Department of Health and Human Services: Vol. 79 Thursday, No. 233 December 4, 2014

Vol.
79 Thursday,
No. 233 December 4, 2014
Part II
Department of Health and Human Services

Food and Drug Administration
21 CFR Part 201
Content and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation Labeling;
Pregnancy, Lactation, and Reproductive Potential: Labeling for Human
Prescription Drug and Biological ProductsContent and Format; Draft
Guidance for Industry; Availability; Final Rule and Notice
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72064 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations
DEPARTMENT OF HEALTH AND Drug Administration, 10903 New to the content and format requirements
HUMAN SERVICES Hampshire Ave., Bldg. 51, Rm. 6246, for prescription drug and biological
Silver Spring, MD 209930002, 301 product labeling are authorized by the
Food and Drug Administration 7963432; or Stephen Ripley, Center for Federal Food, Drug, and Cosmetic Act
Biologics Evaluation and Research, (the FD&C Act) and by the Public Health
21 CFR Part 201 Food and Drug Administration, 10903 Service Act (PHS Act).
[Docket No. FDA2006N0515 (formerly New Hampshire Ave., Bldg. 71, Rm. Summary of the Major Provisions of the
Docket No. 2006N0467)] 7301, Silver Spring, MD 209930002, Regulatory Action in Question
2404027911.
RIN 0910AF11
SUPPLEMENTARY INFORMATION:
The final rule requires that for the
labeling of certain drug products (as
Content and Format of Labeling for Table of Contents described in the Implementation
Human Prescription Drug and section of this document), the
Executive Summary
Biological Products; Requirements for subsections Pregnancy, Nursing
Purpose of the Regulatory Action
Pregnancy and Lactation Labeling Summary of the Major Provisions of the mothers, and Labor and delivery be
AGENCY: Food and Drug Administration, Regulatory Action in Question replaced by three subsections entitled
HHS. Costs and Benefits Pregnancy, Lactation, and
I. Background Females and Males of Reproductive
ACTION: Final rule. A. History of FDA-Approved Pregnancy Potential. The final rule also requires
and Lactation Labeling for Prescription the removal of the pregnancy categories
SUMMARY: The Food and Drug Drugs
Administration (FDA) is amending its A, B, C, D, and X from all drug product
B. Development of the Proposed Rule
regulations governing the content and C. The Proposed Rule
labeling.
format of the Pregnancy, Labor and D. Mental Models Research Pregnancy
delivery, and Nursing mothers II. Overview of the Final Rule Including
Significant Changes to the Proposed Rule The final rule merges the current
subsections of the Use in Specific
A. Overview Pregnancy and Labor and delivery
Populations section of the labeling for
B. Significant Changes to the Proposed subsections into a single Pregnancy
human prescription drug and biological
Rule subsection of labeling. If there is a
products. The final rule requires the
III. Comments on the Proposed Rule scientifically acceptable pregnancy
removal of the pregnancy categories A, A. Proposed Rule as a Whole exposure registry for the drug, the
B, C, D, and X from all human B. Specific Provisions of the Proposed Rule Pregnancy subsection must contain a
prescription drug and biological product IV. Implementation specified statement about the existence
labeling. For human prescription drug V. Legal Authority
of the registry, followed by contact
and biological products subject to the A. Statutory Authority
information needed to enroll or to
Agencys 2006 Physician Labeling Rule, B. First Amendment
VI. Environmental Impact obtain information about the registry.
the final rule requires that the labeling The Agency has concluded that
include a summary of the risks of using VII. Summary of Final Regulatory Impact
Analysis including information about pregnancy
a drug during pregnancy and lactation, exposure registries in prescription drug
A. Introduction
a discussion of the data supporting that B. Summary of Costs and Benefits labeling will encourage participation in
summary, and relevant information to VIII. Paperwork Reduction Act of 1995 registries, thereby improving data
help health care providers make IX. Federalism collection in pregnant women. Under
prescribing decisions and counsel X. References Pregnancy, the final rule also requires
women about the use of drugs during that the labeling include a summary of
pregnancy and lactation. The final rule Executive Summary
the risks of using a drug during
eliminates the Labor and delivery Purpose of the Regulatory Action pregnancy. If data demonstrate that a
subsection because information about FDA is amending its regulations drug is not absorbed systemically, the
labor and delivery is included in the governing the content and format of the Risk Summary must contain only a
Pregnancy subsection. The final rule Pregnancy, Labor and delivery, and specified statement regarding this fact. If
requires that the labeling include Nursing mothers subsections of the data demonstrate that the drug is
relevant information about pregnancy Use in Specific Populations section absorbed systemically, the Risk
testing, contraception, and infertility for (under 201.57 (21 CFR 201.57)) and Summary must include risk statements
health care providers prescribing for the Precautions section (under based on data from all relevant sources
females and males of reproductive 201.80 (21 CFR 201.80)) of the labeling (human, animal, and/or pharmacologic),
potential. The final rule creates a for human prescription drug and that describe, for the drug, the risk of
consistent format for providing biological products (both referred to as adverse developmental outcomes.
information about the risks and benefits drugs or drug products in this final The labeling must also contain
of prescription drug and/or biological rule). In this rulemaking, the Agency is relevant information, if it is available, to
product use during pregnancy and finalizing many of the provisions in the help health care providers make
lactation and by females and males of proposed rule issued on May 29, 2008 prescribing decisions and counsel
reproductive potential. These revisions (73 FR 30831). women about the use of the drug during
will facilitate prescriber counseling for This rulemaking is part of a broad pregnancy; this could include
these populations. effort by the Agency to improve the information on disease-associated
DATES: This rule is effective June 30, content and format of prescription drug maternal and/or embryo/fetal risk, dose
2015. See section IV of this document labeling. The final rule creates a adjustments during pregnancy and the
for the implementation dates of this consistent format for providing postpartum period, maternal adverse
final rule. information about the risks and benefits reactions, fetal/neonatal adverse
FOR FURTHER INFORMATION CONTACT: of drug use during pregnancy and reactions, and/or the effect of the drug
Kathy Schreier, Center for Drug lactation and by females and males of on labor or delivery. FDA believes that
Evaluation and Research, Food and reproductive potential. FDAs revisions including such information supports
Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72065
health care providers understanding of presented elsewhere in the labeling. In and convey the potential risks of drug
drug product risks and benefits and addition, the labeling must also include exposure based on animal or human
facilitates informed prescribing pertinent information about the data data, or both. FDA has determined that
decisions and patient counseling. The that are the basis for the risk summary retaining the pregnancy categories is
labeling must also describe the data that and clinical information included in the inconsistent with the need to accurately
are the basis for the risk statements and Lactation subsection of labeling. and consistently communicate
clinical information included in the Females and Males of Reproductive differences in degrees of fetal risk.
Pregnancy subsection of labeling. Potential Therefore, the final rule requires the
removal of the pregnancy categories A,
Lactation FDA determined that because there B, C, D, and X from all drug product
The final rule requires that the was no consistent placement in the labeling.
Lactation subsection of labeling labeling of information about pregnancy
testing, contraception, and infertility, it Costs and Benefits
contain a summary of the risks of using
a drug during lactation. If data was difficult for health care providers to
find this important information that can We estimate that over 10 years with
demonstrate that the drug is not a 7 percent discount rate, the present
absorbed systemically, this summary affect decisionmaking before or during
pregnancy. Thus, the final rule requires value of one-time costs of the rule equal
must contain only a specified statement $52.4 million and the present value of
regarding this fact. If data demonstrate that the Females and Males of
Reproductive Potential subsection the annual costs equal $14.4 million;
that the drug is absorbed systemically with a 3 percent discount rate, the
by the mother, this summary must include relevant information when
pregnancy testing or contraception is present value of one-time costs equal
include, to the extent it is available, $60.1 million and the present value of
required or recommended before,
relevant information on the presence of the annual costs equal $18.2 million.
during, or after drug therapy or when
the drug in human milk, effects of the The present value of the total costs
there are human or animal data that
drug on the breast-fed child, and effects equal $66.8 million with a 7 percent
suggest drug-associated fertility effects.
of the drug on milk production. For discount rate and $78.2 million with a
drugs absorbed systemically, a risk and Removal of Pregnancy Categories 3 percent discount rate. The annualized
benefit statement must appear at the end Through experience and stakeholder costs of the rule total $9.5 million with
of the summary of risks, unless feedback, FDA learned that the a 7 percent discount rate and $9.2
breastfeeding is contraindicated during pregnancy categories were confusing million with a 3 percent discount rate.
drug therapy. FDA has determined that and did not accurately and consistently The final rule will address issues raised
the inclusion of a risk and benefit communicate differences in degrees of by experts and stakeholders and
statement will provide a useful fetal risk. In addition, FDA learned that improve the quality of the affected
framework for health care providers to the pregnancy categories were heavily sections of prescription drug labeling.
use when making prescribing decisions relied upon by clinicians but were often Better quality prescribing information
for a lactating patient. misinterpreted and misused in that will enhance the usefulness of the
The Lactation subsection must also prescribing decisions were being made labeling. The public health benefits of
include, to the extent information is based on the pregnancy category, rather the final rule would result from
available, relevant information than an understanding of the underlying improved health outcomes. However,
concerning ways to minimize drug information that informed the because we have no information about
exposure in the breast-fed child in assignment of the pregnancy category. how improved labeling will affect
certain situations and concerning FDA believes that a narrative structure prescriber behavior and patient
available interventions for monitoring or for pregnancy labeling, rather than a outcomes, we are unable to quantify the
mitigating the adverse reactions category system, is best able to capture benefits of the final rule.
SUMMARY OF BENEFITS AND COSTS OF THE FINAL RULE

Total Total
annualized annualized
Present value Present value costs over 10 costs over 10
of total costs of total costs years with 3 years with 7
Total benefits with 3 percent with 7 percent percent percent
discount rate discount rate discount discount
($ mil) ($ mil) rate rate
($ mil) ($ mil)
Not estimated ................................................................................................... 78.2 66.8 9.2 9.5
I. Background broad effort by the Agency to improve products (both referred to as drugs or
the content and formatting of drug products in this final rule) are
In the Federal Register of May 29,
prescription drug labeling. accompanied by labeling (including
2008 (73 FR 30831), FDA issued a
prescribing information) that
proposed rule to amend the content and A. History of FDA-Approved Pregnancy
summarizes scientific information

format of the Pregnancy, Labor and and Lactation Labeling for Prescription
delivery, and Nursing mothers concerning their safe and effective use.
Drugs
subsections of the Use in Specific FDA regulations on labeling for use
Populations section of labeling for Under sections 502 and 505 of the during pregnancy, during labor and
human prescription drug and biological FD&C Act (21 U.S.C. 352 and 355), FDA delivery, and by nursing mothers were
products, which appear in 201.57. The has responsibility for ensuring that originally issued in 1979 as part of a
proposed rulemaking was part of a prescription drug and biological rule prescribing the content and format
for labeling for human prescription include information on the effects of the regarding the 1979 regulations
drugs (part 201 (21 CFR part 201)) (44 drug on, among other things, the mother governing labeling of drug products for
FR 37434, June 26, 1979) (the 1979 and the fetus, the duration of labor and use during pregnancy, during labor and
regulations).1 The requirements on delivery, and the effect of the drug on delivery, and while nursing (73 FR
content and format of labeling for drug the later growth, development, and 30831 at 3083230838).
products were revised on January 24, functional maturation of the child.
C. The Proposed Rule
2006, in the final rule on Requirements With regard to labeling on lactation,
on Content and Format of Labeling for the 1979 regulations required, at what FDA proposed to amend the content
Human Prescription Drug and Biological was redesignated in 2006 as and format of the Pregnancy, Labor
Products (71 FR 3922), commonly 201.57(c)(9)(iii) and 201.80(f)(8), that and delivery, and Nursing mothers
referred to as the Physician Labeling a Nursing mothers subsection be subsections of the Use in Specific
Rule (PLR).2 As part of the January included in the Precautions section of Populations section of physician
2006 revision, the subsections of the the labeling. The Nursing mothers labeling for prescription drug products
labeling on pregnancy, labor and subsection provided that if a drug was subject to 201.57. The Agencys
delivery, and nursing mothers were absorbed systemically, the labeling must proposed changes were intended to
moved from the Precautions section contain information about excretion of create a consistent format for providing
under 201.57 to the Use in Specific the drug in human milk and effects on information about the effects of a drug
Populations section. The content of the nursing infant, as well as a on pregnancy and lactation that would
these sections in part 201 was not description of any pertinent adverse be useful for decisionmaking by health
revised, but the sections were effects observed in animal offspring. care providers and their patients. With
redesignated as 201.57(c)(9)(i) through The Nursing mothers subsection respect to the Pregnancy, Labor and
(c)(9)(iii). The previous labeling required the use of certain standard delivery, and Nursing mothers
regulation (adopted in 1979) was statements depending on whether the subsections of the Precautions section
redesignated as 201.80, and applies to drug was known to be excreted in of prescription drug labeling for drug
products not affected by the January human milk and whether it was products subject to 201.80, the Agency
2006, revisions. In redesignated associated with serious adverse proposed only to remove the pregnancy
201.80, the subsections on pregnancy, reactions.4 category from the Pregnancy
labor and delivery, and nursing mothers subsection.
B. Development of the Proposed Rule
are 201.80(f)(6) through (f)(8). 1. Proposed Provisions for New and
The 1979 regulations provided, at Over a number of years after the 1979 Recently Approved Drugs
what was redesignated in 2006 as regulations were issued, FDA received
201.57(c)(9)(i) and 201.80(f)(6)(i), feedback on the issues and concerns FDA proposed the following format
that unless a drug was not absorbed with the Pregnancy, Labor and and content changes to the
systemically and was not known to have delivery, and Nursing mothers Pregnancy, Labor and delivery, and
a potential for indirect harm to a fetus, subsections of prescription drug Nursing mothers subsections of
a Pregnancy subsection must be labeling as defined by the 1979 prescription drug labeling for products
included within the Precautions regulations. In response to this subject to 201.57.
section of the labeling. The 1979 feedback, FDA held a part 15 public Merge the current Pregnancy and
regulations required that the hearing, conducted focus groups, and Labor and delivery subsections into a
Pregnancy subsection contain convened two advisory committees to single Pregnancy subsection
information on the drugs teratogenic provide expert input. During this designated 8.1 under the section 8 Use
effects and other effects on reproduction process, many stakeholders stated that in Specific Populations.
and pregnancy and, when available, a these subsections of prescription drug Rename the Nursing mothers
description of human studies with the labeling lacked clarity, often failed to subsection as Lactation designated
drug and data on its effects on later provide meaningful clinical information with the identifying number 8.2 under
growth, development, and functional about drug exposure during pregnancy the section 8 Use in Specific
maturation of the child. The 1979 and lactation, and did not address the Populations.
Reserve the identifying number 8.3
regulations also required that each potential maternal and fetal
for future use.
product be classified under one of five consequences of discontinuing needed Replace the format and content of
pregnancy categories (A, B, C, D, or X) maternal drug therapy during the Pregnancy subsection in its
on the basis of risk of reproductive and pregnancy. Experts and other entirety with the following:
developmental adverse effects or, for stakeholders noted that the pregnancy If there is a pregnancy exposure
certain categories, on the basis of such categories, although highly relied upon registry for the drug, the telephone
risk weighed against potential benefit.3 by health care providers, were often number or other information needed to
With regard to labor and delivery, the misinterpreted and misused. FDA also enroll in the registry or to obtain
1979 regulations stated, at what was sought input on the development of a information about the registry must be
redesignated in 2006 as 201.57(c)(9)(ii) model format for these subsections of included at the beginning of the
and 201.80(f)(7), that under certain labeling, and the resulting model served Pregnancy subsection of labeling.
circumstances, the labeling must as the basis for the May 29, 2008, Require the inclusion of a general
proposed rule (73 FR 30831). The statement about background risk,
1 Thus, the labeling for drugs originally approved
preamble to the proposed rule contains specifically All pregnancies have a
before 1979 may not contain the information a detailed discussion about the
required by those regulations regarding pregnancy, background risk of birth defect, loss, or
labor and delivery, and nursing mothers. background of the development of the other adverse outcome regardless of
2 FDAs regulations governing the content and proposed rule and additional details drug exposure. The fetal risk summary
format of labeling for human prescription drug and below describes (name of drug)s
biological products are contained in 201.56, 4 For further discussion of the history of both the
201.57, and 201.80. Pregnancy and the Nursing mothers
potential to increase the risk of
3 For further discussion of the pregnancy subsections of prescription drug labeling, see 73 FR developmental abnormalities above the
categories, see 73 FR 30831 at 30832 through 30833. 30831 at 30833. background risk.
Under the subheading Fetal Risk Require the fetal risk summary to the content requirements of Nursing
Summary, require the labeling to refer to the Contraindications and/or mothers in its entirety with the
contain a risk conclusion and a Warnings and Precautions sections of following:
narrative description of the risk(s) (if the the labeling if there is any information Require that the labeling of all
risk conclusion is based on human in those sections on an increased risk to drugs contain a Lactation subsection.
data). the fetus from exposure to the drug. Under the subheading Risk
Require the fetal risk summary to Require under the subheading Summary, if the data demonstrate that
characterize the likelihood that the drug Clinical Considerations the inclusion the drug does not affect the quantity
increases the risk of developmental of information about the known or and/or quality of human milk and there
abnormalities and other risks in predicted risks to the fetus from is reasonable certainty either that the
humans. inadvertent exposure to the drug, drug is not detectable in human milk or
Require that if data demonstrate including human or animal data on that the amount of drug consumed
that a drug is not systemically absorbed, dose, timing, and duration of exposure. through breast milk will not adversely
the fetal risk summary contain only the If there are no data to assess the risk affect the breast-fed child, the labeling
following statement: (Name of drug) is from inadvertent exposure, require the must state: The use of (name of drug) is
not absorbed systemically from (part of labeling to so state. compatible with breastfeeding. After
body) and cannot be detected in the Require under the subheading this statement (if applicable), the
blood. Maternal use is not expected to Clinical Considerations the inclusion labeling must summarize the drugs
result in fetal exposure to the drug. of information related to prescribing effect on milk production, what is
When both human and animal data decisions for pregnant women, known about the presence of the drug in
are available, require that risk including the risk, if known, to the human milk, and the effects on the
conclusions based on human data be pregnant woman and the fetus from the breast-fed child.
disease or condition the drug is The source(s) of the data (e.g.,
presented before risk conclusions based
indicated to treat and the potential human, animal, in vitro) that are the
on animal data. Require that a risk
influence of drug treatment on that risk; basis for the Risk Summary must be
conclusion based on human data be
information about dosing adjustments stated. When there are insufficient data
followed by a narrative description of
during pregnancy; if use of the drug is or no data to assess the drugs effect on
the risks.
associated with any maternal adverse milk production, the presence of the
When human data are sufficient to
reactions that are unique to pregnancy drug in human milk, and/or the effects
reasonably determine the likelihood that or if known adverse reactions occur on the breast-fed child, the Risk
the drug increases the risk of fetal with increased frequency or severity in Summary must so state.
developmental abnormalities or specific pregnant women, a description of such If the drug is not systemically
developmental abnormalities, require adverse reactions; if it is known or absorbed, require that the subheading
the labeling to contain one of two risk anticipated that treatment of the Risk Summary contain only the
conclusions: Human data do not pregnant woman will cause a following statement: (Name of drug) is
indicate that (name of drug) increases complication in the fetus or the neonate, not absorbed systemically from (part of
the risk of (type of developmental a description of the complication, the body) and cannot be detected in the
abnormality or specific developmental severity and reversibility of the mothers blood. Therefore, detectable
abnormality) or Human data indicate complication, and general types of amounts of (name of drug) will not be
that (name of drug) increases the risk of interventions, if any, that may be present in breast milk. Breastfeeding is
(type of developmental abnormality or needed. not expected to result in fetal exposure
specific developmental abnormality). If the drug has a recognized use to the drug.
When human data are available but during labor or delivery, whether or not If the drug is absorbed systemically,
not sufficient to reasonably determine that use is stated as an indication in the require the following under the
the drugs effects on fetal developmental labeling, or is expected to affect labor or subheading Risk Summary:
abnormalities, require the labeling to delivery, require the inclusion of D A description of the effects of the
characterize the likelihood that the drug available information about the effect of drugs impact on milk production,
increases the risk of developmental the drug on the mother; the fetus/ including the effect of the drug on the
abnormalities as low, moderate, or high. neonate; the duration of labor and quality and quantity of milk, including
Require that when the data on delivery; the possibility of milk composition, and the implications
which the risk conclusion is based are complications, including interventions, of these changes to the breast-fed child.
animal data, the fetal risk summary if any, that may be needed; and the later D A description of the presence of the
characterize the likelihood that the drug growth, development, and functional drug in human milk in one of the
increases the risk of developmental maturation of the child. following ways: (1) The drug is not
abnormalities using one of the following Require the inclusion of a Data detectable in human milk, (2) the drug
risk conclusions: Not predicted to subheading that, for human data, has been detected in human milk, (3)
increase the risk, low likelihood of describes positive and negative the drug is predicted to be present in
increased risk, moderate likelihood of experiences during pregnancy, human milk, (4) the drug is not
increased risk, high likelihood of including developmental abnormalities, predicted to be present in human milk,
increased risk, or insufficient animal and, to the extent applicable, the or (5) the data are insufficient to know
data on which to assess the likelihood number of subjects and duration of the or predict whether the drug is present
of increased risk. study. For animal data, require under in human milk.
When human data are available, the subheading Data a description of D Require that if studies demonstrate
require that in addition to the risk the relationship of the exposure and that the drug is not detectable in human
conclusion(s), the fetal risk summary be mechanism of action in the animal milk, the Risk Summary state the
followed by a brief narrative description species to the anticipated exposure and limits of the assay used.
of the risks of developmental mechanism of action in humans. D Require that if the drug has been
abnormalities as well as on other Replace the Nursing mothers detected in human milk, the Risk
relevant risks associated with the drug. subsection with Lactation and replace Summary give the concentration
detected in milk in reference to a stated D. Mental Models Research described in the Implementation
maternal dose (or, if the drug has been In a separate but related effort, FDA section of this document), the
labeled for pediatric use, in reference to contracted with a third party research subsections Pregnancy, Nursing
the pediatric dose), an estimate of the firm to conduct a Mental Models mothers, and Labor and delivery be
amount of the drug consumed daily by Research study in 2009 to better replaced by three subsections entitled
the infant based on an average daily understand the decisionmaking Pregnancy, Lactation, and
milk consumption of 150 milliliters per processes of health care providers Females and Males of Reproductive
kilogram of infant weight per day, and prescribing drugs to pregnant and Potential. Information previously
an estimate of the percentage of the lactating women with chronic placed in Labor and delivery is
maternal dose excreted in human milk. conditions (Ref. 1). Mental Models required to be included in the
D Require the inclusion of Research is an established risk analysis Pregnancy subsection of labeling. The
information about the likelihood and approach that evaluates, using a final rule requires Risk Summary
seriousness of known or predicted structured interview, decisionmaking subheadings in the Pregnancy and
effects on the breast-fed child from practices that require the synthesis of Lactation subsections of labeling. The
exposure to the drug in human milk complex issues. The specific objectives Pregnancy Exposure Registry
based on the pharmacologic and of this study, which involved interviews subheading under Pregnancy is only
toxicologic profile of the drug, the with 54 health care providers, were to required if there is such a registry. The
amount of drug detected or predicted to understand how health care providers Clinical Considerations and Data
be found in human milk, and age- used FDA-approved prescribing subheadings are required under
related differences in absorption, information (in the labeling format in
Pregnancy and under Lactation
distribution, metabolism, and place at the time of the study in 2009),
only to the extent relevant information
elimination. in order to determine the factors that
is available. If data demonstrate that the
influence their treatment decisions for
Under the subheading Clinical drug is systemically absorbed, the Risk
pregnant and lactating women with
Considerations, require the labeling to chronic conditions, and to define Summary in the Pregnancy
provide the following information to the measures that could be used to quantify subsection requires a statement
extent it is available: Information the value of prescribing information as regarding the background risk, in
concerning ways to minimize the a tool for these decision makers. addition to certain other information,
exposure of the breast-fed child to the The findings from the Mental Models and the Risk Summary in the
drug, such as timing the dose relative to Research were consistent with the Lactation subsection of labeling
breastfeeding or pumping and feedback the Agency received during its requires the inclusion of a risk and
discarding milk for a specified period; work on the proposed and final rules. benefit statement, unless breastfeeding
information about potential drug effects For example, the research showed that is contraindicated. The Females and
in the breast-fed child that could be the pregnancy categories were relied Males of Reproductive Potential
useful to caregivers, including upon by many health care providers subsection is not required if none of the
recommendations for monitoring or almost to the exclusion of other subheadings are applicable. However,
responding to these effects; information information found in the labeling. It also when pregnancy testing and/or
about dosing adjustments during showed that providers often relied on contraception is required or
lactation. secondary sources to find the pregnancy recommended before, during, or after
Require that the labeling include, category for a particular product rather drug therapy and/or when there are
under the subheading Data, an than using the products labeling. human and/or animal data that suggest
overview of the data that are the basis Interviewees made suggestions for drug-associated fertility effects, the
for the Risk Summary and Clinical improving prescribing information, Females and Males of Reproductive
Considerations. including simplifying the information Potential subsection requires the
presented, centralizing the relevant inclusion of such information under the
2. Pregnancy Categories and
information, and making the subheadings Pregnancy Testing,
Implementation
information included in labeling Contraception, and Infertility,
FDA proposed to require the new clinically relevant. respectively. The final rule also requires
content and format changes for II. Overview of the Final Rule, statements acknowledging when data on
prescription drug labeling for all Including Significant Changes to the various labeling elements either are not
applications (including new drug Proposed Rule available or do not establish the
applications (NDAs), biologics license presence or absence of drug-associated
applications (BLAs), or efficacy A. Overview
risk In addition, the final rule requires
supplements) required to comply with In this rulemaking, the Agency removal of pregnancy categories from all
the PLR, i.e., for drug products for finalizes many of the provisions in the drug product labeling, including those
which an application was approved on May 2008 proposed rule. In addition, products for which an application was
or after June 30, 2001. FDA proposed the final rule reflects revisions the approved before June 30, 2001.
that holders of applications approved Agency made in response to comments
before June 30, 2001 (i.e., applications on the May 2008 proposed rule. FDA B. Significant Changes to the Proposed
not subject to the PLR), would not be has also made editorial and Rule
required to implement the new content organizational changes to clarify
and format changes. Instead, if the provisions. For the purposes of this The final rule reflects revisions to the
labeling for such applications contains a rulemaking, the term drug or drug proposed rule in response to comments
pregnancy category, the application product is used to refer to human received on the proposed rule, as
holders would be required to remove prescription drugs and biological discussed in detail in section III of this
the pregnancy category designation by 3 products that are regulated as drugs. document. FDA made the following
years after the effective date of the final The final rule requires that for the organizational and content-based
rule. labeling of certain products (as changes to the proposed rule:
1. Pregnancy requirement that, if the drug is and the effects of dose, duration of
The final rule revises the proposed systemically absorbed, the labeling state exposure, and gestational timing of
rule to clarify that the Risk Summary the percentage range of live births in the exposure. The final rule also requires
subheading is always required in the United States with a major birth defect that if the human data indicate that
Pregnancy subsection of labeling. The and the percentage range of pregnancies there is an increased risk for a specific
subheading Pregnancy Exposure in the United States that end in adverse developmental outcome in
Registry is only required when such a miscarriage, regardless of drug infants born to women exposed to the
registry exists; the Clinical exposure. The final rule also requires drug during pregnancy, this risk must be
Considerations and Data that if such information is available for quantitatively compared to the risk for
subheadings are required when relevant the population(s) for which the drug is the same outcome in infants born to
information is available. If the Clinical labeled, it must also be included. women who were not exposed to the
Replaces the term developmental drug but who have the disease or
Considerations subheading is required,
abnormalities with the term adverse condition for which the drug is
the following headings under it are also
developmental outcomes. The final indicated to be used. When risk
required to the extent relevant
rule defines adverse developmental information is not available for women
information is available: Disease-
outcomes as structural abnormalities, with these condition(s), then the risk for
associated maternal and/or embryo/fetal
embryo-fetal and/or infant mortality, the specific outcome must be compared
risk, Dose adjustments during
functional impairment, and alterations to the rate at which the outcome occurs
pregnancy and the postpartum period,
to growth. in the general population.
Maternal adverse reactions, Fetal/
Clarifies that, when applicable, risk Requires that the Risk Summary
Neonatal adverse reactions, and Labor
statements must include a cross- must state when there are no human
or delivery. Similarly, if the Data
reference to additional details located data or when available human data do
subheading is required, the headings
under the Data subheading of not establish the presence or absence of
Human Data and Animal Data are
Pregnancy. drug-associated risk.
required under it to the extent relevant Revises the statement required
information is available. Eliminates the term other human
when a drug is not systemically data and the requirement that when
The final rule revises the proposed absorbed as follows:
Pregnancy Exposure Registry there are other human data, the
D Replaces the phrase from (part of likelihood that the drug increases the
subheading as follows: the body) with following (route of
Requires that contact information risk of developmental abnormalities
administration) to describe how the must be characterized as low, moderate,
and a standard statement on the drug enters the body.
pregnancy exposure registry will be or high.
D Replaces the phrase cannot be
included under its own subheading The Risk conclusions based on
detected in the blood with maternal
Pregnancy Exposure Registry if there animal data in the Risk Summary is
use is not expected to result in fetal
is a pregnancy registry that is revised as follows:
exposure to the drug.
scientifically acceptable. Adds a requirement that when use Replaces the term risk
Eliminates the phrase must be of the drug is contraindicated during conclusions with risk statement.
stated at the beginning of the pregnancy, this must be stated first in Eliminates the requirement that
Pregnancy subsection of the labeling. the Risk Summary. animal data be characterized as not
Revises the phrase telephone Requires that risk statements be predicted to increase the risk, low
number or other information needed to presented in the following order: Based likelihood of increased risk, moderate
enroll to contact information needed on human data, based on animal data, likelihood of increased risk, or high
to enroll. based on pharmacology. likelihood of increased risk.
Adds a requirement that the The Risk conclusions based on Requires that when animal data are
following statement be included in human data in the Risk Summary is available, the labeling must summarize
labeling before the contact information revised as follows: the findings in animals and based on
for the pregnancy exposure registry: Replaces the term risk these findings, describe, for the drug,
There is a pregnancy exposure registry conclusions with risk statement. the potential risk of any adverse
that monitors pregnancy outcomes in Eliminates the term sufficient developmental outcome(s) in humans.
women exposed to (name of drug) human data and the proposed rules The final rule requires that the risk
during pregnancy. requirement that the labeling contain statement include: The number and
The final rule revises the proposed one of the following standardized risk type(s) of species affected, the timing of
Fetal Risk Summary as follows: conclusions about sufficient human exposure, animal doses expressed in
Changes the title of the subheading data: Human data do not indicate that terms of human exposure or dose
Fetal Risk Summary to Risk (name of drug) increases the risk of equivalents, and outcomes for pregnant
Summary. (type of developmental abnormality or animals and offspring. When animal
Eliminates the requirement that the specific abnormality) and Human data studies do not meet current standards
following background risk statement be indicate that (name of drug) increases for nonclinical developmental toxicity
included in the labeling before the fetal the risk of (type of developmental studies, the labeling must so state. The
risk summary: All pregnancies have a abnormality or specific abnormality). final rule requires that when there are
background risk of birth defect, loss, or Replaces the standardized risk no animal data, the Risk Summary
other adverse outcome regardless of conclusions based on human data with must so state.
drug exposure. The fetal risk summary the requirement that when human data Adds a Risk statement based on
below describes (name of drug)s are available that establish the presence pharmacology to the Risk Summary,
potential to increase the risk of or absence of any adverse requiring that when the drug has a well-
developmental abnormalities above the developmental outcome(s) associated understood mechanism of action that
background risk. with maternal use of the drug, the Risk may result in drug-associated adverse
Replaces the proposed standardized Summary must summarize the specific developmental outcome(s), the Risk
background risk statement with the developmental outcome, its incidence, Summary must explain the mechanism
of action and the potential associated with increases or may increase the risk applicable, the types of studies or
risks. of an adverse reaction in the fetus or reports, number of subjects and duration
Eliminates the Narrative neonate. of each study, exposure information,
description of human data requirement Under Fetal/Neonatal adverse and limitations of the data. Requires
from the Risk Summary. reactions, replaces the severity and that both positive and negative study
Removes the requirement that the reversibility of the complication with findings be included.
Risk Summary refer to the the potential severity and reversibility For animal data, retains the
Contraindications or Warnings and of the adverse reaction, and replaces requirement that the labeling describe
Precautions sections of the labeling general types of interventions, if any, the types of studies, animal species,
when those sections contain that may be needed with available dose, duration and timing of exposure,
information on an increased risk to the intervention(s) for monitoring or and adds the requirement that the
fetus from exposure to the drug. mitigating the reaction. labeling also describe study findings,
The final rule revises the Clinical Under Fetal/Neonatal adverse presence or absence of maternal
Considerations component as follows: reactions, adds a requirement that the toxicity, and limitations of the data.
Requires headings, to the extent labeling must describe, if known, the Adds the requirement that the
relevant information is available, for effect of dose, timing, and duration of description of maternal and offspring
Disease-associated maternal and/or exposure on the risk. findings must include information on
embryo/fetal risk, Dose adjustments Revises the heading Drug effects the dose-response and severity of
during pregnancy and the postpartum during labor or delivery to Labor or adverse developmental outcomes.
period, Maternal adverse reactions, delivery. Requires that animal doses or exposures
Fetal/Neonatal adverse reactions, and Under Labor or delivery, revises be described in terms of human dose or
Labor or delivery. [i]f the drug has a recognized use exposure equivalents and that the basis
Eliminates the Inadvertent during labor or delivery, whether or not for those calculations must be included.
exposure during pregnancy heading. the use is stated as an indication in the
Eliminates the Prescribing labeling, or if the drug is expected to 2. Lactation
decisions for pregnant women heading. affect labor or delivery to [i]f the drug The final rule revises the Risk
Revises risk, if known, to the is expected to affect labor or delivery. Summary as follows:
pregnant woman and the fetus from the Under Labor or delivery, revises Requires that when relevant human
disease or condition the drug is the possibility of complications, or animal lactation data are available,
indicated to treat (which was the including interventions, if any, that may the Risk Summary must include a
language used in the proposed rule be needed to the increased risk of cross-reference to Data in the
under the Prescribing decisions for adverse reactions, including their Lactation subsection.
pregnant women heading) to serious potential severity and reversibility. Removes the proposed
known or potential risk to the pregnant Under Labor or delivery, adds a standardized statement The use of
woman and/or the embryo/fetus requirement that the labeling provide (name of drug) is compatible with
associated with the disease or condition information about available breastfeeding.
for which the drug is indicated to be intervention(s) that can mitigate effects Requires that when human data are
used and places this information under and/or adverse reactions. available, animal data must not be
the new heading Disease-associated Under Labor or delivery, clarifies included unless the animal model is
maternal and/or embryo/fetal risk. that the information described under specifically known to be predictive for
Under Dose adjustments during that heading is not required for drugs humans.
pregnancy and the postpartum period, approved only for use during labor and Requires that when use of a drug is
requires the inclusion of information delivery. contraindicated during breastfeeding,
about dose adjustments during Under Labor or delivery, this information must be stated first in
pregnancy and the postpartum period if eliminates the requirement that the the Risk Summary.
supported by pharmacokinetic data. labeling include information about the Revises the standardized statement
Under Dose adjustments during effect of the drug on the later growth, required when the drug is not absorbed
pregnancy and the postpartum period, development, and functional maturation systemically from (Name of drug) is not
removes the requirement that, if there of the child. absorbed systemically from (part of
are no data on dosing in pregnancy, the The final rule revises the Data body) and cannot be detected in the
labeling must so state. subheading of labeling as follows: mothers blood. Therefore, detectable
Under Maternal adverse Replaces provide an overview of amounts of (name of drug) will not be
reactions, replaces the proposed the data that were the basis for the fetal present in breast milk. Breastfeeding is
requirement that the labeling must risk summary with describe the data not expected to result in fetal exposure
describe any interventions that may be that are the basis for the Risk Summary to the drug to (Name of drug) is not
needed (e.g., monitoring blood glucose and Clinical Considerations. absorbed systemically by the mother
for a drug that causes hyperglycemia in Requires the inclusion of the following (route of administration) and
pregnancy) with the requirement that subheading Data, and the headings breastfeeding is not expected to result in
the labeling include a description of Human Data and Animal Data, to exposure of the child to (name of drug).
available intervention(s) for monitoring the extent available information is relied Revises the order of the types of
or mitigating the reaction. on in the Risk Summary and Clinical information required if the drug is
Adds a requirement that the Considerations subheadings. systemically absorbed as follows: (1)
labeling include relevant information Separates the requirements for Presence of drug in human milk, (2)
about fetal/neonatal adverse reactions human data from the requirements for effects of drug on the breast-fed child,
under the heading Fetal/Neonatal animal data. and (3) effects of drug on milk
adverse reactions. For human data, requires that the production.
Under Fetal/Neonatal adverse labeling describe adverse developmental Replaces proposed standardized
reactions, replaces the phrase will outcomes, adverse reactions, and other statements regarding the presence of the
cause a complication in the neonate adverse effects and, to the extent drug in human milk with a requirement
that the Risk Summary state whether Risk Summary must describe the recommended before, during, or after
the drug and/or its active metabolites effects of the drug and/or its active drug therapy and/or when there are
are present in human milk, and when metabolite(s) on milk production. human and/or animal data that suggest
there are no data to assess this, the D Adds a requirement that when there drug-associated fertility effects, this
Risk Summary must so state. are no data to assess the effects of the subsection of labeling must contain this
Under Presence of drug in human drug and/or its active metabolite(s) on information under the subheadings
milk, requires that if studies milk production, the Risk Summary Pregnancy Testing, Contraception,
demonstrate the presence of the drug must so state. and Infertility, in that order.
and/or its active metabolites in human The final rule adds the requirement
milk, the Risk Summary must state that for drugs absorbed systemically, III. Comments on the Proposed Rule
the concentration of the drug and/or its unless breastfeeding is contraindicated The Agency received 72 comments on
active metabolites in human milk and during drug therapy, the following risk the proposed rule. Comments were
the actual or estimated daily dose for an and benefit statement must appear at the received from prescription drug
infant fed exclusively with human milk. end of the Risk Summary: The manufacturers, trade organizations
The estimated amount of drug and/or its developmental and health benefits of representing prescription drug
active metabolites ingested by the infant breastfeeding should be considered manufacturers and other interested
must be compared to the labeled infant along with the mothers clinical need for parties, professional associations and
or pediatric dose, if available, or to the (name of drug) and any potential organizations representing health care
maternal dose. adverse effects on the breast-fed child providers, health care and consumer
Under Presence of drug in human from the drug or from the underlying advocacy organizations, individual
milk, retains the requirement that if maternal condition. physicians, pharmacists, consumers,
studies demonstrate that the drug and/ Under Clinical Considerations, and others.
or its active metabolite(s) are not the final rule: Most of the comments supported
detectable in human milk, the Risk Revises the provisions of the FDAs goal of improving the format and
Summary must state the limits of the proposed rule to require that the content of the Pregnancy, Labor and
assay used. labeling include information concerning delivery, and Nursing mothers
Under Presence of drug in human ways to minimize exposure to the drug subsections of prescription drug
milk, adds the requirement that if and/or its active metabolite(s) in the labeling, and several of these comments
studies demonstrate the presence of the breast-fed child in situations where the stated that the proposed rule would
drug and/or its active metabolite(s) in following conditions are present: The address shortcomings of the previous
human milk but the drug and/or its drug and/or its active metabolite(s) are labeling regulations. Other comments
active metabolite(s) are not expected to present in human milk in clinically noted that the proposed rule would
be systemically bioavailable to the relevant concentrations; do not have an improve the accessibility of relevant
breast-fed child, then the Risk established safety profile in infants; and information, thereby enabling better
Summary must describe the are used either intermittently, in single informed medical decisions regarding
disposition of the drug and/or its active doses, or for short courses of therapy. the risks and benefits of prescription
metabolites. Adds a requirement that, when drug use by pregnant and lactating
Adds a requirement that if only applicable, the labeling must describe women. Although a number of
animal lactation data are available, the ways to minimize a breast-fed childs comments supported all of FDAs
Risk Summary must state only oral intake of topical drugs applied to proposed revisions, many comments
whether or not the drug and/or its active the breast or nipple skin. opposed particular aspects of the
metabolite(s) were detected in animal Under Monitoring for adverse proposed rule.
milk and specify the animal species. reactions, replaces the proposed To make it easier to identify
Under Effects of drug on the requirement that the labeling include comments and our responses, the word
breast-fed child, the final rule: information about potential drug effects Comment and a comment number
D Adds a requirement that the Risk in the breast-fed child that could be appear in parentheses before each
Summary include available useful to caregivers, including comments description, and the word
information on the known or predicted recommendations for monitoring or Response in parentheses precedes
effects on the child from exposure to the responding to those effects, with a each response. Similar comments are
drug and/or its active metabolite(s) requirement that the labeling must grouped together under the same
through human milk or from contact describe available intervention(s) for number. Specific issues raised by the
with breast or nipple skin from a topical monitoring or mitigating the adverse comments and the Agencys responses
product. reaction(s) presented in the Risk follow.
D Requires the inclusion of Summary.
information about systemic and/or local Eliminates the proposed A. Proposed Rule as a Whole
adverse reactions. requirement that the labeling include 1. Plain Language and Intended
D Requires that the Risk Summary information about dosing adjustments Audience
state if there are no data to assess the during lactation.
effects of the drug and/or its active Under Data, the final rule (Comment 1) Several comments
metabolite(s) on the breast-fed child. replaces the phrase provide an suggested that the language used in the
Under Effects of drug on milk overview of the data with the phrase pregnancy and lactation subsections of
production, the final rule: describe the data. prescription drug labeling should be
D Replaces the proposed requirement clear and accessible to a variety of

that the Risk Summary describe the 3. Females and Males of Reproductive audiences. One comment stated that
effect of the drug on the quality and Potential because the intended audience for
quantity of milk, including milk Adds 8.3 Females and Males of prescription pregnancy and lactation
composition, and the implications of Reproductive Potential subsection labeling is females of reproductive
these changes to the milk on the breast- requiring that when pregnancy testing potential and their health care
fed child, with the requirement that the and/or contraception are required or providers, this portion of prescription
drug labeling should not include overly before June 30, 2001, although a in danger, and is often associated with
technical information. Another separate comment agreed with the greater risk to the developing fetus than
comment suggested that to make the proposal to limit the rule to drugs for the risk of exposure to a maternal drug.
information more accessible to the which an application was approved on FDA also declines the suggestion that
general public, FDA should include a or after June 30, 2001. One comment the content changes required by this
plain language summary of the suggested that the rule be expanded to final rule also apply to drugs for which
pregnancy and lactation subsections. include vaccine products (we discuss an application was approved before
Two comments suggested that because this suggestion later in our response to June 30, 2001. In developing this rule,
females of reproductive potential may Comment 8). Two other comments FDA considered the scientific,
read the Pregnancy and Lactation suggested that the rule provide economic, and practical implications of
subsections of labeling, FDA should incentives to industry to perform alternative approaches, including
include a statement that encourages studies on the use of drugs and requiring implementation of the content
patients to always consult a health care biological products during pregnancy and format requirements for the
provider before discontinuing and lactation. One comment suggested Pregnancy, Lactation, and
medication. Another comment that depression should not be treated Females and Males of Reproductive
questioned how patients would access pharmacologically during pregnancy, Potential subsections of labeling for all
the proposed information and asked whereas a separate comment suggested drugs, regardless of approval date. FDA
whether it would be included in that FDA ban the use of all drugs and concluded that requiring the content
patient-specific information that vaccines during pregnancy. Another and format changes only for drugs for
patients receive at the pharmacy. comment suggested that the which an application was approved on
Several other comments suggested that presentation of the information required or after June 30, 2001, (as described in
the final rule should aim to create user- under the rule be standardized as much the Implementation section of this
friendly labeling that contains a concise as possible with applicable coding document) best balanced the public
and accurate presentation of schema for ease of implementation in health benefits and the economic and
information that is of clinical relevance. databases or electronic health record other costs of these labeling changes. In
(Response) FDA acknowledges that systems. addition, this approach provides
some females of reproductive potential (Response) FDA has considered these conformity with the rest of prescription
may use prescribing information in the comments and declines to expand the drug labeling and the scope is consistent
Pregnancy and Lactation scope of the final rule in any of the with the scope of the PLR. FDA,
subsections of prescription drug suggested ways. This final rule amends however, encourages voluntary
labeling. The intended audience of our labeling regulations in 201.57 compliance with these content and
prescription drug labeling, however, is and 201.80, which apply only to format changes for drugs for which an
health care providers, and it is the prescription drug and biological application was approved before June
responsibility of the prescribing health products. It is therefore not within the 30, 2001.
care provider to communicate pertinent scope of this rulemaking to address
3. Combining the Pregnancy and
information regarding drug risks and pregnancy and lactation labeling for
Lactation Subsections
benefits and proper use to his or her nonprescription drug products.
patient. For this reason, we have The primary purpose of this final rule, (Comment 3) One comment suggested
determined that it is not appropriate to and prescription drug labeling in that the Pregnancy and Lactation
require a summary of the Pregnancy general, is to facilitate informed subsections should be combined for
and Lactation subsections of labeling prescribing and safe and effective certain drugs. The comment explained
as a mechanism for all patients to product use. FDA recognizes the that combining these sections would be
readily access full prescribing importance of use of labeling useful, for example, in helping health
information, or a statement that information in electronic health records care providers counsel women who take
encourages patients to always consult a and other databases and agrees that, if selective serotonin reuptake inhibitors
health care provider before possible, the presentation of information (SSRIs) for the treatment of perinatal
discontinuing medication. We note that in labeling should facilitate its depression because clinicians have to
in addition to the professional labeling accessibility. However, this final rule is consider the effects of the medication
that is the subject of this rulemaking, not designed to standardize the required during both pregnancy and the
some drugs also have FDA-approved information with a coding schema for postpartum period.
patient labeling specifically written for use in databases or electronic health (Response) FDA disagrees. The risk
the consumer, such as Medication record systems. It is also beyond the and benefit considerations for drug
Guides (see 21 CFR part 208). Whether scope of this rule to address incentives product use are different between
the information required under the final for collecting data on the use of drugs pregnant and lactating patients, and we
rule will be included in FDA-approved and biological products during have determined that the information is
patient labeling for an individual drug pregnancy and lactation. best presented in separate but adjacent
will be decided on a case-by-case basis FDA does not make recommendations subsections of labeling. FDA believes
in accordance with the applicable FDA about whether particular diseases or that if the sections were combined it
regulations and guidance. conditions should or should not be would be more difficult for a health care
treated pharmacologically, though we provider who has either a pregnant or a
2. Scope of the Rule specifically decline the suggestion to lactating patient to locate the
(Comment 2) Several comments ban the use of all drugs during information relevant to the prescribing
suggested that FDA expand the scope of pregnancy. We note that many diseases decision. For anticipatory counseling,
the rule in various ways. Two comments and conditions are associated with for which the health care provider is
suggested that the rule be expanded to adverse pregnancy outcomes when not discussing the use of the drug with a
include nonprescription products. Four appropriately managed during pregnant patient who in the future may
comments suggested that the proposed pregnancy, and under-treating or not be lactating, we believe that having
content changes also apply to drugs for treating a pregnant womans medical Lactation denoted in a separate,
which an application was approved condition may put the womans health numbered, indexed, and searchable
subsection of labeling will not make it (Response) The requirements for Office of New Drugs at the Center for
harder for a prescriber to find this labeling updates described in Drug Evaluation and Research, includes
information. 201.56(a) apply to this final rule as staff with expertise in obstetrics,
follows: The labeling must be lactation, pediatrics, clinical pharmacy,
4. Updates
informative and accurate and neither and regulatory science. The DPMH is
In the preamble to the proposed rule, promotional in tone nor false or available for consultation by all FDA
FDA stated that under 201.56(a) the misleading in any particular. In drug product review divisions to whom
labeling must be updated when new accordance with 314.70 and 601.12 of the final rule applies for all issues
information becomes available that the chapter, the labeling must be related to labeling content and for
causes the labeling to become updated when new information review of data on the use of drugs
inaccurate, false, or misleading (73 FR becomes available that causes the during pregnancy and lactation. The
30831 at 30841). The Agency also labeling to become inaccurate, false, or DPMH, by working across review
explained that [w]hen new human data misleading ( 201.56(a)(2)). With respect divisions, helps to ensure consistent
concerning the use of a drug during to the comment about updating labeling application of FDA pregnancy and
pregnancy becomes available, if that as human lactation data becomes lactation labeling regulations to
information is clinically relevant, FDA available, although 201.56(a)(3) states different drug products. The DPMH also
believes that it is necessary for the safe that the labeling must be based provides consultation services to and
and effective use of the drug and, whenever possible on data derived from works collaboratively with other Offices
therefore, the pregnancy subsection of human experience, it also requires that and Centers at FDA. FDA intends to
the labeling must be updated to include conclusions based on animal data but provide staff with education and
that information. Failure to include necessary for safe and effective use of training on the changes in the labeling
clinically relevant new information the drug in humans must be identified regulations.
about the use of a drug during as such and included with human data
pregnancy could cause the drugs in the appropriate section of the 6. Process for Development of the
labeling to become inaccurate, false, or labeling. Proposed Rule
misleading (73 FR 30831 at 30841). Because studies are not usually (Comment 6) One comment stated
(Comment 4) Several comments conducted in pregnant women prior to that FDA should have included
requested that FDA clarify its approval, most of the data regarding use pharmacists in the focus tests used
expectations for the process and timing in pregnancy and lactation will be during development of the proposed
of updating the Pregnancy and collected in the postmarketing setting. rule.
Lactation subsections of labeling after Accordingly, in order that a drug (Response) FDA acknowledges the
new data become available. Two of product does not become misbranded, critical role that pharmacists play in
these comments stated that the data the labeling must be updated when new communicating drug information both
should be updated regularly or information becomes available that to patients and health care providers.
continually. Another comment stated causes the labeling to become However, during the development of the
that the labeling should be updated inaccurate, false, or misleading. proposed rule, FDAs priority was to
annually. Several other comments Applicants are responsible for following understand the information health care
requested that FDA define the quantity the medical literature and also for providers need to most effectively make
and quality of data that necessitates that updating labeling as new published and prescribing decisions that consider both
the labeling be updated. One of these unpublished data become available. the risk and benefit to the mother and
comments suggested that FDA state in FDA declines the suggestion to include her fetus or child. Therefore, the focus
the final rule that the labeling should be references to online resources regarding testing was limited to health care
updated if the benefit-risk profile drug use during lactation because the providers who both care for and
changes because of new information, information has not been reviewed by prescribe for pregnant and lactating
and that labeling changes should be FDA. women.
done according to current labeling
regulations. Another comment 5. Responsibility for Drafting and 7. Guidance on Formulating Labeling
questioned whether health care Reviewing Labeling
(Comment 7) FDA received one
providers will be informed of changes to (Comment 5) One comment requested comment requesting that the Agency
the Pregnancy and Lactation that FDA clarify whether industry or provide clear guidance to manufacturers
subsections of labeling. One comment FDA would be responsible for writing regarding how to formulate the
suggested that sponsors electronically and reviewing the new labeling. The pregnancy and lactation labeling
post supplemental information before comment also questioned whether FDA subsections.
updated printed labeling is available, would provide staff with the training (Response) Concurrent with the
and another suggested using and expertise to make necessary publication of this final rule, FDA is
surveillance systems to facilitate judgments. Another comment expressed issuing a draft guidance for industry on
obtaining updated safety information. concern about the potential for Pregnancy, Lactation, and
Two comments expressed specific inconsistent implementation of the new Reproductive Potential: Labeling for
concern that the Lactation subsection rule by FDAs review divisions. This Human Prescription Drug and Biological
of drug labeling will not be updated comment suggested that to increase ProductsContent and Format (the
frequently enough to be useful for labeling consistency, the Agency should draft guidance on pregnancy and
clinicians. One of these comments establish a group of FDA specialists that
lactation labeling).5 The draft guidance

stated that it is critical to routinely review pregnancy and lactation labeling. is intended to assist applicants in
update labeling as human lactation data (Response) As with all prescription drafting the Pregnancy, Lactation,
becomes available. A separate comment drug labeling, both the manufacturer and Females and Males of
suggested including references in and FDA reviewers will play a shared Reproductive Potential subsections of
labeling to online resources regarding role in determining the new labeling
lactation data to provide prescribers and content. The Division of Pediatrics and 5 This guidance, when finalized, will represent
patients with updated information. Maternal Health (DPMH), within the FDAs current thinking on this topic.
labeling for prescription drug products. (Response) As discussed in further development. Labeling development is a
It provides recommendations for detail in section III.B of this document, detailed and iterative process unique to
applicants revising labeling of already in this final rule, FDA designates 8.3 as each prescription drug product, a
approved products and for applicants Females and Males of Reproductive process that is driven by the products
drafting labeling for new products that Potential. Accordingly, we are no characteristics and actions, the efficacy
will be submitted as part of an NDA or longer reserving 8.3 for future use. and safety data submitted to the Agency,
BLA. and the conditions and populations for
10. International Harmonization
and in which the product is intended to
8. Blood Products and Vaccines (Comment 10) Two comments be used. Accordingly, FDA has
(Comment 8) FDA received two suggested that prescription drug concluded that the development of
comments regarding the applicability of labeling should be consistent at an fictitious product labeling would not be
the proposed rule to certain biological international level to reduce confusion useful to drug developers or FDA
products. One comment requested that among health care providers, patients, reviewers who will be responsible for
the final rule be expanded to include and regulators interpreting the risks and developing, revising, and approving
vaccine products. The other comment benefits associated with drug use during product labeling under this new final
stated that blood products are not pregnancy and lactation. rule.
affected by the rule and requested that (Response) FDA declines to adopt this
this be noted when the final rule is suggestion because it is beyond the 12. Cross-Referencing
published. scope of this rule to address the FDA proposed that when the risk
(Response) This final rule applies to international harmonization of conclusion in the fetal risk summary is
vaccine products. Vaccine products are prescription drug labeling. Although we based solely on animal data, it must
prophylactic biological products that are acknowledge the importance of working include a cross-reference to the Data
developed and labeled to prevent with our international regulatory component of the Pregnancy
specific diseases in specific colleagues to harmonize drug subsection, and the effects found in
populations. The types of information development and drug regulatory animals must be described in the Data
that must be communicated about a science where appropriate and component (73 FR 30831 at 30842).
vaccine, in general, parallel the types of beneficial, we also recognize that there (Comment 12) One comment
information that must be communicated is great variation internationally in suggested that any cross-references to
about a drug or therapeutic biologic health care systems, access to care and the Data or Clinical Considerations
through labeling to facilitate safe and drugs, and the regulation and marketing components made anywhere in labeling
effective use, although there are some of drugs. The final rule reflects our specify whether the cross- reference is
unique considerations for vaccines judgment regarding the most useful to the component in the Pregnancy
addressed in the draft guidance on pregnancy and lactation prescription subsection or the component in the
pregnancy and lactation labeling, which drug labeling for prescribers in the Lactation subsection. Another
is being published concurrently with United States, which may not be comment explained that the rule would
this final rule. applicable to prescribers in all other benefit from extensive use of cross-
We disagree that blood products are countries. referencing within the text of each
not affected by the final rule. The final section to ensure that the bases for the
rule applies to any biological products, 11. Examples in an Appendix risk conclusions are thoroughly
including blood products, that are (Comment 11) The proposed rule understood, regardless of whether the
subject to the PLR. included an appendix containing risk conclusions are based on human or
examples, based on the proposed rule, animal data, for both the Pregnancy
9. Numbering of Pregnancy and
of pregnancy and lactation labeling for and Lactation subsections.
Lactation Subsections
fictitious drugs. (Response) FDA agrees that any cross-
(Comment 9) FDA proposed that the FDA received several comments references to components of 8.1
identifying numbers and titles for the suggesting that the examples be revised Pregnancy or 8.2 Lactation must
new labeling content under the section or expanded. One comment requested specify whether the cross-reference is to
8 Use in Specific Populations would that in the final rule, FDA provide the component in the Pregnancy
be 8.1 for Pregnancy and 8.2 for additional examples of sample labeling, subsection or the component in the
Lactation. FDA stated in the proposed including examples for which extensive Lactation subsection. Accordingly, in
rule that the identifying number 8.3 data exists. Another comment suggested the final rule, when applicable, risk
would be available for future use (73 FR that the information included in the statements in the Pregnancy
30831 at 30838). Two comments sample labeling for the fictitious drug subsection must include a cross-
pointed out that under this proposal, the products did not reflect the amount of reference to additional details in the
next subsections after 8.2 Lactation data that is typically available. The relevant portion of the Data
will be 8.4 Pediatric Use and 8.5 comment explained that the examples subheading in the Pregnancy
Geriatric Use. These comments stated would be more useful if they presented subsection. Also in the final rule, when
that the absence of subsection 8.3 may situations where there is extensive data. relevant human and/or animal lactation
be confusing and suggested that FDA Several other comments pointed out data are available, the Risk Summary
renumber the subsections. One that the terminology in the examples must include a cross-reference to the
comment requested that FDA clarify was not consistent with the terminology relevant portion of Data in the
whether the Agency has a specific use in the proposed rule. Lactation subsection.
in mind for 8.3 and, if it does not, (Response) FDA has not included
suggested that the Agency renumber the sample drug labeling with the final rule. 13. Need for Educational Campaign
subheadings to 8.3 Pediatric Use and The draft guidance on pregnancy and (Comment 13) FDA received one
8.4 Geriatric Use. The comment lactation labeling, which is being comment suggesting that the Agency
explained that if a future need for an published concurrently with this final develop educational campaigns for
additional subsection arose, it could rule, provides information about how to patients and health care providers
become 8.5. interpret and apply the rule to labeling regarding the changes to pregnancy and
lactation drug labeling brought about by discussion of FDAs recommendations October 5, 2011). Based on this analysis,
this rulemaking. on the content of the Highlights of to the extent that the discussion in the
(Response) FDA is developing prescribing information may be found proposed rule relied on the discussion
educational materials for FDA staff, in FDAs guidance for industry on about preemption in the preamble to the
health care providers, and patients to Labeling for Human Prescription Drug PLR, we conclude that the statements
inform them about the changes in these and Biological ProductsImplementing we made regarding preemption in the
labeling regulations and how these the PLR Content and Format preamble to the proposed rule are also
changes will have a positive impact on Requirements (February 2013).6 not justified.
labeling regarding the use of drugs and
biologics during pregnancy and 16. Preemption of State Law B. Specific Provisions of the Proposed
lactation. The draft guidance on In the preamble to the proposed rule, Rule
pregnancy and lactation labeling is FDA included a discussion in the 1. 8.1 Pregnancy
being published concurrently with this Federalism section that referred to a
more extensive discussion and analysis a. Comments related to the pregnancy
final rule; however, additional materials
in the PLR regarding the preemption of subsection as a whole.
may be completed following this date.
product liability lawsuits. i. Order of subsectionsFDA
14. Inventory (Comment 16) Comments expressed proposed that information appear in
(Comment 14) FDA received one different views about this discussion. subsection 8.1 Pregnancy in the
comment requesting that the final rule One comment suggested that in the final following order: (1) Pregnancy exposure
address how distributors should manage rule FDA revise the preamble to registry (if applicable), (2) general
drug products in their inventory that eliminate any reference to the statement about background risk, (3)
have outdated labeling. The comment preemption of product liability lawsuits. fetal risk summary, (4) clinical
suggested that product inventory Another comment expressed its considerations, and (5) data (proposed
without the revised labeling should appreciation of FDAs view that the rule 201.57(c)(9)(i)). In the proposed rule,
remain in the supply chain until the would preempt state laws that conflict FDA sought comment on how these
labeled products expiration date, with its requirements. This comment elements should be ordered to optimize
regardless of whether the product bears also expressed its support for FDAs the clinical usefulness of this labeling
the new labeling. intention to consult with State and local subsection (73 FR 30831 at 30839).
(Response) For previously approved officials in an effort to avoid conflict Specifically, FDA asked whether the
products, the implementation plan gives between State law and federally Fetal Risk Summary should precede
sponsors a minimum of 3 years after the protected interests. the pregnancy exposure registry
effective date of this final rule to submit (Response) FDAs statement regarding information and the statement about
labeling with the new content and preemption in the proposed rule relied background risk.
format. As we explained in the on statements made in the preamble to (Comment 17) Comments expressed
preamble to the proposed rule, FDA the PLR (71 FR 3922). In the preamble different opinions about the proposed
believes that this 3-year period will to the PLR, FDA discussed its views on order of information in the Pregnancy
allow industry sufficient time to use up the preemptive effect of both that subsection of labeling. Three comments
any existing labeling stock such that regulations codified provisions and the agreed with the proposed order. One of
none will remain in the supply chain FD&C Act. Subsequent to the these comments explained that the
after the product bears the new labeling publication of the May 2008 proposed proposed order will maximize a
(73 FR 30831 at 30846). rule, the Supreme Court, in Wyeth v. physicians ability to find and
Levine (555 U.S. 555 (2009)), addressed understand important pregnancy-related
15. Highlights the preamble to the PLR and held that information about a given drug product.
FDAs regulations require that all a State tort claim that an NDA-approved Another comment explained that
prescription drug labeling described in drug should have had a stronger placing the pregnancy exposure registry
201.56(b)(1) contain Highlights of warning was not preempted by the information first is preferable because if
prescribing information ( 201.57(a)). FD&C Act or FDAs labeling this information were placed after the
(Comment 15) Two comments requirements. Following the Courts Risk Summary, it may be interpreted
requested that FDA clarify which decision in Wyeth, FDA concluded that to imply that the pregnancy exposure
elements of the Pregnancy and the position on preemption we registry exists because of the data in the
Lactation subsections are likely to be articulated in the preamble to the PLR fetal risk summary. One comment
included in the Highlights of cannot be justified under legal supported placing the pregnancy
prescribing information. One of the principles governing preemption exposure registry information first so
comments expressed hope that adoption (Preemption Review, 76 FR 61565, that it will appear more visible in
of the rule will promote standardization labeling.
with respect to which elements are 6 U.S. Food and Drug Administration, Guidance Many comments disagreed with the
elevated to the Highlights of for Industry, Labeling for Human Prescription Drug proposed order and suggested a variety
prescribing information, thereby and Biological ProductsImplementing the PLR of alternatives. Six comments suggested
Content and Format Requirements, (February
facilitating consistent interpretation and 2013), available at http://www.fda.gov/downloads/
that the Fetal Risk Summary
implementation of the rules Drugs/GuidanceComplianceRegulatoryInformation/ subheading be placed first because it
requirements among FDA reviewers and Guidances/UCM075082.pdf. Many guidances are contains the most important and useful
review divisions. referenced throughout this document. The guidance information. One of these comments
referred to in this footnote, as well as others

(Response) The requirements for referenced throughout the remainder of the
pointed out that past FDA advisory
placement of information in the document, can be found on the FDA Drugs committees have suggested that
Highlights of prescribing information guidance Web page at http://www.fda.gov/Drugs/ summary information should be placed
are specified in 201.57(a). This final GuidanceComplianceRegulatoryInformation/ first. Two comments suggested that the
Guidances/default.htm. We update guidances
rule does not revise or change the periodically. To make sure you have the most
Background Risk Statement should be
requirements for the Highlights of recent version of a guidance, check the FDA Drugs first followed by the Fetal Risk
prescribing information. Additional guidance Web page. Summary. These comments explained
that the most important information Categories were not used to characterize A separate comment supported FDAs
should be placed first, as recommended the risks and benefits associated with proposal to eliminate the pregnancy
by FDA advisory committees. Three drug treatment by lactating women. categories but thought they should be
comments suggested that the pregnancy FDA proposed to remove pregnancy retained until the implementation of the
exposure registry information be placed categories from all prescription drug final rule is complete.
last. Another comment suggested that labeling because we determined that the (Response) FDA has determined that
the information be placed in the categories were confusing and did not retaining the pregnancy categories is
following order: Pregnancy exposure accurately and consistently inconsistent with the need to accurately
registry information, clinical communicate differences in degrees of and consistently communicate
considerations, fetal risk summary, data, fetal risk (73 FR 30831 at 30846). differences in degrees of fetal risk. As
and background risk statement. (Comment 18) Comments expressed discussed in the proposed rule, the
(Response) FDA has determined that different opinions about whether the current pregnancy category system has
placing the pregnancy exposure registry elimination of the pregnancy category long been criticized as being confusing
information first under 8.1 Pregnancy system, in full or in part, would and overly simplistic (73 FR 30831 at
best balances the objectives of this improve or diminish the usefulness of 3083330834). Through experience and
rulemaking. Although we agree that the the Pregnancy subsection of stakeholder feedback, FDA learned that
Risk Summary information is most prescription drug labeling. FDA the pregnancy categories were heavily
important to prescribers and we received 11 comments from medical relied upon by clinicians but
acknowledge that the advisory associations, womens and reproductive misinterpreted, misunderstood, and
committee expressed a preference for health advocacy organizations, erroneously used as a grading system
placing the most important information toxicologists, individual health care where fetal risk increased from A to X.
first, it is also clear that stakeholders practitioners, pharmacists, and drug The categories gave the incorrect
desire greater quality and quantity of manufacturers specifically supporting impression that drugs in the same
human data in pregnancy labeling. FDA our proposal to retire the pregnancy category carried the same risk or
believes that the benefits of prominently category system. Several of these potential for human adverse
placing information about pregnancy comments explained that the categories developmental outcomes. In addition,
registry availability at the beginning of were confusing or misleading. One of the categories did not discriminate
8.1 Pregnancy outweigh the the comments stated that although the among risk information obtained from
downsides of a minor decreased use of pregnancy categories is easier for nonclinical animal studies and
prominence of the Risk Summary some practitioners, it results in postmarketing human studies and did
information, which appears miscommunication and errors in not discriminate among drugs
immediately after the information under decisionmaking. Another comment associated with adverse outcomes of
Pregnancy Exposure Registry. Many explained that reliance on the categories differing severity or incidence.
health care providers are still learning may result in poorly informed clinical Stakeholders also pointed out that the
about pregnancy exposure registries and decisionmaking. pregnancy categories focused on
their purpose. We have concluded that FDA received 16 comments from structural abnormalities and thus did
routinely placing this information first physicians, pharmacists, pharmacy not adequately address the full range of
in pregnancy labeling may increase associations, nurses, manufacturers, potential developmental toxicities.
pregnancy registry enrollment, the drug safety consultants, and individual As described in greater length in the
quality of human data that emerge from consumers, requesting that FDA either preamble of the proposed rule, FDA
these studies, and the quality of retain the pregnancy category system or carefully explored a multitude of
pregnancy labeling (including the Risk replace the pregnancy category system models to determine whether the former
Summary) that follows. Because we with another standardized schema. pregnancy category system or a different
agree that the information under Risk Many of these comments suggested that pregnancy category system could
Summary is most important to FDA add the additional narrative accurately and consistently
prescribers, we also decline the information as proposed, but also retain communicate differences in degrees of
suggestion to place the Risk Summary the category system. Two of these fetal risk (73 FR 30831 at 3083330837).
after Clinical Considerations. The comments explained that the pregnancy FDA found that when it applied these
Pregnancy subsection will include, in categories are simple and effective, and criteria to actual animal and human data
this order, information under the new information may confuse findings for drugs with known risk
Pregnancy Exposure Registry, as patients or prescribers. Another profiles, none of the models produced
applicable, Risk Summary, Clinical comment stated that without a clinically informative and reliable
Considerations, as applicable, and standardized schema, there will not be differentiations of risk (73 FR 30831 at
Data, as applicable. a consistent and useful format for 30838). Prescribing and drug-use
ii. Removal of the pregnancy decisionmaking. Other comments decisions during pregnancy require
categoriesFDA proposed to remove agreed that the pregnancy categories consideration of not only fetal risk
the pregnancy categories from all need to be revised but suggested that information, but also of various clinical
prescription drug labeling. As discussed FDA develop new standardized and individual factors, including
in greater detail in section I of this statements or categories or revise the maternal drug effects, the severity of
document, in 1979 FDA adopted a bases for the current categories. Two maternal disease, maternal tolerance of
pregnancy category system that was comments urged FDA to maintain an the drug, coexisting maternal
used to convey risk and benefit X-like category for drugs where the conditions, the impact of maternal
information related to potential or risks outweigh any benefit to a pregnant disease on the fetus, and available
documented human teratogenic risk and or nursing patient, and one comment alternative therapies. FDA concluded
potential maternal/fetal benefits urged FDA to maintain an X-like that continuing to use a category system
associated with drug treatment during category so that providers and patients to characterize the risks of drug use
pregnancy. Under the 1979 regulations, could easily identify those drugs that during pregnancy would not be
each drug product was identified with are contraindicated for the mother, appropriate because of the complexity
a pregnancy category: A, B, C, D, or X. fetus, and/or a breastfeeding infant. of medical decisionmaking regarding
drug use during pregnancy (73 FR 30831 regulation would not be consistent with scientifically acceptable when it is
at 30838). the Agencys goal to avoid consistent with applicable FDA
FDA continues to believe that a overburdening both the Agency and guidance, including the guidance for
narrative structure for pregnancy industry. industry on Establishing Pregnancy
labeling is best able to capture and b. Comments related to specific Exposure Registries (August 2002). If
convey the potential risks of drug provisions of 8.1 Pregnancy. there are changes to an existing
exposure based on animal or human i. Pregnancy exposure registryFDA pregnancy registry or a new pregnancy
data, or both. This perspective is proposed that if there is a pregnancy registry is initiated after drug approval,
consistent with FDAs approach to other exposure registry for a product labeling will need to be updated to
aspects of product labeling. For described in 201.56(b)(1) (i.e., include this new information.
example, numeric or letter or other prescription drug products for which an (Comment 20) Two comments sought
categorical gradations of risk have never application was approved after June 30, clarification regarding the standards for
been used for safety labeling because 2001), the telephone number or other including contact information for a
safety and risk are complex constructs information necessary to enroll in the pregnancy exposure registry. One
in clinical medicine. For similar registry or to obtain information about comment stated that contact information
reasons, FDA does not apply symbol or the registry must be stated at the should only be included if the registry
letter designations of risk to other beginning of the Pregnancy is scientifically acceptable to the
potential toxicities or adverse effects subsection of prescription drug labeling sponsor and FDA. Another comment
expected with drug product use. (proposed 201.57(c)(9)(i)(A)). For drug asked whether contact information for
For the reasons discussed previously, products that do not have a pregnancy non-U.S. registries must be included.
FDA declines the suggestion to maintain exposure registry, the proposed rule did (Response) As stated previously, if
pregnancy category X. We note, not require the Pregnancy subsection there is a scientifically acceptable
however, that labeling must clearly of prescription drug labeling to contain pregnancy registry for a drug product,
identify populations in which use of a any statement about pregnancy FDA is requiring a standard statement
drug is contraindicated. The labeling exposure registries. concerning the registry as well as
regulations in 201.57 clearly describe (Comment 19) Comments disagreed contact information needed to enroll in
the information that must be included about the mandatory inclusion of the registry or obtain additional
in the Contraindications section and pregnancy exposure registry information about it. For registries that
all contraindications from the full information. Many comments supported include U.S. populations, U.S. contact
prescribing information are always the mandatory inclusion of pregnancy information should be included in the
listed in the Highlights of prescribing exposure registry information in the labeling, regardless of whether the
information ( 201.57(c)(5)). Therefore, Pregnancy subsection of prescription registry is maintained within the United
when use of a drug is contraindicated in drug labeling. These comments States or elsewhere.
pregnancy, this information must be explained, for example, that including (Comment 21) Four comments
stated in the Contraindications pregnancy exposure registry information suggested that the pregnancy exposure
section and listed in the Highlights of in labeling may encourage patient registry information should have its
prescribing information, as well as, per involvement in registries and pave own component header.
the previous discussion, stated first the way for improved registry use by (Response) FDA agrees with the
under the Risk Summary subheading clinicians leading to better suggestion that the pregnancy exposure
of the Pregnancy subsection of documentation of drug effects and use registry information should have its
labeling. during pregnancy. own component header. In the final
To the extent that the comment One comment stated that including a rule, contact information for an existing
suggests that the pregnancy categories reference to an existing pregnancy pregnancy exposure registry and a
should be retained for applications registry should not be mandatory. standard statement on the registry will
subject to 201.80 until the (Response) FDA believes that fall under the subheading Pregnancy
implementation of the new content and appropriately conducted pregnancy Exposure Registry in the Pregnancy
format requirements is complete, we registries are an important mechanism subsection of prescription drug labeling.
decline this suggestion; we believe it is for the collection of clinically relevant Because of this change, FDA eliminated
more consistent with the Agencys data concerning the effects of exposure the phrase must be stated at the
overall concerns with respect to to drugs during pregnancy. The Agency beginning of the Pregnancy subsection
removing the pregnancy categories to believes that including information of the labeling from the final rule.
implement that change within a shorter about pregnancy exposure registries in (Comment 22) Two comments stated
timeframe that nevertheless provides prescription drug labeling will that it should be easier to enroll patients
sufficient time for compliance. We encourage participation in registries, in pregnancy exposure registries.
would like to clarify that for thereby improving their usefulness. (Response) The importance of subject
applications required to implement the Thus, if there is a pregnancy registry recruitment into pregnancy exposure
new content and format requirements, that FDA has reviewed and found registries and the need to build
the pregnancy categories are required to scientifically acceptable, FDA is awareness of pregnancy exposure
be removed at the time the labeling is requiring that the Pregnancy registries among health care providers
revised regardless of whether this will subsection of prescription drug labeling are both factors in FDAs decision to
result in the labeling including a include under its own subheading, place information about existing
pregnancy category for more than 3 Pregnancy Exposure Registry, a pregnancy exposure registries at the
years after the effective date of the final standard statement concerning the beginning of 201.57, 8.1 Pregnancy.
rule (as described in the existence of the registry, as well as the The actual process of enrolling patients,
Implementation section of this contact information necessary to enroll however, is beyond the scope of this
document in response to Comment 92). in the pregnancy exposure registry or to rule.
Requiring that the labeling for some obtain information about the registry. (Comment 23) Comments expressed
applications be revised twice solely as The Agency generally considers a disagreement about whether the
part of the implementation of this pregnancy exposure registry Pregnancy Exposure Registry
subheading should be omitted from the (Response) FDA believes that applicants be given the option to
Pregnancy subsection of prescription including information about pregnancy identify in the background risk
drug labeling when there is no existing exposure registries in the Patient statement the specific risks described in
registry for the drug. One comment Counseling Information section of the fetal risk summary. The comment
suggested that the Pregnancy Exposure labeling would be useful. If the drug proposed that the second sentence of
Registry subheading should not be product has a pregnancy exposure the background statement be modified
omitted even if there is no existing registry, the availability of a pregnancy to state: The fetal risk summary below
registry for the drug, and that it should exposure registry should be noted in the describes the potential of (name of drug)
include a statement that there is no Patient Counseling Information to contribute to risk of (adverse
specific pregnancy exposure registry for section of labeling, and a cross-reference outcomes, including developmental
the drug. Another comment requested should be included to 8.1 Pregnancy abnormalities or identify specific risks)
that FDA consider incorporating a for the contact information necessary to above background risk.
statement that the subheading may be enroll. The preamble to the PLR states Several comments requested
omitted if there is no pregnancy that Highlights summarizes the clarification about whether the
exposure registry. information from the Full Prescribing background risk statement refers to the
(Response) FDA concludes that the Information that is most important for general population or the population
Pregnancy Exposure Registry prescribing the drug safely and with the disease. Two other comments
subheading should be omitted when effectively and organizes it into logical suggested that when the background
there is no pregnancy exposure registry. groups to enhance accessibility, risk of adverse outcomes in the relevant
We have determined that requiring the retention, and access to the more disease population is known to be
Pregnancy Exposure Registry detailed information (71 FR 3922 at higher than in the general population,
subheading in labeling when there is no 3931). Information about the availability this information should be included in
pregnancy exposure registry for the drug of and contact information for a the background risk statement. One of
product, and the inclusion of a pregnancy exposure registry are not these comments suggested that relevant
statement indicating that no registry considered essential information for literature citations should also be
exists, would not further the goal of prescribing and should not appear in included as appropriate.
improving the collection of data in Highlights (see FDAs guidance for One comment asked FDA to clarify
pregnant women who are exposed to a industry on Labeling for Human how it will determine the background
drug. Prescription Drug and Biological rate of adverse pregnancy outcomes.
(Comment 24) One comment ProductsImplementing the PLR Another comment suggested that FDA
suggested that the labeling should state Content and Format Requirements and industry develop a standard
the purpose of the pregnancy exposure (February 2013)). The question of definition of background risk that would
registry and provide the contact whether FDA anticipates requesting provide a common explanation for all
information necessary for enrollment. more pregnancy exposure registries as a labeling, both for the general population
(Response) FDA agrees that including condition of marketing approval is and for any specific disease states or
a statement in the labeling about the outside the scope of this rule. conditions. This comment explained
purpose of the pregnancy exposure In the final rule, FDA revised the that different reviewers may look at
registry would be useful. In the final phrase telephone number or other different criteria for assessing
rule, FDA requires that if there is a information needed to enroll to background risk (i.e., what constitutes a
scientifically acceptable pregnancy contact information needed to enroll. developmental abnormality or a
exposure registry for the drug, the FDA determined that this change would congenital malformation), and a
labeling must include a statement that allow for more flexibility in the type of standard definition would provide for
there is a pregnancy exposure registry contact information included under this consistency. A separate comment stated
that monitors pregnancy outcomes in portion of the labeling. that the background risks of pregnancy
women exposed to the drug during ii. Background risk statementFDA can vary by demographics, location,
pregnancy, and include contact proposed that a general statement about ethnicity, and other variables. The
information needed to enroll in the the background risk of adverse comment suggested that to maintain
registry or to obtain information about pregnancy outcomes be included in uniform and standardized descriptions
the registry. Because the purpose of all labeling. The proposed rule stated in of background risk, FDA should provide
pregnancy registries is to collect 201.57(c)(9)(i)(B) that the following industry with a guidance document
clinically relevant human data that can statement was required to be included describing background risk.
be used in a products labeling to in the labeling: All pregnancies have a One comment recommended against
provide health care providers with background risk of birth defect, loss, or requiring data in the background risk
useful information for treating or other adverse outcome regardless of statement. The comment explained that
counseling patients who are pregnant or drug exposure. The fetal risk summary background statistics change over time
anticipating pregnancy, we do not below describes (name of drug)s as new evidence is made available and
believe it is necessary to include a more potential to increase the risk of accepted by the medical community.
specific statement in labeling about developmental abnormalities above the Several comments suggested that FDA
their purpose. background risk. revise or omit the second sentence of
(Comment 25) Two comments (Comment 26) Two comments the background risk statement. One of
suggested that pregnancy exposure expressed support for the inclusion of a the comments explained that the
registry information be included in background risk statement. One of these sentence implies that the drug
Highlights and in the Patient comments noted that the statement will necessarily has the potential to increase
Counseling Information section of be useful to clinicians when explaining the risk of developmental abnormalities
labeling. One comment requested that the fetal risks associated with drug use above the background risk.
FDA clarify in guidance whether the during pregnancy. (Response) In the final rule, FDA has
Agency anticipates requesting more Several comments suggested eliminated the proposed standardized
pregnancy registries as a condition of modifying the background risk background risk statement. In its place,
marketing approval. statement. One comment suggested that the final rule requires that the labeling
state the percentage range of live births ( 201.57(c)(9)(i)(C)). FDA proposed that outcomes as well as fetal outcomes in
in the general population of the United the section include a risk conclusion, the Fetal Risk Summary.
States with a major birth defect and the contain a narrative description of the (Response) FDA agrees that
percentage range of pregnancies in the risk(s) (if the risk conclusion is based on information on drug-associated maternal
United States that end in miscarriage, human data), and refer to any risk is important, and in the final rule
regardless of drug exposure. The final contraindications or warnings and has created a separate heading,
rule also requires that if such precautions. Maternal adverse reactions, under
information is available for the (Comment 27) One comment Clinical Considerations, which
population(s) for which the drug is expressed support for the proposed requires relevant information, to the
labeled, it must also be included. The Fetal Risk Summary, explaining that extent it is available, about drug-
final rule requires that the background the proposed labeling requirements associated maternal adverse reactions
risk information appear in labeling increase the utility of the Pregnancy that are unique to or more frequent or
under the subheading Risk Summary, subsection by expanding the teratology severe during pregnancy. FDA disagrees
rather than as a standalone statement section to include information about that information on neonatal outcomes
under its own subheading (as in the specific developmental abnormalities as well as fetal outcomes should be
proposed rule). such as incidence, seriousness, included in the Risk Summary.
The Agency has determined that reversibility, potential for correction, Rather, if available, this information is
rather than including a standardized and effect of dose, duration, and included under its own heading, Fetal/
general statement about background gestational timing of exposure. Several Neonatal adverse reactions, under
risk, it is beneficial to include the other comments suggested that the Clinical Considerations. FDA believes
approximate background rates of major proposed Fetal Risk Summary be that consistent placement of this
birth defects and miscarriage. This will revised in various ways, discussed in information under a specified heading
provide some context to the risk detail as follows. under Clinical Considerations will
statement, and a basis for comparison Sources of data. FDA proposed that allow health care providers to easily
with risk estimates from studies in all available data, including human, locate this information. FDA also
pregnant women. Including the animal, and pharmacologic data, that
believes that this approach ensures that
approximate background rates allows are relevant to assessing the likelihood
maternal, fetal, and neonatal risks will
the prescriber to inform patients of the that a drug will increase the risk of
be captured and clearly conveyed in
risk of major birth defects and developmental abnormalities and other
prescription drug labeling.
miscarriage, regardless of drug relevant risks must be considered
(Proposed 201.57(c)(9)(i)(C)(1)). Terms used to describe adverse fetal
exposure. Accordingly, the final rule
(Comment 28) One comment outcomes. FDA proposed that the fetal
requires that the labeling include the
recommended that rather than risk summary must characterize the
approximate background rates of major
considering all available data, the likelihood that the drug increases the
birth defects and miscarriage, regardless
data sources for the Fetal Risk risk of developmental abnormalities in
of drug exposure, in the United States.
FDA agrees, however, that it is possible Summary be limited to scientifically humans (i.e., structural anomalies, fetal
that these numbers may change over rigorous, organized data collection and infant mortality, impaired
time. Therefore, the Agency did not schemes such as clinical or preclinical physiologic function, alterations to
include any specific numbers in the studies, and registries. growth) and other relevant risks (e.g.,
final rule. Instead, the Agency has (Response) FDA declines this transplacental carcinogenesis)
provided information, including suggestion. For example, depending on (proposed 201.57(c)(9)(i)(C)(1)).
relevant literature citations, about the safety signal, valuable information (Comment 30) Several comments
current background rates of major birth may come from epidemiological studies suggested that the term developmental
defects and miscarriage in the draft that are not prospective pregnancy abnormalities should be replaced with
guidance on pregnancy and lactation exposure registries. On occasion, a broader and more accurate term. One
labeling, which is being published adverse event reporting or case series comment suggested FDA replace the
concurrently with this final rule. reporting may raise enough concern term developmental abnormalities
Although the literature citations are about a potential increased risk for a with the term adverse outcomes,
included in the draft guidance, the specific structural malformation or including developmental
Agency does not believe it is either pattern of malformations, or a serious abnormalities. This comment
necessary or appropriate to include adverse event, that the information explained that the phrase
them in the labeling. should be included in labeling. developmental abnormalities does not
FDA agrees that the second sentence (Comment 29) Maternal and neonatal include other relevant risks (e.g.,
in the proposed background risk risk. One comment suggested that FDA transplacental carcinogenesis) that are
statement, which states that the fetal include information regarding maternal also required to be described in the
risk summary describes the drugs and neonatal risks in the Pregnancy Fetal Risk Summary. Several
potential to increase the risk of subsection of labeling. The comment comments suggested replacing the term
developmental abnormalities above the suggested that FDA add a maternal risk developmental abnormalities with the
background risk, could have been subsection, preferably before the Fetal term developmental effects or
misinterpreted as meaning that the drug Risk Summary, which would address adverse developmental effects. These
is associated with an increased risk. As side effects and adverse reactions comments explained that in the field of
discussed previously, the Agency has associated with the use of a drug, developmental toxicology, a
removed the standardized background including those unique to pregnancy. developmental abnormality would
risk statement, including the second The comment explained that placing imply, in general, a dysmorphogenic
sentence, from the final rule. this information higher on the label and effect (malformation or variation), rather
iii. Fetal risk summaryFDA making it a separate subsection would than the wider definition intended by
proposed that under Pregnancy, underscore the importance of the health the proposed rule. Several comments
prescription drug labeling include a of the mother. The comment also noted the importance of using
subheading Fetal Risk Summary suggested that FDA include neonatal terminology consistently in labeling.
(Response) FDA agrees that the terms Several comments stated that because conflicting characterizations of risk
used to describe various developmental there will be frequent conflicts between magnitude.
effects or outcomes should be accurate human and animal data, FDA should FDA disagrees with the suggestion
and understandable, and that standard develop an overall approach to that animal data be presented first in
nomenclature in the field of characterize risk based on both human cases where the human data are
developmental toxicology should be and animal data. One of these comments insufficient. FDA also disagrees that the
used to the extent that it exists. FDA suggested that FDA consider the most robust and clinically relevant
also agrees that terminology should be European Medicines Agencys (EMEAs) datawhether human data or animal
used consistently in labeling. FDA (now EMAs) Integration Table for Risk datashould always be presented first.
concludes that the term developmental Assessment and Recommendation for We have determined that to promote
abnormalities is widely recognizable as Use as an example of how to integrate consistency and to meet readers
referring to structural defects risk conclusions based on animal and expectations that information will
(malformations or variations), rather human data. always be found in the same place, a
than the full range of possible Two comments stated that the fixed order of presentation must be
manifestations of developmental proposed rule gives primary emphasis maintained. Moreover, we have
toxicity as FDA had intended. to human studies, if they exist, while determined that human data should
Therefore, in the final rule, FDA has downgrading the emphasis on animal precede animal data because it is the
included the following terms that data. One of these comments explained most clinically relevant.
describe various developmental that the quality and statistical power of We note that the purpose of this
toxicities, as explained in the following human data often fall well short of rulemaking is to facilitate informed
list: desirable, and suggested that human prescribing and safe and effective drug
Adverse developmental data be accompanied by clear product use; placing restrictions on or
outcomes has replaced developmental acknowledgement of any deficiencies. encouraging any type of studies that
abnormalities as the general term to The other comment explained that may be used as the basis for drug
encompass all manifestations or types of emphasizing minimal human data over labeling is beyond the scope of this rule.
developmental toxicity. strong animal data can misrepresent the Not systemically absorbed. FDA
Structural abnormalities is used fetal risk of a drug. proposed that if the drug is not
Two comments suggested that if
to describe dysmorphology, which systemically absorbed, the fetal risk
human data are insufficient (i.e., do
includes malformations, variations, statement must contain only the
not meet the standard for inclusion in
deformations, and disruptions, rather following statement: (Name of drug) is
proposed 201.57(c)(9)(i)(C)(2)(i)), a risk
than the proposed structural not absorbed systemically from (part of
statement based on human data should
anomalies. body) and cannot be detected in the
not precede a risk statement based on
Embryo-fetal and/or infant animal data. One of these comments blood. Maternal use is not expected to
mortality is used to describe explained that the most robust and result in fetal exposure to the drug
developmental mortality, which clinically relevant data should always (proposed 201.57(c)(9)(i)(C)(1)).
includes miscarriage, stillbirth, and be presented first. (Comment 32) One comment
infant death (including neonatal death), Several comments stated that if risk suggested that this statement should
instead of the proposed fetal and infant conclusions are based on sufficient focus on the route of administration
mortality. human data, sponsors should not be rather than the part of the body.
Functional impairment is used to required to include animal data, even if (Response) FDA agrees that part of
describe functional toxicity, which such data are available. One comment the body could be misconstrued and
includes such outcomes as deafness, also suggested that if sufficient human we have determined that the use of
endocrinopathy, neurodevelopmental data become available after the labeling route of administration to describe
effects, and impairment of reproduction, is approved, animal data should be how the drug enters the body is more
rather than impaired physiologic removed when the human data are consistent with labeling language that
function. added to the labeling. This comment addresses dosing and administration. In
Alterations to growth is used to explained that a risk conclusion based the final rule, FDA has replaced part of
describe such outcomes as growth on animal data might not support, or the body with route of
restriction, excessive growth, and could flatly contradict, a risk conclusion administration. FDA has determined
delayed and early maturations. based on sufficient human data. that cannot be detected in the blood
These terms and descriptions are One comment suggested that FDA ban is redundant and that the statement is
consistent with FDAs guidance for all animal studies because human clear without this phrase. In the final
industry on Reproductive and studies are more accurate. rule, FDA has eliminated that phrase.
Developmental ToxicitiesIntegrating (Response) We continue to believe (Comment 33) Standard statement for
Study Results to Assess Concerns that the Risk Summary is certain drugs. FDA received one
(September 2011). appropriately based on both human and comment suggesting that we develop a
Relationship between animal and animal data. Because of the importance standard statement for drugs that are
human data. FDA proposed that when of human data, we also have determined indicated for use only by males or by
both human and animal data are that when human data provide an females who are not of reproductive
available, risk conclusions based on incomplete assessment, this should be potential.
human data must be presented before stated in the risk statement based on (Response) FDA disagrees. We have
risk conclusions based on animal data human data. Specifically, the Risk determined that a standard statement is
(proposed 201.57(c)(9)(i)(C)(2)). Summary must state when there are no not needed. We believe it is appropriate
(Comment 31) A number of comments human data or when available human that the Risk Summary will be
suggested that FDA reexamine the data do not establish the presence or included in labeling for all drugs,
emphasis that the Fetal Risk absence of a drug-associated risk. FDA regardless of their indicated population.
Summary places on human data as believes that the use of narrative This will promote consistency in drug
compared to animal data. summaries of the data will avoid labeling.
Risk conclusions based on human consistent implementation across conclusions be used to characterize the
data. In the proposed rule, under the review divisions, a dedicated group of likelihood of increased risk. As
subheading Fetal Risk Summary, FDA FDA specialists should review the discussed previously, in the final rule,
proposed that when human data are determination of whether the human FDA requires instead, under Risk
sufficient to reasonably determine the data are sufficient or insufficient for all statement based on human data, that
likelihood that the drug increases the labeling subject to the rule. This when human data are available that
risk of fetal developmental comment also requested that FDA establish the presence or absence of any
abnormalities or specific developmental provide examples of sufficient and adverse developmental outcome(s)
abnormalities, the likelihood of insufficient data and that FDA caution associated with maternal use of the
increased risk must be characterized prescribers that such classifications drug, the labeling must summarize the
using one of the following risk should not be considered as scientific specific developmental outcome; its
conclusions: Human data do not proof that a drug may or may not harm incidence; and the effects of dose,
indicate that (name of drug) increases a particular patient. duration of exposure, and gestational
the risk of (type of developmental (Response) FDA agrees that the term timing of exposure. The final rule also
abnormality or specific developmental sufficient human data is ambiguous requires that if the data indicate that
abnormality) or Human data indicate and has eliminated it from the final rule. there is an increased risk for a specific
that (name of drug) increases the risk of FDA has also eliminated from the final adverse developmental outcome in
(type of developmental abnormality or rule the distinction between sufficient infants born to women exposed to the
specific abnormality) (proposed human data and other human data. drug during pregnancy, this risk must be
201.57(c)(9)(i)(C)(2)(i)). The proposed In the final rule, FDA requires that quantitatively compared to the risk for
rule defined the sources of sufficient when human data are available that the same outcome in infants born to
human data as clinical trials, establish the presence or absence of any women who were not exposed to the
pregnancy exposure registries or other adverse developmental outcome(s) drug but who have the disease or
large scale epidemiologic studies, or associated with maternal use of the condition for which the drug is
case series reporting a rare event drug, the labeling must summarize the indicated to be used. The final rule
(proposed 201.57(c)(9)(i)(C)(2)(i)). specific developmental outcome; its requires that if the data indicate that
incidence; and the effects of dose, there is an increased risk for a specific
(Comment 34) Many comments
duration of exposure, and gestational adverse developmental outcome in
requested that FDA more clearly define timing of exposure. As stated
the criteria for sufficient human data infants born to women exposed to the
previously, the final rule also requires drug during pregnancy, but risk
and provide further guidance on the that the Risk Summary state when
quantity and quality of evidence information is not available for women
there are no human data or when who were not exposed to the drug but
considered to be sufficient human available human data do not establish
data rather than other human data. who have the disease or condition for
the presence or absence of drug- which the drug is indicated to be used,
One comment requested that FDA associated risk.
clarify the standards that constitute then the risk for the specific outcome
FDA has also determined that the
sufficient human data, including how must be compared to the rate at which
term risk conclusion is inappropriate
those standards were developed. the outcome appears in the general
because the available data may not
Another comment stated that there is no population.
always lead to a conclusion regarding
agreement among experts as to how the drugs risk to the fetus. Therefore, in (Comment 36) FDA also received
much data are needed to reach a risk the final rule, FDA has replaced the comments about the proposed sources
conclusion and requested that FDA term risk conclusion with the term of sufficient human data. One comment
clarify what is considered sufficient risk statement. stated that sufficient data must be based
human data to reasonably determine the (Comment 35) Several comments on large-scale epidemiologic studies or
risk of developmental abnormalities. suggested that the Agency revise the clinical trials, and cannot be based on
Several comments questioned whether proposed risk statements to make them pregnancy registries or case reports/
data from an individual study could more straightforward and appropriately series requiring further evaluation. This
ever constitute sufficient human data. qualify the nature of the data and the comment explained that most
These comments explained that inability to draw definitive conclusions pregnancy registries can only serve to
although individual clinical trials, about an absence of risk based on them. rule out a major teratogen and to
pregnancy exposure registries, large- Two of these comments suggested that generally determine the similarity in
scale epidemiologic studies, and case the term human data be replaced with array of effects seen in large registries,
series can provide signals for potential the term available human data. One and they cannot provide a quantitative
adverse pregnancy outcomes, an comment suggested that the risk estimate of population rates of
individual study is not statistically conclusion Human data do not individual defects or abnormalities.
powered to fully assess the incidence indicate that (name of drug) increases Another comment stated that a risk
and form one of the proposed risk the risk of (type of developmental conclusion cannot always be reached
conclusions. A separate comment stated abnormality or specific developmental based on the types of human data
that even if human data has multiple abnormality) be replaced with described in the proposed rule, and
sources, there is often not enough Available human data indicate no questioned whether there is a consistent
human data to make a risk conclusion. additional risk of (type of approach to sufficient human data as it
This comment questioned how often the developmental abnormality or specific relates to case series reporting of a rare
risk statements based on sufficient developmental abnormality) with (name event. This comment explained that
human data would be used. One of drug). One comment suggested that spontaneous reports should not be part
comment stated that the proposed rule the term indicate should be replaced of the basis for this subsection. One
does not discuss who will determine with the term suggest. comment questioned how the labeling
whether the data are sufficient or how (Response) In the final rule, FDA has will summarize seemingly contradictory
such a determination will be made. The eliminated the requirement in the results of well-powered pregnancy
comment suggested that to increase proposed rule that standardized risk exposure registries or studies from
which a definitive clinical conclusion high, the risk should instead be detailed narrative discussion of
cannot be reached. characterized by specific statements insufficient human data in the fetal risk
(Response) FDA recognizes that describing the findings, or whether the summary.
because retrospective voluntary adverse findings should be described at all if (Response) As discussed previously,
event reporting may be biased and they are not readily interpretable. FDA agrees that the term sufficient
incomplete, spontaneous reports cannot Examples of specific statements would human data is ambiguous and we have
rule in or out a causal relationship be: Limited data in humans show removed the term from the final rule, as
between drug exposure and clinical (describe outcomes), or Limited data in well as the distinction between
outcome. However, multiple humans show conflicting results sufficient human data and other
spontaneous reports (or case series) of (describe study types, number of cases, human data. FDA also agrees that the
rare events can be useful in suggesting outcomes, and limitations) (73 FR terms low, moderate, and high
possible associations between adverse 30831 at 30842). are subjective and should not be used to
events and drug exposure during (Comment 38) FDA received 10 describe human data that cannot
pregnancy that warrant further comments from a variety of sources support a statement about fetal risk. The
investigation. Furthermore, FDA has expressing strong disagreement with the final rule requires instead that when
determined that data from studies with proposal to use the terms low, human data are available that establish
small numbers of pregnancy exposures moderate, and high to characterize the presence or absence of any adverse
may provide valuable information about the likelihood of increased risk of developmental outcome(s) associated
potential safety signals, especially when adverse outcomes due to drug exposure with maternal use of the drug, the
corroborated by findings from other based on less than sufficient human labeling must summarize the specific
studies. data. FDA received only one comment developmental outcome; its incidence;
(Comment 37) One comment supporting the proposal. and the effects of dose, duration of
suggested that FDA eliminate the Four comments stated that the
exposure, and gestational timing of
proposed rules requirement that proposal to classify risk as low,
exposure. As discussed earlier, the final
sponsors specify all possible types of moderate, or high based on insufficient
rule also requires that if the human data
developmental abnormalities or specific human data might produce the same
indicate that there is an increased risk
abnormalities for which human data do confusion as the current pregnancy
for a specific adverse developmental
not indicate that the drug increases the category system. These comments
outcome in infants born to women
risk. The comment explained that such explained that, as with the A, B, C, D,
exposed to the drug during pregnancy,
a list could be lengthy and of little X category system, the use of the
this risk must be quantitatively
clinical benefit to health care providers. categories low, moderate, and high to
(Response) FDA did not intend to compared to the risk for the same
characterize the likelihood of increased
imply that every potential type of risk of adverse outcomes would outcome in infants born to women who
developmental abnormality must be oversimplify the data and lump drugs were not exposed to the drug but who
included in labeling when human data with various types and amounts of data have the disease or condition for which
are negative. We note that it is difficult together without describing the basis for the drug is indicated to be used. When
to be certain that a lack of findings the conclusions. Another comment risk information is not available for
equates to a lack of risk because the suggested that these characterizations women with the disease or condition for
failure of a study to detect an are subjective and would be confusing which the drug is indicated, then the
association between a drug exposure to health care providers. risk for the specific outcome must be
and an adverse outcome may be related One comment recommended that compared to the rate at which the
to many factors, including a true lack of when the human data are insufficient, outcome occurs in the general
an association between exposure and FDA require the inclusion of the population. The final rule also requires
outcome, a study of the wrong following risk conclusion: Insufficient that the Risk Summary state when
population, failure to collect or analyze datarisk conclusion not established. there are no human data or when
the right data endpoints, and/or Another comment recommended that available human data do not establish
inadequate power. The intent of this FDA consider adopting something the presence or absence of drug-
final rule is to require accurate similar to the EMAs system. One associated risk.
descriptions of available data and comment suggested that the Risk Narrative description of risk(s) based
facilitate the determination of whether Summary should include information on human data. FDA proposed that
the data demonstrate potential about the findings, such as the when there are human data, the risk
associations between drug exposure and gestational age of exposure, the target conclusion must be followed by a brief
an increased risk for developmental organ or organ system, and the findings description of the risks of
toxicities. should be characterized in terms of developmental abnormalities as well as
FDA proposed that when there are structural, developmental, growth, or other relevant risks associated with the
available human data that are not functional abnormality. Another drug. To the extent possible, this
sufficient to use one of the risk comment recommended that when the description must include the specific
conclusions for sufficient human data, human data are not sufficient, the developmental abnormality (e.g., neural
the likelihood that the drug increases labeling contain statements specific to tube defects); the incidence,
the risk of developmental abnormalities the findings rather than classifying the seriousness, reversibility, and
must be characterized as low, moderate, risk as low, moderate, or high. One correctability of the abnormality; and
or high (proposed comment suggested that when there are the effect on the risk of dose, duration
201.57(c)(9)(i)(C)(2)(ii)). In the insufficient data, the labeling should of exposure, and gestational timing of
preamble to the proposed rule, FDA include a statement explaining that it is exposure. When appropriate, the
sought comment on this subsection. not possible to draw conclusions based description must include the risk above
Specifically, FDA sought comment on on insufficient human data. This the background risk attributed to drug
whether, in situations with human data comment also expressed a preference for exposure and confidence limits and
that are not sufficient, rather than referring to the data portion of the power calculations to establish the
classifying the risk as low, moderate, or labeling rather than including a more statistical power of the study to identify
or rule out a specified level of risk heading, Fetal/Neonatal adverse (Response) As discussed previously,
(proposed 201.57(c)(9)(i)(C)(4)). reactions, under Clinical the Narrative description of risk(s)
In the final rule, FDA has removed the Considerations. This portion of the heading was removed from the final
Narrative description of risk(s) final rule requires that if it is known or rule, and the phrase risk attributed to
heading from the Pregnancy anticipated that maternal drug therapy drug exposure is not used elsewhere in
subsection. FDA has determined that increases or may increase the risk of an the final rule.
much of the information required under adverse reaction in the fetus or neonate, (Comment 43) Two comments stated
that heading by the proposed rule was the labeling must describe the adverse that confidence intervals and power
duplicative of information now required reaction, the potential severity and calculations should not be included in
in the Risk Summary. As discussed reversibility of the adverse reaction, and labeling because they are too technical
previously, when human data are available interventions for monitoring or and not useful for most prescribers.
available that establish the presence or mitigating the reaction. (Response) FDA does not agree. Under
absence of any adverse developmental In response to the comments Data, the final rule requires a
outcome(s) associated with maternal use requesting clarification of the terms description of the limitations of any
of the drug, the Risk Summary in the reversibility and correctability, data included in the labeling.
Pregnancy subsection must FDA considers a condition to be Confidence intervals and power
summarize the specific developmental reversible if it can self-correct with calculations are important for the
outcome; its incidence; and the effects routine care and nurturing or through an review and interpretation of the data. As
of dose, duration of exposure, and intervention such as discontinuing the noted in the draft guidance on
gestational timing of exposure. Because drug. An example of a potentially pregnancy and lactation labeling, which
this information is required to be reversible drug effect in the neonate is is being published concurrently with
included in a narrative form in the provided in the draft guidance on the final rule, the confidence intervals
Risk Summary, we determined that pregnancy and lactation labeling, which and power calculation, when available,
including a separate Narrative is being published concurrently with should be part of that description of
description of risk(s) heading in the the final rule. The term correctable limitations.
labeling was unnecessary. In addition, has been removed from the final rule. (Comment 44) One comment
as explained in the following comments (Comment 41) One comment
suggested that the Narrative
and our responses, some of the suggested that FDA include in the
description of risk(s) include a
information that was required by the Narrative description of risk(s)
discussion about the uncertainties or
proposed rule to appear under information about precautionary
limitations of the Fetal Risk Summary
Narrative description of risk(s) is measures that can be taken to prevent an
when appropriate.
required by the final rule to appear adverse outcome caused by the drug.
(Response) FDA agrees that (Response) As discussed previously,
instead under Clinical
information about precautionary FDA has removed the Narrative
Considerations.
(Comment 39) One comment measures to prevent an adverse drug description of risk(s) heading from the
suggested that FDA add a statement to effect should be included in labeling. In final rule. In the final rule, any
the Narrative description of risk(s) the final rule, under 8.1 Pregnancy, uncertainties or limitations of the data
portion of the Pregnancy subsection Clinical Considerations, Maternal are required to be stated in Data.
of labeling that explains that adverse reactions, FDA requires that if (Comment 45) One comment
spontaneous abortions caused by a drug the use of the drug is associated with a suggested that the Narrative
could potentially mask the risk of maternal adverse reaction that is unique description of risk(s) cross-reference
developmental abnormalities. to pregnancy or if a known adverse Data to direct readers to the
(Response) Although FDA reaction occurs with increased information upon which the narrative is
acknowledges that embryo-fetal death frequency or severity in pregnant based.
(i.e., spontaneous abortion) does women, the labeling must describe the (Response) As discussed previously,
sometimes occur due to severe adverse reaction and available the Narrative description of risk(s)
developmental abnormalities, the intervention(s) for monitoring or was removed from the final rule.
Agency has determined that it is not mitigating it. Also, in the final rule, FDA Risk statement based on animal data.
necessary to explicitly include such a requires that under 8.1 Pregnancy, FDA proposed to require that when the
statement in labeling. Any increase in Clinical Considerations, Fetal/ data on which the risk conclusion is
spontaneous abortions attributed to drug Neonatal adverse reactions, if it is based are animal data, the Fetal Risk
exposure above the background risk is known or anticipated that maternal drug Summary must characterize the
required to be described in the Risk therapy increases or may increase the likelihood that the drug increases the
Summary. risk of an adverse reaction in the fetus risk of developmental abnormalities
(Comment 40) One comment stated or neonate, the labeling must describe using one of the following risk
that the term seriousness is the adverse reaction, the potential conclusions: Not predicted to increase
ambiguous and suggested replacing it severity and reversibility of the adverse the risk, low likelihood of increased
with the phrase impact on health. reaction, and available intervention(s) risk, moderate likelihood of increased
Two comments requested clarification for monitoring or mitigating the risk, high likelihood of increased risk, or
of the terms reversibility and reaction. For further discussion of these insufficient data (proposed
correctability. requirements, see Comment 61 and our 201.57(c)(9)(i)(C)(3)(i)
(Response) FDA agrees that the term response. (c)(9)(i)(C)(3)(v)). In the preamble to the
seriousness is not clear, and it is not (Comment 42) One comment proposed rule, the Agency sought
used in the final rule; it has been suggested that FDA replace the phrase comment on whether these standardized
replaced with a requirement that the risk attributed to drug exposure in the statements can adequately communicate
labeling describe the potential severity Narrative description of risk(s) with different levels of risk based on animal
of the adverse reaction. Information the phrase a drugs potential to data and their potential relevance to
about the reversibility of adverse contribute to the risk of adverse human fetal effects or whether these
reactions should be included under the outcomes. statements are likely to generate
confusion among prescribers (73 FR One comment suggested that rather (Comment 47) Two comments
30831 at 30843). than using the proposed risk statements, suggested that labeling should include
(Comment 46) Comments expressed FDA should instead use the language explaining the limitations of
different opinions about the proposal to standardized statements presented in using animal data to predict the
use standardized statements to the draft reviewer guidance on likelihood that the drug increases the
characterize animal data. FDA received Integration of Study Results to Assess risk of developmental abnormalities.
11 comments, primarily from Concerns about Human Reproductive (Response) FDA declines the
toxicologists, teratologists, and and Developmental Toxicities (October suggestion to include language in
organizations representing toxicologists 2001). labeling explaining the limitations of
and teratologists, as well as a few Most of the comments that disagreed using animal data to predict the
comments from drug manufacturers, with the proposed standardized risk likelihood that the drug increases the
expressing strong disagreement with the statements suggested that the labeling risk of developmental abnormalities,
proposal to use risk statements to instead contain narrative statements because this is beyond the scope of this
characterize animal data. FDA received describing the animal data and its rule, and is discussed in guidance
three comments that supported using potential relationship to human documents, such as FDAs guidance for
standardized statements to characterize pregnancy risk. One of these comments industry on Reproductive and
the likelihood, based on animal data, explained that succinct narrative Developmental ToxicitiesIntegrating
that a drug will increase the risk for a statements will promote a reasoned risk Study Results to Assess Concerns
known developmental abnormality. assessment, facilitate comparisons (September 2011).
These comments explained, for among drugs, and enhance risk (Comment 48) FDA proposed that the
example, that a standardized statement communication. Several of these Risk Summary contain risk
indicating the possible correlation conclusions based on animal data. One
comments suggested that the labeling
between animal and human data would comment suggested that the term risk
should describe animal data
be helpful to clinicians. conclusion be replaced with the term
qualitatively, including the number of
risk statement because it is difficult to
Two comments stated that the species with positive findings,
reach any conclusions about fetal risk
proposed categories are confusing and consistency of findings, and the type of
posed by drugs based solely on animal
subject to variable interpretation. One of findings.
data.
these comments explained that it will be (Response) The Agency has (Response) FDA agrees. As with
very difficult to categorize the results of determined that the terms not human data, in the final rule, the
multiple studies conducted for a single predicted to increase the risk, low Agency has replaced the term risk
drug into one of the proposed likelihood of increased risk, moderate conclusion with the term risk
categories, and there could be likelihood of increased risk, and high statement when discussing risks based
disagreement about whether to likelihood of increased risk are on animal data.
characterize the risk based on the confusing and subject to different (Comment 49) Risk statement based
animal data as low, moderate, or interpretations. The Agency believes on pharmacology. One comment
high. that using standardized risk statements suggested that FDA consider whether a
Several comments stated that the may give the false impression that separate approach is appropriate for a
proposal to use category language to animal data can provide a semi- group of drugs, such as oncology
describe animal data demonstrates a quantitative assessment of human risk. products, for which the pharmacological
misunderstanding of the function and The Agency also agrees that the use of and toxicological mechanisms are
meaning of experimental animal standardized risk statements to similar. The comment suggested that for
studies. These comments explained that characterize the risk of developmental cytotoxic drugs, FDA could use the
although animal data can identify the abnormalities based on animal data following standard risk statement:
potential of a therapeutic agent to cause would potentially have the same (Drug name) is indicated for (cancer
developmental toxicity, it cannot give drawbacks as the current pregnancy type) and is generally used in terminally
rise to an estimate of the probability of category system. Therefore, in the final ill patients. There are very limited data
human harm. rule, FDA removed the requirement that on exposure in pregnant patients and,
Two comments expressed concern a standardized risk statement be used to therefore, no assessment of fetal or
that the use of standardized risk describe human risk based on animal maternal risk is available. The
statements would amount to a category data. Instead, the Risk Summary mechanism of action of this drug is to
system similar to the one that FDA requires that when animal data are kill growing cells and it can be
currently uses and would have all of its available, the labeling must summarize anticipated that there is a risk to the
associated problems. the findings in animals and, based on fetus at all stages of development.
Several comments expressed these findings, describe, for the drug, (Response) FDA agrees that the
particular concern with the proposal to the potential risk of adverse Pregnancy subsection of labeling
use these categories without an developmental outcomes in humans. should address situations in which a
accompanying narrative description of The final rule requires that the drug may result in an increased risk of
the animal studies. One comment statement include the number and adverse developmental outcomes based
suggested that the sample labels type(s) of species affected, timing of on a well-understood mechanism of
provided in the Appendix of the exposure, animal doses expressed in action. The final rule requires that when
proposed rule illustrate the difficulty of terms of human exposure or dose the drug has a well-understood
trying to characterize the risk to humans equivalents, and outcomes for pregnant mechanism of action that may result in
based on animal data. Another comment animals and offspring. The final rule adverse developmental outcome(s), the
stated that the terms risk, medium, also requires that when animal studies Risk Summary must explain the
and high are highly charged terms do not meet current standards for mechanism of action and the potential
and expressed concern that the risk nonclinical developmental toxicity associated risks.
statements will be over-interpreted by studies or when there are no animal Contraindications, warnings, and
anxious consumers and their clinicians. data, the labeling must so state. precautions. FDA proposed that the
Fetal Risk Summary refer to rule. A description of each comment we dictating prescribing decisions. Rather,
information that is included in the received and our responses follow. FDA views the Clinical
Contraindications or Warnings and (Comment 51) General comments. Considerations component of
Precautions section of labeling Comments expressed different opinions Pregnancy as providing information
regarding an increased risk to the fetus about the utility and appropriateness of that supports health care providers
from exposure to the drug (proposed the proposed Clinical Considerations understanding of drug product risks and
201.57(c)(9)(i)(C)(5)). component. Many comments expressed benefits and facilitates informed
(Comment 50) One comment general support for including this prescribing decisions and patient
suggested that FDA specify that any information. One comment stated that counseling.
contraindications or warnings or Clinical Considerations will help Inadvertent exposure. FDA proposed
precautions that must be included in the clinicians and patients to consider all that under the subheading Clinical
Fetal Risk Summary are those that aspects of the patients care when Considerations, the Pregnancy
relate to risk to the fetus. deciding when and how to prescribe subsection of labeling include
(Response) In the final rule, FDA drugs during pregnancy and in women information regarding known or
removed the requirement that the Risk of childbearing potential. Another predicted risks to the fetus from
Summary refer to information that is comment stated that the title Clinical inadvertent exposure to the drug during
included in the Contraindications or Considerations encourages pregnancy (proposed
Warnings and Precautions section of professionals to make their own medical 201.57(c)(9)(i)(D)(1)). The proposed
labeling regarding an increased risk to judgments. A separate comment noted rule would have required that: The
the fetus from exposure to the drug. As that FDA refrained from interfering with labeling must discuss the known or
described in FDAs draft guidance for the physicians discretion by framing predicted risks to the fetus from
industry implementing the PLR, when a Clinical Considerations as a practical inadvertent exposure to the drug
topic is discussed in more than one guide that assists the provider in (exposure in early pregnancy before a
section of labeling, the section decisionmaking. woman knows she is pregnant),
Some comments cautioned that including human or animal data on
containing the most important
Clinical Considerations was too dose, timing, and duration of exposure.
information relevant to prescribing
directive in its advice and requiring this If there are no human or animal data to
should typically include a succinct
information intruded on the practice of
description and should cross-reference assess the risk from inadvertent
medicine and could increase physician
sections that contain additional detail exposure, the labeling must so state.
liability for failure to adhere to labeling
(FDAs guidance for industry on (Comment 52) Comments expressed
instructions. One comment stated that
Labeling for Human Prescription Drug different opinions about the necessity
Clinical Considerations should not
and Biological ProductsImplementing and utility of including this
dictate prescribing by a physician for
the PLR Content and Format pregnant women. The comment information.
Requirements (February 2013)). requested that FDA revisit this Two comments supported including
Consistent with that principle, cross- provision to see whether the content can information about inadvertent exposure.
referencing of information required be made more useful without advising One of these comments explained that
under the final rule will typically physicians how to practice medicine. In the proposed section improves a
appear in the section where the topic is particular, the comment suggested that physicians ability to manage such
briefly summarized, e.g., Warnings and information about known alternative cases.
Precautions, and will refer the reader therapies should be included. Two comments, however, suggested
to the place in labeling where it will be Alternatively, the comment suggested that FDA consider removing this
presented in greater detail, i.e., that FDA consider the use of a general requirement because it will be
Pregnancy. We note that because a statement about clinical considerations duplicative of the information contained
contraindication is important rather than an extensive, clinically in the Fetal Risk Summary. One of
information that needs to be based discussion that may be unable to these comments explained that
communicated to the health care incorporate risk and benefit assuming equal exposure to the drug,
provider, the final rule requires that information. Another comment stated the known or predicted risks to the fetus
when use of a drug is contraindicated that it is the health care providers would be the same regardless of
during pregnancy, this information must responsibility to keep abreast of the whether the exposure was intentional or
be stated first in the Risk Summary. latest information about the disease not. This comment explained that
iv. Clinical considerations. state and its effect on pregnant women because fetal risks are already fully
FDA proposed that the Pregnancy and to apply that knowledge to described in the Fetal Risk Summary,
subsection of prescription drug labeling treatment of each individual patient, including the same information under
include a Clinical Considerations and the professional labeling is not the inadvertent exposure during
component to provide guidance and appropriate place for this information. pregnancy would be redundant. The
information to health care providers (Response) FDA disagrees both that comment suggested that the
about the use of the drug in three Clinical Considerations is too inadvertent exposure during
distinct clinical situations: (1) directive and that professional labeling pregnancy component instead include
Counseling women who were is not the appropriate place for this a cross-reference to the Fetal Risk
inadvertently exposed to the drug information. As a Public Health Agency Summary and describe only
during pregnancy, (2) making with expertise in drug regulation and information not already described in the
prescribing decisions for pregnant safety, FDA has a responsibility to issue Fetal Risk Summary, in particular,
women, and (3) making prescribing regulations that facilitate the any information about ways to manage
decisions during labor and delivery development of drug labeling that or mitigate the effects of inadvertent
(proposed 201.57(c)(9)(i)(D)). communicates how to safely and drug exposure. The other comment
We received many comments on this effectively prescribe drugs in the explained that the risk of drug exposure
proposal. Based on those comments, clinical setting. The Agency does not to the fetus early in pregnancy should
FDA has made some changes to the final regard Clinical Considerations as not be different between women who
choose to become pregnant and those FDA proposed that the Prescribing comment also requested that the
whose pregnancies were unplanned. decisions for pregnant women information be updated on a timely
Another comment suggested that FDA component under Clinical basis.
either delete the statement exposure in Considerations include information (Response) FDA agrees that it is
early pregnancy before a woman knows about the risk, if known, to the pregnant important that information provided in
that she is pregnant or retain it as an woman and the fetus from the disease labeling is consistent and up-to-date,
example. This comment explained that or condition the drug is indicated to and we address this issue in our
although inadvertent exposure is more treat (proposed 201.57(c)(9)(i)(D)(2)(i)). response to Comment 4. FDA is not
likely in early pregnancy, it may occur (Comment 53) Comments disagreed mandating that labeling contain
at any time during pregnancy. about whether the Pregnancy consistent disease-specific text, as
One comment asked for clarification subsection of labeling should include knowledge of disease-associated risk
as to what is expected to be included in information about the effects of not may change over time as more data
this section. Specifically, this comment treating the womans underlying disease become available.
questioned how the risk conclusions or condition. (Comment 55) One comment
from animal data in the Fetal Risk Two comments supported requiring suggested that FDA add a statement
Summary will be used to counsel the inclusion of information about the under Clinical Considerations
clinicians on the risk of inadvertent short- and long-term effects of not taking explicitly stating that untreated or
exposure, and requested that FDA a necessary drug to treat a chronic inadequately treated health conditions
provide examples of this section in an disease or condition for the duration of (such as infections; chronic diseases
Appendix. a pregnancy, as well as information such as diabetes, hypertension, renal
about the severity of the condition for and thyroid diseases; and psychiatric
(Response) The Agency agrees that the
which the drug might be prescribed. disorders such as depression) can
proposed inadvertent exposure during
Two other comments, however, adversely affect the health of the woman
pregnancy component would have disagreed with including information in and the outcomes of the pregnancy, and
required information about drug effects Clinical Considerations about the that decisions about medication usage
on the fetus that is largely redundant of risks of not treating the mothers must be balanced with the risks of
the information that is required to be underlying disease or condition during untreated and/or poorly managed health
included in the Risk Summary in the pregnancy. These comments stated that conditions.
Pregnancy subsection of prescription prescription drug labeling is not the (Response) FDA disagrees with this
drug labeling. FDA has removed the appropriate place for health care suggestion. We have determined that
inadvertent exposure during providers to learn about the risks of requiring a general standardized
pregnancy component from the final diseases that drugs are indicated to statement is less effective than
rule. treat. providing drug-specific information
Prescribing decisions for pregnant (Response) FDA has determined that about the risks of not treating the
women. FDA proposed that the when relevant information is available condition or disease for which the drug
Clinical Considerations portion of the about the serious effects of not treating is indicated to be used.
Pregnancy subsection of prescription conditions or diseases during (Comment 56) One comment
drug labeling contain information about pregnancy, it must be included in this suggested that Clinical Considerations
prescribing decisions for pregnant section of labeling. In the final rule, this should provide information about how
women, including the following: (1) The requirement appears first under to discontinue or switch medications
risk, if known, to the pregnant woman Clinical Considerations under the during pregnancy when necessary.
and the fetus from the disease or heading Disease-associated maternal (Response) FDA agrees that when
condition the drug is indicated to treat; and/or embryo/fetal risk. The wording such information is available, it may be
(2) information about dosing of this portion of the final rule was appropriate to include it in Clinical
adjustments during pregnancy; (3) revised to require that when there is a Considerations. We note that this does
information about maternal adverse serious known or potential risk to the not require a change to the final rule,
reactions associated with use of the pregnant woman and/or the embryo/ because this is consistent with current
drug; and (4) information about any fetus associated with the disease or labeling practices.
known or anticipated complications in condition for which the drug is (Comment 57) One comment
the neonate from treatment of the indicated to be used, the labeling must suggested that Clinical Considerations
pregnant woman (proposed describe the risk. take into account the severity of the
201.57(c)(9)(i)(D)(2)). (Comment 54) Other comments disease, disorder, or condition to the
In the final rule, FDA removed the suggested that the Clinical mother, and the availability and the
heading Prescribing decisions for Considerations component of the benefits and risks of alternative
pregnant women. FDA determined that proposed rule be altered in various therapies for which greater or lesser
because the inadvertent exposure ways. knowledge may be known about their
component was removed from the final Two comments expressed concern use in pregnant women.
rule, the Clinical Considerations that descriptions of risks to the pregnant (Response) FDA disagrees with the
portion of the Pregnancy subsection patient or fetus posed by diseases or suggestion that the labeling address the
was shortened such that having a conditions would vary among drugs that availability and the benefits and risks of
separate heading for Prescribing are indicated to treat the same disease alternative therapies during pregnancy.
decisions for pregnant women was or condition, thereby promoting Because the comparative risks and
unnecessary. confusion. One of these comments benefits for different therapies may vary
FDA received comments about the suggested that FDA develop disease- by patient, this determination must be
information required in the proposed specific text for developmental risks of made by the prescribing health care
rule under the heading Prescribing major disease classes, such as asthma, provider. FDA acknowledges, however,
decisions for pregnant women. A hypertension, diabetes, and epilepsy, that under certain circumstances it may
description of each comment and our which sponsors can use in their be appropriate to include a statement in
responses follow. prescription drug labeling. This the labeling that pregnant women
should consider alternative drug ( 201.57(c)(3)) and FDAs guidance for (Response) FDA agrees with the
therapies, and the appropriateness of industry on Dosage and suggestion to replace the phrase
this would be evaluated on a case-by- Administration Section of Labeling for interventions that may be needed
case basis during the labeling review Human Prescription Drug and Biological with the phrase available
process for a specific application. ProductsContent and Format (March interventions. In the final rule, FDA
Dosing adjustments during 2012), which require that the labeling requires that if use of the drug is
pregnancy. FDA proposed that Clinical provide details on how to adjust or associated with a maternal adverse
Considerations provide information modify the dosage in the Dosage and reaction that is unique to pregnancy or
about dosing adjustments during Administration section of labeling, if a known adverse reaction occurs with
pregnancy (proposed including for specific patient increased frequency or severity in
201.57(c)(9)(i)(D)(2)(ii)). The proposed populations. pregnant women, the labeling must
rule stated that this information must FDA agrees with the suggestion to describe the adverse reaction and
also be included in the Dosage and remove the phrase no data from the available intervention(s) for monitoring
Administration and Clinical final rule. In the final rule, we have or mitigating the reaction. This change
Pharmacology sections of the labeling, removed the requirement to state if also allows for differences that may
and that if there are no data on dosing there are no data available on dose exist in community standards of care
during pregnancy, the labeling must so adjustments during pregnancy and the and available services across the United
state. postpartum period. In addition, as noted States. We note that in the final rule we
(Comment 58) One comment in the draft guidance on pregnancy and removed the following language from
suggested that dosing information lactation labeling, which is being the codified: e.g., monitoring blood
should be restricted to the Dosage and published concurrently with the final glucose for a drug that causes
Administration section of labeling and rule, headings under Clinical hyperglycemia in pregnancy.
that Clinical Considerations should Considerations (including Dose Fetal/Neonatal adverse reactions.
cross-reference the Dosage and adjustments during pregnancy and the FDA proposed that Clinical
Administration and Clinical postpartum period) should be omitted Considerations contain information
Pharmacology sections of the labeling if there are no data available or the about any known or anticipated
rather than repeat dosing adjustment available data are not relevant. complications in the neonate, including
information in the Pregnancy Maternal adverse reactions. FDA any interventions that might be needed
subsection of labeling. The comment proposed that Clinical Considerations (proposed 201.57(c)(9)(i)(D)(2)(iv)).
also suggested replacing the phrase no contain information about maternal (Comment 61) Two comments asked
data because it could become outdated adverse reactions that are unique to FDA to clarify the meaning of the term
and because, in some instances, there pregnancy or adverse reactions that complication. One comment
may be data but it might not be occur with increased frequency or suggested that if FDA intended the term
sufficient to support recommendations severity in pregnant women. The complication to mean adverse
for dosing adjustments. proposed rule required that the labeling reaction in the neonate, the Agency
(Response) We disagree with the also describe any interventions that may should use the term adverse reaction.
suggestion that all information about be needed, such as monitoring blood This comment also suggested that if an
dosing should be restricted to the glucose for a drug that causes adverse reaction/complication has been
Dosage and Administration section of hyperglycemia in pregnancy (proposed described in the Fetal Risk Summary,
labeling. FDA has determined that it is 201.57(c)(9)(i)(D)(2)(iii)). only a cross-reference to
important that labeling information (Comment 59) One comment 201.57(c)(9)(i)(C) should be required to
relevant to the use of the drug during suggested that a cross-reference, see appear in 201.57(c)(9)(i)(D)(2)(iv).
pregnancy be included in the Pregnancy, be added to the Adverse Another comment suggested that FDA
Pregnancy subsection. These issues Reactions section of labeling to ensure state that a complication could be an
are discussed in the draft guidance on that health care providers refer to this adverse drug reaction, and suggested
pregnancy and lactation labeling, which section. that FDA state that the term adverse
is being published concurrently with (Response) FDA disagrees with this drug reaction may be used when
the final rule. If there are comment. The conventions for cross- appropriate.
pharmacokinetic data that support dose referencing are explained in FDAs (Response) FDA agrees that adverse
adjustment(s) during pregnancy and the guidance for industry on Labeling for reaction is a more appropriate term
postpartum period, this information Human Prescription Drug and Biological and that it is more consistent with the
must be provided under the heading, ProductsImplementing the PLR other portions of the final rule. In the
Dose adjustments during pregnancy Content and Format Requirements final rule, the term adverse reaction
and the postpartum period in Clinical (February 2013). The suggestion that (as defined in 201.57(b)(7)) has
Considerations, and there should be a this rule require a cross-reference from replaced complication. Additionally,
cross-reference to other sections of the Adverse Reactions section to the in the final rule FDA is requiring the
labeling that include more details (e.g., Pregnancy subsection of labeling is inclusion of information regarding fetal
Dosage and Administration or not consistent with the conventions set adverse reactions in this section of
Clinical Pharmacology). Although in forth in that guidance. In addition, not labeling. Although the proposed rule
the proposed rule FDA had required a every drug product will have only addressed adverse reactions
cross-reference to Dosage and pregnancy-related adverse reactions; (referred to there as complications) in
Administration and Clinical thus, a required cross-reference is the neonate under what in the final rule
Pharmacology, we have removed that unnecessary. is required in 201.57(c)(9)(i)(C), FDA

requirement. We believe, however, that (Comment 60) One comment concludes that information intended to
when appropriate, a cross-reference suggested that Clinical Considerations inform prescribing decisions for
should be included. This approach is refer to available interventions rather pregnant women appropriately includes
consistent with the regulations and than needed interventions to avoid information on fetal adverse reactions as
guidance applicable to the Dosage and interfering with the practice of well as neonatal adverse reactions. FDA
Administration section of labeling medicine. does not believe that there is a
principled distinction between the long-standing position that off-label FDA received comments about the
importance of such information with information is not to be included in information required under Data in
respect to the fetus and with respect to labeling. the proposed rule and made some
the neonate. The consistent location (Response) We note that, as stated in changes to the final rule. The following
under Clinical Considerations of the proposed rule (73 FR 30831 at discussion addresses these comments,
information about potential adverse 30844), the language proposed for this our responses, and the changes to the
reactions in the fetus as well as in the heading contained only slight final rule.
pregnant woman and the neonate, and modifications from that in existing (Comment 63) References. One
about available interventions, will make 201.57(c)(9)(ii). However, because comment suggested that under Data,
the information in that subsection more important safety information, whether the labeling should include references
useful, as well as easier to identify for for an approved or unapproved use, may for the cited data. The comment
prescribers and other health care be required to be included in labeling explained that including references for
providers. Accordingly, the final rule (see, e.g., 201.57(c)(6)(i)), we the data would allow clinicians and
requires that if it is known or concluded that it is not necessary to other health care workers to further
anticipated that maternal drug therapy include specific language regarding this research pregnancy issues.
increases the risk of an adverse reaction issue. Therefore, FDA has removed the (Response) We decline this
in the fetus or the neonate, the labeling language regarding drugs that have a suggestion. FDA has determined that
must describe the adverse reaction, the recognized use during labor or delivery, prescription drug labeling is intended to
potential severity and reversibility of whether or not the use is stated as an facilitate prescribing decisions and is
the adverse reaction, and available indication in the labeling. In the final not intended as a research tool. We also
intervention(s) for monitoring or rule, FDA revised the heading Drug note that this final rule is a part of
mitigating the reaction. effects during labor or delivery to labeling regulations, found at 201.57,
FDA disagrees with the suggestion Labor or delivery, which is consistent which address the inclusion of
that if an adverse reaction/complication with the level of specificity used in the references in prescription drug labeling
has been described in the Fetal Risk other headings under Clinical (see 201.57(c)(16)).
Summary, only a cross-reference to Considerations. (Comment 64) Postmarketing
201.57(c)(9)(i)(C) should be required to v. Data. reporting of adverse reactions. One
appear in 201.57(c)(9)(i)(D)(2)(iv). As FDA proposed that the following comment stated that if specific numbers
discussed in the draft guidance on information be included in the of adverse event reports are included in
pregnancy and lactation labeling, which Pregnancy subsection of labeling drug labeling, the labeling will need to
is being published concurrently with under the subheading Data: be constantly updated. The comment
the final rule, the Clinical (1) Under the subheading Data, the suggested that the Agency instead
Considerations portion of the labeling Pregnancy subsection of the labeling consider using quantitative measures of
is intended to describe fetal/neonatal must provide an overview of the data frequency to produce a more stable
adverse reactions that are not adverse that were the basis for the fetal risk label.
developmental outcomes. Therefore, summary. (Response) FDA acknowledges that
because the two portions of the labeling (2) Human and animal data must be the inclusion in labeling of actual
address different potential reactions/ presented separately, and human data numbers of postmarketing reports for
outcomes, a cross-reference would not must be presented first. particular adverse reactions is often not
be appropriate. (3) The labeling must describe the appropriate. We agree that the number
Additionally, in the final rule, FDA studies, including study type(s) (e.g., of postmarketing reports of adverse
added the requirement that the labeling controlled clinical or nonclinical, reactions changes over time and labeling
must describe, if known, the effect of ongoing or completed pregnancy may become rapidly outdated. In
dose, timing, and duration of exposure exposure registries, other addition, postmarketing reports of
on the risk of an adverse reaction in the epidemiological or surveillance studies), adverse reactions generally do not
fetus or neonate as FDA has concluded animal species used, exposure establish an incidence or prevalence of
that this information is important for information (e.g., dose, duration, a particular outcome or definitively
informing prescribing decisions. timing), if known, and the nature of any demonstrate an association between
Drug effects during labor or delivery. identified fetal developmental prenatal exposure to the drug in
FDA proposed that the Clinical abnormalities or other adverse effect(s). question and the adverse developmental
Considerations portion of pregnancy Animal doses must be described in outcome. However, FDA also recognizes
labeling contain information about drug terms of human dose equivalents and that there may be isolated situations in
effects during labor or delivery for drugs the basis for those calculations must be which reporting of adverse reactions
that have a recognized use during labor included. corroborates other human data and, in
or delivery, whether or not the use is (4) For human data, positive and these situations, it may be appropriate
stated as an indication in the labeling, negative experiences during pregnancy, to list a specific number of cases with
or are expected to affect labor or including developmental abnormalities, the date when the reporting was
delivery (proposed must be described. To the extent collected. FDA will consider whether
201.57(c)(9)(i)(D)(3)). applicable, the description must include the labeling for a drug product should
(Comment 62) One comment the number of subjects and the duration include specific numbers of reports of
supported the proposal to merge of the study. adverse reactions on a case-by-case basis
information about labor and delivery (5) For animal data, the relationship based on evaluating all available data
into the Pregnancy subsection of of the exposure and mechanism of and principles of epidemiology and data
labeling. action in the animal species to the interpretation.
Another comment expressed concern anticipated exposure and mechanism of In the final rule, FDA replaced the
that including information about drugs action in humans must be described. If phrase provide an overview of the
used during labor or delivery, including this relationship is not known, that data with describe the data. FDA
drugs that are used off-label during should be stated (proposed made this change to clarify our
labor or delivery, conflicts with FDAs 201.57(c)(9)(i)(E)). intention that under the subheading
Data, the labeling must include a in the preamble to the proposed rule, 201.56(d)(1) and 201.57(c)(9)(ii)).
more detailed description of the data the importance of human data in FDA proposed that the Lactation
than might be understood from use of labeling was stressed by physicians who subsection of prescription drug labeling
the term overview. In the final rule, participated in focus group testing of the contain the following subheadings:
FDA also added the requirement that model labeling format and also by the Risk Summary, Clinical
under Data, the labeling describe the FDA advisory committee that provided Considerations, and Data (proposed
data that are the basis for the Clinical input on the proposed format (73 FR 201.57(c)(9)(ii)). FDA received many
Considerations. The proposed rule 30831 at 30841). FDA has determined comments about the proposed
stated that Data must describe the that human data should always be Lactation subsection and made
data that were the basis for the fetal risk presented first because human data are changes to the final rule based on these
summary, and did not address the data often the most relevant to prescribers, comments. The discussion that follows
that were the basis for Clinical and animal data may not always be addresses these comments, our
Considerations. FDA has determined applicable to humans. responses, and the changes FDA made
that there is no principled reason to FDA also proposed that animal doses to the final rule.
distinguish between the data under the must be described in terms of human a. General comments.
fetal risk summary and that underlying dose equivalents and the basis for those i. Support for Lactation subsection
Clinical Considerations. Accordingly, calculations must be included. (Comment 67) FDA received many
the final rule requires that under the (Comment 66) Two comments comments expressing support for the
subheading Data, the labeling suggested that the final rule remove the proposed Lactation subsection. One
describe the data that are the basis for requirement to use administered dose of these comments explained that it is
both the Risk Summary and Clinical as a comparator between animal and essential for drug labeling to carry best
Considerations. This subheading, human data and to replace it with science information that enables
therefore, is only required to the extent comparisons based on systemic clinicians to efficiently and thoroughly
that there are data that are the basis for exposure, if available. One of these review what is known about the drug
these two subheadings and the headings comments explained that basing the and any reported health effects to the
under them. comparison on systemic exposure will breast-fed infant. The comment stated
FDA has also determined that the provide greater consistency within the that the proposed rule would facilitate
information in labeling would be clearer labeling and will also provide a way to more efficient consideration of the data.
if human data and animal data appeared more easily make comparisons between (Response) We agree with these
separately under applicable headings. In drugs. comments, and our final rule requires
the final rule, FDA requires that human (Response) FDA declines this labeling to include a subsection on
and animal data be presented separately suggestion to restrict the comparison to lactation with risk and benefit
under the headings Human Data and only those based on systemic exposure. information related to breastfeeding and
Animal Data. We agree that comparisons based on the breast-fed infant.
In the final rule, FDA requires that for systemic exposure could provide ii. Drug alternatives
human data, the labeling must describe consistency within labeling and (Comment 68) One comment
adverse developmental outcomes, therefore the final rule requires that they suggested that a statement should be
adverse reactions, and other adverse must be included when data are included that many drugs for which we
effects. To the extent applicable, the available, but the data are not always may not have lactation data have a
labeling must describe the types of available for such a comparison. FDA suitable alternative for which we do
studies or reports, number of subjects believes that including the human dose have data.
and the duration of each study, equivalent may be more meaningful (Response) We decline to adopt this
exposure information, and limitations of information for health care providers, comment. We do not believe it would be
the data. The final rule requires that particularly in the absence of data to appropriate to include this type of
both positive and negative study make comparisons based on systemic statement in labeling. Because the
findings be included. The proposed rule exposure, and as such, in the final rule, comparative risks and benefits will vary
listed various types of studies. These a comparison of the animal to human among individual patients, a health care
were removed from the final rule doses must be included using the data provider, in consultation with his or her
because we determined that it is more available. patient, is in the best position to
appropriate to discuss these elements in The proposed rule required that for determine whether there is a suitable
guidance. animal data under the Data alternative for a particular drug.
Animal data. FDA proposed that component the relationship of the iii. Validating data
human and animal data must be exposure and mechanism of action in (Comment 69) One comment
presented separately, and human data the animal species to the anticipated expressed concern about the potential
must be presented first. exposure and mechanism of action in for bias or omissions with respect to
(Comment 65) One comment humans be described. In the final rule, which data the sponsor includes and the
suggested that FDA omit the we removed this requirement because risk statements the sponsor uses to
requirement that human data must be often this relationship is not known. characterize such data. The comment
presented first. The comment explained The final rule requires that animal doses encouraged FDA to employ all
that the most robust data should be or exposures be described in terms of reasonable means to validate the
presented first regardless of whether it human dose or exposure equivalents, sponsors collection, evaluation, and
is animal or human data. and that the basis for those calculations subsequent conclusions regarding
(Response) FDA declines this be included. lactation data.

suggestion. We have determined that to (Response) FDA agrees. FDA will
promote consistency and to meet 2. 8.2 Lactation review data available in literature and
readers expectations that information FDA proposed that the Nursing sponsor-submitted data used for
will always be found in the same place, mothers subsection of prescription developing the Lactation subsection
a fixed order of presentation must be drug labeling be replaced with the of drug labeling. We note that this does
maintained. Additionally, as discussed subsection Lactation (proposed not require a change to the final rule
because FDAs normal review process addition to offering potential FDA proposed that if data
for prescription drug labeling includes therapeutic benefit(s), all drugs have demonstrate that a drug is not
validating the applicants collection, potential side effects and risks involved systemically absorbed, the fetal risk
evaluation, and subsequent conclusions with their use. The balance between summary must contain only the
regarding data. those benefits and risks is taken into following statement: (Name of drug) is
b. Risk summary account not just at the approval stage, not absorbed systemically from (part of
i. Active metabolites but also helps direct diagnostic and body) and cannot be detected in the
(Comment 70) Two comments treatment recommendations for a mothers blood. Therefore, detectable
suggested that FDA revise the Risk particular patient in a particular clinical amounts of (name of drug) will not be
Summary so that it explicitly refers to scenario. Accordingly, in the final rule present in milk. Breastfeeding is not
active metabolites of the drug, in FDA removed the statement The use of expected to result in fetal exposure to
addition to the drug itself. (name of drug) is compatible with the drug (proposed 201.57(c)(9)(ii)(A)).
(Response) FDA agrees with this breastfeeding. (Comment 72) One comment
comment. We also have determined that suggested that the statement be revised
Breastfeeding offers significant health
it is appropriate to include information to focus on the route of administration
benefits to both the child and mother.
about the effects of a drug and/or its rather than on the part of the body
Different drugs and/or their active
active metabolite(s) not only in the where the drug is administered. The
metabolites pass into breast milk in
Risk Summary, but under other comment also suggested that the
different concentrations; they may or
subheadings in the Lactation language cannot be detected in blood
may not be orally bioavailable in the
subsection of labeling. Therefore, the could be omitted because it is
infant, and they may or may not result
final rule has been revised to refer redundant with not systemically
in significant adverse reactions in the
explicitly to drugs and/or their active absorbed.
short term or adverse outcomes in the
metabolites. (Response) FDA agrees with this
ii. Compatible with breastfeeding long term. Often, all of the potential
risks related to drug treatment during comment and we removed the phrase
FDA proposed that under the cannot be detected in blood from the
subheading Risk Summary, if, as lactation are not known even though the
benefits of breastfeeding are known and final rule.
described under 201.57(c)(9)(ii)(A)(1) We also agree with the suggestion to
through (c)(9)(ii)(A)(3) of the section, substantial.
focus on the route of administration.
the data demonstrate that the drug does FDA declines the suggestion to FDA agrees that part of the body
not affect the quantity and/or quality of include a standardized statement that could be misconstrued and we have
human milk and there is reasonable sufficient human data exist to determined that the use of route of
certainty either that the drug is not indicate that the drug does or does not administration to describe how the
detectable in human milk or that the adversely affect the breast-fed child, drug enters the body is more consistent
amount of drug consumed via breast followed by a supportive narrative. with labeling language that addresses
milk will not adversely affect the breast- However, the final rule requires that if dosing and administration. In the final
fed child, the labeling must state: The the drug is absorbed systemically, the rule, FDA has replaced part of the
use of (name of drug) is compatible with labeling must include, under Risk body with route of administration.
breastfeeding. After this statement (if Summary, available information, if (Comment 73) Another comment
applicable), the risk summary must relevant, on the known or predicted suggested revising the language
summarize the drugs effect on milk effects on the breast-fed child from systemically absorbed to has a
production, what is known about the exposure to the drug and/or its active systemic effect to include the action of
presence of the drug in human milk, metabolite(s), including systemic and/or biological products (vaccines) that are
and the effects on the breast-fed child local adverse reactions. If the available immune stimulants rather than
(proposed 201.57(c)(9)(ii)(A)). information is sufficient to determine chemicals that are absorbed.
(Comment 71) Two comments that use of the drug is contraindicated (Response) FDA declines the
suggested that FDA eliminate the during breastfeeding, this significant suggestion to change the language
statement, The use of (name of drug) information is required at the beginning systemically absorbed to has a
is compatible with breastfeeding from of the Risk Summary. The Risk systemic effect. The terms
the Lactation subsection of the final Summary must state when there are no systemically absorbed and absorbed
rule. One of the comments explained data to assess the effects of the drug on systemically refer to the absorption of
that it will be difficult to determine the child. the drug or biological product from its
whether a drug is compatible with FDA also revised the final rule to site of administration into serum and/or
breastfeeding with such definitive require that if studies demonstrate the other body tissues where the drug or
certainty, especially since the term presence of the drug and/or its active biological product, including a vaccine,
compatible implies safety. Another metabolite(s) in human milk but the can reach its receptor or target cell and
comment suggested that in the final rule drug and/or its active metabolite(s) are exert its pharmacological or
FDA should replace the statement not expected to be systemically immunological effect. A drug or
compatible with breastfeeding with a bioavailable to the breast-fed child, then biological product that is not
standardized statement that sufficient the Risk Summary must describe the systemically absorbed will not be
human data exist to indicate that the disposition of the drug and/or its active excreted into human milk and,
drug does or does not adversely affect metabolite(s). FDA added this therefore, breastfeeding should not
the breast-fed child, followed by a requirement to the final rule to identify result in the childs exposure to the
supportive narrative. situations in which a drug and/or its drug. In the final rule, FDA has deleted
(Response) FDA agrees that the term active metabolite(s) are present in the sentence, Therefore, detectable
compatible is not clearly defined and human milk but the breast-fed child amounts of (name of drug) will not be
implies that the use of a drug during does not have any systemic exposure present in breast milk. The final rule
lactation is safe. No drug is because of degradation in the also replaces the sentence,
completely safe even in a person who is gastrointestinal tract. Breastfeeding is not expected to result
not pregnant or breastfeeding. In iii. Not systemically absorbed in fetal exposure to the drug with
breastfeeding is not expected to result not be used in the Risk Summary, and added that clinicians may have
in exposure of the child to (name of that a description of available data, if difficulty interpreting the calculations.
drug). relevant, on the presence of the drug One comment stated that the
(Comment 74) Two comments noted and/or its active metabolite(s) in human concentration of the drug detected in
that the term fetal was used milk should be used instead. In milk should not be made in reference to
improperly in this section of the addition, FDA has determined that, in the maternal dose or the labeled
proposed rule. order to provide clarity in the Risk pediatric dose. The comment explained
(Response) FDA agrees and has Summary, in situations where there are that the concentration of a drug in milk
removed the term fetal from the no data to assess whether the drug and/ may vary widely depending upon
Lactation subsection and replaced it or its active metabolite(s) are present in whether it reflects steady-state or a
with the term child. human milk, the Risk Summary must single dose, and could vary based on the
iv. Presence of drug in human milk so state. timing between the ingestion of the drug
FDA proposed that under the heading and taking the sample. The comment
(Comment 76) Limits of the assay
Presence of drug in human milk: suggested that an estimate of the amount
used. Two comments suggested omitting
(1) The risk summary must describe of the drug consumed daily by the
assay information if the presence of
the presence of the drug in human milk infant could be made in reference to the
drug in milk is not detectable. The
in one of the following ways: The drug maximum maternal daily dose or the
comments stated that assay information
is not detectable in human milk; the maximum labeled pediatric dose and
is overly technical and unfamiliar for
drug has been detected in human milk; that an estimate of the [percentage] of
many health care providers. In addition,
the drug is predicted to be present in the maternal dose excreted in human
the comments explained that it would
human milk; the drug is not predicted milk could be omitted.
be presumed that during its review of
to be present in human milk; or the data One comment suggested that FDA
the data, the review division at FDA
are insufficient to know or predict standardize the approach to presenting
would consider the validity of studies,
whether the drug is present in human drug concentrations in breast milk and
including the assays reliability and
milk; stated that this would ensure that
(2) If studies demonstrate that the sensitivity, before approving the
uniform data are presented by all
drug is not detectable in human milk, inclusion in labeling of a statement that
manufacturers, allowing for easy
the risk summary must state the limits the drug is not detectable in human
comparisons between prescription
of the assay used; and milk.
products. The comment also suggested
(3) If the drug has been detected in (Response) FDA declines this that FDA provide a guidance document
human milk, the risk summary must comment. We have determined that the highlighting the value of breast milk
give the concentration detected in milk limit of the assay is critical to area under the curve (AUC)
in reference to a stated maternal dose understanding the amount of the drug concentrations, explaining that
(or, if the drug has been labeled for and/or its active metabolite(s) that may providing standardized ways of
pediatric use, in reference to the labeled or may not be present in human milk. calculating weight-normalized drug
pediatric dose), an estimate of the We also believe that most health care doses and average breast milk
amount of the drug consumed daily by providers are capable of interpreting consumption could better guide
the infant based on an average daily this data when presented in labeling manufacturers and help create a unified
milk consumption of 150 milliliters per and that health care providers are approach to describing drug
kilogram of infant weight per day, and familiar with the importance of assay concentrations in breast milk.
an estimate of the [percentage] of the limits for all types of laboratory testing. (Response) FDA addresses these
maternal dose excreted in human milk In the final rule, FDA has retained the issues in the draft guidance for industry
(proposed 201.57(c)(9)(ii)(A)(2)(i) requirement from the proposed rule that on Clinical Lactation StudiesStudy
(c)(9)(ii)(A)(2)(iii)). We received if studies demonstrate that the drug Design, Data Analysis, and
comments about this portion of the and/or its active metabolite(s) are not Recommendations for Labeling
Lactation subsection of the proposed detectable in human milk, the Risk (February 2005) (the draft guidance on
rule. The discussion that follows Summary must state the limits of the clinical lactation studies).
addresses these comments, our assay used. FDA agrees that it would be helpful
responses, and the changes FDA made (Comment 77) Concentration of the to clinicians to provide infant drug
to this portion of the Lactation drug detected in human milk. Two exposure dosing in milligrams per
subsection of the final rule. comments expressed support for FDAs kilograms received per day so that a
(Comment 75) Predicting whether proposal that the Lactation subsection clinician may compare it to a labeled
drug is present in human milk. Several of prescription drug labeling provide the infant or pediatric dose if available.
comments objected to the proposal that concentration of the drug detected in However, because of the technical
the Risk Summary state that the drug human milk in reference to a stated considerations for calculating drug and/
is predicted or not predicted to be adult or labeled pediatric dose. One of or active metabolite levels in milk, FDA
present in human milk. One of these these comments suggested that the is not requiring this in the final rule.
comments stated that avoiding labeling should also include the FDA has determined that the actual or
predictions and relying instead on milligrams per kilogram received per calculated infant daily dose must be
clinical data would better assist day and the percentage of the weight- compared to the labeled infant or
providers. Two comments suggested equivalent therapeutic dose pediatric dose, when available, and to
that the statements about whether the administered to the mother. This the maternal dose when pediatric
drug is predicted or not predicted to be comment requested that the doses be dosing is not available. When infant or
present in human milk should be presented according to infant age ranges pediatric dosing is available for a drug
omitted because the other proposed when possible. A separate comment and pediatric pharmacokinetic data are
descriptions effectively cover the range suggested providing a calculation of the available for a drug and/or its active
of potential options. estimated infant daily dose consumed as metabolite(s), these data provide an
(Response) FDA agrees that the terms compared to available pediatric dosing effective way to estimate comparative
predicted and not predicted should rather than to maternal dosing, but exposure (and potentially comparative
safety) of a breast-fed child versus a milk production, and if there are no data patients. In the final rule, FDA requires
child receiving a drug therapeutically. to assess the effects of the drug and/or that for drugs absorbed systemically,
Although not required by the final its active metabolite(s) on milk unless breastfeeding is contraindicated
rule, FDA agrees that data presented production, the Risk Summary must during drug therapy, a statement that
according to infant age groups could be so state. the developmental and health benefits
useful given the changes in infant With respect to milk quality and of breastfeeding should be considered
hepatic and renal function during the composition, there are currently no along with the mothers clinical need for
first few months of life, and infants established standards or documented the drug and any potential adverse
increasing ability with age to metabolize population variability for milk content. effects on the breast-fed child from the
and clear drugs and/or their active It is also not known how much change drug or from the underlying maternal
metabolites. These data may not always in various milk components would condition, must be included at the end
be available, but when they are, their reduce the known benefits of of the Risk Summary in the
presentation stratified by age would be breastfeeding relative to the risks of Lactation subsection of labeling.
clinically relevant and should be exposure to a drug and/or its active
included in labeling. metabolite(s) through breast milk c. Clinical Considerations
(Comment 78) No data. One combined with any potential effects on FDA proposed that under the
comment suggested removing the phrase milk composition and quality. subheading Clinical Considerations,
no data from the Risk Summary in Accordingly, in the final rule, FDA has the labeling must provide the following
the Lactation subsection, because removed the requirement that the Risk information to the extent it is available:
there are rarely no data for a drug. Summary describe the effect of the (1) Information concerning ways to
(Response) FDA disagrees with the drug on the quality and composition of minimize the exposure of the breast-fed
suggestion to remove the phrase no milk, and the implications of these child to the drug, such as timing the
data from the Risk Summary. Often, changes to the milk on the breast-fed dose relative to breastfeeding or
there are no lactation data (either child. pumping and discarding milk for a
human or animal) at the time of specified period; (2) information about
approval of NDAs and BLAs. vi. Sufficient Data potential drug effects in the breast-fed
v. Effects on milk production and (Comment 80) One comment noted child that could be useful to caregivers,
quality that the proposed rule does not require including recommendations for
FDA proposed that if the drug is sufficient data to reach conclusions in monitoring or responding to these
absorbed systemically, the risk summary the Risk Summary in the Lactation effects; and (3) information about dosing
must describe the effect of the drug on subsection, and suggested that FDA adjustments during lactation. This
the quality and quantity of milk, discuss what constitutes sufficient data, information must also be included in
including milk composition, and the as it does in the Pregnancy the Dosage and Administration and
implications of these changes to the subsection. Clinical Pharmacology sections
milk on the breast-fed child (proposed (Response) As discussed previously, (proposed 201.57(c)(9)(ii)(B)(1)
201.57(c)(9)(ii)(A)(1)). many comments disagreed with FDAs (c)(9)(ii)(B)(3)). FDA received comments
(Comment 79) Several comments proposed use of the term sufficient in about the proposed Clinical
stated that it is seldom feasible to the Pregnancy subsection of labeling. Considerations subheading. The
adequately study the effects of a drug on The comments stated that the term was discussion that follows addresses these
the quality and quantity of breast milk, not clearly defined in the proposed rule, comments, our responses, and FDAs
and this information should only be and suggested that it would be difficult changes to the final rule.
provided when available. One comment to apply the term consistently across
explained that to be scientifically valid, drug labeling. Based on FDAs i. Other Therapies
such evaluation requires a study before, consideration of these comments, the In the Proposed rule, FDA included
during, and after drug exposure. This final rule does not refer to sufficient sample labeling for several fictitious
comment explained that further data in either the Pregnancy or the drugs. In the Clinical Considerations
complicating factors are substantial Lactation subsection. portion of the Lactation subsection,
inter- and intra-individual variation and the ALPHAZINE sample stated that
small study sample size. vii. Risk and Benefit Statement Other medical therapies are available
One comment requested that FDA (Comment 81) FDA received seven for treatment of maternal hypertension.
include information about the effects of comments noting that the proposed (Comment 82) Two comments
the drug on the womans milk supply Lactation subsection did not require disagreed with the inclusion of this
and other issues that affect the process the inclusion in labeling of any statement. The comments explained that
of breastfeeding. The comment stated information about the benefits of the statement is confusing because
that many women are advised against breastfeeding. Some of these comments although no comparator data are
taking medications that affect milk recommended that FDA add such a presented, clinicians may infer that
supply while lactating but are not statement to the final rule to prevent other drugs in the class are safe and
informed that this is the reason they patients from unnecessarily foregoing or effective.
should avoid these medications. discontinuing breastfeeding. (Response) We note that the language
(Response) Although FDA agrees that (Response) FDA acknowledges that to which these comments refer was
it is not always possible to determine the proposed rule did not require the included in sample labeling included
the effects of a drug and/or its active inclusion of information about the with the proposed rule, and not in the
metabolite(s) on milk production, we benefits of breastfeeding. The Agency proposed rule itself. FDA included
have determined that when the relevant has determined that the inclusion in the sample labeling with the proposed rule
data are available, this information must Lactation subsection of labeling of a to serve as examples of how to apply the
be included in the labeling. In the final risk and benefit statement will provide requirements of the proposed rule in
rule, FDA requires that the Risk a useful framework for health care different scenarios. We note that the
Summary describe the effects of the providers to use when making final rule does not include sample
drug and/or its active metabolite(s) on prescribing decisions for lactating labeling. FDA agrees, however, that
statements such as, Other medical of topical drugs applied to the breast or the breast-fed child that could be useful
therapies are available for treatment of nipple skin. to caregivers.
maternal hypertension, may be (Comment 84) Topical products. In (Response) FDA acknowledges that
confusing, and should not be included the proposed rule, FDA did not provide this portion of the proposed rule
in the Pregnancy or Lactation for inclusion of data regarding topical appeared to require information
subsections of labeling. drugs that are not absorbed systemically duplicative of information in the Risk
by the mother but that may transfer to Summary. We removed the language,
ii. Minimizing Exposure to the Breast- information about potential drug
Fed Child infants during breastfeeding. One
comment requested that FDA include a effects in the breast-fed child, from the
(Comment 83) General comments. standardized statement in the Risk Clinical Considerations portion of the
Four comments disagreed with the Summary about such drug products. Lactation subsection of the final rule.
proposal to include information (Response) Situations in which a In the final rule, when relevant
regarding minimizing exposure of the topical pharmaceutical product can information is available about potential
breast-fed child in the Clinical adverse effects in an infant due to
result in infant exposure without
Considerations portion of the exposure to the maternal drug and/or its
systemic absorption of the product into
Lactation subsection. These active metabolite(s) through human
maternal serum are limited to topicals
comments explained that inclusion of milk, this information must be included
applied to the skin of the breast,
this information could discourage in the Risk Summary. FDA also
especially that of the nipple and areola.
women from breastfeeding even when concluded that it was not necessary to
For prescription drug products, these
there is no reason for concern. One characterize information about the
topicals would most likely include
comment noted that this information potential effects of a drug and/or its
corticosteroids and anti-infectives. FDA
should only be included when there is active metabolite(s) on a breast-fed child
acknowledges that the proposed rule
information that breastfeeding should be as being useful to caregivers because,
withheld during drug therapy and the did not accommodate a situation in
although caregivers sometimes read
timing of pumping and discarding of which a drug product does not result in
prescription drug labeling, it is not
breast milk can be provided. maternal systemic exposure but could
directed at them, and individual health
Alternatively, the comment suggested result in infant systemic exposure. In
care providers are in the best position to
stating when information regarding the response to this comment, FDA revised
discuss with their patients information
timing of pumping and discarding the Minimizing exposure portion of
that may be useful for the patients to
breast milk cannot be provided. Another Clinical Considerations to
share with other caregivers. Therefore,
comment noted that this information accommodate the inclusion of
the reference to information that may be
should not be obligatory when data information about such products. In the
useful to caregivers also has been
suggest that there is not sufficient final rule, FDA added a requirement removed.
excretion of the drug in milk to cause that, when applicable, the labeling must FDA acknowledges the comment
concern for the infant. The comment also describe ways to minimize a breast- concerning the use of the term
explained that including this fed childs oral intake of topical drugs recommendations in the second part
information when the Risk Summary applied to the breast or nipple skin. of this provision, and in the final rule
and Data components have already iii. Drug Effects in the Breast-Fed Child has removed the term
stated that the drug is compatible with and Monitoring for Adverse Reactions recommendations for monitoring and
breastfeeding could give the false replaced it with available interventions
impression that the drug is unsafe for FDA proposed that the Clinical for monitoring or mitigating. The final
the child and may encourage women to Considerations portion of the rule requires that under Clinical
discontinue breastfeeding. One Lactation subsection of prescription Considerations the labeling describe
comment noted that in cases when the drug labeling include information about information about available
drug disappears from breast milk with a potential drug effects in the breast-fed interventions for monitoring or
known half-life, it is possible to child that could be useful to caregivers, mitigating the adverse reactions
minimize infant exposure by including recommendations for described in the Risk Summary. We
recommending dosing occur at certain monitoring or responding to these note that this language is consistent
times related to feeding. effects (proposed with the language in the Pregnancy
(Response) FDA notes that 201.57(c)(9)(ii)(B)(2)). subsection.
information concerning minimizing (Comment 85) FDA received one
exposure to the breast-fed child must be comment about this portion of the iv. Dose Adjustments
provided only to the extent it is proposed Clinical Considerations. (Comment 86) One comment stated
available and relevant. In addition, the The comment suggested that FDA omit that dose adjustment information
final rule was revised to clarify that the first part of this provision should not be included in the
information concerning minimizing information about potential drug Lactation subsection. The comment
drug exposure in the breast-fed child effects in the breast-fed childbecause suggested that dosing information
must be included only if the drug and/ this information duplicates the generally should be restricted to the
or its active metabolite(s) are present in information required to appear in the Dosage and Administration section of
human milk in clinically relevant Risk Summary under proposed labeling.
concentrations; the drug does not have 201.57(c)(9)(ii)(A)(3), Effects of drug (Response) FDA agrees with the
an established safety profile in infants; on the breast-fed child. The comment suggestion that we omit information
and the drug is used either also stated that the term about dose adjustments from the
intermittently, in single doses, or for recommendations in the second part Lactation subsection of prescription
short courses of therapy. As discussed of this provision could interfere with drug labeling, although this decision is
further in our response to Comment 84, the practice of medicine. The comment not based on a conclusion (as suggested
the final rule also requires that, when suggested the following language: in the comment) that dosing information
applicable, the labeling describe ways to Information about ways to monitor for, generally should be restricted to the
minimize a breast-fed childs oral intake or respond to, potential drug effects in Dosage and Administration section of
labeling. FDA has determined that other animal data in the Lactation infertility be relocated in labeling under
than during the immediate postpartum subsection. subsection 8.3 Females and Males of
period when a womans physiology is (Response) The preamble to the Reproductive Potential. FDA is adding
reverting from a pregnant to a proposed rule did not include a this requirement to the final rule based
nonpregnant state, a lactating woman is discussion of animal lactation data, and on public comments regarding these
unlikely to require dose adjustments for the inclusion of animal lactation data issues, and based on the Agencys
drugs. The physiological changes was not addressed in the codified conclusion that this information should
associated with lactation are unlikely to section of the proposed rule. In the final be presented in labeling in a consistent
result in pharmacokinetic changes rule, under Risk Summary, FDA location. Subsection 8.3 Females and
significant enough to warrant maternal defines situations for which animal Males of Reproductive Potential
dose adjustments. Therefore, FDA has lactation data must and must not be includes three subheadings, Pregnancy
determined that all available and included in the Lactation subsection. Testing, Contraception, and
relevant information about dose Animal lactation data can be helpful in Infertility. Each subheading should
adjustments during pregnancy and the predicting whether a drug and/or its only be included if it is applicable or if
postpartum period must be included in active metabolite(s) will be present in relevant information is available, and
the Pregnancy subsection of labeling. human milk; however, because of Section 8.3 should be omitted in its
In the final rule, FDA has removed the species-specific differences in lactation entirety if none of the subheadings are
requirement that information about physiology, animal lactation data applicable. The comments are discussed
dosing adjustments during lactation be typically do not reliably predict drug in detail in our responses to Comments
included in the Lactation subsection levels in human milk. FDA added a 88, 89, and 90.
of labeling. requirement to the final rule that when Information concerning pregnancy
relevant human lactation data are testing, contraception, and infertility is
d. Data available, animal data must not be important for informing decisions made
FDA proposed that under the included unless the animal model is by patients, in consultation with their
subheading Data, the Lactation specifically known to be predictive for health care providers, regarding the use
subsection of the labeling must provide humans. In addition, under Risk of prescription drugs before or during
an overview of the data that are the Summary, Presence of drug in human pregnancy. This information is in many
basis for the risk summary and clinical milk, FDA clarified that if only animal ways inherently linked to the scientific
considerations (proposed lactation data are available, the Risk and medical rationale underpinning the
201.57(c)(9)(ii)(C)). FDA received Summary must state only whether or Pregnancy subsection of prescription
comments about this portion of the rule. not the drug and/or its active drug labeling. However, in the course of
One comment expressed support for metabolite(s) were detected in animal developing this final rule, and in
presenting lactation data under Data milk and specify the animal species. particular in evaluating comments 88,
when available. The other comments Although animal data do not reliably 89, and 90, FDA concluded that because
and changes we made in response to predict whether a drug and/or its active there was no consistent placement in
those comments are explained in this metabolite(s) will be present in human the labeling of information about
section of the document. milk, in the absence of human data, pregnancy testing, contraception, and
FDA determined that the fact that a drug infertility, it was difficult for health care
(Comment 87) FDA received
and/or its active metabolite(s) were or providers to find this important
comments requesting that the Agency
were not detected in animal milk may information. For example, clinical
clarify when animal lactation data
nevertheless be useful in informing advice on infertility might be found
should be included in labeling. Several
prescribing decisions. with the discussion of animal data in
comments questioned the usefulness of In the final rule, FDA revised the the Nonclinical Toxicology section, in
animal lactation data in the absence of Data portion of the Lactation the Adverse Reactions section, or in
clinical data. One comment stated that subsection to require that the labeling the Warnings and Precautions
extrapolation of animal data to humans describe the data that are the basis for section. Contraception and pregnancy
may not be helpful without stating what the Risk Summary and Clinical testing recommendations for known or
is known about the correlation to Considerations and removed the suspected teratogens might be found in
humans. requirement that the labeling provide the Pregnancy subsection or in the
Several comments stated that only an overview of the data. FDA made Warnings and Precautions section.
human data should be presented when this change to clarify that under Data, (Comment 88) FDA received one
it is available. Two comments requested the labeling must include a more comment suggesting that the new
that if, in cases where both human and detailed description of the data than labeling explicitly state that a woman
animal data are available, FDA decides might be understood from use of the taking drugs with potential or known
to retain the requirement that both kinds term overview, as well as to maintain adverse effects on pregnancy outcomes
of data be presented, the Lactation consistency between the Data should (1) consider using reliable
subsection be revised to state that portions of the Lactation and contraception if she does not intend to
clinical data are to be presented before Pregnancy subsections. Furthermore, become pregnant or (2) if she does
preclinical data. this subheading is only required to the intend to become pregnant, seek
One comment requested additional extent that there are data that are the consultation with her health care
clarification regarding the quantity and basis for the Risk Summary and Clinical provider to discuss medical
quality of animal data that would Considerations subheadings, and the management of her health condition
support inclusion of the data in headings under them. before becoming pregnant, if possible.
labeling, and asked that FDA provide (Response) FDA agrees that when a
sample labeling for a drug for which 3. 8.3 Females and Males of drug has a potential or known adverse
only animal lactation data are available. Reproductive Potential effect on pregnancy outcomes (e.g., is a
Another comment suggested that the In the final rule, FDA is adding a known or suspected human teratogen),
labeling state when there is an absence requirement that information regarding information regarding recommendations
of available or sufficient human and/or pregnancy testing, contraception, and or requirements regarding contraception
use must be included in prescription developmental toxicity and the transfer subsection 8.3. Females and Males of
drug labeling. In the final rule, FDA of semen is unknown. This comment Reproductive Potential. In addition,
requires that when contraception is suggested that statements addressing when there are contraception
required or recommended before, this issue be added when the recommendations based on animal
during, or after drug therapy, this information is required for the product. mutagenesis data, this information must
information must be included under the One of the comments suggested that be included in subsection 8.3 under the
subheading Contraception in FDA add a section to the final rule that Contraception subheading. Because the
subsection 8.3 Females and Males of addresses prescribing information for same concerns about drug-associated
Reproductive Potential. In addition, it male patients with a partner of fertility effects apply to human data,
may be appropriate to include in this reproductive potential or a pregnant FDA has determined that human data
subsection information concerning partner. Another comment suggested that raise such concerns also must be
counseling females of reproductive that the risk conclusion statement included in the Infertility subsection.
potential about pregnancy planning. specify whether it is based on maternal With respect to the question about
Furthermore, the concerns expressed or paternal exposure when that cross-referencing, subsection 8.3 should
in the comment regarding the inclusion information is available. cross-reference the applicable animal
of information about contraception use (Response) FDA agrees that when data included in subsection 13.1,
when taking a drug with potential or relevant information is available, this consistent with FDAs cross-referencing
known adverse effects on pregnancy information should be included in regulations (e.g., 201.57(c)(1),
outcomes apply equally to information labeling. In the final rule, FDA requires (c)(6)(iv), and (c)(15)(ii)). The draft
about pregnancy testing, particularly that information about recommended or guidance on pregnancy and lactation
when a drug is a known or suspected required use of contraception by men be labeling, which is being published
human teratogen. Therefore, FDA has included under the subheading concurrently with this final rule,
determined that information regarding Contraception in subsection 8.3 addresses these issues.
recommendations or requirements Females and Males of Reproductive
IV. Implementation
concerning pregnancy testing before, Potential.
during, or after drug therapy must also (Comment 90) FDA received one FDA proposed that holders of
be included in prescription drug comment requesting that the Agency applications (including an NDA, BLA,
labeling. In the final rule, FDA requires clarify how and when animal data or efficacy supplement) approved before
that this information be included under described in subsection 13.1 of labeling June 30, 2001, would be required to
the subheading Pregnancy Testing in (Carcinogenesis, Mutagenesis, remove the pregnancy category from
subsection 8.3 Females and Males of Impairment of Fertility) that raises their labeling within 3 years after the
Reproductive Potential. concerns about mutagenesis, effective date of this rule. These
(Comment 89) FDA received three impairment of fertility, or pre- applications are those that are not
comments noting that the Pregnancy implantation loss should be included in subject to the requirements of the PLR.
subsection of the proposed rule only subsection 8.1 Pregnancy. The For drugs with applications (including
addresses risks to the fetus when the comment also requested that FDA an NDA, BLA, or efficacy supplement)
drug is administered to a pregnant clarify when it would be appropriate to approved on or after June 30, 2001, FDA
woman, and it does not address the move information from subsection 13.1 proposed a phased-in implementation
potential for manifestations of to subsection 8.1 or to cross-reference plan that would stagger the required
developmental toxicity associated with subsection 13.1 in subsection 8.1. dates these products would be required
fetal drug exposure from transfer of drug (Response) As stated previously, FDA to replace the content and formatting of
through semen to the maternal and fetal concluded that it is important to include the pregnancy and lactation subsections
circulations. One of the three comments information about drug-associated of their labeling with the new content
noted that the proposed rule does not fertility effects in labeling in a and formatting required by this rule.
address the potential for manifestations consistent location and manner. In the These applications are those that are
of developmental toxicity associated final rule, animal data that raise subject to the requirements of the PLR.
with exposure resulting from transfer concerns about drug-associated Table 1 contains the implementation
through the semen or the need for male impairment of fertility and/or pre- plan that was included in the proposed
contraception when a compound is implantation loss effects must be rule. In table 1, Applications includes
determined to have a predicted risk of included under Infertility in NDAs, BLAs, and efficacy supplements.
TABLE 1IMPLEMENTATION PLAN

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

Applications required to conform to new pregnancy/lactation Time by which labeling with new pregnancy/lactation content must be
content requirements submitted to FDA for approval
Applications approved from June 30, 2002, up to and including June 5 years after the effective date of pregnancy final rule.
29, 2005.
(Comment 91) Two comments stated pregnancy categories will be removed FD&C Act and by the PHS Act. Section
that the proposed implementation plan from the labeling for some drugs before 502(a) of the FD&C Act deems a drug to
was confusing. One of these comments the new content required by the rule be misbranded if its labeling is false or
requested that FDA explain the rationale will be added to the labeling, and this misleading in any particular. Under
supporting the implementation could cause confusion among doctors section 201(n) of the FD&C Act (21
schedule. Another comment stated the and patients. U.S.C. 321(n)), labeling is misleading if
proposed phased-in approach for (Response) We would like to clarify it fails to reveal facts that are material
previously approved drugs may generate that a holder of an application that is with respect to consequences that may
confusion. The comment explained that not subject to the PLR, and thus, not result from the use of the drug under the
if drug labeling information and drug subject to the new content and format conditions of use prescribed in the
reference materials contain pregnancy requirements of this final rule, must labeling or under customary or usual
information that is inconsistent between remove the pregnancy category from its conditions of use. Section 502(f) of the
newly approved and previously labeling within 3 years after the FD&C Act deems a drug to be
approved drugs through a 3- to 5-year effective date of this rule. A holder of misbranded if its labeling lacks
period, confusion may limit the an application that is subject to the PLR adequate directions for use and
understanding of the new labeling. and thus, subject to the new content and adequate warnings against use in those
Comments disagreed about whether format requirements of this rule, is not pathological conditions where its use
the length of the implementation required to remove the pregnancy may be dangerous to health, as well as
schedule was reasonable. One comment category until such time that it is adequate warnings against unsafe
stated that the long implementation required to submit revised labeling with dosage or methods or duration of
timeline will delay the delivery of the new content and format, even if that administration or application, in such
complete information. Another occurs more than 3 years after the manner and form, as are necessary for
comment stated that FDA should effective date of the final rule. FDA did the protection of users. Section 502(j) of
expedite the implementation schedule not intend to suggest that application the FD&C Act deems a drug to be
for licensed drugs that are necessary to holders of previously approved misbranded if it is dangerous to health
maintain the health status of the mother applications subject to the PLR might, in when used in the dosage or manner, or
and could harm the fetus if the mother some circumstances, be required to with the frequency or duration,
is left untreated. This comment also revise labeling twice as a part of prescribed, recommended, or suggested
suggested that the Agency should make implementation. Therefore, if a holder in its labeling.
supplemental information available in of an application is subject to the PLR, In addition, the premarket approval
advance of the printed label. Another FDA does not anticipate that the provisions of the FD&C Act authorize
comment, however, expressed support pregnancy category will be removed FDA to require that prescription drug
for the proposal to give sponsors 3 years from the labeling prior to submitting the labeling provide the practitioner with
after the effective date of the rule to revised labeling with the new content adequate information to permit safe and
remove the pregnancy categories. and format for that product under the effective use of the drug product. Under
(Response) The Agency has taken all section 505 of the FD&C Act, FDA will
PLLR implementation schedule. In
of these comments into consideration, approve an NDA only if the drug is
conjunction with the publication of the
and has decided to maintain the shown to be both safe and effective for
final rule, the Agency is planning to
implementation schedule that was use under the conditions set forth in the
launch an education campaign for all
published in the proposed rule. The drugs labeling. Section 701(a) of the
stakeholders, including health care
implementation schedule follows the FD&C Act (21 U.S.C. 371(a)) authorizes
providers and professional
timetable used for implementation of FDA to issue regulations for the efficient
organizations, to ensure that they are
the PLR and works to balance the enforcement of the FD&C Act.
well informed about the changes.
anticipated workload for the review of Under 21 CFR 314.125, FDA will not
labels. The purpose of having a V. Legal Authority approve an NDA unless, among other
staggered approach is to avoid things, there is adequate safety and
A. Statutory Authority
overburdening both the Agency and effectiveness information for the labeled
industry. The implementation plan for FDA is revising its regulations on the uses and the product labeling complies
the final rule (also referred to as the format and content of the Pregnancy, with the requirements of part 201.
Pregnancy and Lactation Labeling Rule Labor and delivery, and Nursing Under 201.100(d) of FDAs
(PLLR)) is modeled from the mothers subsections of the Use in regulations, a prescription drug product
implementation plan for the PLR and Specific Populations section (under must bear labeling that contains
experience acquired from that plan. The 201.57) and the Precautions section adequate information under which
PLLR implementation timeline also (under 201.80) of the labeling for licensed practitioners can use the drug
depends on the PLR implementation human prescription drugs (in addition safely for their intended uses. This final
and the extent to which applications are to the list of headings and subheadings rule amends the regulations specifying
subject to the PLR. under 201.56(d)(1)). the format and content for such labeling.
(Comment 92) One comment FDAs revisions to the content and Section 351 of the PHS Act (42 U.S.C.
expressed concern that under the format requirements for prescription 262) provides legal authority for the
proposed implementation schedule, the drug labeling are authorized by the Agency to regulate the labeling and
shipment of biological products. options that would minimize any annualized costs equal about $9.2
Licenses for biological products are to significant impact of a rule on small million.
be issued only upon a showing that they entities. Because our analysis suggests The final rule will require that
meet standards designed to insure the that some small prescription drug applicants comply with new labeling
continued safety, purity, and potency of manufacturers and prescription drug content and format requirements for
such products prescribed in repackagers and relabelers will incur affected subsections for prescription
regulations (section 351(d) of the PHS costs that total more than 1 percent of drug and biological product labeling
Act). The potency of a biological their annual income in some years, the subject to the PLR under 201.57(c)(9)
product includes its effectiveness (21 Agency finds that the final rule will (PLR labeling) and will require that
CFR 600.3(s)). Section 351(b) of the PHS have a significant economic impact on applicants remove the pregnancy
Act prohibits false labeling of a a substantial number of small entities. category from all prescription drug and
biological product. FDAs regulations in Section 202(a) of the Unfunded biological product labeling subject to
part 201 apply to all prescription drug Mandates Reform Act of 1995 requires 201.80(f)(6)(i) (non-PLR labeling). The
products, including biological products. that Agencies prepare a written Pregnancy, Labor and delivery, and
statement, which includes an Nursing mothers subsections of the
B. First Amendment assessment of anticipated costs and Use in Specific Populations section
FDAs requirements for the content benefits, before proposing any rule that will be replaced by the Pregnancy,
and format of the Pregnancy and includes any Federal mandate that may Lactation, and Females and Males of
Lactation subsections of labeling for result in the expenditure by State, local, Reproductive Potential subsections.
prescription drug products are and tribal governments, in the aggregate, New information will be required to
constitutionally permissible because or by the private sector, of $100,000,000 summarize the key information needed
they are reasonably related to the or more (adjusted annually for inflation) by health care providers treating females
governments interest in ensuring the in any one year. The current threshold and males of reproductive potential.
safe and effective use of prescription after adjustment for inflation is $141 The information in these subsections
drug products and because they do not million, using the most current (2013) will be presented in a narrative,
impose unjustified or unduly Implicit Price Deflator for the Gross following a standardized order and
burdensome disclosure requirements. In Domestic Product. FDA does not expect format with clear subheadings.
the PLR, FDA explained in greater depth this final rule to result in any 1-year
The primary objectives of the final
why that rule passes muster under the expenditure that would meet or exceed
rule are to improve labeling by updating
First Amendment (see 71 FR 3922 at this amount.
The first regulations on the content the content and format of these
3964, January 24, 2006). That analysis is subsections of prescription drug product
equally applicable to this final rule, and and format of prescription drug labeling
were established in 1979, including the labeling, and to remove the pregnancy
we hereby adopt that discussion by category system. The Agency concluded
reference. requirement to assign drugs to one of
five pregnancy categories. Over time, that following a standardized structure
VI. Environmental Impact however, labeling became long, is essential for effective communication.
repetitive, and difficult to use. With the The final rule is needed to ensure that
The Agency has determined under 21 these subsections contain the most up-
CFR 25.30(h) that this action is of a type PLR in 2006, the Agency began to apply
modern principles of effective to-date information available and
that does not individually or provide prescribers with clinically
cumulatively have a significant effect on communication to improve the quality
of prescription drug labeling. However, relevant data that they can use in their
the human environment. Therefore, decisionmaking processes. Consistent
neither an environmental assessment the PLR left the content of the
Pregnancy, Labor and delivery, and with the approach taken by the PLR, the
nor an environmental impact statement Agency intends to provide applicants
is required. Nursing mothers subsections of the
Use in Specific Populations section with clear guidance about the required
VII. Summary of Final Regulatory untouched. This decision gave the content and format. Concurrent with the
Impact Analysis Agency sufficient time to meet with publication of this final rule, FDA is
experts and stakeholders to develop a issuing a draft guidance for industry on
A. Introduction Pregnancy, Lactation, and
regulatory framework that encourages
FDA has examined the impacts of the applicants to prepare content that Reproductive Potential: Labeling for
final rule under Executive Order 12866, clearly communicates available Human Prescription Drug and Biological
Executive Order 13563, the Regulatory information about prescription drug use ProductsContent and Format.
Flexibility Act (5 U.S.C. 601612), and during pregnancy and lactation, and in The level of effort needed to comply
the Unfunded Mandates Reform Act of females and males of reproductive with the requirements of the final rule
1995 (Public Law 1044). Executive potential. With this final rule, the will depend on the type of labeling (PLR
Orders 12866 and 13563 direct Agencies Agency specifically addresses the or non-PLR labeling) and the length of
to assess all costs and benefits of content and format of these subsections. time the product has been marketed.
available regulatory alternatives and, Applicants and persons responsible for
when regulation is necessary, to select B. Summary of Costs and Benefits existing prescription drug and biological
regulatory approaches that maximize The final regulatory impact analysis product labeling will incur one-time
net benefits (including potential of the final rule (Ref. 2) is available at costs to revise existing labeling in years
economic, environmental, public health http://www.fda.gov/AboutFDA/ 3, 4, and 5. Applicants submitting new
and safety, and other advantages; ReportsManualsForms/Reports/ BLAs, NDAs, and certain efficacy
distributive impacts; and equity). The EconomicAnalyses/default.htm. Table 2 supplements will incur one-time costs
Agency believes that this final rule is presents a summary of the annualized to gather and organize new content
not a significant regulatory action under costs and benefits of the final rule over required by the final rule at the time
Executive Order 12866. 10 years. With a 7 percent discount rate, they prepare labeling for the application
The Regulatory Flexibility Act annualized costs equal about $9.5 or supplement. In addition, we estimate
requires Agencies to analyze regulatory million; with a 3 percent discount rate, the additional annual printing costs for
longer PLR labeling that will include million. The present value of the total years, the annualized present value will
new content. costs will equal $78.2 million with a 3 equal $9.2 million with a 3 percent
We estimate that the total cost of the percent discount rate and $66.8 million discount rate and $9.5 million with a 7
rule over 10 years will equal about $88.7 with a 7 percent discount rate. Over 10 percent discount rate.
TABLE 2ECONOMIC DATA: COSTS AND BENEFITS ACCOUNTING STATEMENT

Units
Primary Low High
Category Discount Period Notes
estimate estimate estimate Year rate covered
dollars (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 Title: Content and Format of Labeling and counsel women about the use of
for Human Prescription Drug and drugs during pregnancy and lactation.
This final rule contains information Biological Products; Requirements for The final rule eliminates the current
collection requirements that are subject Pregnancy and Lactation Labeling pregnancy categories A, B, C, D, and X.
to review by the Office of Management Description: The final rule amends In addition, the Labor and delivery
and Budget (OMB) under the Paperwork FDA regulations concerning the content subsection has been eliminated because
Reduction Act of 1995 (the PRA) (44 and format of the Pregnancy, Labor information on labor and delivery is
U.S.C. 35013520). The title, and delivery, and Nursing mothers included in the Pregnancy subsection.
description, and respondent description subsections of the Use in Specific
The final rule also requires that the
of the information collection provisions Populations section of the labeling for
are shown in the following paragraphs labeling include relevant information
human prescription drugs. The final
with an estimate of the total reporting rule requires that labeling include, about pregnancy testing, contraception,
and disclosure burdens. Included in the among other things, a summary of the and infertility for health care providers
estimate is the time for reviewing risks of using a drug during pregnancy prescribing for females and males of
instructions, searching existing data and lactation and a discussion of the reproductive potential. The final rule is
sources, gathering and maintaining the data supporting that summary. The intended to create a consistent format
data needed, and completing and labeling also includes relevant for providing information about the
reviewing each collection of information to help health care risks and benefits of prescription drug
information. providers make prescribing decisions and/or biological product use during
pregnancy and lactation and by females Supplements to applications in accordance with 201.56, 201.57,
and males of reproductive potential. approved from June 30, 2001, to the and 201.80 is approved by OMB under
Under 201.57(c)(9)(i) and (c)(9)(ii), effective date of the final rule control numbers 09100572 and 0910
holders of approved applications are ( 314.70(b), 601.12(f)(1)); 0001.
required to provide new labeling Annual reports for applications In addition, FDA estimates that
content in a new formatthat is, to approved before June 30, 2001, that approximately 10,150 supplements to
rewrite the pregnancy and lactation contain a pregnancy category, to report applications approved from June 30,
portions of each drugs labeling. Under removal of the pregnancy category letter 2001, to the effective date of the final
201.57(c)(9)(iii), these application in their labeling ( 314.70(d), rule, or pending on the effective date,
holders are also required to include a 601.12(f)(3)). will be submitted to FDA during the
new subsection 8.3, Females and Males The information collection third, fourth, and fifth years after the
of Reproductive Potential, which requirements and burden estimates are effective date to update labeling in
requires that when pregnancy testing or summarized in tables 3 and 4 of this accordance with this final rule. This
contraception is required or document. The burden estimates are estimate includes approximately 1,080
recommended before, during, or after based on data and timeframes used for NDA, BLA, and efficacy supplements,
drug therapy or when there are human section VII of this document (Summary approximately 1,320 ANDA
or animal data that suggest drug- of Final Regulatory Impact Analysis) supplements, and labeling supplements
associated fertility effects, this and for the final regulatory impact from repackagers and relabelers for
subsection must contain this analysis of the final rule (available at approximately 7,750 drug products.
information. These application holders http://www.fda.gov/AboutFDA/ FDA estimates that approximately 390
are required to submit supplements ReportsManualsForms/Reports/ application holders and repackagers and
requiring prior approval by FDA before EconomicAnalyses/default.htm). FDA relabelers will submit these
distribution of the new labeling, as estimates that approximately 4,000 supplements, and that it will take
required in 314.70(b) or 601.12(f)(1). applications containing labeling
approximately 120 hours to prepare and
consistent with this rulemaking will be
Under 201.80(f)(6)(i), holders of submit each supplement.
submitted to FDA during the 10-year
approved applications are required to FDA also estimates that
period on or after the effective date of
remove the pregnancy category approximately 5,500 annual reports will
the final rule by approximately 390
designation (e.g., Pregnancy Category be submitted to FDA during the third
applicants and repackagers and
C) from the Pregnancy subsection of relabelers. The estimate of 4,000 year after the effective date for
the Precautions section of the applications includes labeling for applications approved before June 30,
labeling. These application holders approximately 800 applications 2001, that contain a pregnancy category
must report the labeling change in their submitted under section 505(b) of the (5,500 includes annual reports for
annual reports, as required in FD&C Act or section 351 of the PHS Act, approximately 1,340 NDAs and BLAs
314.70(d) or 601.12(f)(3). and 1,200 applications submitted under and approximately 4,160 ANDAs
The new content and format section 505(j) of the FD&C Act, and containing labeling changes resulting
requirements of the final rule apply to revised labeling from repackagers and from this rulemaking). FDA estimates
all applications that are required to relabelers for approximately 2,000 drug that approximately 320 application
comply with the PLR, including: (1) products. This estimate also includes holders will submit these annual
Applications submitted on or after the labeling amendments submitted to FDA reports, and that it will take
effective date of the final rule; (2) for applications pending on the effective approximately 40 hours for each
applications pending on the effective date of the final rule. Based on data submission.
date of the final rule; and (3) provided in section VII of this document As indicated in tables 3 and 4 of this
applications approved from June 30, and in the final regulatory impact document, we estimate that the total
2001, to the effective date of the final analysis of the final rule, FDA estimates hours resulting from the information
rule. that for future approvals it will take collection in this rulemaking will be
The following submissions under the applicants approximately 40 hours to approximately 1,598,000 hours. The
final rule are subject to the PRA: prepare and submit labeling consistent costs associated with this rulemaking,
Applications submitted on or after with this rulemaking. The estimate of 40 including labor costs, are discussed in
the effective date of the final rule hours applies only to the requirements section VII of this document and in the
( 314.50, 314.70(b), 601.2, of this rulemaking and does not indicate final regulatory impact analysis of the
601.12(f)(1)); the total hours required to prepare and final rule.
Amendments to applications submit complete labeling for these Description of Respondents: Persons
pending on the effective date of the final applications. The information collection and businesses, including small
rule ( 314.60, 601.2, 601.12(f)(1)); burden to prepare and submit labeling businesses and manufacturers.
TABLE 3ESTIMATED ANNUAL REPORTING BURDEN 1

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

Number of Average
Type of submission Number of Total annual Total
responses per burden per
(21 CFR section) respondents responses hours
respondent response
Total ....................................................... ........................ ........................ ............................................... ........................ 1,438,000

1 There are no capital costs or operating and maintenance costs associated with this information collection.
TABLE 4ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1

Number of Average
Type of submission Number of disclosures Total annual Total
burden per
(21 CFR section) respondents per disclosures ours
disclosure
respondent
New NDAs/ANDAs/BLAs/efficacy supplements 390 10 4,000 (Submitted during 40 160,000

submitted on or after effective date, including 10-year period after
amendments to applications pending on effec- effective date).
tive date ( 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 through Friday, and are available 7. U.S. Food and Drug Administration
of this final rule have been submitted to electronically at http:// Guidance for industry, Establishing
OMB for review, as required by section www.regulations.gov. (FDA has verified Pregnancy Exposure Registries, 2002.
3507(d) of the PRA. Prior to the effective 8. U.S. Food and Drug Administration
all Web site addresses in this reference
Guidance for Industry, Reproductive
date of this final rule, FDA will publish section, but we are not responsible for and Developmental Toxicities
a notice in the Federal Register any subsequent changes to the Web sites Integrating Study Results to Assess
announcing OMBs decision to approve, after this document publishes in the Concerns, 2011.
modify, or disapprove the information Federal Register.) 9. Rynn, L., J. Cragan, and A. Correa, Update
collection provisions in this final rule. 1. Decision Partners, LLC, Evaluation of
on Overall Prevalence of Major Birth
An Agency may not conduct or sponsor, DefectsAtlanta, Georgia, 19782005.
How Best to Communicate to Healthcare
and a person is not required to respond Centers for Disease Control and
Providers about the Risks and Benefits of Prevention Morbidity and Mortality
to, a collection of information unless it Prescription Drug Use for Pregnant and Weekly Report. 57(01):15, January 11,
displays a currently valid OMB control Nursing Women: A Mental Models 2008.
number. Research Report, September 2009 10. American College of Obstetricians and
(available at http://www.fda.gov/ Gynecologists Frequently Asked
IX. Federalism AboutFDA/ReportsManualsForms/ Questions: Miscarriage and Molar
FDA has analyzed this final rule in Reports/EconomicAnalyses/default.htm). Pregnancy, 2011 (available at http://
accordance with the principles set forth 2. Final Regulatory Impact Analysis for www.acog.org//media/For%20Patients/
in Executive Order 13132. FDA has Docket No. FDA2006N0515 (formerly faq090.pdf?dmc=1&ts=20140130T
determined that this final rule does not Docket No. 2006N0467) (available at 1655496642).
contain policies that have substantial http://www.fda.gov/AboutFDA/Reports 11. U.S. Food and Drug Administration,
direct effects on the States, on the ManualsForms/Reports/Economic Reviewer Guidance, Evaluating the
Analyses/default.htm and at http:// Risks of Drug Exposure in Human
relationship between the National Pregnancies, 2005.
www.regulations.gov).
Government and the States, or on the 12. U.S. Food and Drug Administration,
3. U.S. Food and Drug Administration,
distribution of power and Guidance for Industry, Warnings and Guidance for industry, Considerations
responsibilities among the various Precautions, Contraindications, and for Developmental Toxicity Studies for
levels of government. Accordingly, the Boxed Warning Sections of Labeling for Preventive and Therapeutic Vaccines for
Agency has concluded that the rule does Human Prescription Drug and Biological Infectious Disease Indications, 2006.
not contain policies that have ProductsContent and Format, 2011. 13. U.S. Food and Drug Administration,
federalism implications as defined in Guidance for industry, M3 (R2)
4. Kweder, S.L., Drugs and Biologics in
Nonclinical Safety Studies for the
the Executive order and, consequently, Pregnancy and Breastfeeding: FDA in the
Conduct of Human Clinical Trials and
a federalism summary impact statement 21st Century. Birth Defects Research Marketing Authorization for
is not required. Part A: Clinical and Molecular Pharmaceuticals and the International
Teratology. 82(9):605609, September Conference on Harmonisation S5 (R2)
X. References 2008. Guideline: Detection of Toxicity to
In addition to the references placed 5. Adam, M.P., J.E. Polifka, and J.M. Reproduction for Medicinal Products
on display in the Division of Dockets Friedman, Evolving Knowledge of the and Toxicity to Male Fertility, 2010.
Management for the proposed rule Teratogenicity of Medications in Human 14. Tracy, T.S., et al. Temporal Changes in
under Docket No. FDA2006N0515 Pregnancy. American Journal of Drug Metabolism (CYP1A2, CYP2D6 and
Medical Genetics Part C: Seminars in CYP3A Activity) During Pregnancy.

(formerly Docket No. 2006N0467), the
Medical Genetics. 157C(3):175182, American Journal of Obstetrics and
following references are on display in August 15, 2011. Gynecology. 192(2):633639, February
the Division of Dockets Management 6. Law, R., P. Bozzo, G. Koren, et al. FDA 2005.
under Docket No. FDA2006N0515 Pregnancy Risk Categories and the CPS. 15. Anderson, G.D., Pregnancy-Induced
(formerly Docket No. 2006N0467) and Do They Help or Are They a Changes in Pharmacokinetics. Clinical
may be seen by interested persons Hindrance? Canadian Family Pharmacokinetics. 44(10):9891008,
between 9 a.m. and 4 p.m., Monday Physician. 56:239241, March 2010. 2005.
16. American Academy of Pediatrics Policy enroll in the registry or to obtain indicated to be used. When risk
Statement. Breastfeeding and the Use of information about the registry must be information is not available for women
Human Milk. Pediatrics. 129(3):e827 provided following the statement: with the disease or condition for which
841, 2012. There is a pregnancy exposure registry the drug is indicated, the risk for the
17. Sachs, H.C. and Committee on Drugs.
The Transfer of Drugs and Therapeutics
that monitors pregnancy outcomes in specific outcome must be compared to
Into Human Breast Milk: An Update on women exposed to (name of drug) the rate at which the outcome occurs in
Selected Topics. Pediatrics. during pregnancy. the general population. The Risk
132(3):e796809, September 2013. (B) Risk summary. The Risk Summary Summary must state when there are no
18. U.S. Food and Drug Administration, must contain risk statement(s) based on human data or when available human
Draft Guidance for industry Clinical data from all relevant sources (human, data do not establish the presence or
Lactation StudiesStudy Design, Data animal, and/or pharmacologic) that absence of drug-associated risk.
Analysis, and Recommendations for describe, for the drug, the risk of (2) Risk statement based on animal
Labeling, 2005. adverse developmental outcomes (i.e., data. When animal data are available,
19. Proposed Pregnancy and Lactation structural abnormalities, embryo-fetal the Risk Summary must summarize the
Labeling Rule (available at http:// and/or infant mortality, functional findings in animals and based on these
www.fda.gov/Drugs/Development
ApprovalProcess/Development
impairment, alterations to growth). findings, describe, for the drug, the
Resources/Labeling/ucm093307.htm). When multiple data sources are potential risk of any adverse
20. Public Comments on Proposed Pregnancy available, the statements must be developmental outcome(s) in humans.
and Lactation Labeling Rule (available at presented in the following order: This statement must include: The
http://www.regulations.gov/#!docket Human, animal, pharmacologic. The number and type(s) of species affected,
Detail;D=FDA-2006-N-0515). source(s) of the data must be stated. The timing of exposure, animal doses
labeling must state the percentage range expressed in terms of human dose or
List of Subjects in 21 CFR Part 201 of live births in the United States with exposure equivalents, and outcomes for
Drugs, Labeling, Reporting and a major birth defect and the percentage pregnant animals and offspring. When
recordkeeping requirements. range of pregnancies in the United animal studies do not meet current
States that end in miscarriage, standards for nonclinical developmental
Therefore, under the Federal Food,
regardless of drug exposure. If such toxicity studies, the Risk Summary must
Drug, and Cosmetic Act and under
information is available for the so state. When there are no animal data,
authority delegated to the Commissioner
population(s) for which the drug is the Risk Summary must so state.
of Food and Drugs, 21 CFR part 201 is (3) Risk statement based on
labeled, it must also be included. When
amended as follows: pharmacology. When the drug has a
use of a drug is contraindicated during
PART 201LABELING pregnancy, this information must be well-understood mechanism of action
stated first in the Risk Summary. When that may result in adverse
1. The authority citation for 21 CFR applicable, risk statements as described developmental outcome(s), the Risk
part 201 continues to read as follows: in paragraphs (c)(9)(i)(B)(1) and (2) of Summary must explain the mechanism
this section must include a cross- of action and the potential associated
Authority: 21 U.S.C. 321, 331, 351, 352,
353, 355, 358, 360, 360b, 360gg360ss, 371, reference to additional details in the risks.
374, 379e; 42 U.S.C. 216, 241, 262, 264. relevant portion of the Data (C) Clinical considerations. Under the
subheading in the Pregnancy subheading Clinical Considerations,
201.56 [Amended] subsection of the labeling. If data the labeling must provide relevant
2. Amend 201.56 in paragraph (d)(1) demonstrate that a drug is not information, to the extent it is available,
by removing from the list of headings systemically absorbed following a under the headings Disease-associated
and subheadings the subheadings 8.2 particular route of administration, the maternal and/or embryo/fetal risk,
Labor and delivery and 8.3 Nursing Risk Summary must contain only the Dose adjustments during pregnancy
mothers and adding in their places the following statement: (Name of drug) is and the postpartum period, Maternal
subheadings 8.2 Lactation and 8.3 not absorbed systemically following adverse reactions, Fetal/Neonatal
Females and Males of Reproductive (route of administration), and maternal adverse reactions, and Labor or
Potential, respectively. use is not expected to result in fetal delivery:
3. Amend 201.57 by revising exposure to the drug. (1) Disease-associated maternal and/
paragraphs (c)(9)(i), (ii), and (iii) to read (1) Risk statement based on human or embryo/fetal risk. If there is a serious
as follows: data. When human data are available known or potential risk to the pregnant
that establish the presence or absence of woman and/or the embryo/fetus
201.57 Specific requirements on content any adverse developmental outcome(s) associated with the disease or condition
and format of labeling for human associated with maternal use of the for which the drug is indicated to be
prescription drug and biological products drug, the Risk Summary must used, the labeling must describe the
described in 201.56(b)(1). summarize the specific developmental risk.
* * * * * outcome(s); their incidence; and the (2) Dose adjustments during
(c) * * * effects of dose, duration of exposure, pregnancy and the postpartum period. If
(9) * * * and gestational timing of exposure. If there are pharmacokinetic data that
(i) 8.1 Pregnancy. This subsection of human data indicate that there is an support dose adjustment(s) during
the labeling must contain the following increased risk for a specific adverse pregnancy and the postpartum period, a
information in the following order developmental outcome in infants born summary of this information must be
under the subheadings Pregnancy to women exposed to the drug during provided.
Exposure Registry, Risk Summary, pregnancy, this risk must be (3) Maternal adverse reactions. If use
Clinical Considerations, and Data: quantitatively compared to the risk for of the drug is associated with a maternal
(A) Pregnancy exposure registry. If the same outcome in infants born to adverse reaction that is unique to
there is a scientifically acceptable women who were not exposed to the pregnancy or if a known adverse
pregnancy exposure registry for the drug but who have the disease or reaction occurs with increased
drug, contact information needed to condition for which the drug is frequency or severity in pregnant
women, the labeling must describe the Animal doses or exposures must be data are available, the Risk Summary
adverse reaction and available described in terms of human dose or must state only whether or not the drug
intervention(s) for monitoring or exposure equivalents and the basis for and/or its active metabolite(s) were
mitigating the reaction. The labeling those calculations must be included. detected in animal milk and specify the
must describe, if known, the effect of (ii) 8.2 Lactation. This subsection of animal species.
dose, timing, and duration of exposure the labeling must contain the following (ii) Effects of drug on the breast-fed
on the risk to the pregnant woman of information in the following order child. The Risk Summary must include
experiencing the adverse reaction. under the subheadings Risk information, on the known or predicted
(4) Fetal/Neonatal adverse reactions. Summary, Clinical Considerations, effects on the child from exposure to the
If it is known or anticipated that and Data: drug and/or its active metabolite(s)
treatment of the pregnant woman (A) Risk summary. When relevant through human milk or from contact
increases or may increase the risk of an human and/or animal lactation data are with breast or nipple skin (for topical
adverse reaction in the fetus or neonate, available, the Risk Summary must products). The Risk Summary also must
the labeling must describe the adverse include a cross-reference to the Data include information on systemic and/or
reaction, the potential severity and subheading in the Lactation local adverse reactions. If there are no
reversibility of the adverse reaction, and subsection of the labeling. When human data to assess the effects of the drug
available intervention(s) for monitoring data are available, animal data must not and/or its active metabolite(s) on the
or mitigating the reaction. The labeling be included unless the animal model is breast-fed child, the Risk Summary
must describe, if known, the effect of specifically known to be predictive for must so state.
dose, timing, and duration of exposure humans. When use of a drug is (iii) Effects of drug on milk
on the risk. contraindicated during breastfeeding, production. The Risk Summary must
(5) Labor or delivery. If the drug is this information must be stated first in describe the effects of the drug and/or
expected to affect labor or delivery, the the Risk Summary. its active metabolite(s) on milk
labeling must provide information about (1) Drug not absorbed systemically. If production. If there are no data to assess
the effect of the drug on the pregnant data demonstrate that the drug is not the effects of the drug and/or its active
woman and the fetus or neonate; the systemically absorbed by the mother, metabolite(s) on milk production, the
effect of the drug on the duration of the Risk Summary must contain only Risk Summary must so state.
labor and delivery; any increased risk of the following statement: (Name of (3) Risk and benefit statement. For
adverse reactions, including their drug) is not absorbed systemically by drugs absorbed systemically, unless
potential severity and reversibility; and the mother following (route of breastfeeding is contraindicated during
must provide information about administration), and breastfeeding is not drug therapy, the following risk and
available intervention(s) that can expected to result in exposure of the benefit statement must appear at the end
mitigate these effects and/or adverse child to (name of drug). of the Risk Summary: The
reactions. The information described (2) Drug absorbed systemically. If the developmental and health benefits of
under this heading is not required for drug is absorbed systemically, the Risk breastfeeding should be considered
drugs approved for use only during Summary must describe the following to along with the mothers clinical need for
labor and delivery. the extent relevant information is (name of drug) and any potential
(D) Data(1) Data subheading. available: adverse effects on the breast-fed child
Under the subheading Data, the (i) Presence of drug in human milk. from (name of drug) or from the
labeling must describe the data that are The Risk Summary must state whether underlying maternal condition.
the basis for the Risk Summary and the drug and/or its active metabolite(s) (B) Clinical considerations. Under
Clinical Considerations. are present in human milk. If there are Clinical Considerations, the following
(2) Human and animal data headings. no data to assess this, the Risk Summary information must be provided to the
Human and animal data must be must so state. If studies demonstrate extent it is available and relevant:
presented separately, beneath the that the drug and/or its active (1) Minimizing exposure. The labeling
headings Human Data and Animal metabolite(s) are not detectable in must describe ways to minimize
Data, and human data must be human milk, the Risk Summary must exposure in the breast-fed child if: The
presented first. state the limits of the assay used. If drug and/or its active metabolite(s) are
(3) Description of human data. For studies demonstrate the presence of the present in human milk in clinically
human data, the labeling must describe drug and/or its active metabolite(s) in relevant concentrations; the drug does
adverse developmental outcomes, human milk, the Risk Summary must not have an established safety profile in
adverse reactions, and other adverse state the concentration of the drug and/ infants; and the drug is used either
effects. To the extent applicable, the or its active metabolite(s) in human milk intermittently, in single doses, or for
labeling must describe the types of and the actual or estimated daily dose short courses of therapy. When
studies or reports, number of subjects for an infant fed exclusively with applicable, the labeling must also
and the duration of each study, human milk. The actual or estimated describe ways to minimize a breast-fed
exposure information, and limitations of amount of the drug and/or its active childs oral intake of topical drugs
the data. Both positive and negative metabolite(s) ingested by the infant applied to the breast or nipple skin.
study findings must be included. must be compared to the labeled infant (2) Monitoring for adverse reactions.
(4) Description of animal data. For or pediatric dose, if available, or to the The labeling must describe available
animal data, the labeling must describe maternal dose. If studies demonstrate intervention(s) for monitoring or
the following: Types of studies, animal the presence of the drug and/or its mitigating the adverse reaction(s)
species, dose, duration and timing of active metabolite(s) in human milk but presented in the Risk Summary.
exposure, study findings, presence or the drug and/or its active metabolite(s) (C) Data. Under the subheading
absence of maternal toxicity, and are not expected to be systemically Data, the labeling must describe the
limitations of the data. Description of bioavailable to the breast-fed child, the data that are the basis for the Risk
maternal and offspring findings must Risk Summary must describe the Summary and Clinical Considerations.
include dose-response and severity of disposition of the drug and/or its active (iii) 8.3 Females and males of
adverse developmental outcomes. metabolite(s). If only animal lactation reproductive potential. When pregnancy
testing and/or contraception are 201.80 [Amended] d. Remove the paragraph heading
required or recommended before, 4. Amend 201.80 as follows: Pregnancy category D. and the words
during, or after drug therapy and/or a. Remove the paragraph heading Pregnancy Category D. from
when there are human and/or animal Pregnancy category A. and the words paragraph (f)(6)(i)(d); and
data that suggest drug-associated Pregnancy Category A. from e. Remove the paragraph heading
fertility effects, this subsection of paragraph (f)(6)(i)(a); Pregnancy category X. and the words
labeling must contain this information b. Remove the paragraph heading Pregnancy Category X. from
under the subheadings Pregnancy Pregnancy category B. and the words paragraph (f)(6)(i)(e).
Testing, Contraception, and Pregnancy Category B. both times
Dated: November 25, 2014.
Infertility, in that order. they appear from paragraph (f)(6)(i)(b);
c. Remove the paragraph heading Leslie Kux,
* * * * * Pregnancy category C. and the words Associate Commissioner for Policy.
Pregnancy Category C. both times [FR Doc. 201428241 Filed 12314; 8:45 am]
they appear from paragraph (f)(6)(i)(c); BILLING CODE 416401P

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SUMMARY OF BENEFITS AND COSTS OF THE FINAL RULE

Not estimated ................................................................................................... 78.2 66.8 9.2 9.5

summarizes scientific information

D Replaces the proposed requirement clear and accessible to a variety of

lactation labeling).5 The draft guidance

referred to in this footnote, as well as others

Pharmacology, we have removed that unnecessary. is required in 201.57(c)(9)(i)(C), FDA

(Response) FDA declines this be included. lactation data.

TABLE 1IMPLEMENTATION PLAN

New or Pending Applications

Approved Applications Subject to the Physician Labeling Rule

TABLE 1IMPLEMENTATION PLANContinued

TABLE 2ECONOMIC DATA: COSTS AND BENEFITS ACCOUNTING STATEMENT

Qualitative ............. Improved quality of prescription drug labeling for

From/To: From: To:

Other Annualized .. ........................ ........................ ........................ ........................ 7 ........................ ........................

From/To: From: To:

State, Local or Tribal Government: No effect

TABLE 3ESTIMATED ANNUAL REPORTING BURDEN 1

TABLE 3ESTIMATED ANNUAL REPORTING BURDEN 1Continued

Total ....................................................... ........................ ........................ ............................................... ........................ 1,438,000

TABLE 4ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1

New NDAs/ANDAs/BLAs/efficacy supplements 390 10 4,000 (Submitted during 40 160,000

Medical Genetics Part C: Seminars in CYP3A Activity) During Pregnancy.

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