ``Clinical 
Considerations'' encourages professionals to make their own medical 
judgments. A separate comment noted that FDA refrained from interfering 
with the physician's discretion by framing ``Clinical Considerations'' 
as a practical guide that assists the provider in decisionmaking.
    Some comments cautioned that ``Clinical Considerations'' was too 
directive in its advice and requiring this information intruded on the 
practice of medicine and could increase physician liability for failure 
to adhere to labeling instructions. One comment stated that ``Clinical 
Considerations'' should not dictate prescribing by a physician for 
pregnant women. The comment requested that FDA revisit this provision 
to see whether the content can be made more useful without advising 
physicians how to practice medicine. In particular, the comment 
suggested that information about known alternative therapies should be 
included. Alternatively, the comment suggested that FDA consider the 
use of a general statement about clinical considerations rather than an 
extensive, clinically based discussion that may be unable to 
incorporate risk and benefit information. Another comment stated that 
it is the health care provider's responsibility to keep abreast of the 
latest information about the disease state and its effect on pregnant 
women and to apply that knowledge to treatment of each individual 
patient, and the professional labeling is not the appropriate place for 
this information.
    (Response) FDA disagrees both that ``Clinical Considerations'' is 
too directive and that professional labeling is not the appropriate 
place for this information. As a Public Health Agency with expertise in 
drug regulation and safety, FDA has a responsibility to issue 
regulations that facilitate the development of drug labeling that 
communicates how to safely and effectively prescribe drugs in the 
clinical setting. The Agency does not regard ``Clinical 
Considerations'' as dictating prescribing decisions. Rather, FDA views 
the ``Clinical Considerations'' component of ``Pregnancy'' as providing 
information that supports health care providers' understanding of drug 
product risks and benefits and facilitates informed prescribing 
decisions and patient counseling.
    Inadvertent exposure. FDA proposed that under the subheading 
``Clinical Considerations,'' the ``Pregnancy'' subsection of labeling 
include information regarding known or predicted risks to the fetus 
from inadvertent exposure to the drug during pregnancy (proposed Sec.  
201.57(c)(9)(i)(D)(1)). The proposed rule would have required that: The 
labeling must discuss the known or predicted risks to the fetus from 
inadvertent exposure to the drug (exposure in early pregnancy before a 
woman knows she is pregnant), including human or animal data on dose, 
timing, and duration of exposure. If there are no human or animal data 
to assess the risk from inadvertent exposure, the labeling must so 
state.
    (Comment 52) Comments expressed different opinions about the 
necessity and utility of including this information.
    Two comments supported including information about inadvertent 
exposure. One of these comments explained that the proposed section 
improves a physician's ability to manage such cases.
    Two comments, however, suggested that FDA consider removing this 
requirement because it will be duplicative of the information contained 
in the ``Fetal Risk Summary.'' One of these comments explained that 
assuming equal exposure to the drug, the known or predicted risks to 
the fetus would be the same regardless of whether the exposure was 
intentional or not. This comment explained that because fetal risks are 
already fully described in the ``Fetal Risk Summary,'' including the 
same information under ``inadvertent exposure during pregnancy'' would 
be redundant. The comment suggested that the ``inadvertent exposure 
during pregnancy'' component instead include a cross-reference to the 
``Fetal Risk Summary'' and describe only information not already 
described in the ``Fetal Risk Summary,'' in particular, any information 
about ways to manage or mitigate the effects of inadvertent drug 
exposure. The other comment explained that the risk of drug exposure to 
the fetus early in pregnancy should not be different between women who

[[Page 72086]]

choose to become pregnant and those whose pregnancies were unplanned.
    Another comment suggested that FDA either delete the statement 
``exposure in early pregnancy before a woman knows that she is 
pregnant'' or retain it as an example. This comment explained that 
although inadvertent exposure is more likely in early pregnancy, it may 
occur at any time during pregnancy.
    One comment asked for clarification as to what is expected to be 
included in this section. Specifically, this comment questioned how the 
risk conclusions from animal data in the ``Fetal Risk Summary'' will be 
used to counsel clinicians on the risk of inadvertent exposure, and 
requested that FDA provide examples of this section in an Appendix.
    (Response) The Agency agrees that the proposed ``inadvertent 
exposure during pregnancy'' component would have required information 
about drug effects on the fetus that is largely redundant of the 
information that is required to be included in the ``Risk Summary'' in 
the ``Pregnancy'' subsection of prescription drug labeling. FDA has 
removed the ``inadvertent exposure during pregnancy'' component from 
the final rule.
    Prescribing decisions for pregnant women. FDA proposed that the 
``Clinical Considerations'' portion of the ``Pregnancy'' subsection of 
prescription drug labeling contain information about prescribing 
decisions for pregnant women, including the following: (1) The risk, if 
known, to the pregnant woman and the fetus from the disease or 
condition the drug is indicated to treat; (2) information about dosing 
adjustments during pregnancy; (3) information about maternal adverse 
reactions associated with use of the drug; and (4) information about 
any known or anticipated complications in the neonate from treatment of 
the pregnant woman (proposed Sec.  201.57(c)(9)(i)(D)(2)).
    In the final rule, FDA removed the heading ``Prescribing decisions 
for pregnant women.'' FDA determined that because the ``inadvertent 
exposure'' component was removed from the final rule, the ``Clinical 
Considerations'' portion of the ``Pregnancy'' subsection was shortened 
such that having a separate heading for ``Prescribing decisions for 
pregnant women'' was unnecessary.
    FDA received comments about the information required in the 
proposed rule under the heading ``Prescribing decisions for pregnant 
women.'' A description of each comment and our responses follow.
    FDA proposed that the ``Prescribing decisions for pregnant women'' 
component under ``Clinical Considerations'' include information about 
the risk, if known, to the pregnant woman and the fetus from the 
disease or condition the drug is indicated to treat (proposed Sec.  
201.57(c)(9)(i)(D)(2)(i)).
    (Comment 53) Comments disagreed about whether the ``Pregnancy'' 
subsection of labeling should include information about the effects of 
not treating the woman's underlying disease or condition.
    Two comments supported requiring the inclusion of information about 
the short- and long-term effects of not taking a necessary drug to 
treat a chronic disease or condition for the duration of a pregnancy, 
as well as information about the severity of the condition for which 
the drug might be prescribed.
    Two other comments, however, disagreed with including information 
in ``Clinical Considerations'' about the risks of not treating the 
mother's underlying disease or condition during pregnancy. These 
comments stated that prescription drug labeling is not the appropriate 
place for health care providers to learn about the risks of diseases 
that drugs are indicated to treat.
    (Response) FDA has determined that when relevant information is 
available about the serious effects of not treating conditions or 
diseases during pregnancy, it must be included in this section of 
labeling. In the final rule, this requirement appears first under 
``Clinical Considerations'' under the heading ``Disease-associated 
maternal and/or embryo/fetal risk.'' The wording of this portion of the 
final rule was revised to require that when there is a serious known or 
potential risk to the pregnant woman and/or the embryo/fetus associated 
with the disease or condition for which the drug is indicated to be 
used, the labeling must describe the risk.
    (Comment 54) Other comments suggested that the ``Clinical 
Considerations'' component of the proposed rule be altered in various 
ways.
    Two comments expressed concern that descriptions of risks to the 
pregnant patient or fetus posed by diseases or conditions would vary 
among drugs that are indicated to treat the same disease or condition, 
thereby promoting confusion. One of these comments suggested that FDA 
develop disease-specific text for developmental risks of major disease 
classes, such as asthma, hypertension, diabetes, and epilepsy, which 
sponsors can use in their prescription drug labeling. This comment also 
requested that the information be updated on a timely basis.
    (Response) FDA agrees that it is important that information 
provided in labeling is consistent and up-to-date, and we address this 
issue in our response to Comment 4. FDA is not mandating that labeling 
contain consistent disease-specific text, as knowledge of disease-
associated risk may change over time as more data become available.
    (Comment 55) One comment suggested that FDA add a statement under 
``Clinical Considerations'' explicitly stating that untreated or 
inadequately treated health conditions (such as infections; chronic 
diseases such as diabetes, hypertension, renal and thyroid diseases; 
and psychiatric disorders such as depression) can adversely affect the 
health of the woman and the outcomes of the pregnancy, and that 
decisions about medication usage must be balanced with the risks of 
untreated and/or poorly managed health conditions.
    (Response) FDA disagrees with this suggestion. We have determined 
that requiring a general standardized statement is less effective than 
providing drug-specific information about the risks of not treating the 
condition or disease for which the drug is indicated to be used.
    (Comment 56) One comment suggested that ``Clinical Considerations'' 
should provide information about how to discontinue or switch 
medications during pregnancy when necessary.
    (Response) FDA agrees that when such information is available, it 
may be appropriate to include it in ``Clinical Considerations.'' We 
note that this does not require a change to the final rule, because 
this is consistent with current labeling practices.
    (Comment 57) One comment suggested that ``Clinical Considerations'' 
take into account the severity of the disease, disorder, or condition 
to the mother, and the availability and the benefits and risks of 
alternative therapies for which greater or lesser knowledge may be 
known about their use in pregnant women.
    (Response) FDA disagrees with the suggestion that the labeling 
address the availability and the benefits and risks of alternative 
therapies during pregnancy. Because the comparative risks and benefits 
for different therapies may vary by patient, this determination must be 
made by the prescribing health care provider. FDA acknowledges, 
however, that under certain circumstances it may be appropriate to 
include a statement in the labeling that pregnant women

[[Page 72087]]

should consider alternative drug therapies, and the appropriateness of 
this would be evaluated on a case-by-case basis during the labeling 
review process for a specific application.
    Dosing adjustments during pregnancy. FDA proposed that ``Clinical 
Considerations'' provide information about dosing adjustments during 
pregnancy (proposed Sec.  201.57(c)(9)(i)(D)(2)(ii)). The proposed rule 
stated that this information must also be included in the ``Dosage and 
Administration'' and ``Clinical Pharmacology'' sections of the 
labeling, and that if there are no data on dosing during pregnancy, the 
labeling must so state.
    (Comment 58) One comment suggested that dosing information should 
be restricted to the ``Dosage and Administration'' section of labeling 
and that ``Clinical Considerations'' should cross-reference the 
``Dosage and Administration'' and ``Clinical Pharmacology'' sections of 
the labeling rather than repeat dosing adjustment information in the 
``Pregnancy'' subsection of labeling. The comment also suggested 
replacing the phrase ``no data'' because it could become outdated and 
because, in some instances, there may be data but it might not be 
sufficient to support recommendations for dosing adjustments.
    (Response) We disagree with the suggestion that all information 
about dosing should be restricted to the ``Dosage and Administration'' 
section of labeling. FDA has determined that it is important that 
labeling information relevant to the use of the drug during pregnancy 
be included in the ``Pregnancy'' subsection. These issues are discussed 
in the draft guidance on pregnancy and lactation labeling, which is 
being published concurrently with the final rule. If there are 
pharmacokinetic data that support dose adjustment(s) during pregnancy 
and the postpartum period, this information must be provided under the 
heading, ``Dose adjustments during pregnancy and the postpartum 
period'' in ``Clinical Considerations,'' and there should be a cross-
reference to other sections of labeling that include more details 
(e.g., ``Dosage and Administration'' or ``Clinical Pharmacology''). 
Although in the proposed rule FDA had required a cross-reference to 
``Dosage and Administration'' and ``Clinical Pharmacology,'' we have 
removed that requirement. We believe, however, that when appropriate, a 
cross-reference should be included. This approach is consistent with 
the regulations and guidance applicable to the ``Dosage and 
Administration'' section of labeling (Sec.  201.57(c)(3)) and FDA's 
guidance for industry on ``Dosage and Administration Section of 
Labeling for Human Prescription Drug and Biological Products--Content 
and Format'' (March 2012), which require that the labeling provide 
details on how to adjust or modify the dosage in the ``Dosage and 
Administration'' section of labeling, including for specific patient 
populations.
    FDA agrees with the suggestion to remove the phrase ``no data'' 
from the final rule. In the final rule, we have removed the requirement 
to state if there are no data available on dose adjustments during 
pregnancy and the postpartum period. In addition, as noted in the draft 
guidance on pregnancy and lactation labeling, which is being published 
concurrently with the final rule, headings under ``Clinical 
Considerations'' (including ''Dose adjustments during pregnancy and the 
postpartum period'') should be omitted if there are no data available 
or the available data are not relevant.
    Maternal adverse reactions. FDA proposed that ``Clinical 
Considerations'' contain information about maternal adverse reactions 
that are unique to pregnancy or adverse reactions that occur with 
increased frequency or severity in pregnant women. The proposed rule 
required that the labeling also describe any interventions that may be 
needed, such as monitoring blood glucose for a drug that causes 
hyperglycemia in pregnancy (proposed Sec.  201.57(c)(9)(i)(D)(2)(iii)).
    (Comment 59) One comment suggested that a cross-reference, ``see 
Pregnancy,'' be added to the ``Adverse Reactions'' section of labeling 
to ensure that health care providers refer to this section.
    (Response) FDA disagrees with this comment. The conventions for 
cross-referencing are explained in FDA's guidance for industry on 
``Labeling for Human Prescription Drug and Biological Products--
Implementing the PLR Content and Format Requirements'' (February 2013). 
The suggestion that this rule require a cross-reference from the 
``Adverse Reactions'' section to the ``Pregnancy'' subsection of 
labeling is not consistent with the conventions set forth in that 
guidance. In addition, not every drug product will have pregnancy-
related adverse reactions; thus, a required cross-reference is 
unnecessary.
    (Comment 60) One comment suggested that ``Clinical Considerations'' 
refer to ``available'' interventions rather than ``needed'' 
interventions to avoid interfering with the practice of medicine.
    (Response) FDA agrees with the suggestion to replace the phrase 
``interventions that may be needed'' with the phrase ``available 
interventions.'' In the final rule, FDA requires that if use of the 
drug is associated with a maternal adverse reaction that is unique to 
pregnancy or if a known adverse reaction occurs with increased 
frequency or severity in pregnant women, the labeling must describe the 
adverse reaction and available intervention(s) for monitoring or 
mitigating the reaction. This change also allows for differences that 
may exist in community standards of care and available services across 
the United States. We note that in the final rule we removed the 
following language from the codified: ``e.g., monitoring blood glucose 
for a drug that causes hyperglycemia in pregnancy.''
    Fetal/Neonatal adverse reactions. FDA proposed that ``Clinical 
Considerations'' contain information about any known or anticipated 
complications in the neonate, including any interventions that might be 
needed (proposed Sec.  201.57(c)(9)(i)(D)(2)(iv)).
    (Comment 61) Two comments asked FDA to clarify the meaning of the 
term ``complication.'' One comment suggested that if FDA intended the 
term ``complication'' to mean adverse reaction in the neonate, the 
Agency should use the term ``adverse reaction.'' This comment also 
suggested that if an adverse reaction/complication has been described 
in the ``Fetal Risk Summary,'' only a cross-reference to Sec.  
201.57(c)(9)(i)(C) should be required to appear in Sec.  
201.57(c)(9)(i)(D)(2)(iv). Another comment suggested that FDA state 
that a ``complication'' could be an ``adverse drug reaction,'' and 
suggested that FDA state that the term ``adverse drug reaction'' may be 
used when appropriate.
    (Response) FDA agrees that ``adverse reaction'' is a more 
appropriate term and that it is more consistent with the other portions 
of the final rule. In the final rule, the term ``adverse reaction'' (as 
defined in Sec.  201.57(b)(7)) has replaced ``complication.'' 
Additionally, in the final rule FDA is requiring the inclusion of 
information regarding fetal adverse reactions in this section of 
labeling. Although the proposed rule only addressed adverse reactions 
(referred to there as ``complications'') in the neonate under what in 
the final rule is required in Sec.  201.57(c)(9)(i)(C), FDA concludes 
that information intended to inform prescribing decisions for pregnant 
women appropriately includes information on fetal adverse reactions as 
well as neonatal adverse reactions. FDA does not believe that there is 
a

[[Page 72088]]

principled distinction between the importance of such information with 
respect to the fetus and with respect to the neonate. The consistent 
location under ``Clinical Considerations'' of information about 
potential adverse reactions in the fetus as well as in the pregnant 
woman and the neonate, and about available interventions, will make the 
information in that subsection more useful, as well as easier to 
identify for prescribers and other health care providers. Accordingly, 
the final rule requires that if it is known or anticipated that 
maternal drug therapy increases the risk of an adverse reaction in the 
fetus or the neonate, the labeling must describe the adverse reaction, 
the potential severity and reversibility of the adverse reaction, and 
available intervention(s) for monitoring or mitigating the reaction.
    FDA disagrees with the suggestion that if an adverse reaction/
complication has been described in the ``Fetal Risk Summary,'' only a 
cross-reference to Sec.  201.57(c)(9)(i)(C) should be required to 
appear in Sec.  201.57(c)(9)(i)(D)(2)(iv). As discussed in the draft 
guidance on pregnancy and lactation labeling, which is being published 
concurrently with the final rule, the ``Clinical Considerations'' 
portion of the labeling is intended to describe fetal/neonatal adverse 
reactions that are not adverse developmental outcomes. Therefore, 
because the two portions of the labeling address different potential 
reactions/outcomes, a cross-reference would not be appropriate.
    Additionally, in the final rule, FDA added the requirement that the 
labeling must describe, if known, the effect of dose, timing, and 
duration of exposure on the risk of an adverse reaction in the fetus or 
neonate as FDA has concluded that this information is important for 
informing prescribing decisions.
    Drug effects during labor or delivery. FDA proposed that the 
``Clinical Considerations'' portion of pregnancy labeling contain 
information about drug effects during labor or delivery for drugs that 
have a recognized use during labor or delivery, whether or not the use 
is stated as an indication in the labeling, or are expected to affect 
labor or delivery (proposed Sec.  201.57(c)(9)(i)(D)(3)).
    (Comment 62) One comment supported the proposal to merge 
information about labor and delivery into the ``Pregnancy'' subsection 
of labeling.
    Another comment expressed concern that including information about 
drugs used during labor or delivery, including drugs that are used off-
label during labor or delivery, conflicts with FDA's long-standing 
position that off-label information is not to be included in labeling.
    (Response) We note that, as stated in the proposed rule (73 FR 
30831 at 30844), the language proposed for this heading contained only 
slight modifications from that in existing Sec.  201.57(c)(9)(ii). 
However, because important safety information, whether for an approved 
or unapproved use, may be required to be included in labeling (see, 
e.g., Sec.  201.57(c)(6)(i)), we concluded that it is not necessary to 
include specific language regarding this issue. Therefore, FDA has 
removed the language regarding ``drugs that have a recognized use 
during labor or delivery, whether or not the use is stated as an 
indication in the labeling.'' In the final rule, FDA revised the 
heading ``Drug effects during labor or delivery'' to ``Labor or 
delivery,'' which is consistent with the level of specificity used in 
the other headings under ``Clinical Considerations.''
    v. Data.
    FDA proposed that the following information be included in the 
``Pregnancy'' subsection of labeling under the subheading ``Data'':
    (1) Under the subheading ``Data,'' the ``Pregnancy'' subsection of 
the labeling must provide an overview of the data that were the basis 
for the fetal risk summary.
    (2) Human and animal data must be presented separately, and human 
data must be presented first.
    (3) The labeling must describe the studies, including study type(s) 
(e.g., controlled clinical or nonclinical, ongoing or completed 
pregnancy exposure registries, other epidemiological or surveillance 
studies), animal species used, exposure information (e.g., dose, 
duration, timing), if known, and the nature of any identified fetal 
developmental abnormalities or other adverse effect(s). Animal doses 
must be described in terms of human dose equivalents and the basis for 
those calculations must be included.
    (4) For human data, positive and negative experiences during 
pregnancy, including developmental abnormalities, must be described. To 
the extent applicable, the description must include the number of 
subjects and the duration of the study.
    (5) For animal data, the relationship of the exposure and mechanism 
of action in the animal species to the anticipated exposure and 
mechanism of action in humans must be described. If this relationship 
is not known, that should be stated (proposed Sec.  
201.57(c)(9)(i)(E)).
    FDA received comments about the information required under ``Data'' 
in the proposed rule and made some changes to the final rule. The 
following discussion addresses these comments, our responses, and the 
changes to the final rule.
    (Comment 63) References. One comment suggested that under ``Data,'' 
the labeling should include references for the cited data. The comment 
explained that including references for the data would allow clinicians 
and other health care workers to further research pregnancy issues.
    (Response) We decline this suggestion. FDA has determined that 
prescription drug labeling is intended to facilitate prescribing 
decisions and is not intended as a research tool. We also note that 
this final rule is a part of labeling regulations, found at Sec.  
201.57, which address the inclusion of references in prescription drug 
labeling (see Sec.  201.57(c)(16)).
    (Comment 64) Postmarketing reporting of adverse reactions. One 
comment stated that if specific numbers of adverse event reports are 
included in drug labeling, the labeling will need to be constantly 
updated. The comment suggested that the Agency instead consider using 
quantitative measures of frequency to produce a more stable label.
    (Response) FDA acknowledges that the inclusion in labeling of 
actual numbers of postmarketing reports for particular adverse 
reactions is often not appropriate. We agree that the number of 
postmarketing reports of adverse reactions changes over time and 
labeling may become rapidly outdated. In addition, postmarketing 
reports of adverse reactions generally do not establish an incidence or 
prevalence of a particular outcome or definitively demonstrate an 
association between prenatal exposure to the drug in question and the 
adverse developmental outcome. However, FDA also recognizes that there 
may be isolated situations in which reporting of adverse reactions 
corroborates other human data and, in these situations, it may be 
appropriate to list a specific number of cases with the date when the 
reporting was collected. FDA will consider whether the labeling for a 
drug product should include specific numbers of reports of adverse 
reactions on a case-by-case basis based on evaluating all available 
data and principles of epidemiology and data interpretation.
    In the final rule, FDA replaced the phrase ``provide an overview of 
the data'' with ``describe the data.'' FDA made this change to clarify 
our intention that under the subheading

[[Page 72089]]

``Data,'' the labeling must include a more detailed description of the 
data than might be understood from use of the term ``overview.'' In the 
final rule, FDA also added the requirement that under ``Data,'' the 
labeling describe the data that are the basis for the ``Clinical 
Considerations.'' The proposed rule stated that ``Data'' must describe 
the data that were the basis for the fetal risk summary, and did not 
address the data that were the basis for ``Clinical Considerations.'' 
FDA has determined that there is no principled reason to distinguish 
between the data under the fetal risk summary and that underlying 
``Clinical Considerations.'' Accordingly, the final rule requires that 
under the subheading ``Data,'' the labeling describe the data that are 
the basis for both the ``Risk Summary'' and ``Clinical 
Considerations.'' This subheading, therefore, is only required to the 
extent that there are data that are the basis for these two subheadings 
and the headings under them.
    FDA has also determined that the information in labeling would be 
clearer if human data and animal data appeared separately under 
applicable headings. In the final rule, FDA requires that human and 
animal data be presented separately under the headings ``Human Data'' 
and ``Animal Data.''
    In the final rule, FDA requires that for human data, the labeling 
must describe adverse developmental outcomes, adverse reactions, and 
other adverse effects. To the extent applicable, the labeling must 
describe the types of studies or reports, number of subjects and the 
duration of each study, exposure information, and limitations of the 
data. The final rule requires that both positive and negative study 
findings be included. The proposed rule listed various types of 
studies. These were removed from the final rule because we determined 
that it is more appropriate to discuss these elements in guidance.
    Animal data. FDA proposed that human and animal data must be 
presented separately, and human data must be presented first.
    (Comment 65) One comment suggested that FDA omit the requirement 
that human data must be presented first. The comment explained that the 
most robust data should be presented first regardless of whether it is 
animal or human data.
    (Response) FDA declines this suggestion. We have determined that to 
promote consistency and to meet readers' expectations that information 
will always be found in the same place, a fixed order of presentation 
must be maintained. Additionally, as discussed in the preamble to the 
proposed rule, the importance of human data in labeling was stressed by 
physicians who participated in focus group testing of the model 
labeling format and also by the FDA advisory committee that provided 
input on the proposed format (73 FR 30831 at 30841). FDA has determined 
that human data should always be presented first because human data are 
often the most relevant to prescribers, and animal data may not always 
be applicable to humans.
    FDA also proposed that animal doses must be described in terms of 
human dose equivalents and the basis for those calculations must be 
included.
    (Comment 66) Two comments suggested that the final rule remove the 
requirement to use ``administered dose'' as a comparator between animal 
and human data and to replace it with comparisons based on systemic 
exposure, if available. One of these comments explained that basing the 
comparison on systemic exposure will provide greater consistency within 
the labeling and will also provide a way to more easily make 
comparisons between drugs.
    (Response) FDA declines this suggestion to restrict the comparison 
to only those based on systemic exposure. We agree that comparisons 
based on systemic exposure could provide consistency within labeling 
and therefore the final rule requires that they must be included when 
data are available, but the data are not always available for such a 
comparison. FDA believes that including the human dose equivalent may 
be more meaningful information for health care providers, particularly 
in the absence of data to make comparisons based on systemic exposure, 
and as such, in the final rule, a comparison of the animal to human 
doses must be included using the data available.
    The proposed rule required that for animal data under the ``Data'' 
component the relationship of the exposure and mechanism of action in 
the animal species to the anticipated exposure and mechanism of action 
in humans be described. In the final rule, we removed this requirement 
because often this relationship is not known. The final rule requires 
that animal doses or exposures be described in terms of human dose or 
exposure equivalents, and that the basis for those calculations be 
included.
2. 8.2 Lactation
    FDA proposed that the ``Nursing mothers'' subsection of 
prescription drug labeling be replaced with the subsection 
``Lactation'' (proposed Sec. Sec.  201.56(d)(1) and 201.57(c)(9)(ii)). 
FDA proposed that the ``Lactation'' subsection of prescription drug 
labeling contain the following subheadings: ``Risk Summary,'' 
``Clinical Considerations,'' and ``Data'' (proposed Sec.  
201.57(c)(9)(ii)). FDA received many comments about the proposed 
``Lactation'' subsection and made changes to the final rule based on 
these comments. The discussion that follows addresses these comments, 
our responses, and the changes FDA made to the final rule.
    a. General comments.
    i. Support for ``Lactation'' subsection
    (Comment 67) FDA received many comments expressing support for the 
proposed ``Lactation'' subsection. One of these comments explained that 
it is essential for drug labeling ``to carry 'best science' information 
that enables clinicians to efficiently and thoroughly review what is 
known about the drug and any reported health effects to the breast-fed 
infant.'' The comment stated that the proposed rule would facilitate 
more efficient consideration of the data.
    (Response) We agree with these comments, and our final rule 
requires labeling to include a subsection on lactation with risk and 
benefit information related to breastfeeding and the breast-fed infant.
    ii. Drug alternatives
    (Comment 68) One comment suggested that a statement should be 
included that many drugs for which we may not have lactation data have 
a suitable alternative for which we do have data.
    (Response) We decline to adopt this comment. We do not believe it 
would be appropriate to include this type of statement in labeling. 
Because the comparative risks and benefits will vary among individual 
patients, a health care provider, in consultation with his or her 
patient, is in the best position to determine whether there is a 
``suitable alternative'' for a particular drug.
    iii. Validating data
    (Comment 69) One comment expressed concern about the potential for 
bias or omissions with respect to which data the sponsor includes and 
the risk statements the sponsor uses to characterize such data. The 
comment encouraged FDA to employ all reasonable means to validate the 
sponsor's collection, evaluation, and subsequent conclusions regarding 
lactation data.
    (Response) FDA agrees. FDA will review data available in literature 
and sponsor-submitted data used for developing the ``Lactation'' 
subsection of drug labeling. We note that this does not require a 
change to the final rule

[[Page 72090]]

because FDA's normal review process for prescription drug labeling 
includes validating the applicant's collection, evaluation, and 
subsequent conclusions regarding data.
    b. Risk summary
    i. ``Active metabolites''
    (Comment 70) Two comments suggested that FDA revise the ``Risk 
Summary'' so that it explicitly refers to active metabolites of the 
drug, in addition to the drug itself.
    (Response) FDA agrees with this comment. We also have determined 
that it is appropriate to include information about the effects of a 
drug and/or its active metabolite(s) not only in the ``Risk Summary,'' 
but under other subheadings in the ``Lactation'' subsection of 
labeling. Therefore, the final rule has been revised to refer 
explicitly to drugs and/or their active metabolites.
    ii. ``Compatible with breastfeeding''
    FDA proposed that under the subheading ``Risk Summary,'' if, as 
described under Sec.  201.57(c)(9)(ii)(A)(1) through (c)(9)(ii)(A)(3) 
of the section, the data demonstrate that the drug does not affect the 
quantity and/or quality of human milk and there is reasonable certainty 
either that the drug is not detectable in human milk or that the amount 
of drug consumed via breast milk will not adversely affect the breast-
fed child, the labeling must state: The use of (name of drug) is 
compatible with breastfeeding. After this statement (if applicable), 
the risk summary must summarize the drug's effect on milk production, 
what is known about the presence of the drug in human milk, and the 
effects on the breast-fed child (proposed Sec.  201.57(c)(9)(ii)(A)).
    (Comment 71) Two comments suggested that FDA eliminate the 
statement, ``The use of (name of drug) is compatible with 
breastfeeding'' from the ``Lactation'' subsection of the final rule. 
One of the comments explained that it will be difficult to determine 
whether a drug is compatible with breastfeeding with such definitive 
certainty, especially since the term ``compatible'' implies safety. 
Another comment suggested that in the final rule FDA should replace the 
statement ``compatible with breastfeeding'' with a standardized 
statement that ``sufficient'' human data exist to indicate that the 
drug does or does not adversely affect the breast-fed child, followed 
by a supportive narrative.
    (Response) FDA agrees that the term ``compatible'' is not clearly 
defined and implies that the use of a drug during lactation is 
``safe.'' No drug is completely safe even in a person who is not 
pregnant or breastfeeding. In addition to offering potential 
therapeutic benefit(s), all drugs have potential side effects and risks 
involved with their use. The balance between those benefits and risks 
is taken into account not just at the approval stage, but also helps 
direct diagnostic and treatment recommendations for a particular 
patient in a particular clinical scenario. Accordingly, in the final 
rule FDA removed the statement ``The use of (name of drug) is 
compatible with breastfeeding.''
    Breastfeeding offers significant health benefits to both the child 
and mother. Different drugs and/or their active metabolites pass into 
breast milk in different concentrations; they may or may not be orally 
bioavailable in the infant, and they may or may not result in 
significant adverse reactions in the short term or adverse outcomes in 
the long term. Often, all of the potential risks related to drug 
treatment during lactation are not known even though the benefits of 
breastfeeding are known and substantial.
    FDA declines the suggestion to include a standardized statement 
that ``sufficient'' human data exist to indicate that the drug does or 
does not adversely affect the breast-fed child, followed by a 
supportive narrative. However, the final rule requires that if the drug 
is absorbed systemically, the labeling must include, under ``Risk 
Summary,'' available information, if relevant, on the known or 
predicted effects on the breast-fed child from exposure to the drug 
and/or its active metabolite(s), including systemic and/or local 
adverse reactions. If the available information is sufficient to 
determine that use of the drug is contraindicated during breastfeeding, 
this significant information is required at the beginning of the ``Risk 
Summary.'' The ``Risk Summary'' must state when there are no data to 
assess the effects of the drug on the child.
    FDA also revised the final rule to require that if studies 
demonstrate the presence of the drug and/or its active metabolite(s) in 
human milk but the drug and/or its active metabolite(s) are not 
expected to be systemically bioavailable to the breast-fed child, then 
the ``Risk Summary'' must describe the disposition of the drug and/or 
its active metabolite(s). FDA added this requirement to the final rule 
to identify situations in which a drug and/or its active metabolite(s) 
are present in human milk but the breast-fed child does not have any 
systemic exposure because of degradation in the gastrointestinal tract.
    iii. Not systemically absorbed
    FDA proposed that if data demonstrate that a drug is not 
systemically absorbed, the fetal risk summary must contain only the 
following statement: (Name of drug) is not absorbed systemically from 
(part of body) and cannot be detected in the mother's blood. Therefore, 
detectable amounts of (name of drug) will not be present in milk. 
Breastfeeding is not expected to result in fetal exposure to the drug 
(proposed Sec.  201.57(c)(9)(ii)(A)).
    (Comment 72) One comment suggested that the statement be revised to 
focus on the route of administration rather than on the part of the 
body where the drug is administered. The comment also suggested that 
the language ``cannot be detected in blood'' could be omitted because 
it is redundant with ``not systemically absorbed.''
    (Response) FDA agrees with this comment and we removed the phrase 
``cannot be detected in blood'' from the final rule.
    We also agree with the suggestion to focus on the route of 
administration. FDA agrees that ``part of the body'' could be 
misconstrued and we have determined that the use of ``route of 
administration'' to describe how the drug enters the body is more 
consistent with labeling language that addresses dosing and 
administration. In the final rule, FDA has replaced ``part of the 
body'' with ``route of administration.''
    (Comment 73) Another comment suggested revising the language 
``systemically absorbed'' to ``has a systemic effect'' to include the 
action of biological products (vaccines) that are immune stimulants 
rather than chemicals that are absorbed.
    (Response) FDA declines the suggestion to change the language 
``systemically absorbed'' to ``has a systemic effect.'' The terms 
``systemically absorbed'' and ``absorbed systemically'' refer to the 
absorption of the drug or biological product from its site of 
administration into serum and/or other body tissues where the drug or 
biological product, including a vaccine, can reach its receptor or 
target cell and exert its pharmacological or immunological effect. A 
drug or biological product that is not systemically absorbed will not 
be excreted into human milk and, therefore, breastfeeding should not 
result in the child's exposure to the drug. In the final rule, FDA has 
deleted the sentence, ``Therefore, detectable amounts of (name of drug) 
will not be present in breast milk.'' The final rule also replaces the 
sentence, ``Breastfeeding is not expected to result in fetal exposure 
to the drug'' with

[[Page 72091]]

``breastfeeding is not expected to result in exposure of the child to 
(name of drug).''
    (Comment 74) Two comments noted that the term ``fetal'' was used 
improperly in this section of the proposed rule.
    (Response) FDA agrees and has removed the term ``fetal'' from the 
``Lactation'' subsection and replaced it with the term ``child.''
    iv. Presence of drug in human milk
    FDA proposed that under the heading ``Presence of drug in human 
milk'':
    (1) The risk summary must describe the presence of the drug in 
human milk in one of the following ways: The drug is not detectable in 
human milk; the drug has been detected in human milk; the drug is 
predicted to be present in human milk; the drug is not predicted to be 
present in human milk; or the data are insufficient to know or predict 
whether the drug is present in human milk;
    (2) If studies demonstrate that the drug is not detectable in human 
milk, the risk summary must state the limits of the assay used; and
    (3) If the drug has been detected in human milk, the risk summary 
must give the concentration detected in milk in reference to a stated 
maternal dose (or, if the drug has been labeled for pediatric use, in 
reference to the labeled pediatric dose), an estimate of the amount of 
the drug consumed daily by the infant based on an average daily milk 
consumption of 150 milliliters per kilogram of infant weight per day, 
and an estimate of the [percentage] of the maternal dose excreted in 
human milk (proposed Sec.  201.57(c)(9)(ii)(A)(2)(i)-
(c)(9)(ii)(A)(2)(iii)). We received comments about this portion of the 
``Lactation'' subsection of the proposed rule. The discussion that 
follows addresses these comments, our responses, and the changes FDA 
made to this portion of the ``Lactation'' subsection of the final rule.
    (Comment 75) Predicting whether drug is present in human milk. 
Several comments objected to the proposal that the ``Risk Summary'' 
state that the drug is ``predicted'' or ``not predicted'' to be present 
in human milk. One of these comments stated that avoiding predictions 
and relying instead on clinical data would better assist providers. Two 
comments suggested that the statements about whether the drug is 
predicted or not predicted to be present in human milk should be 
omitted because the other proposed descriptions effectively cover the 
range of potential options.
    (Response) FDA agrees that the terms ``predicted'' and ``not 
predicted'' should not be used in the ``Risk Summary,'' and that a 
description of available data, if relevant, on the presence of the drug 
and/or its active metabolite(s) in human milk should be used instead. 
In addition, FDA has determined that, in order to provide clarity in 
the ``Risk Summary,'' in situations where there are no data to assess 
whether the drug and/or its active metabolite(s) are present in human 
milk, the ``Risk Summary'' must so state.
    (Comment 76) Limits of the assay used. Two comments suggested 
omitting assay information if the presence of drug in milk is not 
detectable. The comments stated that assay information is overly 
technical and unfamiliar for many health care providers. In addition, 
the comments explained that it would be presumed that during its review 
of the data, the review division at FDA would consider the validity of 
studies, including the assay's reliability and sensitivity, before 
approving the inclusion in labeling of a statement that the drug is not 
detectable in human milk.
    (Response) FDA declines this comment. We have determined that the 
limit of the assay is critical to understanding the amount of the drug 
and/or its active metabolite(s) that may or may not be present in human 
milk. We also believe that most health care providers are capable of 
interpreting this data when presented in labeling and that health care 
providers are familiar with the importance of assay limits for all 
types of laboratory testing. In the final rule, FDA has retained the 
requirement from the proposed rule that if studies demonstrate that the 
drug and/or its active metabolite(s) are not detectable in human milk, 
the ``Risk Summary'' must state the limits of the assay used.
    (Comment 77) Concentration of the drug detected in human milk. Two 
comments expressed support for FDA's proposal that the ``Lactation'' 
subsection of prescription drug labeling provide the concentration of 
the drug detected in human milk in reference to a stated adult or 
labeled pediatric dose. One of these comments suggested that the 
labeling should also include the milligrams per kilogram received per 
day and the percentage of the weight-equivalent therapeutic dose 
administered to the mother. This comment requested that the doses be 
presented according to infant age ranges when possible. A separate 
comment suggested providing a calculation of the estimated infant daily 
dose consumed as compared to available pediatric dosing rather than to 
maternal dosing, but added that clinicians may have difficulty 
interpreting the calculations.
    One comment stated that the concentration of the drug detected in 
milk should not be made in reference to the maternal dose or the 
labeled pediatric dose. The comment explained that the concentration of 
a drug in milk may vary widely depending upon whether it reflects 
steady-state or a single dose, and could vary based on the timing 
between the ingestion of the drug and taking the sample. The comment 
suggested that an estimate of the amount of the drug consumed daily by 
the infant could be made in reference to the maximum maternal daily 
dose or the maximum labeled pediatric dose and that ``an estimate of 
the [percentage] of the maternal dose excreted in human milk'' could be 
omitted.
    One comment suggested that FDA standardize the approach to 
presenting drug concentrations in breast milk and stated that this 
would ensure that uniform data are presented by all manufacturers, 
allowing for easy comparisons between prescription products. The 
comment also suggested that FDA provide a guidance document 
highlighting the value of breast milk area under the curve (AUC) 
concentrations, explaining that providing standardized ways of 
calculating weight-normalized drug doses and average breast milk 
consumption could better guide manufacturers and help create a unified 
approach to describing drug concentrations in breast milk.
    (Response) FDA addresses these issues in the draft guidance for 
industry on ``Clinical Lactation Studies--Study Design, Data Analysis, 
and Recommendations for Labeling'' (February 2005) (the draft guidance 
on clinical lactation studies).
    FDA agrees that it would be helpful to clinicians to provide infant 
drug exposure dosing in milligrams per kilograms received per day so 
that a clinician may compare it to a labeled infant or pediatric dose 
if available. However, because of the technical considerations for 
calculating drug and/or active metabolite levels in milk, FDA is not 
requiring this in the final rule.
    FDA has determined that the actual or calculated infant daily dose 
must be compared to the labeled infant or pediatric dose, when 
available, and to the maternal dose when pediatric dosing is not 
available. When infant or pediatric dosing is available for a drug and 
pediatric pharmacokinetic data are available for a drug and/or its 
active metabolite(s), these data provide an effective way to estimate 
comparative exposure (and potentially comparative

[[Page 72092]]

safety) of a breast-fed child versus a child receiving a drug 
therapeutically.
    Although not required by the final rule, FDA agrees that data 
presented according to infant age groups could be useful given the 
changes in infant hepatic and renal function during the first few 
months of life, and infants' increasing ability with age to metabolize 
and clear drugs and/or their active metabolites. These data may not 
always be available, but when they are, their presentation stratified 
by age would be clinically relevant and should be included in labeling.
    (Comment 78) ``No data.'' One comment suggested removing the phrase 
``no data'' from the ``Risk Summary'' in the ``Lactation'' subsection, 
because there are rarely no data for a drug.
    (Response) FDA disagrees with the suggestion to remove the phrase 
``no data'' from the ``Risk Summary.'' Often, there are no lactation 
data (either human or animal) at the time of approval of NDAs and BLAs.
    v. Effects on milk production and quality
    FDA proposed that if the drug is absorbed systemically, the risk 
summary must describe the effect of the drug on the quality and 
quantity of milk, including milk composition, and the implications of 
these changes to the milk on the breast-fed child (proposed Sec.  
201.57(c)(9)(ii)(A)(1)).
    (Comment 79) Several comments stated that it is seldom feasible to 
adequately study the effects of a drug on the quality and quantity of 
breast milk, and this information should only be provided when 
available. One comment explained that to be scientifically valid, such 
evaluation requires a study before, during, and after drug exposure. 
This comment explained that further complicating factors are 
substantial inter- and intra-individual variation and small study 
sample size.
    One comment requested that FDA include information about the 
effects of the drug on the woman's milk supply and other issues that 
affect the process of breastfeeding. The comment stated that many women 
are advised against taking medications that affect milk supply while 
lactating but are not informed that this is the reason they should 
avoid these medications.
    (Response) Although FDA agrees that it is not always possible to 
determine the effects of a drug and/or its active metabolite(s) on milk 
production, we have determined that when the relevant data are 
available, this information must be included in the labeling. In the 
final rule, FDA requires that the ``Risk Summary'' describe the effects 
of the drug and/or its active metabolite(s) on milk production, and if 
there are no data to assess the effects of the drug and/or its active 
metabolite(s) on milk production, the ``Risk Summary'' must so state.
    With respect to milk quality and composition, there are currently 
no established standards or documented population variability for milk 
content. It is also not known how much change in various milk 
components would reduce the known benefits of breastfeeding relative to 
the risks of exposure to a drug and/or its active metabolite(s) through 
breast milk combined with any potential effects on milk composition and 
quality. Accordingly, in the final rule, FDA has removed the 
requirement that the ``Risk Summary'' describe the effect of the drug 
on the quality and composition of milk, and the implications of these 
changes to the milk on the breast-fed child.
vi. Sufficient Data
    (Comment 80) One comment noted that the proposed rule does not 
require sufficient data to reach conclusions in the ``Risk Summary'' in 
the ``Lactation'' subsection, and suggested that FDA discuss what 
constitutes sufficient data, as it does in the ``Pregnancy'' 
subsection.
    (Response) As discussed previously, many comments disagreed with 
FDA's proposed use of the term ``sufficient'' in the ``Pregnancy'' 
subsection of labeling. The comments stated that the term was not 
clearly defined in the proposed rule, and suggested that it would be 
difficult to apply the term consistently across drug labeling. Based on 
FDA's consideration of these comments, the final rule does not refer to 
``sufficient'' data in either the ``Pregnancy'' or the ``Lactation'' 
subsection.
vii. Risk and Benefit Statement
    (Comment 81) FDA received seven comments noting that the proposed 
``Lactation'' subsection did not require the inclusion in labeling of 
any information about the benefits of breastfeeding. Some of these 
comments recommended that FDA add such a statement to the final rule to 
prevent patients from unnecessarily foregoing or discontinuing 
breastfeeding.
    (Response) FDA acknowledges that the proposed rule did not require 
the inclusion of information about the benefits of breastfeeding. The 
Agency has determined that the inclusion in the ``Lactation'' 
subsection of labeling of a risk and benefit statement will provide a 
useful framework for health care providers to use when making 
prescribing decisions for lactating patients. In the final rule, FDA 
requires that for drugs absorbed systemically, unless breastfeeding is 
contraindicated during drug therapy, a statement that the developmental 
and health benefits of breastfeeding should be considered along with 
the mother's clinical need for the drug and any potential adverse 
effects on the breast-fed child from the drug or from the underlying 
maternal condition, must be included at the end of the ``Risk Summary'' 
in the ``Lactation'' subsection of labeling.
c. Clinical Considerations
    FDA proposed that under the subheading ``Clinical Considerations,'' 
the labeling must provide the following information to the extent it is 
available: (1) Information concerning ways to minimize the exposure of 
the breast-fed child to the drug, such as timing the dose relative to 
breastfeeding or pumping and discarding milk for a specified period; 
(2) information about potential drug effects in the breast-fed child 
that could be useful to caregivers, including recommendations for 
monitoring or responding to these effects; and (3) information about 
dosing adjustments during lactation. This information must also be 
included in the `Dosage and Administration' and `Clinical Pharmacology' 
sections (proposed Sec.  201.57(c)(9)(ii)(B)(1)-(c)(9)(ii)(B)(3)). FDA 
received comments about the proposed ``Clinical Considerations'' 
subheading. The discussion that follows addresses these comments, our 
responses, and FDA's changes to the final rule.
i. Other Therapies
    In the Proposed rule, FDA included sample labeling for several 
fictitious drugs. In the ``Clinical Considerations'' portion of the 
``Lactation'' subsection, the ALPHAZINE sample stated that ``Other 
medical therapies are available for treatment of maternal 
hypertension.''
    (Comment 82) Two comments disagreed with the inclusion of this 
statement. The comments explained that the statement is confusing 
because although no comparator data are presented, clinicians may infer 
that other drugs in the class are safe and effective.
    (Response) We note that the language to which these comments refer 
was included in sample labeling included with the proposed rule, and 
not in the proposed rule itself. FDA included sample labeling with the 
proposed rule to serve as examples of how to apply the requirements of 
the proposed rule in different scenarios. We note that the final rule 
does not include sample labeling. FDA agrees, however, that

[[Page 72093]]

statements such as, ``Other medical therapies are available for 
treatment of maternal hypertension,'' may be confusing, and should not 
be included in the ``Pregnancy'' or ``Lactation'' subsections of 
labeling.
ii. Minimizing Exposure to the Breast-Fed Child
    (Comment 83) General comments. Four comments disagreed with the 
proposal to include information regarding minimizing exposure of the 
breast-fed child in the ``Clinical Considerations'' portion of the 
``Lactation'' subsection. These comments explained that inclusion of 
this information could discourage women from breastfeeding even when 
there is no reason for concern. One comment noted that this information 
should only be included when there is information that breastfeeding 
should be withheld during drug therapy and the timing of pumping and 
discarding of breast milk can be provided. Alternatively, the comment 
suggested stating when information regarding the timing of pumping and 
discarding breast milk cannot be provided. Another comment noted that 
this information should not be obligatory when data suggest that there 
is not sufficient excretion of the drug in milk to cause concern for 
the infant. The comment explained that including this information when 
the ``Risk Summary'' and ``Data'' components have already stated that 
the drug is compatible with breastfeeding could give the false 
impression that the drug is unsafe for the child and may encourage 
women to discontinue breastfeeding. One comment noted that in cases 
when the drug disappears from breast milk with a known half-life, it is 
possible to minimize infant exposure by recommending dosing occur at 
certain times related to feeding.
    (Response) FDA notes that information concerning minimizing 
exposure to the breast-fed child must be provided only to the extent it 
is available and relevant. In addition, the final rule was revised to 
clarify that information concerning minimizing drug exposure in the 
breast-fed child must be included only if the drug and/or its active 
metabolite(s) are present in human milk in clinically relevant 
concentrations; the drug does not have an established safety profile in 
infants; and the drug is used either intermittently, in single doses, 
or for short courses of therapy. As discussed further in our response 
to Comment 84, the final rule also requires that, when applicable, the 
labeling describe ways to minimize a breast-fed child's oral intake of 
topical drugs applied to the breast or nipple skin.
    (Comment 84) Topical products. In the proposed rule, FDA did not 
provide for inclusion of data regarding topical drugs that are not 
absorbed systemically by the mother but that may transfer to infants 
during breastfeeding. One comment requested that FDA include a 
standardized statement in the ``Risk Summary'' about such drug 
products.
    (Response) Situations in which a topical pharmaceutical product can 
result in infant exposure without systemic absorption of the product 
into maternal serum are limited to topicals applied to the skin of the 
breast, especially that of the nipple and areola. For prescription drug 
products, these topicals would most likely include corticosteroids and 
anti-infectives. FDA acknowledges that the proposed rule did not 
accommodate a situation in which a drug product does not result in 
maternal systemic exposure but could result in infant systemic 
exposure. In response to this comment, FDA revised the ``Minimizing 
exposure'' portion of ``Clinical Considerations'' to accommodate the 
inclusion of information about such products. In the final rule, FDA 
added a requirement that, when applicable, the labeling must also 
describe ways to minimize a breast-fed child's oral intake of topical 
drugs applied to the breast or nipple skin.
iii. Drug Effects in the Breast-Fed Child and Monitoring for Adverse 
Reactions
    FDA proposed that the ``Clinical Considerations'' portion of the 
``Lactation'' subsection of prescription drug labeling include 
information about potential drug effects in the breast-fed child that 
could be useful to caregivers, including recommendations for monitoring 
or responding to these effects (proposed Sec.  201.57(c)(9)(ii)(B)(2)).
    (Comment 85) FDA received one comment about this portion of the 
proposed ``Clinical Considerations.'' The comment suggested that FDA 
omit the first part of this provision--''information about potential 
drug effects in the breast-fed child''--because this information 
duplicates the information required to appear in the ``Risk Summary'' 
under proposed Sec.  201.57(c)(9)(ii)(A)(3), ``Effects of drug on the 
breast-fed child.'' The comment also stated that the term 
``recommendations'' in the second part of this provision could 
interfere with the practice of medicine. The comment suggested the 
following language: ``Information about ways to monitor for, or respond 
to, potential drug effects in the breast-fed child that could be useful 
to caregivers.''
    (Response) FDA acknowledges that this portion of the proposed rule 
appeared to require information duplicative of information in the 
``Risk Summary.'' We removed the language, ``information about 
potential drug effects in the breast-fed child,'' from the ``Clinical 
Considerations'' portion of the ``Lactation'' subsection of the final 
rule. In the final rule, when relevant information is available about 
potential adverse effects in an infant due to exposure to the maternal 
drug and/or its active metabolite(s) through human milk, this 
information must be included in the ``Risk Summary.'' FDA also 
concluded that it was not necessary to characterize information about 
the potential effects of a drug and/or its active metabolite(s) on a 
breast-fed child as being useful to caregivers because, although 
caregivers sometimes read prescription drug labeling, it is not 
directed at them, and individual health care providers are in the best 
position to discuss with their patients information that may be useful 
for the patients to share with other caregivers. Therefore, the 
reference to information that may be useful to caregivers also has been 
removed.
    FDA acknowledges the comment concerning the use of the term 
``recommendations'' in the second part of this provision, and in the 
final rule has removed the term ``recommendations for monitoring'' and 
replaced it with ``available interventions for monitoring or 
mitigating.'' The final rule requires that under ``Clinical 
Considerations'' the labeling describe information about available 
interventions for monitoring or mitigating the adverse reactions 
described in the ``Risk Summary.'' We note that this language is 
consistent with the language in the ``Pregnancy'' subsection.
iv. Dose Adjustments
    (Comment 86) One comment stated that dose adjustment information 
should not be included in the ``Lactation'' subsection. The comment 
suggested that dosing information generally should be restricted to the 
``Dosage and Administration'' section of labeling.
    (Response) FDA agrees with the suggestion that we omit information 
about dose adjustments from the ``Lactation'' subsection of 
prescription drug labeling, although this decision is not based on a 
conclusion (as suggested in the comment) that dosing information 
generally should be restricted to the ``Dosage and Administration'' 
section of

[[Page 72094]]

labeling. FDA has determined that other than during the immediate 
postpartum period when a woman's physiology is reverting from a 
pregnant to a nonpregnant state, a lactating woman is unlikely to 
require dose adjustments for drugs. The physiological changes 
associated with lactation are unlikely to result in pharmacokinetic 
changes significant enough to warrant maternal dose adjustments. 
Therefore, FDA has determined that all available and relevant 
information about dose adjustments during pregnancy and the postpartum 
period must be included in the ``Pregnancy'' subsection of labeling. In 
the final rule, FDA has removed the requirement that information about 
dosing adjustments during lactation be included in the ``Lactation'' 
subsection of labeling.
d. Data
    FDA proposed that under the subheading `Data,' the `Lactation' 
subsection of the labeling must provide an overview of the data that 
are the basis for the risk summary and clinical considerations 
(proposed Sec.  201.57(c)(9)(ii)(C)). FDA received comments about this 
portion of the rule. One comment expressed support for presenting 
lactation data under ``Data'' when available. The other comments and 
changes we made in response to those comments are explained in this 
section of the document.
    (Comment 87) FDA received comments requesting that the Agency 
clarify when animal lactation data should be included in labeling. 
Several comments questioned the usefulness of animal lactation data in 
the absence of clinical data. One comment stated that extrapolation of 
animal data to humans may not be helpful without stating what is known 
about the correlation to humans.
    Several comments stated that only human data should be presented 
when it is available. Two comments requested that if, in cases where 
both human and animal data are available, FDA decides to retain the 
requirement that both kinds of data be presented, the ``Lactation'' 
subsection be revised to state that clinical data are to be presented 
before preclinical data.
    One comment requested additional clarification regarding the 
quantity and quality of animal data that would support inclusion of the 
data in labeling, and asked that FDA provide sample labeling for a drug 
for which only animal lactation data are available. Another comment 
suggested that the labeling state when there is an absence of available 
or sufficient human and/or animal data in the ``Lactation'' subsection.
    (Response) The preamble to the proposed rule did not include a 
discussion of animal lactation data, and the inclusion of animal 
lactation data was not addressed in the codified section of the 
proposed rule. In the final rule, under ``Risk Summary,'' FDA defines 
situations for which animal lactation data must and must not be 
included in the ``Lactation'' subsection. Animal lactation data can be 
helpful in predicting whether a drug and/or its active metabolite(s) 
will be present in human milk; however, because of species-specific 
differences in lactation physiology, animal lactation data typically do 
not reliably predict drug levels in human milk. FDA added a requirement 
to the final rule that when relevant human lactation data are 
available, animal data must not be included unless the animal model is 
specifically known to be predictive for humans. In addition, under 
``Risk Summary,'' ``Presence of drug in human milk,'' FDA clarified 
that if only animal lactation data are available, the ``Risk Summary'' 
must state only whether or not the drug and/or its active metabolite(s) 
were detected in animal milk and specify the animal species. Although 
animal data do not reliably predict whether a drug and/or its active 
metabolite(s) will be present in human milk, in the absence of human 
data, FDA determined that the fact that a drug and/or its active 
metabolite(s) were or were not detected in animal milk may nevertheless 
be useful in informing prescribing decisions.
    In the final rule, FDA revised the ``Data'' portion of the 
``Lactation'' subsection to require that the labeling ``describe the 
data that are the basis for the Risk Summary and Clinical 
Considerations'' and removed the requirement that the labeling 
``provide an overview of the data.'' FDA made this change to clarify 
that under ``Data,'' the labeling must include a more detailed 
description of the data than might be understood from use of the term 
``overview,'' as well as to maintain consistency between the ``Data'' 
portions of the ``Lactation'' and ``Pregnancy'' subsections. 
Furthermore, this subheading is only required to the extent that there 
are data that are the basis for the Risk Summary and Clinical 
Considerations subheadings, and the headings under them.
3. 8.3 Females and Males of Reproductive Potential
    In the final rule, FDA is adding a requirement that information 
regarding pregnancy testing, contraception, and infertility be 
relocated in labeling under subsection ``8.3 Females and Males of 
Reproductive Potential.'' FDA is adding this requirement to the final 
rule based on public comments regarding these issues, and based on the 
Agency's conclusion that this information should be presented in 
labeling in a consistent location. Subsection ``8.3 Females and Males 
of Reproductive Potential'' includes three subheadings, ``Pregnancy 
Testing,'' ``Contraception,'' and ``Infertility.'' Each subheading 
should only be included if it is applicable or if relevant information 
is available, and Section 8.3 should be omitted in its entirety if none 
of the subheadings are applicable. The comments are discussed in detail 
in our responses to Comments 88, 89, and 90.
    Information concerning pregnancy testing, contraception, and 
infertility is important for informing decisions made by patients, in 
consultation with their health care providers, regarding the use of 
prescription drugs before or during pregnancy. This information is in 
many ways inherently linked to the scientific and medical rationale 
underpinning the Pregnancy subsection of prescription drug labeling. 
However, in the course of developing this final rule, and in particular 
in evaluating comments 88, 89, and 90, FDA concluded that because there 
was no consistent placement in the labeling of information about 
pregnancy testing, contraception, and infertility, it was difficult for 
health care providers to find this important information. For example, 
clinical advice on infertility might be found with the discussion of 
animal data in the ``Nonclinical Toxicology'' section, in the ``Adverse 
Reactions'' section, or in the ``Warnings and Precautions'' section. 
Contraception and pregnancy testing recommendations for known or 
suspected teratogens might be found in the ``Pregnancy'' subsection or 
in the ``Warnings and Precautions'' section.
    (Comment 88) FDA received one comment suggesting that the new 
labeling explicitly state that a woman taking drugs with potential or 
known adverse effects on pregnancy outcomes should (1) consider using 
reliable contraception if she does not intend to become pregnant or (2) 
if she does intend to become pregnant, seek consultation with her 
health care provider to discuss medical management of her health 
condition before becoming pregnant, if possible.
    (Response) FDA agrees that when a drug has a potential or known 
adverse effect on pregnancy outcomes (e.g., is a known or suspected 
human teratogen), information regarding recommendations or requirements 
regarding contraception

[[Page 72095]]

use must be included in prescription drug labeling. In the final rule, 
FDA requires that when contraception is required or recommended before, 
during, or after drug therapy, this information must be included under 
the subheading ``Contraception'' in subsection ``8.3 Females and Males 
of Reproductive Potential.'' In addition, it may be appropriate to 
include in this subsection information concerning counseling females of 
reproductive potential about pregnancy planning.
    Furthermore, the concerns expressed in the comment regarding the 
inclusion of information about contraception use when taking a drug 
with potential or known adverse effects on pregnancy outcomes apply 
equally to information about pregnancy testing, particularly when a 
drug is a known or suspected human teratogen. Therefore, FDA has 
determined that information regarding recommendations or requirements 
concerning pregnancy testing before, during, or after drug therapy must 
also be included in prescription drug labeling. In the final rule, FDA 
requires that this information be included under the subheading 
``Pregnancy Testing'' in subsection ``8.3 Females and Males of 
Reproductive Potential.''
    (Comment 89) FDA received three comments noting that the 
``Pregnancy'' subsection of the proposed rule only addresses risks to 
the fetus when the drug is administered to a pregnant woman, and it 
does not address the potential for manifestations of developmental 
toxicity associated with fetal drug exposure from transfer of drug 
through semen to the maternal and fetal circulations. One of the three 
comments noted that the proposed rule does not address the potential 
for manifestations of developmental toxicity associated with exposure 
resulting from transfer through the semen or the need for male 
contraception when a compound is determined to have a predicted risk of 
developmental toxicity and the transfer of semen is unknown. This 
comment suggested that statements addressing this issue be added when 
the information is required for the product. One of the comments 
suggested that FDA add a section to the final rule that addresses 
prescribing information for male patients with a partner of 
reproductive potential or a pregnant partner. Another comment suggested 
that the risk conclusion statement specify whether it is based on 
maternal or paternal exposure when that information is available.
    (Response) FDA agrees that when relevant information is available, 
this information should be included in labeling. In the final rule, FDA 
requires that information about recommended or required use of 
contraception by men be included under the subheading ``Contraception'' 
in subsection ``8.3 Females and Males of Reproductive Potential.''
    (Comment 90) FDA received one comment requesting that the Agency 
clarify how and when animal data described in subsection 13.1 of 
labeling (``Carcinogenesis, Mutagenesis, Impairment of Fertility'') 
that raises concerns about mutagenesis, impairment of fertility, or 
pre-implantation loss should be included in subsection ``8.1 
Pregnancy.'' The comment also requested that FDA clarify when it would 
be appropriate to move information from subsection 13.1 to subsection 
8.1 or to cross-reference subsection 13.1 in subsection 8.1.
    (Response) As stated previously, FDA concluded that it is important 
to include information about drug-associated fertility effects in 
labeling in a consistent location and manner. In the final rule, animal 
data that raise concerns about drug-associated impairment of fertility 
and/or pre-implantation loss effects must be included under 
``Infertility'' in subsection ``8.3. Females and Males of Reproductive 
Potential.'' In addition, when there are contraception recommendations 
based on animal mutagenesis data, this information must be included in 
subsection 8.3 under the Contraception subheading. Because the same 
concerns about drug-associated fertility effects apply to human data, 
FDA has determined that human data that raise such concerns also must 
be included in the ``Infertility'' subsection. With respect to the 
question about cross-referencing, subsection 8.3 should cross-reference 
the applicable animal data included in subsection 13.1, consistent with 
FDA's cross-referencing regulations (e.g., Sec.  201.57(c)(1), 
(c)(6)(iv), and (c)(15)(ii)). The draft guidance on pregnancy and 
lactation labeling, which is being published concurrently with this 
final rule, addresses these issues.

IV. Implementation

    FDA proposed that holders of applications (including an NDA, BLA, 
or efficacy supplement) approved before June 30, 2001, would be 
required to remove the pregnancy category from their labeling within 3 
years after the effective date of this rule. These applications are 
those that are not subject to the requirements of the PLR. For drugs 
with applications (including an NDA, BLA, or efficacy supplement) 
approved on or after June 30, 2001, FDA proposed a phased-in 
implementation plan that would stagger the required dates these 
products would be required to replace the content and formatting of the 
pregnancy and lactation subsections of their labeling with the new 
content and formatting required by this rule. These applications are 
those that are subject to the requirements of the PLR.
    Table 1 contains the implementation plan that was included in the 
proposed rule. In table 1, ``Applications'' includes NDAs, BLAs, and 
efficacy supplements.

                      Table 1--Implementation Plan
------------------------------------------------------------------------
                                         Time by which labeling with new
Applications required to conform to new    pregnancy/lactation content
      pregnancy/lactation  content         must be submitted to FDA for
              requirements                           approval
------------------------------------------------------------------------
                       New or Pending Applications
------------------------------------------------------------------------
Applications submitted on or after the   Time of submission.
 effective date of the pregnancy final
 rule.
Applications pending on the effective    4 years after the effective
 date of the pregnancy final rule.        date of pregnancy final rule
                                          or at time of approval,
                                          whichever is later.
------------------------------------------------------------------------
      Approved Applications Subject to the Physician Labeling Rule
------------------------------------------------------------------------
Applications approved any time from      3 years after the effective
 June 30, 2001, up to and including       date of pregnancy final rule.
 June 29, 2002, and from June 30, 2005,
 up to and including June 29, 2007.
Applications approved any time from      4 years after the effective
 June 30, 2007, up to and including the   date of pregnancy final rule.
 effective date of the pregnancy final
 rule.

[[Page 72096]]

 
Applications approved from June 30,      5 years after the effective
 2002, up to and including June 29,       date of pregnancy final rule.
 2005.
------------------------------------------------------------------------

    (Comment 91) Two comments stated that the proposed implementation 
plan was confusing. One of these comments requested that FDA explain 
the rationale supporting the implementation schedule. Another comment 
stated the proposed phased-in approach for previously approved drugs 
may generate confusion. The comment explained that if drug labeling 
information and drug reference materials contain pregnancy information 
that is inconsistent between newly approved and previously approved 
drugs through a 3- to 5-year period, confusion may limit the 
understanding of the new labeling.
    Comments disagreed about whether the length of the implementation 
schedule was reasonable. One comment stated that the long 
implementation timeline will delay the delivery of complete 
information. Another comment stated that FDA should expedite the 
implementation schedule for licensed drugs that are necessary to 
maintain the health status of the mother and could harm the fetus if 
the mother is left untreated. This comment also suggested that the 
Agency should make supplemental information available in advance of the 
printed label. Another comment, however, expressed support for the 
proposal to give sponsors 3 years after the effective date of the rule 
to remove the pregnancy categories.
    (Response) The Agency has taken all of these comments into 
consideration, and has decided to maintain the implementation schedule 
that was published in the proposed rule. The implementation schedule 
follows the timetable used for implementation of the PLR and works to 
balance the anticipated workload for the review of labels. The purpose 
of having a staggered approach is to avoid overburdening both the 
Agency and industry. The implementation plan for the final rule (also 
referred to as the Pregnancy and Lactation Labeling Rule (PLLR)) is 
modeled from the implementation plan for the PLR and experience 
acquired from that plan. The PLLR implementation timeline also depends 
on the PLR implementation and the extent to which applications are 
subject to the PLR.
    (Comment 92) One comment expressed concern that under the proposed 
implementation schedule, the pregnancy categories will be removed from 
the labeling for some drugs before the new content required by the rule 
will be added to the labeling, and this could cause confusion among 
doctors and patients.
    (Response) We would like to clarify that a holder of an application 
that is not subject to the PLR, and thus, not subject to the new 
content and format requirements of this final rule, must remove the 
pregnancy category from its labeling within 3 years after the effective 
date of this rule. A holder of an application that is subject to the 
PLR and thus, subject to the new content and format requirements of 
this rule, is not required to remove the pregnancy category until such 
time that it is required to submit revised labeling with the new 
content and format, even if that occurs more than 3 years after the 
effective date of the final rule. FDA did not intend to suggest that 
application holders of previously approved applications subject to the 
PLR might, in some circumstances, be required to revise labeling twice 
as a part of implementation. Therefore, if a holder of an application 
is subject to the PLR, FDA does not anticipate that the pregnancy 
category will be removed from the labeling prior to submitting the 
revised labeling with the new content and format for that product under 
the PLLR implementation schedule. In conjunction with the publication 
of the final rule, the Agency is planning to launch an education 
campaign for all stakeholders, including health care providers and 
professional organizations, to ensure that they are well informed about 
the changes.

V. Legal Authority

A. Statutory Authority

    FDA is revising its regulations on the format and content of the 
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers'' 
subsections of the ``Use in Specific Populations'' section (under Sec.  
201.57) and the ``Precautions'' section (under Sec.  201.80) of the 
labeling for human prescription drugs (in addition to the list of 
headings and subheadings under Sec.  201.56(d)(1)).
    FDA's revisions to the content and format requirements for 
prescription drug labeling are authorized by the FD&C Act and by the 
PHS Act. Section 502(a) of the FD&C Act deems a drug to be misbranded 
if its labeling is false or misleading ``in any particular.'' Under 
section 201(n) of the FD&C Act (21 U.S.C. 321(n)), labeling is 
misleading if it fails to reveal facts that are material with respect 
to consequences that may result from the use of the drug under the 
conditions of use prescribed in the labeling or under customary or 
usual conditions of use. Section 502(f) of the FD&C Act deems a drug to 
be misbranded if its labeling lacks adequate directions for use and 
adequate warnings against use in those pathological conditions where 
its use may be dangerous to health, as well as adequate warnings 
against unsafe dosage or methods or duration of administration or 
application, in such manner and form, as are necessary for the 
protection of users. Section 502(j) of the FD&C Act deems a drug to be 
misbranded if it is dangerous to health when used in the dosage or 
manner, or with the frequency or duration, prescribed, recommended, or 
suggested in its labeling.
    In addition, the premarket approval provisions of the FD&C Act 
authorize FDA to require that prescription drug labeling provide the 
practitioner with adequate information to permit safe and effective use 
of the drug product. Under section 505 of the FD&C Act, FDA will 
approve an NDA only if the drug is shown to be both safe and effective 
for use under the conditions set forth in the drug's labeling. Section 
701(a) of the FD&C Act (21 U.S.C. 371(a)) authorizes FDA to issue 
regulations for the efficient enforcement of the FD&C Act.
    Under 21 CFR 314.125, FDA will not approve an NDA unless, among 
other things, there is adequate safety and effectiveness information 
for the labeled uses and the product labeling complies with the 
requirements of part 201. Under Sec.  201.100(d) of FDA's regulations, 
a prescription drug product must bear labeling that contains adequate 
information under which licensed practitioners can use the drug safely 
for their intended uses. This final rule amends the regulations 
specifying the format and content for such labeling.
    Section 351 of the PHS Act (42 U.S.C. 262) provides legal authority 
for the Agency to regulate the labeling and

[[Page 72097]]

shipment of biological products. Licenses for biological products are 
to be issued only upon a showing that they meet standards ``designed to 
insure the continued safety, purity, and potency of such products'' 
prescribed in regulations (section 351(d) of the PHS Act). The 
``potency'' of a biological product includes its effectiveness (21 CFR 
600.3(s)). Section 351(b) of the PHS Act prohibits false labeling of a 
biological product. FDA's regulations in part 201 apply to all 
prescription drug products, including biological products.

B. First Amendment

    FDA's requirements for the content and format of the ``Pregnancy'' 
and ``Lactation'' subsections of labeling for prescription drug 
products are constitutionally permissible because they are reasonably 
related to the government's interest in ensuring the safe and effective 
use of prescription drug products and because they do not impose 
unjustified or unduly burdensome disclosure requirements. In the PLR, 
FDA explained in greater depth why that rule passes muster under the 
First Amendment (see 71 FR 3922 at 3964, January 24, 2006). That 
analysis is equally applicable to this final rule, and we hereby adopt 
that discussion by reference.

VI. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Summary of Final Regulatory Impact Analysis

A. Introduction

    FDA has examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Public 
Law 104-4). Executive Orders 12866 and 13563 direct Agencies to assess 
all costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The Agency believes that this final rule is not a significant 
regulatory action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because our analysis suggests that some small 
prescription drug manufacturers and prescription drug repackagers and 
relabelers will incur costs that total more than 1 percent of their 
annual income in some years, the Agency finds that the final rule will 
have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $141 million, using the most current (2013) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
final rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The first regulations on the content and format of prescription 
drug labeling were established in 1979, including the requirement to 
assign drugs to one of five pregnancy categories. Over time, however, 
labeling became long, repetitive, and difficult to use. With the PLR in 
2006, the Agency began to apply modern principles of effective 
communication to improve the quality of prescription drug labeling. 
However, the PLR left the content of the ``Pregnancy,'' ``Labor and 
delivery,'' and ``Nursing mothers'' subsections of the ``Use in 
Specific Populations'' section untouched. This decision gave the Agency 
sufficient time to meet with experts and stakeholders to develop a 
regulatory framework that encourages applicants to prepare content that 
clearly communicates available information about prescription drug use 
during pregnancy and lactation, and in females and males of 
reproductive potential. With this final rule, the Agency specifically 
addresses the content and format of these subsections.

B. Summary of Costs and Benefits

    The final regulatory impact analysis of the final rule (Ref. 2) is 
available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm. Table 2 presents a summary of the 
annualized costs and benefits of the final rule over 10 years. With a 7 
percent discount rate, annualized costs equal about $9.5 million; with 
a 3 percent discount rate, annualized costs equal about $9.2 million.
    The final rule will require that applicants comply with new 
labeling content and format requirements for affected subsections for 
prescription drug and biological product labeling subject to the PLR 
under Sec.  201.57(c)(9) (PLR labeling) and will require that 
applicants remove the pregnancy category from all prescription drug and 
biological product labeling subject to Sec.  201.80(f)(6)(i) (non-PLR 
labeling). The ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing 
mothers'' subsections of the ``Use in Specific Populations'' section 
will be replaced by the ``Pregnancy,'' ``Lactation,'' and ``Females and 
Males of Reproductive Potential'' subsections. New information will be 
required to summarize the key information needed by health care 
providers treating females and males of reproductive potential. The 
information in these subsections will be presented in a narrative, 
following a standardized order and format with clear subheadings.
    The primary objectives of the final rule are to improve labeling by 
updating the content and format of these subsections of prescription 
drug product labeling, and to remove the pregnancy category system. The 
Agency concluded that following a standardized structure is essential 
for effective communication. The final rule is needed to ensure that 
these subsections contain the most up-to-date information available and 
provide prescribers with clinically relevant data that they can use in 
their decisionmaking processes. Consistent with the approach taken by 
the PLR, the Agency intends to provide applicants with clear guidance 
about the required content and format. Concurrent with the publication 
of this final rule, FDA is issuing a draft guidance for industry on 
``Pregnancy, Lactation, and Reproductive Potential: Labeling for Human 
Prescription Drug and Biological Products--Content and Format.''
    The level of effort needed to comply with the requirements of the 
final rule will depend on the type of labeling (PLR or non-PLR 
labeling) and the length of time the product has been marketed. 
Applicants and persons responsible for existing prescription drug and 
biological product labeling will incur one-time costs to revise 
existing labeling in years 3, 4, and 5. Applicants submitting new BLAs, 
NDAs, and certain efficacy supplements will incur one-time costs to 
gather and organize new content required by the final rule at the time 
they prepare labeling for the application or supplement. In addition, 
we estimate the additional annual printing costs for

[[Page 72098]]

longer PLR labeling that will include new content.
    We estimate that the total cost of the rule over 10 years will 
equal about $88.7 million. The present value of the total costs will 
equal $78.2 million with a 3 percent discount rate and $66.8 million 
with a 7 percent discount rate. Over 10 years, the annualized present 
value will equal $9.2 million with a 3 percent discount rate and $9.5 
million with a 7 percent discount rate.

                                             Table 2--Economic Data: Costs and Benefits Accounting Statement
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                               Units
                                                                                         ------------------------------------------------
                Category                      Primary      Low  estimate  High  estimate                                      Period           Notes
                                             estimate                                      Year  dollars  Discount  rate      covered
                                                                                                             (percent)        (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized..........................  ..............  ..............  ..............  ..............               7  ..............  ..............
    Monetized $millions/year............  ..............  ..............  ..............  ..............               3  ..............  ..............
    Annualized..........................  ..............  ..............  ..............  ..............               7  ..............  ..............
    Quantified..........................  ..............  ..............  ..............  ..............               3  ..............  ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Qualitative.........................  Improved quality of prescription drug labeling
                                                     for health care providers
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized..........................            $9.5  ..............  ..............            2011               7              10  ..............
    Monetized $millions/year............             9.2  ..............  ..............            2011               3              10  ..............
    Annualized..........................  ..............  ..............  ..............  ..............               7  ..............  ..............
    Quantified..........................  ..............  ..............  ..............  ..............               3  ..............  ..............
    Qualitative.........................  ..............  ..............  ..............  ..............  ..............  ..............  ..............
Transfers:
    Federal Annualized..................  ..............  ..............  ..............  ..............               7  ..............  ..............
    Monetized $millions/year............  ..............  ..............  ..............  ..............               3  ..............  ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To:                                  From:
                                          To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Other Annualized....................  ..............  ..............  ..............  ..............               7  ..............  ..............
    Monetized $millions/year............  ..............  ..............  ..............  ..............               3  ..............  ..............
--------------------------------------------------------------------------------------------------------------------------------------------------------
From/To:                                  From:
                                          To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
--------------------------------------------------------------------------------------------------------------------------------------------------------
    State, Local or Tribal Government: No effect
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Small Business: The final rule will have significant impacts on some small pharmaceutical manufacturers and prescription drug
     repackagers and relabelers.
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Wages: No effect
--------------------------------------------------------------------------------------------------------------------------------------------------------
    Growth: No effect
--------------------------------------------------------------------------------------------------------------------------------------------------------

VIII. Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and respondent description of the 
information collection provisions are shown in the following paragraphs 
with an estimate of the total reporting and disclosure burdens. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    Title: Content and Format of Labeling for Human Prescription Drug 
and Biological Products; Requirements for Pregnancy and Lactation 
Labeling
    Description: The final rule amends FDA regulations concerning the 
content and format of the ``Pregnancy,'' ``Labor and delivery,'' and 
``Nursing mothers'' subsections of the ``Use in Specific Populations'' 
section of the labeling for human prescription drugs. The final rule 
requires that labeling include, among other things, a summary of the 
risks of using a drug during pregnancy and lactation and a discussion 
of the data supporting that summary. The labeling also includes 
relevant information to help health care providers make prescribing 
decisions and counsel women about the use of drugs during pregnancy and 
lactation. The final rule eliminates the current pregnancy categories 
A, B, C, D, and X. In addition, the ``Labor and delivery'' subsection 
has been eliminated because information on labor and delivery is 
included in the ``Pregnancy'' subsection. The final rule also requires 
that the labeling include relevant information about pregnancy testing, 
contraception, and infertility for health care providers prescribing 
for females and males of reproductive potential. The final rule is 
intended to create a consistent format for providing information about 
the risks and benefits of prescription drug and/or biological product 
use during

[[Page 72099]]

pregnancy and lactation and by females and males of reproductive 
potential.
    Under Sec.  201.57(c)(9)(i) and (c)(9)(ii), holders of approved 
applications are required to provide new labeling content in a new 
format--that is, to rewrite the pregnancy and lactation portions of 
each drug's labeling. Under Sec.  201.57(c)(9)(iii), these application 
holders are also required to include a new subsection 8.3, ``Females 
and Males of Reproductive Potential,'' which requires that when 
pregnancy testing or contraception is required or recommended before, 
during, or after drug therapy or when there are human or animal data 
that suggest drug-associated fertility effects, this subsection must 
contain this information. These application holders are required to 
submit supplements requiring prior approval by FDA before distribution 
of the new labeling, as required in Sec.  314.70(b) or Sec.  
601.12(f)(1).
    Under Sec.  201.80(f)(6)(i), holders of approved applications are 
required to remove the pregnancy category designation (e.g., 
``Pregnancy Category C'') from the ``Pregnancy'' subsection of the 
``Precautions'' section of the labeling. These application holders must 
report the labeling change in their annual reports, as required in 
Sec.  314.70(d) or Sec.  601.12(f)(3).
    The new content and format requirements of the final rule apply to 
all applications that are required to comply with the PLR, including: 
(1) Applications submitted on or after the effective date of the final 
rule; (2) applications pending on the effective date of the final rule; 
and (3) applications approved from June 30, 2001, to the effective date 
of the final rule.
    The following submissions under the final rule are subject to the 
PRA:
     Applications submitted on or after the effective date of 
the final rule (Sec. Sec.  314.50, 314.70(b), 601.2, 601.12(f)(1));
     Amendments to applications pending on the effective date 
of the final rule (Sec. Sec.  314.60, 601.2, 601.12(f)(1));
     Supplements to applications approved from June 30, 2001, 
to the effective date of the final rule (Sec. Sec.  314.70(b), 
601.12(f)(1));
     Annual reports for applications approved before June 30, 
2001, that contain a pregnancy category, to report removal of the 
pregnancy category letter in their labeling (Sec. Sec.  314.70(d), 
601.12(f)(3)).
    The information collection requirements and burden estimates are 
summarized in tables 3 and 4 of this document. The burden estimates are 
based on data and timeframes used for section VII of this document 
(Summary of Final Regulatory Impact Analysis) and for the final 
regulatory impact analysis of the final rule (available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm). FDA estimates that approximately 4,000 applications 
containing labeling consistent with this rulemaking will be submitted 
to FDA during the 10-year period on or after the effective date of the 
final rule by approximately 390 applicants and repackagers and 
relabelers. The estimate of 4,000 applications includes labeling for 
approximately 800 applications submitted under section 505(b) of the 
FD&C Act or section 351 of the PHS Act, and 1,200 applications 
submitted under section 505(j) of the FD&C Act, and revised labeling 
from repackagers and relabelers for approximately 2,000 drug products. 
This estimate also includes labeling amendments submitted to FDA for 
applications pending on the effective date of the final rule. Based on 
data provided in section VII of this document and in the final 
regulatory impact analysis of the final rule, FDA estimates that for 
future approvals it will take applicants approximately 40 hours to 
prepare and submit labeling consistent with this rulemaking. The 
estimate of 40 hours applies only to the requirements of this 
rulemaking and does not indicate the total hours required to prepare 
and submit complete labeling for these applications. The information 
collection burden to prepare and submit labeling in accordance with 
Sec. Sec.  201.56, 201.57, and 201.80 is approved by OMB under control 
numbers 0910-0572 and 0910-0001.
    In addition, FDA estimates that approximately 10,150 supplements to 
applications approved from June 30, 2001, to the effective date of the 
final rule, or pending on the effective date, will be submitted to FDA 
during the third, fourth, and fifth years after the effective date to 
update labeling in accordance with this final rule. This estimate 
includes approximately 1,080 NDA, BLA, and efficacy supplements, 
approximately 1,320 ANDA supplements, and labeling supplements from 
repackagers and relabelers for approximately 7,750 drug products. FDA 
estimates that approximately 390 application holders and repackagers 
and relabelers will submit these supplements, and that it will take 
approximately 120 hours to prepare and submit each supplement.
    FDA also estimates that approximately 5,500 annual reports will be 
submitted to FDA during the third year after the effective date for 
applications approved before June 30, 2001, that contain a pregnancy 
category (5,500 includes annual reports for approximately 1,340 NDAs 
and BLAs and approximately 4,160 ANDAs containing labeling changes 
resulting from this rulemaking). FDA estimates that approximately 320 
application holders will submit these annual reports, and that it will 
take approximately 40 hours for each submission.
    As indicated in tables 3 and 4 of this document, we estimate that 
the total hours resulting from the information collection in this 
rulemaking will be approximately 1,598,000 hours. The costs associated 
with this rulemaking, including labor costs, are discussed in section 
VII of this document and in the final regulatory impact analysis of the 
final rule.
    Description of Respondents: Persons and businesses, including small 
businesses and manufacturers.

                                 Table 3--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                   Number of                          Average
  Type of submission  (21 CFR      Number of     responses per    Total annual      burden per     Total  hours
           section)               respondents     respondent        responses        response
----------------------------------------------------------------------------------------------------------------
Supplements to applications                390              26  10,150                       120       1,218,000
 approved 6/30/01 to effective                                   (Submitted 3rd,
 date (Sec.  Sec.   314.70(b),                                   4th, and 5th
 601.12(f)(1)).                                                  years after
                                                                 effective date).
Annual report submission of                320              17  5,500 (Submitted              40         220,000
 revised labeling for                                            3rd year after
 applications approved before                                    effective date).
 6/30/01 that contain a
 pregnancy category (Sec.
 Sec.   314.70(d),
 601.12(f)(3)).
                               ---------------------------------------------------------------------------------

[[Page 72100]]

 
    Total.....................  ..............  ..............  ................  ..............       1,438,000
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.


                                               Table 4--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                      Number of
       Type of submission (21 CFR section)           Number of     disclosures per       Total annual disclosures        Average burden    Total  hours
                                                    respondents       respondent                                         per disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
New NDAs/ANDAs/BLAs/efficacy supplements                     390               10   4,000 (Submitted during 10-year                 40          160,000
 submitted on or after effective date, including                                     period after effective date).
 amendments to applications pending on effective
 date (Sec.  Sec.   314.50, 314.60, 314.70(b),
 601.2, 601.12(f)(1)).
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this information collection.

    The information collection provisions of this final rule have been 
submitted to OMB for review, as required by section 3507(d) of the PRA. 
Prior to the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

IX. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that this final 
rule does not contain policies that have substantial direct effects on 
the States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the Agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the Executive order and, consequently, a 
federalism summary impact statement is not required.

X. References

    In addition to the references placed on display in the Division of 
Dockets Management for the proposed rule under Docket No. FDA-2006-N-
0515 (formerly Docket No. 2006N-0467), the following references are on 
display in the Division of Dockets Management under Docket No. FDA-
2006-N-0515 (formerly Docket No. 2006N-0467) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified all Web site addresses in this reference section, but we 
are not responsible for any subsequent changes to the Web sites after 
this document publishes in the Federal Register.)

1. Decision Partners, LLC, ``Evaluation of How Best to Communicate 
to Healthcare Providers about the Risks and Benefits of Prescription 
Drug Use for Pregnant and Nursing Women: A Mental Models Research 
Report,'' September 2009 (available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm).
2. Final Regulatory Impact Analysis for Docket No. FDA-2006-N-0515 
(formerly Docket No. 2006N-0467) (available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm 
and at http://www.regulations.gov).
3. U.S. Food and Drug Administration, ``Guidance for Industry, 
Warnings and Precautions, Contraindications, and Boxed Warning 
Sections of Labeling for Human Prescription Drug and Biological 
Products--Content and Format,'' 2011.
4. Kweder, S.L., ``Drugs and Biologics in Pregnancy and 
Breastfeeding: FDA in the 21st Century.'' Birth Defects Research 
Part A: Clinical and Molecular Teratology. 82(9):605-609, September 
2008.
5. Adam, M.P., J.E. Polifka, and J.M. Friedman, ``Evolving Knowledge 
of the Teratogenicity of Medications in Human Pregnancy.'' American 
Journal of Medical Genetics Part C: Seminars in Medical Genetics. 
157C(3):175-182, August 15, 2011.
6. Law, R., P. Bozzo, G. Koren, et al. ``FDA Pregnancy Risk 
Categories and the CPS. Do They Help or Are They a Hindrance?'' 
Canadian Family Physician. 56:239-241, March 2010.
7. U.S. Food and Drug Administration ``Guidance for industry, 
Establishing Pregnancy Exposure Registries,'' 2002.
8. U.S. Food and Drug Administration ``Guidance for Industry, 
Reproductive and Developmental Toxicities--Integrating Study Results 
to Assess Concerns,'' 2011.
9. Rynn, L., J. Cragan, and A. Correa, ``Update on Overall 
Prevalence of Major Birth Defects--Atlanta, Georgia, 1978-2005.'' 
Centers for Disease Control and Prevention Morbidity and Mortality 
Weekly Report. 57(01):1-5, January 11, 2008.
10. American College of Obstetricians and Gynecologists Frequently 
Asked Questions: Miscarriage and Molar Pregnancy, 2011 (available at 
http://www.acog.org/~/media/For%20Patients/
faq090.pdf?dmc=1&ts=20140130T1655496642).
11. U.S. Food and Drug Administration, ``Reviewer Guidance, 
Evaluating the Risks of Drug Exposure in Human Pregnancies,'' 2005.
12. U.S. Food and Drug Administration, ``Guidance for industry, 
Considerations for Developmental Toxicity Studies for Preventive and 
Therapeutic Vaccines for Infectious Disease Indications,'' 2006.
13. U.S. Food and Drug Administration, ``Guidance for industry, M3 
(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals and the 
International Conference on Harmonisation S5 (R2) Guideline: 
Detection of Toxicity to Reproduction for Medicinal Products and 
Toxicity to Male Fertility,'' 2010.
14. Tracy, T.S., et al. ``Temporal Changes in Drug Metabolism 
(CYP1A2, CYP2D6 and CYP3A Activity) During Pregnancy.'' American 
Journal of Obstetrics and Gynecology. 192(2):633-639, February 2005.
15. Anderson, G.D., ``Pregnancy-Induced Changes in 
Pharmacokinetics.'' Clinical Pharmacokinetics. 44(10):989-1008, 
2005.

[[Page 72101]]

16. American Academy of Pediatrics Policy Statement. ``Breastfeeding 
and the Use of Human Milk.'' Pediatrics. 129(3):e827-841, 2012.
17. Sachs, H.C. and Committee on Drugs. ``The Transfer of Drugs and 
Therapeutics Into Human Breast Milk: An Update on Selected Topics.'' 
Pediatrics. 132(3):e796-809, September 2013.
18. U.S. Food and Drug Administration, ``Draft Guidance for industry 
Clinical Lactation Studies--Study Design, Data Analysis, and 
Recommendations for Labeling,'' 2005.
19. Proposed Pregnancy and Lactation Labeling Rule (available at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm).
20. Public Comments on Proposed Pregnancy and Lactation Labeling 
Rule (available at http://www.regulations.gov/#!docketDetail;D=FDA-
2006-N-0515).

List of Subjects in 21 CFR Part 201

    Drugs, Labeling, Reporting and recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
201 is amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360, 
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.


Sec.  201.56  [Amended]

0
2. Amend Sec.  201.56 in paragraph (d)(1) by removing from the list of 
headings and subheadings the subheadings ``8.2 Labor and delivery'' and 
``8.3 Nursing mothers'' and adding in their places the subheadings 
``8.2 Lactation'' and ``8.3 Females and Males of Reproductive 
Potential'', respectively.
0
3. Amend Sec.  201.57 by revising paragraphs (c)(9)(i), (ii), and (iii) 
to read as follows:


Sec.  201.57  Specific requirements on content and format of labeling 
for human prescription drug and biological products described in Sec.  
201.56(b)(1).

* * * * *
    (c) * * *
    (9) * * *
    (i) 8.1 Pregnancy. This subsection of the labeling must contain the 
following information in the following order under the subheadings 
``Pregnancy Exposure Registry,'' ``Risk Summary,'' ``Clinical 
Considerations,'' and ``Data'':
    (A) Pregnancy exposure registry. If there is a scientifically 
acceptable pregnancy exposure registry for the drug, contact 
information needed to enroll in the registry or to obtain information 
about the registry must be provided following the statement: ``There is 
a pregnancy exposure registry that monitors pregnancy outcomes in women 
exposed to (name of drug) during pregnancy.''
    (B) Risk summary. The Risk Summary must contain risk statement(s) 
based on data from all relevant sources (human, animal, and/or 
pharmacologic) that describe, for the drug, the risk of adverse 
developmental outcomes (i.e., structural abnormalities, embryo-fetal 
and/or infant mortality, functional impairment, alterations to growth). 
When multiple data sources are available, the statements must be 
presented in the following order: Human, animal, pharmacologic. The 
source(s) of the data must be stated. The labeling must state the 
percentage range of live births in the United States with a major birth 
defect and the percentage range of pregnancies in the United States 
that end in miscarriage, regardless of drug exposure. If such 
information is available for the population(s) for which the drug is 
labeled, it must also be included. When use of a drug is 
contraindicated during pregnancy, this information must be stated first 
in the Risk Summary. When applicable, risk statements as described in 
paragraphs (c)(9)(i)(B)(1) and (2) of this section must include a 
cross-reference to additional details in the relevant portion of the 
``Data'' subheading in the ``Pregnancy'' subsection of the labeling. If 
data demonstrate that a drug is not systemically absorbed following a 
particular route of administration, the Risk Summary must contain only 
the following statement: ``(Name of drug) is not absorbed systemically 
following (route of administration), and maternal use is not expected 
to result in fetal exposure to the drug.''
    (1) Risk statement based on human data. When human data are 
available that establish the presence or absence of any adverse 
developmental outcome(s) associated with maternal use of the drug, the 
Risk Summary must summarize the specific developmental outcome(s); 
their incidence; and the effects of dose, duration of exposure, and 
gestational timing of exposure. If human data indicate that there is an 
increased risk for a specific adverse developmental outcome in infants 
born to women exposed to the drug during pregnancy, this risk must be 
quantitatively compared to the risk for the same outcome in infants 
born to women who were not exposed to the drug but who have the disease 
or condition for which the drug is indicated to be used. When risk 
information is not available for women with the disease or condition 
for which the drug is indicated, the risk for the specific outcome must 
be compared to the rate at which the outcome occurs in the general 
population. The Risk Summary must state when there are no human data or 
when available human data do not establish the presence or absence of 
drug-associated risk.
    (2) Risk statement based on animal data. When animal data are 
available, the Risk Summary must summarize the findings in animals and 
based on these findings, describe, for the drug, the potential risk of 
any adverse developmental outcome(s) in humans. This statement must 
include: The number and type(s) of species affected, timing of 
exposure, animal doses expressed in terms of human dose or exposure 
equivalents, and outcomes for pregnant animals and offspring. When 
animal studies do not meet current standards for nonclinical 
developmental toxicity studies, the Risk Summary must so state. When 
there are no animal data, the Risk Summary must so state.
    (3) Risk statement based on pharmacology. When the drug has a well-
understood mechanism of action that may result in adverse developmental 
outcome(s), the Risk Summary must explain the mechanism of action and 
the potential associated risks.
    (C) Clinical considerations. Under the subheading ``Clinical 
Considerations,'' the labeling must provide relevant information, to 
the extent it is available, under the headings ``Disease-associated 
maternal and/or embryo/fetal risk,'' ``Dose adjustments during 
pregnancy and the postpartum period,'' ``Maternal adverse reactions,'' 
``Fetal/Neonatal adverse reactions,'' and ``Labor or delivery'':
    (1) Disease-associated maternal and/or embryo/fetal risk. If there 
is a serious known or potential risk to the pregnant woman and/or the 
embryo/fetus associated with the disease or condition for which the 
drug is indicated to be used, the labeling must describe the risk.
    (2) Dose adjustments during pregnancy and the postpartum period. If 
there are pharmacokinetic data that support dose adjustment(s) during 
pregnancy and the postpartum period, a summary of this information must 
be provided.
    (3) Maternal adverse reactions. If use of the drug is associated 
with a maternal adverse reaction that is unique to pregnancy or if a 
known adverse reaction occurs with increased frequency or severity in 
pregnant

[[Page 72102]]

women, the labeling must describe the adverse reaction and available 
intervention(s) for monitoring or mitigating the reaction. The labeling 
must describe, if known, the effect of dose, timing, and duration of 
exposure on the risk to the pregnant woman of experiencing the adverse 
reaction.
    (4) Fetal/Neonatal adverse reactions. If it is known or anticipated 
that treatment of the pregnant woman increases or may increase the risk 
of an adverse reaction in the fetus or neonate, the labeling must 
describe the adverse reaction, the potential severity and reversibility 
of the adverse reaction, and available intervention(s) for monitoring 
or mitigating the reaction. The labeling must describe, if known, the 
effect of dose, timing, and duration of exposure on the risk.
    (5) Labor or delivery. If the drug is expected to affect labor or 
delivery, the labeling must provide information about the effect of the 
drug on the pregnant woman and the fetus or neonate; the effect of the 
drug on the duration of labor and delivery; any increased risk of 
adverse reactions, including their potential severity and 
reversibility; and must provide information about available 
intervention(s) that can mitigate these effects and/or adverse 
reactions. The information described under this heading is not required 
for drugs approved for use only during labor and delivery.
    (D) Data--(1) ``Data'' subheading. Under the subheading ``Data,'' 
the labeling must describe the data that are the basis for the Risk 
Summary and Clinical Considerations.
    (2) Human and animal data headings. Human and animal data must be 
presented separately, beneath the headings ``Human Data'' and ``Animal 
Data,'' and human data must be presented first.
    (3) Description of human data. For human data, the labeling must 
describe adverse developmental outcomes, adverse reactions, and other 
adverse effects. To the extent applicable, the labeling must describe 
the types of studies or reports, number of subjects and the duration of 
each study, exposure information, and limitations of the data. Both 
positive and negative study findings must be included.
    (4) Description of animal data. For animal data, the labeling must 
describe the following: Types of studies, animal species, dose, 
duration and timing of exposure, study findings, presence or absence of 
maternal toxicity, and limitations of the data. Description of maternal 
and offspring findings must include dose-response and severity of 
adverse developmental outcomes. Animal doses or exposures must be 
described in terms of human dose or exposure equivalents and the basis 
for those calculations must be included.
    (ii) 8.2 Lactation. This subsection of the labeling must contain 
the following information in the following order under the subheadings 
``Risk Summary,'' ``Clinical Considerations,'' and ``Data'':
    (A) Risk summary. When relevant human and/or animal lactation data 
are available, the Risk Summary must include a cross-reference to the 
``Data'' subheading in the ``Lactation'' subsection of the labeling. 
When human data are available, animal data must not be included unless 
the animal model is specifically known to be predictive for humans. 
When use of a drug is contraindicated during breastfeeding, this 
information must be stated first in the Risk Summary.
    (1) Drug not absorbed systemically. If data demonstrate that the 
drug is not systemically absorbed by the mother, the Risk Summary must 
contain only the following statement: ``(Name of drug) is not absorbed 
systemically by the mother following (route of administration), and 
breastfeeding is not expected to result in exposure of the child to 
(name of drug).''
    (2) Drug absorbed systemically. If the drug is absorbed 
systemically, the Risk Summary must describe the following to the 
extent relevant information is available:
    (i) Presence of drug in human milk. The Risk Summary must state 
whether the drug and/or its active metabolite(s) are present in human 
milk. If there are no data to assess this, the Risk Summary must so 
state. If studies demonstrate that the drug and/or its active 
metabolite(s) are not detectable in human milk, the Risk Summary must 
state the limits of the assay used. If studies demonstrate the presence 
of the drug and/or its active metabolite(s) in human milk, the Risk 
Summary must state the concentration of the drug and/or its active 
metabolite(s) in human milk and the actual or estimated daily dose for 
an infant fed exclusively with human milk. The actual or estimated 
amount of the drug and/or its active metabolite(s) ingested by the 
infant must be compared to the labeled infant or pediatric dose, if 
available, or to the maternal dose. If studies demonstrate the presence 
of the drug and/or its active metabolite(s) in human milk but the drug 
and/or its active metabolite(s) are not expected to be systemically 
bioavailable to the breast-fed child, the Risk Summary must describe 
the disposition of the drug and/or its active metabolite(s). If only 
animal lactation data are available, the Risk Summary must state only 
whether or not the drug and/or its active metabolite(s) were detected 
in animal milk and specify the animal species.
    (ii) Effects of drug on the breast-fed child. The Risk Summary must 
include information, on the known or predicted effects on the child 
from exposure to the drug and/or its active metabolite(s) through human 
milk or from contact with breast or nipple skin (for topical products). 
The Risk Summary also must include information on systemic and/or local 
adverse reactions. If there are no data to assess the effects of the 
drug and/or its active metabolite(s) on the breast-fed child, the Risk 
Summary must so state.
    (iii) Effects of drug on milk production. The Risk Summary must 
describe the effects of the drug and/or its active metabolite(s) on 
milk production. If there are no data to assess the effects of the drug 
and/or its active metabolite(s) on milk production, the Risk Summary 
must so state.
    (3) Risk and benefit statement. For drugs absorbed systemically, 
unless breastfeeding is contraindicated during drug therapy, the 
following risk and benefit statement must appear at the end of the Risk 
Summary: ``The developmental and health benefits of breastfeeding 
should be considered along with the mother's clinical need for (name of 
drug) and any potential adverse effects on the breast-fed child from 
(name of drug) or from the underlying maternal condition.''
    (B) Clinical considerations. Under ``Clinical Considerations,'' the 
following information must be provided to the extent it is available 
and relevant:
    (1) Minimizing exposure. The labeling must describe ways to 
minimize exposure in the breast-fed child if: The drug and/or its 
active metabolite(s) are present in human milk in clinically relevant 
concentrations; the drug does not have an established safety profile in 
infants; and the drug is used either intermittently, in single doses, 
or for short courses of therapy. When applicable, the labeling must 
also describe ways to minimize a breast-fed child's oral intake of 
topical drugs applied to the breast or nipple skin.
    (2) Monitoring for adverse reactions. The labeling must describe 
available intervention(s) for monitoring or mitigating the adverse 
reaction(s) presented in the Risk Summary.
    (C) Data. Under the subheading ``Data,'' the labeling must describe 
the data that are the basis for the Risk Summary and Clinical 
Considerations.
    (iii) 8.3 Females and males of reproductive potential. When 
pregnancy

[[Page 72103]]

testing and/or contraception are required or recommended before, 
during, or after drug therapy and/or when there are human and/or animal 
data that suggest drug-associated fertility effects, this subsection of 
labeling must contain this information under the subheadings 
``Pregnancy Testing,'' ``Contraception,'' and ``Infertility,'' in that 
order.
* * * * *


Sec.  201.80  [Amended]

0
4. Amend Sec.  201.80 as follows:
0
a. Remove the paragraph heading ``Pregnancy category A.'' and the words 
``Pregnancy Category A.'' from paragraph (f)(6)(i)(a);
0
b. Remove the paragraph heading ``Pregnancy category B.'' and the words 
``Pregnancy Category B.'' both times they appear from paragraph 
(f)(6)(i)(b);
0
c. Remove the paragraph heading ``Pregnancy category C.'' and the words 
``Pregnancy Category C.'' both times they appear from paragraph 
(f)(6)(i)(c);
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d. Remove the paragraph heading ``Pregnancy category D.'' and the words 
``Pregnancy Category D.'' from paragraph (f)(6)(i)(d); and
0
e. Remove the paragraph heading ``Pregnancy category X.'' and the words 
``Pregnancy Category X.'' from paragraph (f)(6)(i)(e).

    Dated: November 25, 2014.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2014-28241 Filed 12-3-14; 8:45 am]
BILLING CODE 4164-01-P


