72064 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 201 

[Docket No. FDA–2006–N–0515 (formerly 

Docket No. 2006N–0467)] 

RIN 0910–AF11 

Content and Format of Labeling for 

Human Prescription Drug and 

Biological Products; Requirements for 

Pregnancy and Lactation Labeling 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Final rule. 

SUMMARY: The Food and Drug 

Administration (FDA) is amending its 

regulations governing the content and 

format of the ‘‘Pregnancy,’’ ‘‘Labor and 

delivery,’’ and ‘‘Nursing mothers’’ 

subsections of the ‘‘Use in Specific 

Populations’’ section of the labeling for 

human prescription drug and biological 

products. The final rule requires the 

removal of the pregnancy categories A, 

B, C, D, and X from all human 

prescription drug and biological product 

labeling. For human prescription drug 

and biological products subject to the 

Agency’s 2006 Physician Labeling Rule, 

the final rule requires that the labeling 

include a summary of the risks of using 

a drug during pregnancy and lactation, 

a discussion of the data supporting that 

summary, and relevant information to 

help health care providers make 

prescribing decisions and counsel 

women about the use of drugs during 

pregnancy and lactation. The final rule 

eliminates the ‘‘Labor and delivery’’ 

subsection because information about 

labor and delivery is included in the 

‘‘Pregnancy’’ subsection. The final rule 

requires that the labeling include 

relevant information about pregnancy 

testing, contraception, and infertility for 

health care providers prescribing for 

females and males of reproductive 

potential. The final rule creates a 

consistent format for providing 

information about the risks and benefits 

of prescription drug and/or biological 

product use during pregnancy and 

lactation and by females and males of 

reproductive potential. These revisions 

will facilitate prescriber counseling for 

these populations. 

DATES: This rule is effective June 30, 

2015. See section IV of this document 

for the implementation dates of this 

final rule. 

FOR FURTHER INFORMATION CONTACT: 

Kathy Schreier, Center for Drug 

Evaluation and Research, Food and 

Drug Administration, 10903 New 

Hampshire Ave., Bldg. 51, Rm. 6246, 

Silver Spring, MD 20993–0002, 301– 

796–3432; or Stephen Ripley, Center for 

Biologics Evaluation and Research, 

Food and Drug Administration, 10903 

New Hampshire Ave., Bldg. 71, Rm. 

7301, Silver Spring, MD 20993–0002, 

240–402–7911. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

Executive Summary 

Purpose of the Regulatory Action 

Summary of the Major Provisions of the 

Regulatory Action in Question 

Costs and Benefits 

I. Background 

A. History of FDA-Approved Pregnancy 

and Lactation Labeling for Prescription 

Drugs 

B. Development of the Proposed Rule 

C. The Proposed Rule 

D. Mental Models Research 

II. Overview of the Final Rule Including 

Significant Changes to the Proposed Rule 

A. Overview 

B. Significant Changes to the Proposed 

Rule 

III. Comments on the Proposed Rule 

A. Proposed Rule as a Whole 

B. Specific Provisions of the Proposed Rule 

IV. Implementation 

V. Legal Authority 

A. Statutory Authority 

B. First Amendment 

VI. Environmental Impact 

VII. Summary of Final Regulatory Impact 

Analysis 

A. Introduction 

B. Summary of Costs and Benefits 

VIII. Paperwork Reduction Act of 1995 

IX. Federalism 

X. References 

Executive Summary 

Purpose of the Regulatory Action 

FDA is amending its regulations 

governing the content and format of the 

‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and 

‘‘Nursing mothers’’ subsections of the 

‘‘Use in Specific Populations’’ section 

(under § 201.57 (21 CFR 201.57)) and 

the ‘‘Precautions’’ section (under 

§ 201.80 (21 CFR 201.80)) of the labeling 

for human prescription drug and 

biological products (both referred to as 

‘‘drugs’’ or ‘‘drug products’’ in this final 

rule). In this rulemaking, the Agency is 

finalizing many of the provisions in the 

proposed rule issued on May 29, 2008 

(73 FR 30831). 

This rulemaking is part of a broad 

effort by the Agency to improve the 

content and format of prescription drug 

labeling. The final rule creates a 

consistent format for providing 

information about the risks and benefits 

of drug use during pregnancy and 

lactation and by females and males of 

reproductive potential. FDA’s revisions 

to the content and format requirements 

for prescription drug and biological 

product labeling are authorized by the 

Federal Food, Drug, and Cosmetic Act 

(the FD&C Act) and by the Public Health 

Service Act (PHS Act). 

Summary of the Major Provisions of the 

Regulatory Action in Question 

The final rule requires that for the 

labeling of certain drug products (as 

described in the ‘‘Implementation’’ 

section of this document), the 

subsections ‘‘Pregnancy,’’ ‘‘Nursing 

mothers,’’ and ‘‘Labor and delivery’’ be 

replaced by three subsections entitled 

‘‘Pregnancy,’’ ‘‘Lactation,’’ and 

‘‘Females and Males of Reproductive 

Potential.’’ The final rule also requires 

the removal of the pregnancy categories 

A, B, C, D, and X from all drug product 

labeling. 

‘‘Pregnancy’’ 

The final rule merges the current 

‘‘Pregnancy’’ and ‘‘Labor and delivery’’ 

subsections into a single ‘‘Pregnancy’’ 

subsection of labeling. If there is a 

scientifically acceptable pregnancy 

exposure registry for the drug, the 

‘‘Pregnancy’’ subsection must contain a 

specified statement about the existence 

of the registry, followed by contact 

information needed to enroll or to 

obtain information about the registry. 

The Agency has concluded that 

including information about pregnancy 

exposure registries in prescription drug 

labeling will encourage participation in 

registries, thereby improving data 

collection in pregnant women. Under 

‘‘Pregnancy,’’ the final rule also requires 

that the labeling include a summary of 

the risks of using a drug during 

pregnancy. If data demonstrate that a 

drug is not absorbed systemically, the 

‘‘Risk Summary’’ must contain only a 

specified statement regarding this fact. If 

data demonstrate that the drug is 

absorbed systemically, the ‘‘Risk 

Summary’’ must include risk statements 

based on data from all relevant sources 

(human, animal, and/or pharmacologic), 

that describe, for the drug, the risk of 

adverse developmental outcomes. 

The labeling must also contain 

relevant information, if it is available, to 

help health care providers make 

prescribing decisions and counsel 

women about the use of the drug during 

pregnancy; this could include 

information on disease-associated 

maternal and/or embryo/fetal risk, dose 

adjustments during pregnancy and the 

postpartum period, maternal adverse 

reactions, fetal/neonatal adverse 

reactions, and/or the effect of the drug 

on labor or delivery. FDA believes that 

including such information supports 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72065 

health care providers’ understanding of 

drug product risks and benefits and 

facilitates informed prescribing 

decisions and patient counseling. The 

labeling must also describe the data that 

are the basis for the risk statements and 

clinical information included in the 

‘‘Pregnancy’’ subsection of labeling. 

‘‘Lactation’’ 

The final rule requires that the 

‘‘Lactation’’ subsection of labeling 

contain a summary of the risks of using 

a drug during lactation. If data 

demonstrate that the drug is not 

absorbed systemically, this summary 

must contain only a specified statement 

regarding this fact. If data demonstrate 

that the drug is absorbed systemically 

by the mother, this summary must 

include, to the extent it is available, 

relevant information on the presence of 

the drug in human milk, effects of the 

drug on the breast-fed child, and effects 

of the drug on milk production. For 

drugs absorbed systemically, a risk and 

benefit statement must appear at the end 

of the summary of risks, unless 

breastfeeding is contraindicated during 

drug therapy. FDA has determined that 

the inclusion of a risk and benefit 

statement will provide a useful 

framework for health care providers to 

use when making prescribing decisions 

for a lactating patient. 

The ‘‘Lactation’’ subsection must also 

include, to the extent information is 

available, relevant information 

concerning ways to minimize drug 

exposure in the breast-fed child in 

certain situations and concerning 

available interventions for monitoring or 

mitigating the adverse reactions 

presented elsewhere in the labeling. In 

addition, the labeling must also include 

pertinent information about the data 

that are the basis for the risk summary 

and clinical information included in the 

‘‘Lactation’’ subsection of labeling. 

‘‘Females and Males of Reproductive 

Potential’’ 

FDA determined that because there 

was no consistent placement in the 

labeling of information about pregnancy 

testing, contraception, and infertility, it 

was difficult for health care providers to 

find this important information that can 

affect decisionmaking before or during 

pregnancy. Thus, the final rule requires 

that the ‘‘Females and Males of 

Reproductive Potential’’ subsection 

include relevant information when 

pregnancy testing or contraception is 

required or recommended before, 

during, or after drug therapy or when 

there are human or animal data that 

suggest drug-associated fertility effects. 

Removal of Pregnancy Categories 

Through experience and stakeholder 

feedback, FDA learned that the 

pregnancy categories were confusing 

and did not accurately and consistently 

communicate differences in degrees of 

fetal risk. In addition, FDA learned that 

the pregnancy categories were heavily 

relied upon by clinicians but were often 

misinterpreted and misused in that 

prescribing decisions were being made 

based on the pregnancy category, rather 

than an understanding of the underlying 

information that informed the 

assignment of the pregnancy category. 

FDA believes that a narrative structure 

for pregnancy labeling, rather than a 

category system, is best able to capture 

and convey the potential risks of drug 

exposure based on animal or human 

data, or both. FDA has determined that 

retaining the pregnancy categories is 

inconsistent with the need to accurately 

and consistently communicate 

differences in degrees of fetal risk. 

Therefore, the final rule requires the 

removal of the pregnancy categories A, 

B, C, D, and X from all drug product 

labeling. 

Costs and Benefits 

We estimate that over 10 years with 

a 7 percent discount rate, the present 

value of one-time costs of the rule equal 

$52.4 million and the present value of 

the annual costs equal $14.4 million; 

with a 3 percent discount rate, the 

present value of one-time costs equal 

$60.1 million and the present value of 

the annual costs equal $18.2 million. 

The present value of the total costs 

equal $66.8 million with a 7 percent 

discount rate and $78.2 million with a 

3 percent discount rate. The annualized 

costs of the rule total $9.5 million with 

a 7 percent discount rate and $9.2 

million with a 3 percent discount rate. 

The final rule will address issues raised 

by experts and stakeholders and 

improve the quality of the affected 

sections of prescription drug labeling. 

Better quality prescribing information 

will enhance the usefulness of the 

labeling. The public health benefits of 

the final rule would result from 

improved health outcomes. However, 

because we have no information about 

how improved labeling will affect 

prescriber behavior and patient 

outcomes, we are unable to quantify the 

benefits of the final rule. 

SUMMARY OF BENEFITS AND COSTS OF THE FINAL RULE

Total benefits 

Present value 

of total costs 

with 3 percent 

discount rate 

($ mil) 

Present value 

of total costs 

with 7 percent 

discount rate 

($ mil) 

Total 

annualized 

costs over 10 

years with 3 

percent 

discount 

rate 

($ mil) 

Total 

annualized 

costs over 10 

years with 7 

percent 

discount 

rate 

($ mil) 

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

I. Background 

In the Federal Register of May 29, 

2008 (73 FR 30831), FDA issued a 

proposed rule to amend the content and 

format of the ‘‘Pregnancy,’’ ‘‘Labor and 

delivery,’’ and ‘‘Nursing mothers’’ 

subsections of the ‘‘Use in Specific 

Populations’’ section of labeling for 

human prescription drug and biological 

products, which appear in § 201.57. The 

proposed rulemaking was part of a 

broad effort by the Agency to improve 

the content and formatting of 

prescription drug labeling. 

A. History of FDA-Approved Pregnancy 

and Lactation Labeling for Prescription 

Drugs 

Under sections 502 and 505 of the 

FD&C Act (21 U.S.C. 352 and 355), FDA 

has responsibility for ensuring that 

prescription drug and biological 

products (both referred to as ‘‘drugs’’ or 

‘‘drug products’’ in this final rule) are 

accompanied by labeling (including 

prescribing information) that 

summarizes scientific information 

concerning their safe and effective use. 

FDA regulations on labeling for use 

during pregnancy, during labor and 

delivery, and by nursing mothers were 

originally issued in 1979 as part of a 

rule prescribing the content and format 

mstockstill on DSK4VPTVN1PROD with RULES2

72066 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

1Thus, the labeling for drugs originally approved 

before 1979 may not contain the information 

required by those regulations regarding pregnancy, 

labor and delivery, and nursing mothers. 

2FDA’s regulations governing the content and 

format of labeling for human prescription drug and 

biological products are contained in §§ 201.56, 

201.57, and 201.80. 

3For further discussion of the pregnancy 

categories, see 73 FR 30831 at 30832 through 30833. 

4For further discussion of the history of both the 

‘‘Pregnancy’’ and the ‘‘Nursing mothers’’ 

subsections of prescription drug labeling, see 73 FR 

30831 at 30833. 

for labeling for human prescription 

drugs (part 201 (21 CFR part 201)) (44 

FR 37434, June 26, 1979) (the 1979 

regulations).1 The requirements on 

content and format of labeling for drug 

products were revised on January 24, 

2006, in the final rule on ‘‘Requirements 

on Content and Format of Labeling for 

Human Prescription Drug and Biological 

Products’’ (71 FR 3922), commonly 

referred to as the ‘‘Physician Labeling 

Rule’’ (PLR).2 As part of the January 

2006 revision, the subsections of the 

labeling on pregnancy, labor and 

delivery, and nursing mothers were 

moved from the ‘‘Precautions’’ section 

under § 201.57 to the ‘‘Use in Specific 

Populations’’ section. The content of 

these sections in part 201 was not 

revised, but the sections were 

redesignated as § 201.57(c)(9)(i) through 

(c)(9)(iii). The previous labeling 

regulation (adopted in 1979) was 

redesignated as § 201.80, and applies to 

products not affected by the January 

2006, revisions. In redesignated 

§ 201.80, the subsections on pregnancy, 

labor and delivery, and nursing mothers 

are § 201.80(f)(6) through (f)(8). 

The 1979 regulations provided, at 

what was redesignated in 2006 as 

§ 201.57(c)(9)(i) and § 201.80(f)(6)(i), 

that unless a drug was not absorbed 

systemically and was not known to have 

a potential for indirect harm to a fetus, 

a ‘‘Pregnancy’’ subsection must be 

included within the ‘‘Precautions’’ 

section of the labeling. The 1979 

regulations required that the 

‘‘Pregnancy’’ subsection contain 

information on the drug’s teratogenic 

effects and other effects on reproduction 

and pregnancy and, when available, a 

description of human studies with the 

drug and data on its effects on later 

growth, development, and functional 

maturation of the child. The 1979 

regulations also required that each 

product be classified under one of five 

pregnancy categories (A, B, C, D, or X) 

on the basis of risk of reproductive and 

developmental adverse effects or, for 

certain categories, on the basis of such 

risk weighed against potential benefit.3

With regard to labor and delivery, the 

1979 regulations stated, at what was 

redesignated in 2006 as § 201.57(c)(9)(ii) 

and § 201.80(f)(7), that under certain 

circumstances, the labeling must 

include information on the effects of the 

drug on, among other things, the mother 

and the fetus, the duration of labor and 

delivery, and the effect of the drug on 

the later growth, development, and 

functional maturation of the child. 

With regard to labeling on lactation, 

the 1979 regulations required, at what 

was redesignated in 2006 as 

§ 201.57(c)(9)(iii) and § 201.80(f)(8), that 

a ‘‘Nursing mothers’’ subsection be 

included in the ‘‘Precautions’’ section of 

the labeling. The ‘‘Nursing mothers’’ 

subsection provided that if a drug was 

absorbed systemically, the labeling must 

contain information about excretion of 

the drug in human milk and effects on 

the nursing infant, as well as a 

description of any pertinent adverse 

effects observed in animal offspring. 

The ‘‘Nursing mothers’’ subsection 

required the use of certain standard 

statements depending on whether the 

drug was known to be excreted in 

human milk and whether it was 

associated with serious adverse 

reactions.4

B. Development of the Proposed Rule 

Over a number of years after the 1979 

regulations were issued, FDA received 

feedback on the issues and concerns 

with the ‘‘Pregnancy,’’ ‘‘Labor and 

delivery,’’ and ‘‘Nursing mothers’’ 

subsections of prescription drug 

labeling as defined by the 1979 

regulations. In response to this 

feedback, FDA held a part 15 public 

hearing, conducted focus groups, and 

convened two advisory committees to 

provide expert input. During this 

process, many stakeholders stated that 

these subsections of prescription drug 

labeling lacked clarity, often failed to 

provide meaningful clinical information 

about drug exposure during pregnancy 

and lactation, and did not address the 

potential maternal and fetal 

consequences of discontinuing needed 

maternal drug therapy during 

pregnancy. Experts and other 

stakeholders noted that the pregnancy 

categories, although highly relied upon 

by health care providers, were often 

misinterpreted and misused. FDA also 

sought input on the development of a 

model format for these subsections of 

labeling, and the resulting model served 

as the basis for the May 29, 2008, 

proposed rule (73 FR 30831). The 

preamble to the proposed rule contains 

a detailed discussion about the 

background of the development of the 

proposed rule and additional details 

regarding the 1979 regulations 

governing labeling of drug products for 

use during pregnancy, during labor and 

delivery, and while nursing (73 FR 

30831 at 30832–30838). 

C. The Proposed Rule 

FDA proposed to amend the content 

and format of the ‘‘Pregnancy,’’ ‘‘Labor 

and delivery,’’ and ‘‘Nursing mothers’’ 

subsections of the ‘‘Use in Specific 

Populations’’ section of physician 

labeling for prescription drug products 

subject to § 201.57. The Agency’s 

proposed changes were intended to 

create a consistent format for providing 

information about the effects of a drug 

on pregnancy and lactation that would 

be useful for decisionmaking by health 

care providers and their patients. With 

respect to the ‘‘Pregnancy,’’ ‘‘Labor and 

delivery,’’ and ‘‘Nursing mothers’’ 

subsections of the ‘‘Precautions’’ section 

of prescription drug labeling for drug 

products subject to § 201.80, the Agency 

proposed only to remove the pregnancy 

category from the ‘‘Pregnancy’’ 

subsection. 

1. Proposed Provisions for New and 

Recently Approved Drugs 

FDA proposed the following format 

and content changes to the 

‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and 

‘‘Nursing mothers’’ subsections of 

prescription drug labeling for products 

subject to § 201.57. 

• Merge the current ‘‘Pregnancy’’ and 

‘‘Labor and delivery’’ subsections into a 

single ‘‘Pregnancy’’ subsection 

designated 8.1 under the section ‘‘8 Use 

in Specific Populations.’’ 

• Rename the ‘‘Nursing mothers’’ 

subsection as ‘‘Lactation’’ designated 

with the identifying number 8.2 under 

the section ‘‘8 Use in Specific 

Populations.’’ 

• Reserve the identifying number 8.3 

for future use. 

• Replace the format and content of 

the ‘‘Pregnancy’’ subsection in its 

entirety with the following: 

Æ If there is a pregnancy exposure 

registry for the drug, the telephone 

number or other information needed to 

enroll in the registry or to obtain 

information about the registry must be 

included at the beginning of the 

‘‘Pregnancy’’ subsection of labeling. 

Æ Require the inclusion of a general 

statement about background risk, 

specifically ‘‘All pregnancies have a 

background risk of birth defect, loss, or 

other adverse outcome regardless of 

drug exposure. The fetal risk summary 

below describes (name of drug)’s 

potential to increase the risk of 

developmental abnormalities above the 

background risk.’’ 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72067 

Æ Under the subheading ‘‘Fetal Risk 

Summary,’’ require the labeling to 

contain a risk conclusion and a 

narrative description of the risk(s) (if the 

risk conclusion is based on human 

data). 

Æ Require the fetal risk summary to 

characterize the likelihood that the drug 

increases the risk of developmental 

abnormalities and other risks in 

humans. 

Æ Require that if data demonstrate 

that a drug is not systemically absorbed, 

the fetal risk summary contain only the 

following statement: (Name of drug) is 

not absorbed systemically from (part of 

body) and cannot be detected in the 

blood. Maternal use is not expected to 

result in fetal exposure to the drug. 

Æ When both human and animal data 

are available, require that risk 

conclusions based on human data be 

presented before risk conclusions based 

on animal data. Require that a risk 

conclusion based on human data be 

followed by a narrative description of 

the risks. 

Æ When human data are sufficient to 

reasonably determine the likelihood that 

the drug increases the risk of fetal 

developmental abnormalities or specific 

developmental abnormalities, require 

the labeling to contain one of two risk 

conclusions: Human data do not 

indicate that (name of drug) increases 

the risk of (type of developmental 

abnormality or specific developmental 

abnormality) or Human data indicate 

that (name of drug) increases the risk of 

(type of developmental abnormality or 

specific developmental abnormality). 

Æ When human data are available but 

not sufficient to reasonably determine 

the drug’s effects on fetal developmental 

abnormalities, require the labeling to 

characterize the likelihood that the drug 

increases the risk of developmental 

abnormalities as low, moderate, or high. 

Æ Require that when the data on 

which the risk conclusion is based are 

animal data, the fetal risk summary 

characterize the likelihood that the drug 

increases the risk of developmental 

abnormalities using one of the following 

risk conclusions: Not predicted to 

increase the risk, low likelihood of 

increased risk, moderate likelihood of 

increased risk, high likelihood of 

increased risk, or insufficient animal 

data on which to assess the likelihood 

of increased risk. 

Æ When human data are available, 

require that in addition to the risk 

conclusion(s), the fetal risk summary be 

followed by a brief narrative description 

of the risks of developmental 

abnormalities as well as on other 

relevant risks associated with the drug. 

Æ Require the fetal risk summary to 

refer to the ‘‘Contraindications’’ and/or 

‘‘Warnings and Precautions’’ sections of 

the labeling if there is any information 

in those sections on an increased risk to 

the fetus from exposure to the drug. 

Æ Require under the subheading 

‘‘Clinical Considerations’’ the inclusion 

of information about the known or 

predicted risks to the fetus from 

inadvertent exposure to the drug, 

including human or animal data on 

dose, timing, and duration of exposure. 

If there are no data to assess the risk 

from inadvertent exposure, require the 

labeling to so state. 

Æ Require under the subheading 

‘‘Clinical Considerations’’ the inclusion 

of information related to prescribing 

decisions for pregnant women, 

including the risk, if known, to the 

pregnant woman and the fetus from the 

disease or condition the drug is 

indicated to treat and the potential 

influence of drug treatment on that risk; 

information about dosing adjustments 

during pregnancy; if use of the drug is 

associated with any maternal adverse 

reactions that are unique to pregnancy 

or if known adverse reactions occur 

with increased frequency or severity in 

pregnant women, a description of such 

adverse reactions; if it is known or 

anticipated that treatment of the 

pregnant woman will cause a 

complication in the fetus or the neonate, 

a description of the complication, the 

severity and reversibility of the 

complication, and general types of 

interventions, if any, that may be 

needed. 

Æ If the drug has a recognized use 

during labor or delivery, whether or not 

that use is stated as an indication in the 

labeling, or is expected to affect labor or 

delivery, require the inclusion of 

available information about the effect of 

the drug on the mother; the fetus/

neonate; the duration of labor and 

delivery; the possibility of 

complications, including interventions, 

if any, that may be needed; and the later 

growth, development, and functional 

maturation of the child. 

Æ Require the inclusion of a ‘‘Data’’ 

subheading that, for human data, 

describes positive and negative 

experiences during pregnancy, 

including developmental abnormalities, 

and, to the extent applicable, the 

number of subjects and duration of the 

study. For animal data, require under 

the subheading ‘‘Data’’ a description of 

the relationship of the exposure and 

mechanism of action in the animal 

species to the anticipated exposure and 

mechanism of action in humans. 

• Replace the ‘‘Nursing mothers’’ 

subsection with ‘‘Lactation’’ and replace 

the content requirements of ‘‘Nursing 

mothers’’ in its entirety with the 

following: 

Æ Require that the labeling of all 

drugs contain a ‘‘Lactation’’ subsection. 

Æ Under the subheading ‘‘Risk 

Summary,’’ if the data demonstrate that 

the drug does not affect the quantity 

and/or quality of human milk and there 

is reasonable certainty either that the 

drug is not detectable in human milk or 

that the amount of drug consumed 

through breast milk will not adversely 

affect the breast-fed child, the labeling 

must state: The use of (name of drug) is 

compatible with breastfeeding. After 

this statement (if applicable), the 

labeling must summarize the drug’s 

effect on milk production, what is 

known about the presence of the drug in 

human milk, and the effects on the 

breast-fed child. 

Æ The source(s) of the data (e.g., 

human, animal, in vitro) that are the 

basis for the ‘‘Risk Summary’’ must be 

stated. When there are insufficient data 

or no data to assess the drug’s effect on 

milk production, the presence of the 

drug in human milk, and/or the effects 

on the breast-fed child, the ‘‘Risk 

Summary’’ must so state. 

Æ If the drug is not systemically 

absorbed, require that the subheading 

‘‘Risk Summary’’ contain only the 

following statement: (Name of drug) is 

not absorbed systemically from (part of 

body) and cannot be detected in the 

mother’s blood. Therefore, detectable 

amounts of (name of drug) will not be 

present in breast milk. Breastfeeding is 

not expected to result in fetal exposure 

to the drug. 

Æ If the drug is absorbed systemically, 

require the following under the 

subheading ‘‘Risk Summary’’: 

D A description of the effects of the 

drug’s impact on milk production, 

including the effect of the drug on the 

quality and quantity of milk, including 

milk composition, and the implications 

of these changes to the breast-fed child. 

D A description of the presence of the 

drug in human milk in one of the 

following ways: (1) The drug is not 

detectable in human milk, (2) the drug 

has been detected in human milk, (3) 

the drug is predicted to be present in 

human milk, (4) the drug is not 

predicted to be present in human milk, 

or (5) the data are insufficient to know 

or predict whether the drug is present 

in human milk. 

D Require that if studies demonstrate 

that the drug is not detectable in human 

milk, the ‘‘Risk Summary’’ state the 

limits of the assay used. 

D Require that if the drug has been 

detected in human milk, the ‘‘Risk 

Summary’’ give the concentration 

mstockstill on DSK4VPTVN1PROD with RULES2

72068 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

detected in milk in reference to a stated 

maternal dose (or, if the drug has been 

labeled for pediatric use, in reference to 

the pediatric dose), an estimate of the 

amount of the drug consumed daily by 

the infant based on an average daily 

milk consumption of 150 milliliters per 

kilogram of infant weight per day, and 

an estimate of the percentage of the 

maternal dose excreted in human milk. 

D Require the inclusion of 

information about the likelihood and 

seriousness of known or predicted 

effects on the breast-fed child from 

exposure to the drug in human milk 

based on the pharmacologic and 

toxicologic profile of the drug, the 

amount of drug detected or predicted to 

be found in human milk, and agerelated differences in absorption, 

distribution, metabolism, and 

elimination. 

Æ Under the subheading ‘‘Clinical 

Considerations,’’ require the labeling to 

provide the following information to the 

extent it is available: Information 

concerning ways to minimize the 

exposure of the breast-fed child to the 

drug, such as timing the dose relative to 

breastfeeding or pumping and 

discarding milk for a specified period; 

information about potential drug effects 

in the breast-fed child that could be 

useful to caregivers, including 

recommendations for monitoring or 

responding to these effects; information 

about dosing adjustments during 

lactation. 

Æ Require that the labeling include, 

under the subheading ‘‘Data,’’ an 

overview of the data that are the basis 

for the ‘‘Risk Summary’’ and ‘‘Clinical 

Considerations.’’ 

2. Pregnancy Categories and 

Implementation 

FDA proposed to require the new 

content and format changes for 

prescription drug labeling for all 

applications (including new drug 

applications (NDAs), biologics license 

applications (BLAs), or efficacy 

supplements) required to comply with 

the PLR, i.e., for drug products for 

which an application was approved on 

or after June 30, 2001. FDA proposed 

that holders of applications approved 

before June 30, 2001 (i.e., applications 

not subject to the PLR), would not be 

required to implement the new content 

and format changes. Instead, if the 

labeling for such applications contains a 

pregnancy category, the application 

holders would be required to remove 

the pregnancy category designation by 3 

years after the effective date of the final 

rule. 

D. Mental Models Research 

In a separate but related effort, FDA 

contracted with a third party research 

firm to conduct a Mental Models 

Research study in 2009 to better 

understand the decisionmaking 

processes of health care providers 

prescribing drugs to pregnant and 

lactating women with chronic 

conditions (Ref. 1). Mental Models 

Research is an established risk analysis 

approach that evaluates, using a 

structured interview, decisionmaking 

practices that require the synthesis of 

complex issues. The specific objectives 

of this study, which involved interviews 

with 54 health care providers, were to 

understand how health care providers 

used FDA-approved prescribing 

information (in the labeling format in 

place at the time of the study in 2009), 

in order to determine the factors that 

influence their treatment decisions for 

pregnant and lactating women with 

chronic conditions, and to define 

measures that could be used to quantify 

the value of prescribing information as 

a tool for these decision makers. 

The findings from the Mental Models 

Research were consistent with the 

feedback the Agency received during its 

work on the proposed and final rules. 

For example, the research showed that 

the pregnancy categories were relied 

upon by many health care providers 

almost to the exclusion of other 

information found in the labeling. It also 

showed that providers often relied on 

secondary sources to find the pregnancy 

category for a particular product rather 

than using the product’s labeling. 

Interviewees made suggestions for 

improving prescribing information, 

including simplifying the information 

presented, centralizing the relevant 

information, and making the 

information included in labeling 

clinically relevant. 

II. Overview of the Final Rule, 

Including Significant Changes to the 

Proposed Rule 

A. Overview 

In this rulemaking, the Agency 

finalizes many of the provisions in the 

May 2008 proposed rule. In addition, 

the final rule reflects revisions the 

Agency made in response to comments 

on the May 2008 proposed rule. FDA 

has also made editorial and 

organizational changes to clarify 

provisions. For the purposes of this 

rulemaking, the term ‘‘drug’’ or ‘‘drug 

product’’ is used to refer to human 

prescription drugs and biological 

products that are regulated as drugs. 

The final rule requires that for the 

labeling of certain products (as 

described in the ‘‘Implementation’’ 

section of this document), the 

subsections ‘‘Pregnancy,’’ ‘‘Nursing 

mothers,’’ and ‘‘Labor and delivery’’ be 

replaced by three subsections entitled 

‘‘Pregnancy,’’ ‘‘Lactation,’’ and 

‘‘Females and Males of Reproductive 

Potential.’’ Information previously 

placed in ‘‘Labor and delivery’’ is 

required to be included in the 

‘‘Pregnancy’’ subsection of labeling. The 

final rule requires ‘‘Risk Summary’’ 

subheadings in the ‘‘Pregnancy’’ and 

‘‘Lactation’’ subsections of labeling. The 

‘‘Pregnancy Exposure Registry’’ 

subheading under ‘‘Pregnancy’’ is only 

required if there is such a registry. The 

‘‘Clinical Considerations’’ and ‘‘Data’’ 

subheadings are required under 

‘‘Pregnancy’’ and under ‘‘Lactation’’ 

only to the extent relevant information 

is available. If data demonstrate that the 

drug is systemically absorbed, the ‘‘Risk 

Summary’’ in the ‘‘Pregnancy’’ 

subsection requires a statement 

regarding the background risk, in 

addition to certain other information, 

and the ‘‘Risk Summary’’ in the 

‘‘Lactation’’ subsection of labeling 

requires the inclusion of a risk and 

benefit statement, unless breastfeeding 

is contraindicated. The ‘‘Females and 

Males of Reproductive Potential’’ 

subsection is not required if none of the 

subheadings are applicable. However, 

when pregnancy testing and/or 

contraception is required or 

recommended before, during, or after 

drug therapy and/or when there are 

human and/or animal data that suggest 

drug-associated fertility effects, the 

‘‘Females and Males of Reproductive 

Potential’’ subsection requires the 

inclusion of such information under the 

subheadings ‘‘Pregnancy Testing,’’ 

‘‘Contraception,’’ and ‘‘Infertility,’’ 

respectively. The final rule also requires 

statements acknowledging when data on 

various labeling elements either are not 

available or do not establish the 

presence or absence of drug-associated 

risk In addition, the final rule requires 

removal of pregnancy categories from all 

drug product labeling, including those 

products for which an application was 

approved before June 30, 2001. 

B. Significant Changes to the Proposed 

Rule 

The final rule reflects revisions to the 

proposed rule in response to comments 

received on the proposed rule, as 

discussed in detail in section III of this 

document. FDA made the following 

organizational and content-based 

changes to the proposed rule: 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72069 

1. Pregnancy 

• The final rule revises the proposed 

rule to clarify that the ‘‘Risk Summary’’ 

subheading is always required in the 

‘‘Pregnancy’’ subsection of labeling. The 

subheading ‘‘Pregnancy Exposure 

Registry’’ is only required when such a 

registry exists; the ‘‘Clinical 

Considerations’’ and ‘‘Data’’ 

subheadings are required when relevant 

information is available. If the ‘‘Clinical 

Considerations’’ subheading is required, 

the following headings under it are also 

required to the extent relevant 

information is available: ‘‘Diseaseassociated maternal and/or embryo/fetal 

risk,’’ ‘‘Dose adjustments during 

pregnancy and the postpartum period,’’ 

‘‘Maternal adverse reactions,’’ ‘‘Fetal/

Neonatal adverse reactions,’’ and ‘‘Labor 

or delivery.’’ Similarly, if the ‘‘Data’’ 

subheading is required, the headings 

‘‘Human Data’’ and ‘‘Animal Data’’ are 

required under it to the extent relevant 

information is available. 

• The final rule revises the proposed 

‘‘Pregnancy Exposure Registry’’ 

subheading as follows: 

Æ Requires that contact information 

and a standard statement on the 

pregnancy exposure registry will be 

included under its own subheading 

‘‘Pregnancy Exposure Registry’’ if there 

is a pregnancy registry that is 

scientifically acceptable. 

Æ Eliminates the phrase ‘‘must be 

stated at the beginning of the 

‘Pregnancy’ subsection of the labeling.’’ 

Æ Revises the phrase ‘‘telephone 

number or other information needed to 

enroll’’ to ‘‘contact information needed 

to enroll.’’ 

Æ Adds a requirement that the 

following statement be included in 

labeling before the contact information 

for the pregnancy exposure registry: 

There is a pregnancy exposure registry 

that monitors pregnancy outcomes in 

women exposed to (name of drug) 

during pregnancy. 

• The final rule revises the proposed 

‘‘Fetal Risk Summary’’ as follows: 

Æ Changes the title of the subheading 

‘‘Fetal Risk Summary’’ to ‘‘Risk 

Summary.’’ 

Æ Eliminates the requirement that the 

following background risk statement be 

included in the labeling before the fetal 

risk summary: All pregnancies have a 

background risk of birth defect, loss, or 

other adverse outcome regardless of 

drug exposure. The fetal risk summary 

below describes (name of drug)’s 

potential to increase the risk of 

developmental abnormalities above the 

background risk. 

Æ Replaces the proposed standardized 

background risk statement with the 

requirement that, if the drug is 

systemically absorbed, the labeling state 

the percentage range of live births in the 

United States with a major birth defect 

and the percentage range of pregnancies 

in the United States that end in 

miscarriage, regardless of drug 

exposure. The final rule also requires 

that if such information is available for 

the population(s) for which the drug is 

labeled, it must also be included. 

Æ Replaces the term ‘‘developmental 

abnormalities’’ with the term ‘‘adverse 

developmental outcomes.’’ The final 

rule defines ‘‘adverse developmental 

outcomes’’ as structural abnormalities, 

embryo-fetal and/or infant mortality, 

functional impairment, and alterations 

to growth. 

Æ Clarifies that, when applicable, risk 

statements must include a crossreference to additional details located 

under the ‘‘Data’’ subheading of 

‘‘Pregnancy.’’ 

Æ Revises the statement required 

when a drug is not systemically 

absorbed as follows: 

D Replaces the phrase ‘‘from (part of 

the body)’’ with ‘‘following (route of 

administration)’’ to describe how the 

drug enters the body. 

D Replaces the phrase ‘‘cannot be 

detected in the blood’’ with ‘‘maternal 

use is not expected to result in fetal 

exposure to the drug.’’ 

Æ Adds a requirement that when use 

of the drug is contraindicated during 

pregnancy, this must be stated first in 

the ‘‘Risk Summary.’’ 

Æ Requires that risk statements be 

presented in the following order: Based 

on human data, based on animal data, 

based on pharmacology. 

• The ‘‘Risk conclusions based on 

human data’’ in the ‘‘Risk Summary’’ is 

revised as follows: 

Æ Replaces the term ‘‘risk 

conclusions’’ with ‘‘risk statement.’’ 

Æ Eliminates the term ‘‘sufficient 

human data’’ and the proposed rule’s 

requirement that the labeling contain 

one of the following standardized risk 

conclusions about sufficient human 

data: Human data do not indicate that 

(name of drug) increases the risk of 

(type of developmental abnormality or 

specific abnormality) and Human data 

indicate that (name of drug) increases 

the risk of (type of developmental 

abnormality or specific abnormality). 

Æ Replaces the standardized risk 

conclusions based on human data with 

the requirement that when human data 

are available that establish the presence 

or absence of any adverse 

developmental outcome(s) associated 

with maternal use of the drug, the Risk 

Summary must summarize the specific 

developmental outcome, its incidence, 

and the effects of dose, duration of 

exposure, and gestational timing of 

exposure. The final rule also requires 

that if the human data indicate that 

there is an increased risk for a specific 

adverse developmental outcome in 

infants born to women exposed to the 

drug during pregnancy, this risk must be 

quantitatively compared to the risk for 

the same outcome in infants born to 

women who were not exposed to the 

drug but who have the disease or 

condition for which the drug is 

indicated to be used. When risk 

information is not available for women 

with these condition(s), then the risk for 

the specific outcome must be compared 

to the rate at which the outcome occurs 

in the general population. 

Æ Requires that the ‘‘Risk Summary’’ 

must state when there are no human 

data or when available human data do 

not establish the presence or absence of 

drug-associated risk. 

Æ Eliminates the term ‘‘other human 

data’’ and the requirement that when 

there are other human data, the 

likelihood that the drug increases the 

risk of developmental abnormalities 

must be characterized as low, moderate, 

or high. 

• The ‘‘Risk conclusions based on 

animal data’’ in the ‘‘Risk Summary’’ is 

revised as follows: 

Æ Replaces the term ‘‘risk 

conclusions’’ with ‘‘risk statement.’’ 

Æ Eliminates the requirement that 

animal data be characterized as ‘‘not 

predicted to increase the risk,’’ ‘‘low 

likelihood of increased risk,’’ ‘‘moderate 

likelihood of increased risk,’’ or ‘‘high 

likelihood of increased risk.’’ 

Æ Requires that when animal data are 

available, the labeling must summarize 

the findings in animals and based on 

these findings, describe, for the drug, 

the potential risk of any adverse 

developmental outcome(s) in humans. 

The final rule requires that the risk 

statement include: The number and 

type(s) of species affected, the timing of 

exposure, animal doses expressed in 

terms of human exposure or dose 

equivalents, and outcomes for pregnant 

animals and offspring. When animal 

studies do not meet current standards 

for nonclinical developmental toxicity 

studies, the labeling must so state. The 

final rule requires that when there are 

no animal data, the ‘‘Risk Summary’’ 

must so state. 

• Adds a ‘‘Risk statement based on 

pharmacology’’ to the ‘‘Risk Summary,’’ 

requiring that when the drug has a wellunderstood mechanism of action that 

may result in drug-associated adverse 

developmental outcome(s), the ‘‘Risk 

Summary’’ must explain the mechanism 

mstockstill on DSK4VPTVN1PROD with RULES2

72070 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

of action and the potential associated 

risks. 

• Eliminates the ‘‘Narrative 

description of human data’’ requirement 

from the ‘‘Risk Summary.’’ 

• Removes the requirement that the 

‘‘Risk Summary’’ refer to the 

‘‘Contraindications’’ or ‘‘Warnings and 

Precautions’’ sections of the labeling 

when those sections contain 

information on an increased risk to the 

fetus from exposure to the drug. 

• The final rule revises the ‘‘Clinical 

Considerations’’ component as follows: 

Æ Requires headings, to the extent 

relevant information is available, for 

‘‘Disease-associated maternal and/or 

embryo/fetal risk,’’ ‘‘Dose adjustments 

during pregnancy and the postpartum 

period,’’ ‘‘Maternal adverse reactions,’’ 

‘‘Fetal/Neonatal adverse reactions,’’ and 

‘‘Labor or delivery’’. 

Æ Eliminates the ‘‘Inadvertent 

exposure during pregnancy’’ heading. 

Æ Eliminates the ‘‘Prescribing 

decisions for pregnant women’’ heading. 

Æ Revises ‘‘risk, if known, to the 

pregnant woman and the fetus from the 

disease or condition the drug is 

indicated to treat’’ (which was the 

language used in the proposed rule 

under the ‘‘Prescribing decisions for 

pregnant women’’ heading) to ‘‘serious 

known or potential risk to the pregnant 

woman and/or the embryo/fetus 

associated with the disease or condition 

for which the drug is indicated to be 

used’’ and places this information under 

the new heading ‘‘Disease-associated 

maternal and/or embryo/fetal risk.’’ 

Æ Under ‘‘Dose adjustments during 

pregnancy and the postpartum period,’’ 

requires the inclusion of information 

about dose adjustments during 

pregnancy and the postpartum period if 

supported by pharmacokinetic data. 

Æ Under ‘‘Dose adjustments during 

pregnancy and the postpartum period,’’ 

removes the requirement that, if there 

are no data on dosing in pregnancy, the 

labeling must so state. 

Æ Under ‘‘Maternal adverse 

reactions,’’ replaces the proposed 

requirement that the ‘‘labeling must 

describe any interventions that may be 

needed (e.g., monitoring blood glucose 

for a drug that causes hyperglycemia in 

pregnancy)’’ with the requirement that 

the labeling include a description of 

available intervention(s) for monitoring 

or mitigating the reaction. 

Æ Adds a requirement that the 

labeling include relevant information 

about fetal/neonatal adverse reactions 

under the heading ‘‘Fetal/Neonatal 

adverse reactions’’. 

Æ Under ‘‘Fetal/Neonatal adverse 

reactions,’’ replaces the phrase ‘‘will 

cause a complication in the neonate’’ 

with ‘‘increases or may increase the risk 

of an adverse reaction in the fetus or 

neonate.’’ 

Æ Under ‘‘Fetal/Neonatal adverse 

reactions,’’ replaces ‘‘the severity and 

reversibility of the complication’’ with 

‘‘the potential severity and reversibility 

of the adverse reaction,’’ and replaces 

‘‘general types of interventions, if any, 

that may be needed’’ with ‘‘available 

intervention(s) for monitoring or 

mitigating the reaction.’’ 

Æ Under ‘‘Fetal/Neonatal adverse 

reactions,’’ adds a requirement that the 

labeling must describe, if known, the 

effect of dose, timing, and duration of 

exposure on the risk. 

Æ Revises the heading ‘‘Drug effects 

during labor or delivery’’ to ‘‘Labor or 

delivery.’’ 

Æ Under ‘‘Labor or delivery,’’ revises 

‘‘[i]f the drug has a recognized use 

during labor or delivery, whether or not 

the use is stated as an indication in the 

labeling, or if the drug is expected to 

affect labor or delivery’’ to ‘‘[i]f the drug 

is expected to affect labor or delivery.’’ 

Æ Under ‘‘Labor or delivery,’’ revises 

‘‘the possibility of complications, 

including interventions, if any, that may 

be needed’’ to ‘‘the increased risk of 

adverse reactions, including their 

potential severity and reversibility.’’ 

Æ Under ‘‘Labor or delivery,’’ adds a 

requirement that the labeling provide 

information about available 

intervention(s) that can mitigate effects 

and/or adverse reactions. 

Æ Under ‘‘Labor or delivery,’’ clarifies 

that the information described under 

that heading is not required for drugs 

approved only for use during labor and 

delivery. 

Æ Under ‘‘Labor or delivery,’’ 

eliminates the requirement that the 

labeling include information about the 

effect of the drug on the later growth, 

development, and functional maturation 

of the child. 

• The final rule revises the ‘‘Data’’ 

subheading of labeling as follows: 

Æ Replaces ‘‘provide an overview of 

the data that were the basis for the fetal 

risk summary’’ with ‘‘describe the data 

that are the basis for the Risk Summary 

and Clinical Considerations.’’ 

Æ Requires the inclusion of the 

subheading ‘‘Data,’’ and the headings 

‘‘Human Data’’ and ‘‘Animal Data,’’ to 

the extent available information is relied 

on in the Risk Summary and Clinical 

Considerations subheadings. 

Æ Separates the requirements for 

human data from the requirements for 

animal data. 

Æ For human data, requires that the 

labeling describe adverse developmental 

outcomes, adverse reactions, and other 

adverse effects and, to the extent 

applicable, the types of studies or 

reports, number of subjects and duration 

of each study, exposure information, 

and limitations of the data. Requires 

that both positive and negative study 

findings be included. 

Æ For animal data, retains the 

requirement that the labeling describe 

the types of studies, animal species, 

dose, duration and timing of exposure, 

and adds the requirement that the 

labeling also describe study findings, 

presence or absence of maternal 

toxicity, and limitations of the data. 

Adds the requirement that the 

description of maternal and offspring 

findings must include information on 

the dose-response and severity of 

adverse developmental outcomes. 

Requires that animal doses or exposures 

be described in terms of human dose or 

exposure equivalents and that the basis 

for those calculations must be included. 

2. Lactation 

• The final rule revises the ‘‘Risk 

Summary’’ as follows: 

Æ Requires that when relevant human 

or animal lactation data are available, 

the ‘‘Risk Summary’’ must include a 

cross-reference to ‘‘Data’’ in the 

‘‘Lactation’’ subsection. 

Æ Removes the proposed 

standardized statement ‘‘The use of 

(name of drug) is compatible with 

breastfeeding.’’ 

Æ Requires that when human data are 

available, animal data must not be 

included unless the animal model is 

specifically known to be predictive for 

humans. 

Æ Requires that when use of a drug is 

contraindicated during breastfeeding, 

this information must be stated first in 

the ‘‘Risk Summary.’’ 

Æ Revises the standardized statement 

required when the drug is not absorbed 

systemically from (Name of drug) is not 

absorbed systemically from (part of 

body) and cannot be detected in the 

mother’s blood. Therefore, detectable 

amounts of (name of drug) will not be 

present in breast milk. Breastfeeding is 

not expected to result in fetal exposure 

to the drug to (Name of drug) is not 

absorbed systemically by the mother 

following (route of administration) and 

breastfeeding is not expected to result in 

exposure of the child to (name of drug). 

Æ Revises the order of the types of 

information required if the drug is 

systemically absorbed as follows: (1) 

Presence of drug in human milk, (2) 

effects of drug on the breast-fed child, 

and (3) effects of drug on milk 

production. 

Æ Replaces proposed standardized 

statements regarding the presence of the 

drug in human milk with a requirement 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72071 

that the ‘‘Risk Summary’’ state whether 

the drug and/or its active metabolites 

are present in human milk, and when 

there are no data to assess this, the 

‘‘Risk Summary’’ must so state. 

Æ Under ‘‘Presence of drug in human 

milk,’’ requires that if studies 

demonstrate the presence of the drug 

and/or its active metabolites in human 

milk, the ‘‘Risk Summary’’ must state 

the concentration of the drug and/or its 

active metabolites in human milk and 

the actual or estimated daily dose for an 

infant fed exclusively with human milk. 

The estimated amount of drug and/or its 

active metabolites ingested by the infant 

must be compared to the labeled infant 

or pediatric dose, if available, or to the 

maternal dose. 

Æ Under ‘‘Presence of drug in human 

milk,’’ retains the requirement that if 

studies demonstrate that the drug and/ 

or its active metabolite(s) are not 

detectable in human milk, the Risk 

Summary must state the limits of the 

assay used. 

Æ Under ‘‘Presence of drug in human 

milk,’’ adds the requirement that if 

studies demonstrate the presence of the 

drug and/or its active metabolite(s) in 

human milk but the drug and/or its 

active metabolite(s) are not expected to 

be systemically bioavailable to the 

breast-fed child, then the ‘‘Risk 

Summary’’ must describe the 

disposition of the drug and/or its active 

metabolites. 

Æ Adds a requirement that if only 

animal lactation data are available, the 

‘‘Risk Summary’’ must state only 

whether or not the drug and/or its active 

metabolite(s) were detected in animal 

milk and specify the animal species. 

Æ Under ‘‘Effects of drug on the 

breast-fed child,’’ the final rule: 

D Adds a requirement that the ‘‘Risk 

Summary’’ include available 

information on the known or predicted 

effects on the child from exposure to the 

drug and/or its active metabolite(s) 

through human milk or from contact 

with breast or nipple skin from a topical 

product. 

D Requires the inclusion of 

information about systemic and/or local 

adverse reactions. 

D Requires that the ‘‘Risk Summary’’ 

state if there are no data to assess the 

effects of the drug and/or its active 

metabolite(s) on the breast-fed child. 

Æ Under ‘‘Effects of drug on milk 

production,’’ the final rule: 

D Replaces the proposed requirement 

that the ‘‘Risk Summary’’ describe the 

effect of the drug on the quality and 

quantity of milk, including milk 

composition, and the implications of 

these changes to the milk on the breastfed child, with the requirement that the 

‘‘Risk Summary’’ must describe the 

effects of the drug and/or its active 

metabolite(s) on milk production. 

D Adds a requirement that when there 

are no data to assess the effects of the 

drug and/or its active metabolite(s) on 

milk production, the ‘‘Risk Summary’’ 

must so state. 

Æ The final rule adds the requirement 

that for drugs absorbed systemically, 

unless breastfeeding is contraindicated 

during drug therapy, the following risk 

and benefit statement must appear at the 

end of the ‘‘Risk Summary’’: The 

developmental and health benefits of 

breastfeeding should be considered 

along with the mother’s clinical need for 

(name of drug) and any potential 

adverse effects on the breast-fed child 

from the drug or from the underlying 

maternal condition. 

• Under ‘‘Clinical Considerations,’’ 

the final rule: 

Æ Revises the provisions of the 

proposed rule to require that the 

labeling include information concerning 

ways to minimize exposure to the drug 

and/or its active metabolite(s) in the 

breast-fed child in situations where the 

following conditions are present: The 

drug and/or its active metabolite(s) are 

present in human milk in clinically 

relevant concentrations; do not have an 

established safety profile in infants; and 

are used either intermittently, in single 

doses, or for short courses of therapy. 

Æ Adds a requirement that, when 

applicable, the labeling must describe 

ways to minimize a breast-fed child’s 

oral intake of topical drugs applied to 

the breast or nipple skin. 

Æ Under ‘‘Monitoring for adverse 

reactions,’’ replaces the proposed 

requirement that the labeling include 

information about potential drug effects 

in the breast-fed child that could be 

useful to caregivers, including 

recommendations for monitoring or 

responding to those effects, with a 

requirement that the labeling must 

describe available intervention(s) for 

monitoring or mitigating the adverse 

reaction(s) presented in the ‘‘Risk 

Summary.’’ 

Æ Eliminates the proposed 

requirement that the labeling include 

information about dosing adjustments 

during lactation. 

• Under ‘‘Data,’’ the final rule 

replaces the phrase ‘‘provide an 

overview of the data’’ with the phrase 

‘‘describe the data.’’ 

3. Females and Males of Reproductive 

Potential 

• Adds ‘‘8.3 Females and Males of 

Reproductive Potential’’ subsection 

requiring that when pregnancy testing 

and/or contraception are required or 

recommended before, during, or after 

drug therapy and/or when there are 

human and/or animal data that suggest 

drug-associated fertility effects, this 

subsection of labeling must contain this 

information under the subheadings 

‘‘Pregnancy Testing,’’ ‘‘Contraception,’’ 

and ‘‘Infertility,’’ in that order. 

III. Comments on the Proposed Rule 

The Agency received 72 comments on 

the proposed rule. Comments were 

received from prescription drug 

manufacturers, trade organizations 

representing prescription drug 

manufacturers and other interested 

parties, professional associations and 

organizations representing health care 

providers, health care and consumer 

advocacy organizations, individual 

physicians, pharmacists, consumers, 

and others. 

Most of the comments supported 

FDA’s goal of improving the format and 

content of the ‘‘Pregnancy,’’ ‘‘Labor and 

delivery,’’ and ‘‘Nursing mothers’’ 

subsections of prescription drug 

labeling, and several of these comments 

stated that the proposed rule would 

address shortcomings of the previous 

labeling regulations. Other comments 

noted that the proposed rule would 

improve the accessibility of relevant 

information, thereby enabling better 

informed medical decisions regarding 

the risks and benefits of prescription 

drug use by pregnant and lactating 

women. Although a number of 

comments supported all of FDA’s 

proposed revisions, many comments 

opposed particular aspects of the 

proposed rule. 

To make it easier to identify 

comments and our responses, the word 

‘‘Comment’’ and a comment number 

appear in parentheses before each 

comment’s description, and the word 

‘‘Response’’ in parentheses precedes 

each response. Similar comments are 

grouped together under the same 

number. Specific issues raised by the 

comments and the Agency’s responses 

follow. 

A. Proposed Rule as a Whole 

1. Plain Language and Intended 

Audience 

(Comment 1) Several comments 

suggested that the language used in the 

pregnancy and lactation subsections of 

prescription drug labeling should be 

clear and accessible to a variety of 

audiences. One comment stated that 

because the intended audience for 

prescription pregnancy and lactation 

labeling is females of reproductive 

potential and their health care 

providers, this portion of prescription 

mstockstill on DSK4VPTVN1PROD with RULES2

72072 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

drug labeling should not include overly 

technical information. Another 

comment suggested that to make the 

information more accessible to the 

general public, FDA should include a 

plain language summary of the 

pregnancy and lactation subsections. 

Two comments suggested that because 

females of reproductive potential may 

read the ‘‘Pregnancy’’ and ‘‘Lactation’’ 

subsections of labeling, FDA should 

include a statement that encourages 

patients to always consult a health care 

provider before discontinuing 

medication. Another comment 

questioned how patients would access 

the proposed information and asked 

whether it would be included in 

patient-specific information that 

patients receive at the pharmacy. 

Several other comments suggested that 

the final rule should aim to create userfriendly labeling that contains a concise 

and accurate presentation of 

information that is of clinical relevance. 

(Response) FDA acknowledges that 

some females of reproductive potential 

may use prescribing information in the 

‘‘Pregnancy’’ and ‘‘Lactation’’ 

subsections of prescription drug 

labeling. The intended audience of 

prescription drug labeling, however, is 

health care providers, and it is the 

responsibility of the prescribing health 

care provider to communicate pertinent 

information regarding drug risks and 

benefits and proper use to his or her 

patient. For this reason, we have 

determined that it is not appropriate to 

require a summary of the ‘‘Pregnancy’’ 

and ‘‘Lactation’’ subsections of labeling 

as a mechanism for all patients to 

readily access full prescribing 

information, or a statement that 

encourages patients to always consult a 

health care provider before 

discontinuing medication. We note that 

in addition to the professional labeling 

that is the subject of this rulemaking, 

some drugs also have FDA-approved 

patient labeling specifically written for 

the consumer, such as Medication 

Guides (see 21 CFR part 208). Whether 

the information required under the final 

rule will be included in FDA-approved 

patient labeling for an individual drug 

will be decided on a case-by-case basis 

in accordance with the applicable FDA 

regulations and guidance. 

2. Scope of the Rule 

(Comment 2) Several comments 

suggested that FDA expand the scope of 

the rule in various ways. Two comments 

suggested that the rule be expanded to 

include nonprescription products. Four 

comments suggested that the proposed 

content changes also apply to drugs for 

which an application was approved 

before June 30, 2001, although a 

separate comment agreed with the 

proposal to limit the rule to drugs for 

which an application was approved on 

or after June 30, 2001. One comment 

suggested that the rule be expanded to 

include vaccine products (we discuss 

this suggestion later in our response to 

Comment 8). Two other comments 

suggested that the rule provide 

incentives to industry to perform 

studies on the use of drugs and 

biological products during pregnancy 

and lactation. One comment suggested 

that depression should not be treated 

pharmacologically during pregnancy, 

whereas a separate comment suggested 

that FDA ban the use of all drugs and 

vaccines during pregnancy. Another 

comment suggested that the 

presentation of the information required 

under the rule be standardized as much 

as possible with applicable coding 

schema for ease of implementation in 

databases or electronic health record 

systems. 

(Response) FDA has considered these 

comments and declines to expand the 

scope of the final rule in any of the 

suggested ways. This final rule amends 

our labeling regulations in §§ 201.57 

and 201.80, which apply only to 

prescription drug and biological 

products. It is therefore not within the 

scope of this rulemaking to address 

pregnancy and lactation labeling for 

nonprescription drug products. 

The primary purpose of this final rule, 

and prescription drug labeling in 

general, is to facilitate informed 

prescribing and safe and effective 

product use. FDA recognizes the 

importance of use of labeling 

information in electronic health records 

and other databases and agrees that, if 

possible, the presentation of information 

in labeling should facilitate its 

accessibility. However, this final rule is 

not designed to standardize the required 

information with a coding schema for 

use in databases or electronic health 

record systems. It is also beyond the 

scope of this rule to address incentives 

for collecting data on the use of drugs 

and biological products during 

pregnancy and lactation. 

FDA does not make recommendations 

about whether particular diseases or 

conditions should or should not be 

treated pharmacologically, though we 

specifically decline the suggestion to 

ban the use of all drugs during 

pregnancy. We note that many diseases 

and conditions are associated with 

adverse pregnancy outcomes when not 

appropriately managed during 

pregnancy, and under-treating or not 

treating a pregnant woman’s medical 

condition may put the woman’s health 

in danger, and is often associated with 

greater risk to the developing fetus than 

the risk of exposure to a maternal drug. 

FDA also declines the suggestion that 

the content changes required by this 

final rule also apply to drugs for which 

an application was approved before 

June 30, 2001. In developing this rule, 

FDA considered the scientific, 

economic, and practical implications of 

alternative approaches, including 

requiring implementation of the content 

and format requirements for the 

‘‘Pregnancy,’’ ‘‘Lactation,’’ and 

‘‘Females and Males of Reproductive 

Potential’’ subsections of labeling for all 

drugs, regardless of approval date. FDA 

concluded that requiring the content 

and format changes only for drugs for 

which an application was approved on 

or after June 30, 2001, (as described in 

the ‘‘Implementation’’ section of this 

document) best balanced the public 

health benefits and the economic and 

other costs of these labeling changes. In 

addition, this approach provides 

conformity with the rest of prescription 

drug labeling and the scope is consistent 

with the scope of the PLR. FDA, 

however, encourages voluntary 

compliance with these content and 

format changes for drugs for which an 

application was approved before June 

30, 2001. 

3. Combining the ‘‘Pregnancy’’ and 

‘‘Lactation’’ Subsections 

(Comment 3) One comment suggested 

that the ‘‘Pregnancy’’ and ‘‘Lactation’’ 

subsections should be combined for 

certain drugs. The comment explained 

that combining these sections would be 

useful, for example, in helping health 

care providers counsel women who take 

selective serotonin reuptake inhibitors 

(SSRIs) for the treatment of perinatal 

depression because clinicians have to 

consider the effects of the medication 

during both pregnancy and the 

postpartum period. 

(Response) FDA disagrees. The risk 

and benefit considerations for drug 

product use are different between 

pregnant and lactating patients, and we 

have determined that the information is 

best presented in separate but adjacent 

subsections of labeling. FDA believes 

that if the sections were combined it 

would be more difficult for a health care 

provider who has either a pregnant or a 

lactating patient to locate the 

information relevant to the prescribing 

decision. For anticipatory counseling, 

for which the health care provider is 

discussing the use of the drug with a 

pregnant patient who in the future may 

be lactating, we believe that having 

‘‘Lactation’’ denoted in a separate, 

numbered, indexed, and searchable 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72073 

5This guidance, when finalized, will represent 

FDA’s current thinking on this topic. 

subsection of labeling will not make it 

harder for a prescriber to find this 

information. 

4. Updates 

In the preamble to the proposed rule, 

FDA stated that under § 201.56(a) ‘‘the 

labeling must be updated when new 

information becomes available that 

causes the labeling to become 

inaccurate, false, or misleading’’ (73 FR 

30831 at 30841). The Agency also 

explained that ‘‘[w]hen new human data 

concerning the use of a drug during 

pregnancy becomes available, if that 

information is clinically relevant, FDA 

believes that it is necessary for the safe 

and effective use of the drug and, 

therefore, the pregnancy subsection of 

the labeling must be updated to include 

that information. Failure to include 

clinically relevant new information 

about the use of a drug during 

pregnancy could cause the drug’s 

labeling to become inaccurate, false, or 

misleading’’ (73 FR 30831 at 30841). 

(Comment 4) Several comments 

requested that FDA clarify its 

expectations for the process and timing 

of updating the ‘‘Pregnancy’’ and 

‘‘Lactation’’ subsections of labeling after 

new data become available. Two of 

these comments stated that the data 

should be updated regularly or 

continually. Another comment stated 

that the labeling should be updated 

annually. Several other comments 

requested that FDA define the quantity 

and quality of data that necessitates that 

the labeling be updated. One of these 

comments suggested that FDA state in 

the final rule that the labeling should be 

updated if the benefit-risk profile 

changes because of new information, 

and that labeling changes should be 

done according to ‘‘current labeling 

regulations.’’ Another comment 

questioned whether health care 

providers will be informed of changes to 

the ‘‘Pregnancy’’ and ‘‘Lactation’’ 

subsections of labeling. One comment 

suggested that sponsors electronically 

post supplemental information before 

updated printed labeling is available, 

and another suggested using 

surveillance systems to facilitate 

obtaining updated safety information. 

Two comments expressed specific 

concern that the ‘‘Lactation’’ subsection 

of drug labeling will not be updated 

frequently enough to be useful for 

clinicians. One of these comments 

stated that it is critical to routinely 

update labeling as human lactation data 

becomes available. A separate comment 

suggested including references in 

labeling to online resources regarding 

lactation data to provide prescribers and 

patients with updated information. 

(Response) The requirements for 

labeling updates described in 

§ 201.56(a) apply to this final rule as 

follows: The labeling must be 

informative and accurate and neither 

promotional in tone nor false or 

misleading in any particular. In 

accordance with §§ 314.70 and 601.12 of 

the chapter, the labeling must be 

updated when new information 

becomes available that causes the 

labeling to become inaccurate, false, or 

misleading (§ 201.56(a)(2)). With respect 

to the comment about updating labeling 

as human lactation data becomes 

available, although § 201.56(a)(3) states 

that the labeling must be based 

whenever possible on data derived from 

human experience, it also requires that 

conclusions based on animal data but 

necessary for safe and effective use of 

the drug in humans must be identified 

as such and included with human data 

in the appropriate section of the 

labeling. 

Because studies are not usually 

conducted in pregnant women prior to 

approval, most of the data regarding use 

in pregnancy and lactation will be 

collected in the postmarketing setting. 

Accordingly, in order that a drug 

product does not become misbranded, 

the labeling must be updated when new 

information becomes available that 

causes the labeling to become 

inaccurate, false, or misleading. 

Applicants are responsible for following 

the medical literature and also for 

updating labeling as new published and 

unpublished data become available. 

FDA declines the suggestion to include 

references to online resources regarding 

drug use during lactation because the 

information has not been reviewed by 

FDA. 

5. Responsibility for Drafting and 

Reviewing Labeling 

(Comment 5) One comment requested 

that FDA clarify whether industry or 

FDA would be responsible for writing 

and reviewing the new labeling. The 

comment also questioned whether FDA 

would provide staff with the training 

and expertise to make necessary 

judgments. Another comment expressed 

concern about the potential for 

inconsistent implementation of the new 

rule by FDA’s review divisions. This 

comment suggested that to increase 

labeling consistency, the Agency should 

establish a group of FDA specialists that 

review pregnancy and lactation labeling. 

(Response) As with all prescription 

drug labeling, both the manufacturer 

and FDA reviewers will play a shared 

role in determining the new labeling 

content. The Division of Pediatrics and 

Maternal Health (DPMH), within the 

Office of New Drugs at the Center for 

Drug Evaluation and Research, includes 

staff with expertise in obstetrics, 

lactation, pediatrics, clinical pharmacy, 

and regulatory science. The DPMH is 

available for consultation by all FDA 

drug product review divisions to whom 

the final rule applies for all issues 

related to labeling content and for 

review of data on the use of drugs 

during pregnancy and lactation. The 

DPMH, by working across review 

divisions, helps to ensure consistent 

application of FDA pregnancy and 

lactation labeling regulations to 

different drug products. The DPMH also 

provides consultation services to and 

works collaboratively with other Offices 

and Centers at FDA. FDA intends to 

provide staff with education and 

training on the changes in the labeling 

regulations. 

6. Process for Development of the 

Proposed Rule 

(Comment 6) One comment stated 

that FDA should have included 

pharmacists in the focus tests used 

during development of the proposed 

rule. 

(Response) FDA acknowledges the 

critical role that pharmacists play in 

communicating drug information both 

to patients and health care providers. 

However, during the development of the 

proposed rule, FDA’s priority was to 

understand the information health care 

providers need to most effectively make 

prescribing decisions that consider both 

the risk and benefit to the mother and 

her fetus or child. Therefore, the focus 

testing was limited to health care 

providers who both care for and 

prescribe for pregnant and lactating 

women. 

7. Guidance on Formulating Labeling 

(Comment 7) FDA received one 

comment requesting that the Agency 

provide clear guidance to manufacturers 

regarding how to formulate the 

pregnancy and lactation labeling 

subsections. 

(Response) Concurrent with the 

publication of this final rule, FDA is 

issuing a draft guidance for industry on 

‘‘Pregnancy, Lactation, and 

Reproductive Potential: Labeling for 

Human Prescription Drug and Biological 

Products—Content and Format’’ (the 

draft guidance on pregnancy and 

lactation labeling).5 The draft guidance 

is intended to assist applicants in 

drafting the ‘‘Pregnancy,’’ ‘‘Lactation,’’ 

and ‘‘Females and Males of 

Reproductive Potential’’ subsections of 

mstockstill on DSK4VPTVN1PROD with RULES2

72074 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

labeling for prescription drug products. 

It provides recommendations for 

applicants revising labeling of already 

approved products and for applicants 

drafting labeling for new products that 

will be submitted as part of an NDA or 

BLA. 

8. Blood Products and Vaccines 

(Comment 8) FDA received two 

comments regarding the applicability of 

the proposed rule to certain biological 

products. One comment requested that 

the final rule be expanded to include 

vaccine products. The other comment 

stated that blood products are not 

affected by the rule and requested that 

this be noted when the final rule is 

published. 

(Response) This final rule applies to 

vaccine products. Vaccine products are 

prophylactic biological products that are 

developed and labeled to prevent 

specific diseases in specific 

populations. The types of information 

that must be communicated about a 

vaccine, in general, parallel the types of 

information that must be communicated 

about a drug or therapeutic biologic 

through labeling to facilitate safe and 

effective use, although there are some 

unique considerations for vaccines 

addressed in the draft guidance on 

pregnancy and lactation labeling, which 

is being published concurrently with 

this final rule. 

We disagree that blood products are 

not affected by the final rule. The final 

rule applies to any biological products, 

including blood products, that are 

subject to the PLR. 

9. Numbering of ‘‘Pregnancy’’ and 

‘‘Lactation’’ Subsections 

(Comment 9) FDA proposed that the 

identifying numbers and titles for the 

new labeling content under the section 

‘‘8 Use in Specific Populations’’ would 

be 8.1 for ‘‘Pregnancy’’ and 8.2 for 

‘‘Lactation.’’ FDA stated in the proposed 

rule that the identifying number 8.3 

would be available for future use (73 FR 

30831 at 30838). Two comments 

pointed out that under this proposal, the 

next subsections after ‘‘8.2 Lactation’’ 

will be ‘‘8.4 Pediatric Use’’ and ‘‘8.5 

Geriatric Use.’’ These comments stated 

that the absence of subsection 8.3 may 

be confusing and suggested that FDA 

renumber the subsections. One 

comment requested that FDA clarify 

whether the Agency has a specific use 

in mind for 8.3 and, if it does not, 

suggested that the Agency renumber the 

subheadings to ‘‘8.3 Pediatric Use’’ and 

‘‘8.4 Geriatric Use.’’ The comment 

explained that if a future need for an 

additional subsection arose, it could 

become 8.5. 

(Response) As discussed in further 

detail in section III.B of this document, 

in this final rule, FDA designates 8.3 as 

‘‘Females and Males of Reproductive 

Potential.’’ Accordingly, we are no 

longer reserving 8.3 for future use. 

10. International Harmonization 

(Comment 10) Two comments 

suggested that prescription drug 

labeling should be consistent at an 

international level to reduce confusion 

among health care providers, patients, 

and regulators interpreting the risks and 

benefits associated with drug use during 

pregnancy and lactation. 

(Response) FDA declines to adopt this 

suggestion because it is beyond the 

scope of this rule to address the 

international harmonization of 

prescription drug labeling. Although we 

acknowledge the importance of working 

with our international regulatory 

colleagues to harmonize drug 

development and drug regulatory 

science where appropriate and 

beneficial, we also recognize that there 

is great variation internationally in 

health care systems, access to care and 

drugs, and the regulation and marketing 

of drugs. The final rule reflects our 

judgment regarding the most useful 

pregnancy and lactation prescription 

drug labeling for prescribers in the 

United States, which may not be 

applicable to prescribers in all other 

countries. 

11. Examples in an Appendix 

(Comment 11) The proposed rule 

included an appendix containing 

examples, based on the proposed rule, 

of pregnancy and lactation labeling for 

fictitious drugs. 

FDA received several comments 

suggesting that the examples be revised 

or expanded. One comment requested 

that in the final rule, FDA provide 

additional examples of sample labeling, 

including examples for which extensive 

data exists. Another comment suggested 

that the information included in the 

sample labeling for the fictitious drug 

products did not reflect the amount of 

data that is typically available. The 

comment explained that the examples 

would be more useful if they presented 

situations where there is extensive data. 

Several other comments pointed out 

that the terminology in the examples 

was not consistent with the terminology 

in the proposed rule. 

(Response) FDA has not included 

sample drug labeling with the final rule. 

The draft guidance on pregnancy and 

lactation labeling, which is being 

published concurrently with this final 

rule, provides information about how to 

interpret and apply the rule to labeling 

development. Labeling development is a 

detailed and iterative process unique to 

each prescription drug product, a 

process that is driven by the product’s 

characteristics and actions, the efficacy 

and safety data submitted to the Agency, 

and the conditions and populations for 

and in which the product is intended to 

be used. Accordingly, FDA has 

concluded that the development of 

fictitious product labeling would not be 

useful to drug developers or FDA 

reviewers who will be responsible for 

developing, revising, and approving 

product labeling under this new final 

rule. 

12. Cross-Referencing 

FDA proposed that when the risk 

conclusion in the fetal risk summary is 

based solely on animal data, it must 

include a cross-reference to the ‘‘Data’’ 

component of the ‘‘Pregnancy’’ 

subsection, and the effects found in 

animals must be described in the ‘‘Data’’ 

component (73 FR 30831 at 30842). 

(Comment 12) One comment 

suggested that any cross-references to 

the ‘‘Data’’ or ‘‘Clinical Considerations’’ 

components made anywhere in labeling 

specify whether the cross- reference is 

to the component in the ‘‘Pregnancy’’ 

subsection or the component in the 

‘‘Lactation’’ subsection. Another 

comment explained that the rule would 

benefit from extensive use of crossreferencing within the text of each 

section to ensure that the bases for the 

risk conclusions are thoroughly 

understood, regardless of whether the 

risk conclusions are based on human or 

animal data, for both the ‘‘Pregnancy’’ 

and ‘‘Lactation’’ subsections. 

(Response) FDA agrees that any crossreferences to components of ‘‘8.1 

Pregnancy’’ or ‘‘8.2 Lactation’’ must 

specify whether the cross-reference is to 

the component in the ‘‘Pregnancy’’ 

subsection or the component in the 

‘‘Lactation’’ subsection. Accordingly, in 

the final rule, when applicable, risk 

statements in the ‘‘Pregnancy’’ 

subsection must include a crossreference to additional details in the 

relevant portion of the ‘‘Data’’ 

subheading in the ‘‘Pregnancy’’ 

subsection. Also in the final rule, when 

relevant human and/or animal lactation 

data are available, the ‘‘Risk Summary’’ 

must include a cross-reference to the 

relevant portion of ‘‘Data’’ in the 

‘‘Lactation’’ subsection. 

13. Need for Educational Campaign 

(Comment 13) FDA received one 

comment suggesting that the Agency 

develop educational campaigns for 

patients and health care providers 

regarding the changes to pregnancy and 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72075 

6U.S. Food and Drug Administration, ‘‘Guidance 

for Industry, Labeling for Human Prescription Drug 

and Biological Products—Implementing the PLR 

Content and Format Requirements,’’ (February 

2013), available at http://www.fda.gov/downloads/

Drugs/GuidanceComplianceRegulatoryInformation/

Guidances/UCM075082.pdf. Many guidances are 

referenced throughout this document. The guidance 

referred to in this footnote, as well as others 

referenced throughout the remainder of the 

document, can be found on the FDA Drugs 

guidance Web page at http://www.fda.gov/Drugs/

GuidanceComplianceRegulatoryInformation/

Guidances/default.htm. We update guidances 

periodically. To make sure you have the most 

recent version of a guidance, check the FDA Drugs 

guidance Web page. 

lactation drug labeling brought about by 

this rulemaking. 

(Response) FDA is developing 

educational materials for FDA staff, 

health care providers, and patients to 

inform them about the changes in these 

labeling regulations and how these 

changes will have a positive impact on 

labeling regarding the use of drugs and 

biologics during pregnancy and 

lactation. The draft guidance on 

pregnancy and lactation labeling is 

being published concurrently with this 

final rule; however, additional materials 

may be completed following this date. 

14. Inventory 

(Comment 14) FDA received one 

comment requesting that the final rule 

address how distributors should manage 

drug products in their inventory that 

have outdated labeling. The comment 

suggested that product inventory 

without the revised labeling should 

remain in the supply chain until the 

labeled product’s expiration date, 

regardless of whether the product bears 

the new labeling. 

(Response) For previously approved 

products, the implementation plan gives 

sponsors a minimum of 3 years after the 

effective date of this final rule to submit 

labeling with the new content and 

format. As we explained in the 

preamble to the proposed rule, FDA 

believes that this 3-year period will 

allow industry sufficient time to use up 

any existing labeling stock such that 

none will remain in the supply chain 

after the product bears the new labeling 

(73 FR 30831 at 30846). 

15. Highlights 

FDA’s regulations require that all 

prescription drug labeling described in 

§ 201.56(b)(1) contain ‘‘Highlights of 

prescribing information’’ (§ 201.57(a)). 

(Comment 15) Two comments 

requested that FDA clarify which 

elements of the ‘‘Pregnancy’’ and 

‘‘Lactation’’ subsections are likely to be 

included in the ‘‘Highlights of 

prescribing information.’’ One of the 

comments expressed hope that adoption 

of the rule will promote standardization 

with respect to which elements are 

elevated to the ‘‘Highlights of 

prescribing information,’’ thereby 

facilitating consistent interpretation and 

implementation of the rule’s 

requirements among FDA reviewers and 

review divisions. 

(Response) The requirements for 

placement of information in the 

‘‘Highlights of prescribing information’’ 

are specified in § 201.57(a). This final 

rule does not revise or change the 

requirements for the ‘‘Highlights of 

prescribing information.’’ Additional 

discussion of FDA’s recommendations 

on the content of the ‘‘Highlights of 

prescribing information’’ may be found 

in FDA’s guidance for industry on 

‘‘Labeling for Human Prescription Drug 

and Biological Products—Implementing 

the PLR Content and Format 

Requirements’’ (February 2013).6

16. Preemption of State Law 

In the preamble to the proposed rule, 

FDA included a discussion in the 

Federalism section that referred to a 

more extensive discussion and analysis 

in the PLR regarding the preemption of 

product liability lawsuits. 

(Comment 16) Comments expressed 

different views about this discussion. 

One comment suggested that in the final 

rule FDA revise the preamble to 

eliminate any reference to the 

preemption of product liability lawsuits. 

Another comment expressed its 

appreciation of FDA’s view that the rule 

would preempt state laws that conflict 

with its requirements. This comment 

also expressed its support for FDA’s 

intention to consult with State and local 

officials in an effort to avoid conflict 

between State law and federally 

protected interests. 

(Response) FDA’s statement regarding 

preemption in the proposed rule relied 

on statements made in the preamble to 

the PLR (71 FR 3922). In the preamble 

to the PLR, FDA discussed its views on 

the preemptive effect of both that 

regulation’s codified provisions and the 

FD&C Act. Subsequent to the 

publication of the May 2008 proposed 

rule, the Supreme Court, in Wyeth v. 

Levine (555 U.S. 555 (2009)), addressed 

the preamble to the PLR and held that 

a State tort claim that an NDA-approved 

drug should have had a stronger 

warning was not preempted by the 

FD&C Act or FDA’s labeling 

requirements. Following the Court’s 

decision in Wyeth, FDA concluded that 

the position on preemption we 

articulated in the preamble to the PLR 

cannot be justified under legal 

principles governing preemption 

(Preemption Review, 76 FR 61565, 

October 5, 2011). Based on this analysis, 

to the extent that the discussion in the 

proposed rule relied on the discussion 

about preemption in the preamble to the 

PLR, we conclude that the statements 

we made regarding preemption in the 

preamble to the proposed rule are also 

not justified. 

B. Specific Provisions of the Proposed 

Rule 

1. 8.1 Pregnancy 

a. Comments related to the pregnancy 

subsection as a whole. 

i. Order of subsections—FDA 

proposed that information appear in 

subsection ‘‘8.1 Pregnancy’’ in the 

following order: (1) Pregnancy exposure 

registry (if applicable), (2) general 

statement about background risk, (3) 

fetal risk summary, (4) clinical 

considerations, and (5) data (proposed 

§ 201.57(c)(9)(i)). In the proposed rule, 

FDA sought comment on how these 

elements should be ordered to optimize 

the clinical usefulness of this labeling 

subsection (73 FR 30831 at 30839). 

Specifically, FDA asked whether the 

‘‘Fetal Risk Summary’’ should precede 

the pregnancy exposure registry 

information and the statement about 

background risk. 

(Comment 17) Comments expressed 

different opinions about the proposed 

order of information in the ‘‘Pregnancy’’ 

subsection of labeling. Three comments 

agreed with the proposed order. One of 

these comments explained that the 

proposed order will maximize a 

physician’s ability to find and 

understand important pregnancy-related 

information about a given drug product. 

Another comment explained that 

placing the pregnancy exposure registry 

information first is preferable because if 

this information were placed after the 

‘‘Risk Summary,’’ it may be interpreted 

to imply that the pregnancy exposure 

registry exists because of the data in the 

fetal risk summary. One comment 

supported placing the pregnancy 

exposure registry information first so 

that it will appear more visible in 

labeling. 

Many comments disagreed with the 

proposed order and suggested a variety 

of alternatives. Six comments suggested 

that the ‘‘Fetal Risk Summary’’ 

subheading be placed first because it 

contains the most important and useful 

information. One of these comments 

pointed out that past FDA advisory 

committees have suggested that 

summary information should be placed 

first. Two comments suggested that the 

‘‘Background Risk Statement’’ should be 

first followed by the ‘‘Fetal Risk 

Summary.’’ These comments explained 

mstockstill on DSK4VPTVN1PROD with RULES2

72076 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

that the most important information 

should be placed first, as recommended 

by FDA advisory committees. Three 

comments suggested that the pregnancy 

exposure registry information be placed 

last. Another comment suggested that 

the information be placed in the 

following order: Pregnancy exposure 

registry information, clinical 

considerations, fetal risk summary, data, 

and background risk statement. 

(Response) FDA has determined that 

placing the pregnancy exposure registry 

information first under ‘‘8.1 Pregnancy’’ 

best balances the objectives of this 

rulemaking. Although we agree that the 

‘‘Risk Summary’’ information is most 

important to prescribers and we 

acknowledge that the advisory 

committee expressed a preference for 

placing the most important information 

first, it is also clear that stakeholders 

desire greater quality and quantity of 

human data in pregnancy labeling. FDA 

believes that the benefits of prominently 

placing information about pregnancy 

registry availability at the beginning of 

‘‘8.1 Pregnancy’’ outweigh the 

downsides of a minor decreased 

prominence of the ‘‘Risk Summary’’ 

information, which appears 

immediately after the information under 

‘‘Pregnancy Exposure Registry.’’ Many 

health care providers are still learning 

about pregnancy exposure registries and 

their purpose. We have concluded that 

routinely placing this information first 

in pregnancy labeling may increase 

pregnancy registry enrollment, the 

quality of human data that emerge from 

these studies, and the quality of 

pregnancy labeling (including the ‘‘Risk 

Summary’’) that follows. Because we 

agree that the information under ‘‘Risk 

Summary’’ is most important to 

prescribers, we also decline the 

suggestion to place the ‘‘Risk Summary’’ 

after ‘‘Clinical Considerations.’’ The 

‘‘Pregnancy’’ subsection will include, in 

this order, information under 

‘‘Pregnancy Exposure Registry,’’ as 

applicable, ‘‘Risk Summary,’’ ‘‘Clinical 

Considerations,’’ as applicable, and 

‘‘Data,’’ as applicable. 

ii. Removal of the pregnancy 

categories—FDA proposed to remove 

the pregnancy categories from all 

prescription drug labeling. As discussed 

in greater detail in section I of this 

document, in 1979 FDA adopted a 

pregnancy category system that was 

used to convey risk and benefit 

information related to potential or 

documented human teratogenic risk and 

potential maternal/fetal benefits 

associated with drug treatment during 

pregnancy. Under the 1979 regulations, 

each drug product was identified with 

a pregnancy category: A, B, C, D, or X. 

Categories were not used to characterize 

the risks and benefits associated with 

drug treatment by lactating women. 

FDA proposed to remove pregnancy 

categories from all prescription drug 

labeling because we determined that the 

categories were confusing and did not 

accurately and consistently 

communicate differences in degrees of 

fetal risk (73 FR 30831 at 30846). 

(Comment 18) Comments expressed 

different opinions about whether the 

elimination of the pregnancy category 

system, in full or in part, would 

improve or diminish the usefulness of 

the Pregnancy subsection of 

prescription drug labeling. FDA 

received 11 comments from medical 

associations, women’s and reproductive 

health advocacy organizations, 

toxicologists, individual health care 

practitioners, pharmacists, and drug 

manufacturers specifically supporting 

our proposal to retire the pregnancy 

category system. Several of these 

comments explained that the categories 

were confusing or misleading. One of 

the comments stated that although the 

use of pregnancy categories is easier for 

some practitioners, it results in 

miscommunication and errors in 

decisionmaking. Another comment 

explained that reliance on the categories 

may result in poorly informed clinical 

decisionmaking. 

FDA received 16 comments from 

physicians, pharmacists, pharmacy 

associations, nurses, manufacturers, 

drug safety consultants, and individual 

consumers, requesting that FDA either 

retain the pregnancy category system or 

replace the pregnancy category system 

with another standardized schema. 

Many of these comments suggested that 

FDA add the additional narrative 

information as proposed, but also retain 

the category system. Two of these 

comments explained that the pregnancy 

categories are simple and effective, and 

the new information may confuse 

patients or prescribers. Another 

comment stated that without a 

standardized schema, there will not be 

a consistent and useful format for 

decisionmaking. Other comments 

agreed that the pregnancy categories 

need to be revised but suggested that 

FDA develop new standardized 

statements or categories or revise the 

bases for the current categories. Two 

comments urged FDA to maintain an 

‘‘X’’-like category for drugs where the 

risks outweigh any benefit to a pregnant 

or nursing patient, and one comment 

urged FDA to maintain an ‘‘X’’-like 

category so that providers and patients 

could easily identify those drugs that 

are contraindicated for the mother, 

fetus, and/or a breastfeeding infant. 

A separate comment supported FDA’s 

proposal to eliminate the pregnancy 

categories but thought they should be 

retained until the implementation of the 

final rule is complete. 

(Response) FDA has determined that 

retaining the pregnancy categories is 

inconsistent with the need to accurately 

and consistently communicate 

differences in degrees of fetal risk. As 

discussed in the proposed rule, the 

current pregnancy category system has 

long been criticized as being confusing 

and overly simplistic (73 FR 30831 at 

30833–30834). Through experience and 

stakeholder feedback, FDA learned that 

the pregnancy categories were heavily 

relied upon by clinicians but 

misinterpreted, misunderstood, and 

erroneously used as a grading system 

where fetal risk increased from A to X. 

The categories gave the incorrect 

impression that drugs in the same 

category carried the same risk or 

potential for human adverse 

developmental outcomes. In addition, 

the categories did not discriminate 

among risk information obtained from 

nonclinical animal studies and 

postmarketing human studies and did 

not discriminate among drugs 

associated with adverse outcomes of 

differing severity or incidence. 

Stakeholders also pointed out that the 

pregnancy categories focused on 

structural abnormalities and thus did 

not adequately address the full range of 

potential developmental toxicities. 

As described in greater length in the 

preamble of the proposed rule, FDA 

carefully explored a multitude of 

models to determine whether the former 

pregnancy category system or a different 

pregnancy category system could 

accurately and consistently 

communicate differences in degrees of 

fetal risk (73 FR 30831 at 30833–30837). 

FDA found that when it applied these 

criteria to actual animal and human data 

findings for drugs with known risk 

profiles, none of the models produced 

clinically informative and reliable 

differentiations of risk (73 FR 30831 at 

30838). Prescribing and drug-use 

decisions during pregnancy require 

consideration of not only fetal risk 

information, but also of various clinical 

and individual factors, including 

maternal drug effects, the severity of 

maternal disease, maternal tolerance of 

the drug, coexisting maternal 

conditions, the impact of maternal 

disease on the fetus, and available 

alternative therapies. FDA concluded 

that continuing to use a category system 

to characterize the risks of drug use 

during pregnancy would not be 

appropriate because of the complexity 

of medical decisionmaking regarding 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72077 

drug use during pregnancy (73 FR 30831 

at 30838). 

FDA continues to believe that a 

narrative structure for pregnancy 

labeling is best able to capture and 

convey the potential risks of drug 

exposure based on animal or human 

data, or both. This perspective is 

consistent with FDA’s approach to other 

aspects of product labeling. For 

example, numeric or letter or other 

categorical gradations of risk have never 

been used for safety labeling because 

safety and risk are complex constructs 

in clinical medicine. For similar 

reasons, FDA does not apply symbol or 

letter designations of risk to other 

potential toxicities or adverse effects 

expected with drug product use. 

For the reasons discussed previously, 

FDA declines the suggestion to maintain 

pregnancy category X. We note, 

however, that labeling must clearly 

identify populations in which use of a 

drug is contraindicated. The labeling 

regulations in § 201.57 clearly describe 

the information that must be included 

in the ‘‘Contraindications’’ section and 

all contraindications from the full 

prescribing information are always 

listed in the ‘‘Highlights of prescribing 

information’’ (§ 201.57(c)(5)). Therefore, 

when use of a drug is contraindicated in 

pregnancy, this information must be 

stated in the ‘‘Contraindications’’ 

section and listed in the ‘‘Highlights of 

prescribing information,’’ as well as, per 

the previous discussion, stated first 

under the ‘‘Risk Summary’’ subheading 

of the ‘‘Pregnancy’’ subsection of 

labeling. 

To the extent that the comment 

suggests that the pregnancy categories 

should be retained for applications 

subject to § 201.80 until the 

implementation of the new content and 

format requirements is complete, we 

decline this suggestion; we believe it is 

more consistent with the Agency’s 

overall concerns with respect to 

removing the pregnancy categories to 

implement that change within a shorter 

timeframe that nevertheless provides 

sufficient time for compliance. We 

would like to clarify that for 

applications required to implement the 

new content and format requirements, 

the pregnancy categories are required to 

be removed at the time the labeling is 

revised regardless of whether this will 

result in the labeling including a 

pregnancy category for more than 3 

years after the effective date of the final 

rule (as described in the 

‘‘Implementation’’ section of this 

document in response to Comment 92). 

Requiring that the labeling for some 

applications be revised twice solely as 

part of the implementation of this 

regulation would not be consistent with 

the Agency’s goal to avoid 

overburdening both the Agency and 

industry. 

b. Comments related to specific 

provisions of 8.1 Pregnancy. 

i. Pregnancy exposure registry—FDA 

proposed that if there is a pregnancy 

exposure registry for a product 

described in § 201.56(b)(1) (i.e., 

prescription drug products for which an 

application was approved after June 30, 

2001), the telephone number or other 

information necessary to enroll in the 

registry or to obtain information about 

the registry must be stated at the 

beginning of the ‘‘Pregnancy’’ 

subsection of prescription drug labeling 

(proposed § 201.57(c)(9)(i)(A)). For drug 

products that do not have a pregnancy 

exposure registry, the proposed rule did 

not require the ‘‘Pregnancy’’ subsection 

of prescription drug labeling to contain 

any statement about pregnancy 

exposure registries. 

(Comment 19) Comments disagreed 

about the mandatory inclusion of 

pregnancy exposure registry 

information. Many comments supported 

the mandatory inclusion of pregnancy 

exposure registry information in the 

‘‘Pregnancy’’ subsection of prescription 

drug labeling. These comments 

explained, for example, that including 

pregnancy exposure registry information 

in labeling may ‘‘encourage patient 

involvement in registries’’ and ‘‘pave 

the way for improved registry use by 

clinicians leading to better 

documentation of drug effects and use 

during pregnancy.’’ 

One comment stated that including a 

reference to an existing pregnancy 

registry should not be mandatory. 

(Response) FDA believes that 

appropriately conducted pregnancy 

registries are an important mechanism 

for the collection of clinically relevant 

data concerning the effects of exposure 

to drugs during pregnancy. The Agency 

believes that including information 

about pregnancy exposure registries in 

prescription drug labeling will 

encourage participation in registries, 

thereby improving their usefulness. 

Thus, if there is a pregnancy registry 

that FDA has reviewed and found 

scientifically acceptable, FDA is 

requiring that the ‘‘Pregnancy’’ 

subsection of prescription drug labeling 

include under its own subheading, 

‘‘Pregnancy Exposure Registry,’’ a 

standard statement concerning the 

existence of the registry, as well as the 

contact information necessary to enroll 

in the pregnancy exposure registry or to 

obtain information about the registry. 

The Agency generally considers a 

pregnancy exposure registry 

scientifically acceptable when it is 

consistent with applicable FDA 

guidance, including the guidance for 

industry on ‘‘Establishing Pregnancy 

Exposure Registries’’ (August 2002). If 

there are changes to an existing 

pregnancy registry or a new pregnancy 

registry is initiated after drug approval, 

labeling will need to be updated to 

include this new information. 

(Comment 20) Two comments sought 

clarification regarding the standards for 

including contact information for a 

pregnancy exposure registry. One 

comment stated that contact information 

should only be included if the registry 

is scientifically acceptable to the 

sponsor and FDA. Another comment 

asked whether contact information for 

non-U.S. registries must be included. 

(Response) As stated previously, if 

there is a scientifically acceptable 

pregnancy registry for a drug product, 

FDA is requiring a standard statement 

concerning the registry as well as 

contact information needed to enroll in 

the registry or obtain additional 

information about it. For registries that 

include U.S. populations, U.S. contact 

information should be included in the 

labeling, regardless of whether the 

registry is maintained within the United 

States or elsewhere. 

(Comment 21) Four comments 

suggested that the pregnancy exposure 

registry information should have its 

own component header. 

(Response) FDA agrees with the 

suggestion that the pregnancy exposure 

registry information should have its 

own component header. In the final 

rule, contact information for an existing 

pregnancy exposure registry and a 

standard statement on the registry will 

fall under the subheading ‘‘Pregnancy 

Exposure Registry’’ in the ‘‘Pregnancy’’ 

subsection of prescription drug labeling. 

Because of this change, FDA eliminated 

the phrase ‘‘must be stated at the 

beginning of the ‘Pregnancy’ subsection 

of the labeling’’ from the final rule. 

(Comment 22) Two comments stated 

that it should be easier to enroll patients 

in pregnancy exposure registries. 

(Response) The importance of subject 

recruitment into pregnancy exposure 

registries and the need to build 

awareness of pregnancy exposure 

registries among health care providers 

are both factors in FDA’s decision to 

place information about existing 

pregnancy exposure registries at the 

beginning of § 201.57, ‘‘8.1 Pregnancy.’’ 

The actual process of enrolling patients, 

however, is beyond the scope of this 

rule. 

(Comment 23) Comments expressed 

disagreement about whether the 

‘‘Pregnancy Exposure Registry’’ 

mstockstill on DSK4VPTVN1PROD with RULES2

72078 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

subheading should be omitted from the 

‘‘Pregnancy’’ subsection of prescription 

drug labeling when there is no existing 

registry for the drug. One comment 

suggested that the ‘‘Pregnancy Exposure 

Registry’’ subheading should not be 

omitted even if there is no existing 

registry for the drug, and that it should 

include a statement that there is no 

specific pregnancy exposure registry for 

the drug. Another comment requested 

that FDA consider incorporating a 

statement that the subheading may be 

omitted if there is no pregnancy 

exposure registry. 

(Response) FDA concludes that the 

‘‘Pregnancy Exposure Registry’’ 

subheading should be omitted when 

there is no pregnancy exposure registry. 

We have determined that requiring the 

‘‘Pregnancy Exposure Registry’’ 

subheading in labeling when there is no 

pregnancy exposure registry for the drug 

product, and the inclusion of a 

statement indicating that no registry 

exists, would not further the goal of 

improving the collection of data in 

pregnant women who are exposed to a 

drug. 

(Comment 24) One comment 

suggested that the labeling should state 

the purpose of the pregnancy exposure 

registry and provide the contact 

information necessary for enrollment. 

(Response) FDA agrees that including 

a statement in the labeling about the 

purpose of the pregnancy exposure 

registry would be useful. In the final 

rule, FDA requires that if there is a 

scientifically acceptable pregnancy 

exposure registry for the drug, the 

labeling must include a statement that 

there is a pregnancy exposure registry 

that monitors pregnancy outcomes in 

women exposed to the drug during 

pregnancy, and include contact 

information needed to enroll in the 

registry or to obtain information about 

the registry. Because the purpose of all 

pregnancy registries is to collect 

clinically relevant human data that can 

be used in a product’s labeling to 

provide health care providers with 

useful information for treating or 

counseling patients who are pregnant or 

anticipating pregnancy, we do not 

believe it is necessary to include a more 

specific statement in labeling about 

their purpose. 

(Comment 25) Two comments 

suggested that pregnancy exposure 

registry information be included in 

‘‘Highlights’’ and in the ‘‘Patient 

Counseling Information’’ section of 

labeling. One comment requested that 

FDA clarify in guidance whether the 

Agency anticipates requesting more 

pregnancy registries as a condition of 

marketing approval. 

(Response) FDA believes that 

including information about pregnancy 

exposure registries in the ‘‘Patient 

Counseling Information’’ section of 

labeling would be useful. If the drug 

product has a pregnancy exposure 

registry, the availability of a pregnancy 

exposure registry should be noted in the 

‘‘Patient Counseling Information’’ 

section of labeling, and a cross-reference 

should be included to ‘‘8.1 Pregnancy’’ 

for the contact information necessary to 

enroll. The preamble to the PLR states 

that ‘‘Highlights’’ summarizes the 

information from the ‘‘Full Prescribing 

Information’’ that is most important for 

prescribing the drug safely and 

effectively and organizes it into logical 

groups to enhance accessibility, 

retention, and access to the more 

detailed information (71 FR 3922 at 

3931). Information about the availability 

of and contact information for a 

pregnancy exposure registry are not 

considered essential information for 

prescribing and should not appear in 

‘‘Highlights’’ (see FDA’s guidance for 

industry on ‘‘Labeling for Human 

Prescription Drug and Biological 

Products—Implementing the PLR 

Content and Format Requirements’’ 

(February 2013)). The question of 

whether FDA anticipates requesting 

more pregnancy exposure registries as a 

condition of marketing approval is 

outside the scope of this rule. 

In the final rule, FDA revised the 

phrase ‘‘telephone number or other 

information needed to enroll’’ to 

‘‘contact information needed to enroll.’’ 

FDA determined that this change would 

allow for more flexibility in the type of 

contact information included under this 

portion of the labeling. 

ii. Background risk statement—FDA 

proposed that a general statement about 

the background risk of adverse 

pregnancy outcomes be included in 

labeling. The proposed rule stated in 

§ 201.57(c)(9)(i)(B) that the following 

statement was required to be included 

in the labeling: All pregnancies have a 

background risk of birth defect, loss, or 

other adverse outcome regardless of 

drug exposure. The fetal risk summary 

below describes (name of drug)’s 

potential to increase the risk of 

developmental abnormalities above the 

background risk. 

(Comment 26) Two comments 

expressed support for the inclusion of a 

background risk statement. One of these 

comments noted that the statement will 

be useful to clinicians when explaining 

the fetal risks associated with drug use 

during pregnancy. 

Several comments suggested 

modifying the background risk 

statement. One comment suggested that 

applicants be given the option to 

identify in the background risk 

statement the specific risks described in 

the fetal risk summary. The comment 

proposed that the second sentence of 

the background statement be modified 

to state: ‘‘The fetal risk summary below 

describes the potential of (name of drug) 

to contribute to risk of (‘adverse 

outcomes, including developmental 

abnormalities’ or identify specific risks) 

above background risk.’’ 

Several comments requested 

clarification about whether the 

background risk statement refers to the 

general population or the population 

with the disease. Two other comments 

suggested that when the background 

risk of adverse outcomes in the relevant 

disease population is known to be 

higher than in the general population, 

this information should be included in 

the background risk statement. One of 

these comments suggested that relevant 

literature citations should also be 

included as appropriate. 

One comment asked FDA to clarify 

how it will determine the background 

rate of adverse pregnancy outcomes. 

Another comment suggested that FDA 

and industry develop a standard 

definition of background risk that would 

provide a common explanation for all 

labeling, both for the general population 

and for any specific disease states or 

conditions. This comment explained 

that different reviewers may look at 

different criteria for assessing 

background risk (i.e., what constitutes a 

developmental abnormality or a 

congenital malformation), and a 

standard definition would provide for 

consistency. A separate comment stated 

that the background risks of pregnancy 

can vary by demographics, location, 

ethnicity, and other variables. The 

comment suggested that to maintain 

uniform and standardized descriptions 

of background risk, FDA should provide 

industry with a guidance document 

describing background risk. 

One comment recommended against 

requiring data in the background risk 

statement. The comment explained that 

background statistics change over time 

as new evidence is made available and 

accepted by the medical community. 

Several comments suggested that FDA 

revise or omit the second sentence of 

the background risk statement. One of 

the comments explained that the 

sentence implies that the drug 

necessarily has the potential to increase 

the risk of developmental abnormalities 

above the background risk. 

(Response) In the final rule, FDA has 

eliminated the proposed standardized 

background risk statement. In its place, 

the final rule requires that the labeling 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72079 

state the percentage range of live births 

in the general population of the United 

States with a major birth defect and the 

percentage range of pregnancies in the 

United States that end in miscarriage, 

regardless of drug exposure. The final 

rule also requires that if such 

information is available for the 

population(s) for which the drug is 

labeled, it must also be included. The 

final rule requires that the background 

risk information appear in labeling 

under the subheading ‘‘Risk Summary,’’ 

rather than as a standalone statement 

under its own subheading (as in the 

proposed rule). 

The Agency has determined that 

rather than including a standardized 

general statement about background 

risk, it is beneficial to include the 

approximate background rates of major 

birth defects and miscarriage. This will 

provide some context to the risk 

statement, and a basis for comparison 

with risk estimates from studies in 

pregnant women. Including the 

approximate background rates allows 

the prescriber to inform patients of the 

risk of major birth defects and 

miscarriage, regardless of drug 

exposure. Accordingly, the final rule 

requires that the labeling include the 

approximate background rates of major 

birth defects and miscarriage, regardless 

of drug exposure, in the United States. 

FDA agrees, however, that it is possible 

that these numbers may change over 

time. Therefore, the Agency did not 

include any specific numbers in the 

final rule. Instead, the Agency has 

provided information, including 

relevant literature citations, about 

current background rates of major birth 

defects and miscarriage in the draft 

guidance on pregnancy and lactation 

labeling, which is being published 

concurrently with this final rule. 

Although the literature citations are 

included in the draft guidance, the 

Agency does not believe it is either 

necessary or appropriate to include 

them in the labeling. 

FDA agrees that the second sentence 

in the proposed background risk 

statement, which states that the fetal 

risk summary describes the drug’s 

potential to increase the risk of 

developmental abnormalities above the 

background risk, could have been 

misinterpreted as meaning that the drug 

is associated with an increased risk. As 

discussed previously, the Agency has 

removed the standardized background 

risk statement, including the second 

sentence, from the final rule. 

iii. Fetal risk summary—FDA 

proposed that under ‘‘Pregnancy,’’ 

prescription drug labeling include a 

subheading ‘‘Fetal Risk Summary’’ 

(§ 201.57(c)(9)(i)(C)). FDA proposed that 

the section include a risk conclusion, 

contain a narrative description of the 

risk(s) (if the risk conclusion is based on 

human data), and refer to any 

contraindications or warnings and 

precautions. 

(Comment 27) One comment 

expressed support for the proposed 

‘‘Fetal Risk Summary,’’ explaining that 

the proposed labeling requirements 

increase the utility of the ‘‘Pregnancy’’ 

subsection by expanding the teratology 

section to include information about 

specific developmental abnormalities 

such as incidence, seriousness, 

reversibility, potential for correction, 

and effect of dose, duration, and 

gestational timing of exposure. Several 

other comments suggested that the 

proposed ‘‘Fetal Risk Summary’’ be 

revised in various ways, discussed in 

detail as follows. 

Sources of data. FDA proposed that 

all available data, including human, 

animal, and pharmacologic data, that 

are relevant to assessing the likelihood 

that a drug will increase the risk of 

developmental abnormalities and other 

relevant risks must be considered 

(Proposed § 201.57(c)(9)(i)(C)(1)). 

(Comment 28) One comment 

recommended that rather than 

considering ‘‘all available data,’’ the 

data sources for the ‘‘Fetal Risk 

Summary’’ be limited to ‘‘scientifically 

rigorous, organized data collection 

schemes such as clinical or preclinical 

studies, and registries.’’ 

(Response) FDA declines this 

suggestion. For example, depending on 

the safety signal, valuable information 

may come from epidemiological studies 

that are not prospective pregnancy 

exposure registries. On occasion, 

adverse event reporting or case series 

reporting may raise enough concern 

about a potential increased risk for a 

specific structural malformation or 

pattern of malformations, or a serious 

adverse event, that the information 

should be included in labeling. 

(Comment 29) Maternal and neonatal 

risk. One comment suggested that FDA 

include information regarding maternal 

and neonatal risks in the ‘‘Pregnancy’’ 

subsection of labeling. The comment 

suggested that FDA add a ‘‘maternal risk 

subsection,’’ preferably before the ‘‘Fetal 

Risk Summary,’’ which would address 

side effects and adverse reactions 

associated with the use of a drug, 

including those unique to pregnancy. 

The comment explained that placing 

this information higher on the label and 

making it a separate subsection would 

underscore the importance of the health 

of the mother. The comment also 

suggested that FDA include neonatal 

outcomes as well as fetal outcomes in 

the ‘‘Fetal Risk Summary.’’ 

(Response) FDA agrees that 

information on drug-associated maternal 

risk is important, and in the final rule 

has created a separate heading, 

‘‘Maternal adverse reactions,’’ under 

‘‘Clinical Considerations,’’ which 

requires relevant information, to the 

extent it is available, about drugassociated maternal adverse reactions 

that are unique to or more frequent or 

severe during pregnancy. FDA disagrees 

that information on neonatal outcomes 

as well as fetal outcomes should be 

included in the ‘‘Risk Summary.’’ 

Rather, if available, this information is 

included under its own heading, ‘‘Fetal/ 

Neonatal adverse reactions,’’ under 

‘‘Clinical Considerations.’’ FDA believes 

that consistent placement of this 

information under a specified heading 

under ‘‘Clinical Considerations’’ will 

allow health care providers to easily 

locate this information. FDA also 

believes that this approach ensures that 

maternal, fetal, and neonatal risks will 

be captured and clearly conveyed in 

prescription drug labeling. 

Terms used to describe adverse fetal 

outcomes. FDA proposed that the fetal 

risk summary must characterize the 

likelihood that the drug increases the 

risk of developmental abnormalities in 

humans (i.e., structural anomalies, fetal 

and infant mortality, impaired 

physiologic function, alterations to 

growth) and other relevant risks (e.g., 

transplacental carcinogenesis) 

(proposed § 201.57(c)(9)(i)(C)(1)). 

(Comment 30) Several comments 

suggested that the term ‘‘developmental 

abnormalities’’ should be replaced with 

a broader and more accurate term. One 

comment suggested FDA replace the 

term ‘‘developmental abnormalities’’ 

with the term ‘‘adverse outcomes, 

including developmental 

abnormalities.’’ This comment 

explained that the phrase 

‘‘developmental abnormalities’’ does not 

include ‘‘other relevant risks (e.g., 

transplacental carcinogenesis)’’ that are 

also required to be described in the 

‘‘Fetal Risk Summary.’’ Several 

comments suggested replacing the term 

‘‘developmental abnormalities’’ with the 

term ‘‘developmental effects’’ or 

‘‘adverse developmental effects.’’ These 

comments explained that in the field of 

developmental toxicology, a 

developmental abnormality would 

imply, in general, a dysmorphogenic 

effect (malformation or variation), rather 

than the wider definition intended by 

the proposed rule. Several comments 

noted the importance of using 

terminology consistently in labeling. 

mstockstill on DSK4VPTVN1PROD with RULES2

72080 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

(Response) FDA agrees that the terms 

used to describe various developmental 

effects or outcomes should be accurate 

and understandable, and that standard 

nomenclature in the field of 

developmental toxicology should be 

used to the extent that it exists. FDA 

also agrees that terminology should be 

used consistently in labeling. FDA 

concludes that the term ‘‘developmental 

abnormalities’’ is widely recognizable as 

referring to structural defects 

(malformations or variations), rather 

than the full range of possible 

manifestations of developmental 

toxicity as FDA had intended. 

Therefore, in the final rule, FDA has 

included the following terms that 

describe various developmental 

toxicities, as explained in the following 

list: 

• ‘‘Adverse developmental 

outcomes’’ has replaced ‘‘developmental 

abnormalities’’ as the general term to 

encompass all manifestations or types of 

developmental toxicity. 

• ‘‘Structural abnormalities’’ is used 

to describe dysmorphology, which 

includes malformations, variations, 

deformations, and disruptions, rather 

than the proposed ‘‘structural 

anomalies.’’ 

• ‘‘Embryo-fetal and/or infant 

mortality’’ is used to describe 

developmental mortality, which 

includes miscarriage, stillbirth, and 

infant death (including neonatal death), 

instead of the proposed ‘‘fetal and infant 

mortality.’’ 

• ‘‘Functional impairment’’ is used to 

describe functional toxicity, which 

includes such outcomes as deafness, 

endocrinopathy, neurodevelopmental 

effects, and impairment of reproduction, 

rather than ‘‘impaired physiologic 

function.’’ 

• ‘‘Alterations to growth’’ is used to 

describe such outcomes as growth 

restriction, excessive growth, and 

delayed and early maturations. 

These terms and descriptions are 

consistent with FDA’s guidance for 

industry on ‘‘Reproductive and 

Developmental Toxicities—Integrating 

Study Results to Assess Concerns’’ 

(September 2011). 

Relationship between animal and 

human data. FDA proposed that when 

both human and animal data are 

available, risk conclusions based on 

human data must be presented before 

risk conclusions based on animal data 

(proposed § 201.57(c)(9)(i)(C)(2)). 

(Comment 31) A number of comments 

suggested that FDA reexamine the 

emphasis that the ‘‘Fetal Risk 

Summary’’ places on human data as 

compared to animal data. 

Several comments stated that because 

there will be frequent conflicts between 

human and animal data, FDA should 

develop an overall approach to 

characterize risk based on both human 

and animal data. One of these comments 

suggested that FDA consider the 

European Medicines Agency’s (EMEA’s) 

(now EMA’s) Integration Table for Risk 

Assessment and Recommendation for 

Use as an example of how to integrate 

risk conclusions based on animal and 

human data. 

Two comments stated that the 

proposed rule gives primary emphasis 

to human studies, if they exist, while 

downgrading the emphasis on animal 

data. One of these comments explained 

that the quality and statistical power of 

human data often fall well short of 

desirable, and suggested that human 

data be accompanied by clear 

acknowledgement of any deficiencies. 

The other comment explained that 

emphasizing minimal human data over 

strong animal data can misrepresent the 

fetal risk of a drug. 

Two comments suggested that if 

human data are ‘‘insufficient’’ (i.e., do 

not meet the standard for inclusion in 

proposed § 201.57(c)(9)(i)(C)(2)(i)), a risk 

statement based on human data should 

not precede a risk statement based on 

animal data. One of these comments 

explained that the most robust and 

clinically relevant data should always 

be presented first. 

Several comments stated that if risk 

conclusions are based on sufficient 

human data, sponsors should not be 

required to include animal data, even if 

such data are available. One comment 

also suggested that if sufficient human 

data become available after the labeling 

is approved, animal data should be 

removed when the human data are 

added to the labeling. This comment 

explained that ‘‘a risk conclusion based 

on animal data might not support, or 

could flatly contradict, a risk conclusion 

based on sufficient human data.’’ 

One comment suggested that FDA ban 

all animal studies because human 

studies are more accurate. 

(Response) We continue to believe 

that the ‘‘Risk Summary’’ is 

appropriately based on both human and 

animal data. Because of the importance 

of human data, we also have determined 

that when human data provide an 

incomplete assessment, this should be 

stated in the risk statement based on 

human data. Specifically, the ‘‘Risk 

Summary’’ must state when there are no 

human data or when available human 

data do not establish the presence or 

absence of a drug-associated risk. FDA 

believes that the use of narrative 

summaries of the data will avoid 

conflicting characterizations of risk 

magnitude. 

FDA disagrees with the suggestion 

that animal data be presented first in 

cases where the human data are 

insufficient. FDA also disagrees that the 

most robust and clinically relevant 

data—whether human data or animal 

data—should always be presented first. 

We have determined that to promote 

consistency and to meet readers’ 

expectations that information will 

always be found in the same place, a 

fixed order of presentation must be 

maintained. Moreover, we have 

determined that human data should 

precede animal data because it is the 

most clinically relevant. 

We note that the purpose of this 

rulemaking is to facilitate informed 

prescribing and safe and effective drug 

product use; placing restrictions on or 

encouraging any type of studies that 

may be used as the basis for drug 

labeling is beyond the scope of this rule. 

Not systemically absorbed. FDA 

proposed that if the drug is not 

systemically absorbed, the fetal risk 

statement must contain only the 

following statement: (Name of drug) is 

not absorbed systemically from (part of 

body) and cannot be detected in the 

blood. Maternal use is not expected to 

result in fetal exposure to the drug 

(proposed § 201.57(c)(9)(i)(C)(1)). 

(Comment 32) One comment 

suggested that this statement should 

focus on the route of administration 

rather than the part of the body. 

(Response) FDA agrees that ‘‘part of 

the body’’ could be misconstrued and 

we have determined that the use of 

‘‘route of administration’’ to describe 

how the drug enters the body is more 

consistent with labeling language that 

addresses dosing and administration. In 

the final rule, FDA has replaced ‘‘part of 

the body’’ with ‘‘route of 

administration.’’ FDA has determined 

that ‘‘cannot be detected in the blood’’ 

is redundant and that the statement is 

clear without this phrase. In the final 

rule, FDA has eliminated that phrase. 

(Comment 33) Standard statement for 

certain drugs. FDA received one 

comment suggesting that we develop a 

standard statement for drugs that are 

indicated for use only by males or by 

females who are not of reproductive 

potential. 

(Response) FDA disagrees. We have 

determined that a standard statement is 

not needed. We believe it is appropriate 

that the ‘‘Risk Summary’’ will be 

included in labeling for all drugs, 

regardless of their indicated population. 

This will promote consistency in drug 

labeling. 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72081 

Risk conclusions based on human 

data. In the proposed rule, under the 

subheading ‘‘Fetal Risk Summary,’’ FDA 

proposed that when human data are 

sufficient to reasonably determine the 

likelihood that the drug increases the 

risk of fetal developmental 

abnormalities or specific developmental 

abnormalities, the likelihood of 

increased risk must be characterized 

using one of the following risk 

conclusions: Human data do not 

indicate that (name of drug) increases 

the risk of (type of developmental 

abnormality or specific developmental 

abnormality) or Human data indicate 

that (name of drug) increases the risk of 

(type of developmental abnormality or 

specific abnormality) (proposed 

§ 201.57(c)(9)(i)(C)(2)(i)). The proposed 

rule defined the sources of ‘‘sufficient 

human data’’ as clinical trials, 

pregnancy exposure registries or other 

large scale epidemiologic studies, or 

case series reporting a rare event 

(proposed § 201.57(c)(9)(i)(C)(2)(i)). 

(Comment 34) Many comments 

requested that FDA more clearly define 

the criteria for ‘‘sufficient human data’’ 

and provide further guidance on the 

quantity and quality of evidence 

considered to be ‘‘sufficient human 

data’’ rather than ‘‘other human data.’’ 

One comment requested that FDA 

clarify the standards that constitute 

‘‘sufficient human data,’’ including how 

those standards were developed. 

Another comment stated that there is no 

agreement among experts as to how 

much data are needed to reach a risk 

conclusion and requested that FDA 

clarify what is considered sufficient 

human data to reasonably determine the 

risk of developmental abnormalities. 

Several comments questioned whether 

data from an individual study could 

ever constitute ‘‘sufficient human data.’’ 

These comments explained that 

although individual clinical trials, 

pregnancy exposure registries, largescale epidemiologic studies, and case 

series can provide signals for potential 

adverse pregnancy outcomes, an 

individual study is not statistically 

powered to fully assess the incidence 

and form one of the proposed risk 

conclusions. A separate comment stated 

that even if human data has multiple 

sources, there is often not enough 

human data to make a risk conclusion. 

This comment questioned how often the 

risk statements based on sufficient 

human data would be used. One 

comment stated that the proposed rule 

does not discuss who will determine 

whether the data are sufficient or how 

such a determination will be made. The 

comment suggested that to increase 

consistent implementation across 

review divisions, a dedicated group of 

FDA specialists should review the 

determination of whether the human 

data are sufficient or insufficient for all 

labeling subject to the rule. This 

comment also requested that FDA 

provide examples of sufficient and 

insufficient data and that FDA caution 

prescribers that such classifications 

should not be considered as scientific 

proof that a drug may or may not harm 

a particular patient. 

(Response) FDA agrees that the term 

‘‘sufficient human data’’ is ambiguous 

and has eliminated it from the final rule. 

FDA has also eliminated from the final 

rule the distinction between ‘‘sufficient 

human data’’ and ‘‘other human data.’’ 

In the final rule, FDA requires that 

when human data are available that 

establish the presence or absence of any 

adverse developmental outcome(s) 

associated with maternal use of the 

drug, the labeling must summarize the 

specific developmental outcome; its 

incidence; and the effects of dose, 

duration of exposure, and gestational 

timing of exposure. As stated 

previously, the final rule also requires 

that the ‘‘Risk Summary’’ state when 

there are no human data or when 

available human data do not establish 

the presence or absence of drugassociated risk. 

FDA has also determined that the 

term ‘‘risk conclusion’’ is inappropriate 

because the available data may not 

always lead to a conclusion regarding 

the drug’s risk to the fetus. Therefore, in 

the final rule, FDA has replaced the 

term ‘‘risk conclusion’’ with the term 

‘‘risk statement.’’ 

(Comment 35) Several comments 

suggested that the Agency revise the 

proposed risk statements to make them 

more straightforward and appropriately 

qualify the nature of the data and the 

inability to draw definitive conclusions 

about an absence of risk based on them. 

Two of these comments suggested that 

the term ‘‘human data’’ be replaced with 

the term ‘‘available human data.’’ One 

comment suggested that the risk 

conclusion ‘‘Human data do not 

indicate that (name of drug) increases 

the risk of (type of developmental 

abnormality or specific developmental 

abnormality)’’ be replaced with 

‘‘Available human data indicate no 

additional risk of (type of 

developmental abnormality or specific 

developmental abnormality) with (name 

of drug).’’ One comment suggested that 

the term ‘‘indicate’’ should be replaced 

with the term ‘‘suggest.’’ 

(Response) In the final rule, FDA has 

eliminated the requirement in the 

proposed rule that standardized risk 

conclusions be used to characterize the 

likelihood of increased risk. As 

discussed previously, in the final rule, 

FDA requires instead, under ‘‘Risk 

statement based on human data,’’ that 

when human data are available that 

establish the presence or absence of any 

adverse developmental outcome(s) 

associated with maternal use of the 

drug, the labeling must summarize the 

specific developmental outcome; its 

incidence; and the effects of dose, 

duration of exposure, and gestational 

timing of exposure. The final rule also 

requires that if the data indicate that 

there is an increased risk for a specific 

adverse developmental outcome in 

infants born to women exposed to the 

drug during pregnancy, this risk must be 

quantitatively compared to the risk for 

the same outcome in infants born to 

women who were not exposed to the 

drug but who have the disease or 

condition for which the drug is 

indicated to be used. The final rule 

requires that if the data indicate that 

there is an increased risk for a specific 

adverse developmental outcome in 

infants born to women exposed to the 

drug during pregnancy, but risk 

information is not available for women 

who were not exposed to the drug but 

who have the disease or condition for 

which the drug is indicated to be used, 

then the risk for the specific outcome 

must be compared to the rate at which 

the outcome appears in the general 

population. 

(Comment 36) FDA also received 

comments about the proposed sources 

of sufficient human data. One comment 

stated that sufficient data must be based 

on large-scale epidemiologic studies or 

clinical trials, and cannot be based on 

pregnancy registries or case reports/

series requiring further evaluation. This 

comment explained that most 

pregnancy registries can only serve to 

rule out a major teratogen and to 

generally determine the similarity in 

array of effects seen in large registries, 

and they cannot provide a quantitative 

estimate of population rates of 

individual defects or abnormalities. 

Another comment stated that a risk 

conclusion cannot always be reached 

based on the types of human data 

described in the proposed rule, and 

questioned whether there is a consistent 

approach to sufficient human data as it 

relates to case series reporting of a rare 

event. This comment explained that 

spontaneous reports should not be part 

of the basis for this subsection. One 

comment questioned how the labeling 

will summarize seemingly contradictory 

results of well-powered pregnancy 

exposure registries or studies from 

mstockstill on DSK4VPTVN1PROD with RULES2

72082 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

which a definitive clinical conclusion 

cannot be reached. 

(Response) FDA recognizes that 

because retrospective voluntary adverse 

event reporting may be biased and 

incomplete, spontaneous reports cannot 

rule in or out a causal relationship 

between drug exposure and clinical 

outcome. However, multiple 

spontaneous reports (or case series) of 

rare events can be useful in suggesting 

possible associations between adverse 

events and drug exposure during 

pregnancy that warrant further 

investigation. Furthermore, FDA has 

determined that data from studies with 

small numbers of pregnancy exposures 

may provide valuable information about 

potential safety signals, especially when 

corroborated by findings from other 

studies. 

(Comment 37) One comment 

suggested that FDA eliminate the 

proposed rule’s requirement that 

sponsors specify all possible types of 

developmental abnormalities or specific 

abnormalities for which human data do 

not indicate that the drug increases the 

risk. The comment explained that such 

a list could be lengthy and of little 

clinical benefit to health care providers. 

(Response) FDA did not intend to 

imply that every potential type of 

developmental abnormality must be 

included in labeling when human data 

are negative. We note that it is difficult 

to be certain that a lack of findings 

equates to a lack of risk because the 

failure of a study to detect an 

association between a drug exposure 

and an adverse outcome may be related 

to many factors, including a true lack of 

an association between exposure and 

outcome, a study of the wrong 

population, failure to collect or analyze 

the right data endpoints, and/or 

inadequate power. The intent of this 

final rule is to require accurate 

descriptions of available data and 

facilitate the determination of whether 

the data demonstrate potential 

associations between drug exposure and 

an increased risk for developmental 

toxicities. 

FDA proposed that when there are 

available human data that are not 

sufficient to use one of the risk 

conclusions for sufficient human data, 

the likelihood that the drug increases 

the risk of developmental abnormalities 

must be characterized as low, moderate, 

or high (proposed 

§ 201.57(c)(9)(i)(C)(2)(ii)). In the 

preamble to the proposed rule, FDA 

sought comment on this subsection. 

Specifically, FDA sought ‘‘comment on 

whether, in situations with human data 

that are not sufficient, rather than 

classifying the risk as low, moderate, or 

high, the risk should instead be 

characterized by specific statements 

describing the findings, or whether the 

findings should be described at all if 

they are not readily interpretable. 

Examples of specific statements would 

be: ‘Limited data in humans show 

(describe outcomes),’ or ‘Limited data in 

humans show conflicting results 

(describe study types, number of cases, 

outcomes, and limitations)’’’ (73 FR 

30831 at 30842). 

(Comment 38) FDA received 10 

comments from a variety of sources 

expressing strong disagreement with the 

proposal to use the terms ‘‘low,’’ 

‘‘moderate,’’ and ‘‘high’’ to characterize 

the likelihood of increased risk of 

adverse outcomes due to drug exposure 

based on less than sufficient human 

data. FDA received only one comment 

supporting the proposal. 

Four comments stated that the 

proposal to classify risk as low, 

moderate, or high based on insufficient 

human data might produce the same 

confusion as the current pregnancy 

category system. These comments 

explained that, as with the A, B, C, D, 

X category system, the use of the 

categories low, moderate, and high to 

characterize the likelihood of increased 

risk of adverse outcomes would 

oversimplify the data and lump drugs 

with various types and amounts of data 

together without describing the basis for 

the conclusions. Another comment 

suggested that these characterizations 

are subjective and would be confusing 

to health care providers. 

One comment recommended that 

when the human data are insufficient, 

FDA require the inclusion of the 

following risk conclusion: ‘‘Insufficient 

data—risk conclusion not established.’’ 

Another comment recommended that 

FDA consider adopting something 

similar to the EMA’s system. One 

comment suggested that the ‘‘Risk 

Summary’’ should include information 

about the findings, such as the 

gestational age of exposure, the target 

organ or organ system, and the findings 

should be characterized in terms of 

structural, developmental, growth, or 

functional abnormality. Another 

comment recommended that when the 

human data are not sufficient, the 

labeling contain statements specific to 

the findings rather than classifying the 

risk as low, moderate, or high. One 

comment suggested that when there are 

insufficient data, the labeling should 

include a statement explaining that it is 

not possible to draw conclusions based 

on insufficient human data. This 

comment also expressed a preference for 

referring to the data portion of the 

labeling rather than including a more 

detailed narrative discussion of 

insufficient human data in the fetal risk 

summary. 

(Response) As discussed previously, 

FDA agrees that the term ‘‘sufficient 

human data’’ is ambiguous and we have 

removed the term from the final rule, as 

well as the distinction between 

‘‘sufficient human data’’ and ‘‘other 

human data.’’ FDA also agrees that the 

terms ‘‘low,’’ ‘‘moderate,’’ and ‘‘high’’ 

are subjective and should not be used to 

describe human data that cannot 

support a statement about fetal risk. The 

final rule requires instead that when 

human data are available that establish 

the presence or absence of any adverse 

developmental outcome(s) associated 

with maternal use of the drug, the 

labeling must summarize the specific 

developmental outcome; its incidence; 

and the effects of dose, duration of 

exposure, and gestational timing of 

exposure. As discussed earlier, the final 

rule also requires that if the human data 

indicate that there is an increased risk 

for a specific adverse developmental 

outcome in infants born to women 

exposed to the drug during pregnancy, 

this risk must be quantitatively 

compared to the risk for the same 

outcome in infants born to women who 

were not exposed to the drug but who 

have the disease or condition for which 

the drug is indicated to be used. When 

risk information is not available for 

women with the disease or condition for 

which the drug is indicated, then the 

risk for the specific outcome must be 

compared to the rate at which the 

outcome occurs in the general 

population. The final rule also requires 

that the ‘‘Risk Summary’’ state when 

there are no human data or when 

available human data do not establish 

the presence or absence of drugassociated risk. 

Narrative description of risk(s) based 

on human data. FDA proposed that 

when there are human data, the risk 

conclusion must be followed by a brief 

description of the risks of 

developmental abnormalities as well as 

other relevant risks associated with the 

drug. To the extent possible, this 

description must include the specific 

developmental abnormality (e.g., neural 

tube defects); the incidence, 

seriousness, reversibility, and 

correctability of the abnormality; and 

the effect on the risk of dose, duration 

of exposure, and gestational timing of 

exposure. When appropriate, the 

description must include the risk above 

the background risk attributed to drug 

exposure and confidence limits and 

power calculations to establish the 

statistical power of the study to identify 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72083 

or rule out a specified level of risk 

(proposed § 201.57(c)(9)(i)(C)(4)). 

In the final rule, FDA has removed the 

‘‘Narrative description of risk(s)’’ 

heading from the ‘‘Pregnancy’’ 

subsection. FDA has determined that 

much of the information required under 

that heading by the proposed rule was 

duplicative of information now required 

in the ‘‘Risk Summary.’’ As discussed 

previously, when human data are 

available that establish the presence or 

absence of any adverse developmental 

outcome(s) associated with maternal use 

of the drug, the ‘‘Risk Summary’’ in the 

‘‘Pregnancy’’ subsection must 

summarize the specific developmental 

outcome; its incidence; and the effects 

of dose, duration of exposure, and 

gestational timing of exposure. Because 

this information is required to be 

included in a narrative form in the 

‘‘Risk Summary,’’ we determined that 

including a separate ‘‘Narrative 

description of risk(s)’’ heading in the 

labeling was unnecessary. In addition, 

as explained in the following comments 

and our responses, some of the 

information that was required by the 

proposed rule to appear under 

‘‘Narrative description of risk(s)’’ is 

required by the final rule to appear 

instead under ‘‘Clinical 

Considerations.’’ 

(Comment 39) One comment 

suggested that FDA add a statement to 

the ‘‘Narrative description of risk(s)’’ 

portion of the ‘‘Pregnancy’’ subsection 

of labeling that explains that 

spontaneous abortions caused by a drug 

could potentially mask the risk of 

developmental abnormalities. 

(Response) Although FDA 

acknowledges that embryo-fetal death 

(i.e., spontaneous abortion) does 

sometimes occur due to severe 

developmental abnormalities, the 

Agency has determined that it is not 

necessary to explicitly include such a 

statement in labeling. Any increase in 

spontaneous abortions attributed to drug 

exposure above the background risk is 

required to be described in the ‘‘Risk 

Summary.’’ 

(Comment 40) One comment stated 

that the term ‘‘seriousness’’ is 

ambiguous and suggested replacing it 

with the phrase ‘‘impact on health.’’ 

Two comments requested clarification 

of the terms ‘‘reversibility’’ and 

‘‘correctability.’’ 

(Response) FDA agrees that the term 

‘‘seriousness’’ is not clear, and it is not 

used in the final rule; it has been 

replaced with a requirement that the 

labeling describe the potential severity 

of the adverse reaction. Information 

about the reversibility of adverse 

reactions should be included under the 

heading, ‘‘Fetal/Neonatal adverse 

reactions,’’ under ‘‘Clinical 

Considerations.’’ This portion of the 

final rule requires that if it is known or 

anticipated that maternal drug therapy 

increases or may increase the risk of an 

adverse reaction in the fetus or neonate, 

the labeling must describe the adverse 

reaction, the potential severity and 

reversibility of the adverse reaction, and 

available interventions for monitoring or 

mitigating the reaction. 

In response to the comments 

requesting clarification of the terms 

‘‘reversibility’’ and ‘‘correctability,’’ 

FDA considers a condition to be 

reversible if it can self-correct with 

routine care and nurturing or through an 

intervention such as discontinuing the 

drug. An example of a potentially 

reversible drug effect in the neonate is 

provided in the draft guidance on 

pregnancy and lactation labeling, which 

is being published concurrently with 

the final rule. The term ‘‘correctable’’ 

has been removed from the final rule. 

(Comment 41) One comment 

suggested that FDA include in the 

‘‘Narrative description of risk(s)’’ 

information about precautionary 

measures that can be taken to prevent an 

adverse outcome caused by the drug. 

(Response) FDA agrees that 

information about precautionary 

measures to prevent an adverse drug 

effect should be included in labeling. In 

the final rule, under ‘‘8.1 Pregnancy,’’ 

‘‘Clinical Considerations,’’ ‘‘Maternal 

adverse reactions,’’ FDA requires that if 

the use of the drug is associated with a 

maternal adverse reaction that is unique 

to pregnancy or if a known adverse 

reaction occurs with increased 

frequency or severity in pregnant 

women, the labeling must describe the 

adverse reaction and available 

intervention(s) for monitoring or 

mitigating it. Also, in the final rule, FDA 

requires that under ‘‘8.1 Pregnancy,’’ 

‘‘Clinical Considerations,’’ ‘‘Fetal/

Neonatal adverse reactions,’’ if it is 

known or anticipated that maternal drug 

therapy increases or may increase the 

risk of an adverse reaction in the fetus 

or neonate, the labeling must describe 

the adverse reaction, the potential 

severity and reversibility of the adverse 

reaction, and available intervention(s) 

for monitoring or mitigating the 

reaction. For further discussion of these 

requirements, see Comment 61 and our 

response. 

(Comment 42) One comment 

suggested that FDA replace the phrase 

‘‘risk attributed to drug exposure’’ in the 

‘‘Narrative description of risk(s)’’ with 

the phrase ‘‘a drug’s potential to 

contribute to the risk of adverse 

outcomes.’’ 

(Response) As discussed previously, 

the ‘‘Narrative description of risk(s)’’ 

heading was removed from the final 

rule, and the phrase ‘‘risk attributed to 

drug exposure’’ is not used elsewhere in 

the final rule. 

(Comment 43) Two comments stated 

that confidence intervals and power 

calculations should not be included in 

labeling because they are too technical 

and not useful for most prescribers. 

(Response) FDA does not agree. Under 

‘‘Data,’’ the final rule requires a 

description of the limitations of any 

data included in the labeling. 

Confidence intervals and power 

calculations are important for the 

review and interpretation of the data. As 

noted in the draft guidance on 

pregnancy and lactation labeling, which 

is being published concurrently with 

the final rule, the confidence intervals 

and power calculation, when available, 

should be part of that description of 

limitations. 

(Comment 44) One comment 

suggested that the ‘‘Narrative 

description of risk(s)’’ include a 

discussion about the uncertainties or 

limitations of the ‘‘Fetal Risk Summary’’ 

when appropriate. 

(Response) As discussed previously, 

FDA has removed the ‘‘Narrative 

description of risk(s)’’ heading from the 

final rule. In the final rule, any 

uncertainties or limitations of the data 

are required to be stated in ‘‘Data.’’ 

(Comment 45) One comment 

suggested that the ‘‘Narrative 

description of risk(s)’’ cross-reference 

‘‘Data’’ to direct readers to the 

information upon which the narrative is 

based. 

(Response) As discussed previously, 

the ‘‘Narrative description of risk(s)’’ 

was removed from the final rule. 

Risk statement based on animal data. 

FDA proposed to require that when the 

data on which the risk conclusion is 

based are animal data, the ‘‘Fetal Risk 

Summary’’ must characterize the 

likelihood that the drug increases the 

risk of developmental abnormalities 

using one of the following risk 

conclusions: Not predicted to increase 

the risk, low likelihood of increased 

risk, moderate likelihood of increased 

risk, high likelihood of increased risk, or 

insufficient data (proposed 

§ 201.57(c)(9)(i)(C)(3)(i)– 

(c)(9)(i)(C)(3)(v)). In the preamble to the 

proposed rule, the Agency sought 

comment on whether these standardized 

statements can adequately communicate 

different levels of risk based on animal 

data and their potential relevance to 

human fetal effects or whether these 

statements are likely to generate 

mstockstill on DSK4VPTVN1PROD with RULES2

72084 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

confusion among prescribers (73 FR 

30831 at 30843). 

(Comment 46) Comments expressed 

different opinions about the proposal to 

use standardized statements to 

characterize animal data. FDA received 

11 comments, primarily from 

toxicologists, teratologists, and 

organizations representing toxicologists 

and teratologists, as well as a few 

comments from drug manufacturers, 

expressing strong disagreement with the 

proposal to use risk statements to 

characterize animal data. FDA received 

three comments that supported using 

standardized statements to characterize 

the likelihood, based on animal data, 

that a drug will increase the risk for a 

known developmental abnormality. 

These comments explained, for 

example, that a standardized statement 

indicating the possible correlation 

between animal and human data would 

be helpful to clinicians. 

Two comments stated that the 

proposed categories are confusing and 

subject to variable interpretation. One of 

these comments explained that it will be 

very difficult to categorize the results of 

multiple studies conducted for a single 

drug into one of the proposed 

categories, and there could be 

disagreement about whether to 

characterize the risk based on the 

animal data as ‘‘low,’’ ‘‘moderate,’’ or 

‘‘high.’’ 

Several comments stated that the 

proposal to use category language to 

describe animal data demonstrates a 

misunderstanding of the function and 

meaning of experimental animal 

studies. These comments explained that 

although animal data can identify the 

potential of a therapeutic agent to cause 

developmental toxicity, it cannot give 

rise to an estimate of the probability of 

human harm. 

Two comments expressed concern 

that the use of standardized risk 

statements would amount to a category 

system similar to the one that FDA 

currently uses and would have all of its 

associated problems. 

Several comments expressed 

particular concern with the proposal to 

use these categories without an 

accompanying narrative description of 

the animal studies. One comment 

suggested that the sample labels 

provided in the Appendix of the 

proposed rule illustrate the difficulty of 

trying to characterize the risk to humans 

based on animal data. Another comment 

stated that ‘‘the terms ‘risk,’ ‘medium,’ 

and ‘high’ are highly charged terms’’ 

and expressed concern that the risk 

statements will be over-interpreted by 

anxious consumers and their clinicians. 

One comment suggested that rather 

than using the proposed risk statements, 

FDA should instead use the 

standardized statements presented in 

the draft reviewer guidance on 

‘‘Integration of Study Results to Assess 

Concerns about Human Reproductive 

and Developmental Toxicities’’ (October 

2001). 

Most of the comments that disagreed 

with the proposed standardized risk 

statements suggested that the labeling 

instead contain narrative statements 

describing the animal data and its 

potential relationship to human 

pregnancy risk. One of these comments 

explained that ‘‘succinct narrative 

statements will promote a reasoned risk 

assessment, facilitate comparisons 

among drugs, and enhance risk 

communication.’’ Several of these 

comments suggested that the labeling 

should describe animal data 

qualitatively, including the number of 

species with positive findings, 

consistency of findings, and the type of 

findings. 

(Response) The Agency has 

determined that the terms ‘‘not 

predicted to increase the risk,’’ ‘‘low 

likelihood of increased risk,’’ ‘‘moderate 

likelihood of increased risk,’’ and ‘‘high 

likelihood of increased risk’’ are 

confusing and subject to different 

interpretations. The Agency believes 

that using standardized risk statements 

may give the false impression that 

animal data can provide a semiquantitative assessment of human risk. 

The Agency also agrees that the use of 

standardized risk statements to 

characterize the risk of developmental 

abnormalities based on animal data 

would potentially have the same 

drawbacks as the current pregnancy 

category system. Therefore, in the final 

rule, FDA removed the requirement that 

a standardized risk statement be used to 

describe human risk based on animal 

data. Instead, the ‘‘Risk Summary’’ 

requires that when animal data are 

available, the labeling must summarize 

the findings in animals and, based on 

these findings, describe, for the drug, 

the potential risk of adverse 

developmental outcomes in humans. 

The final rule requires that the 

statement include the number and 

type(s) of species affected, timing of 

exposure, animal doses expressed in 

terms of human exposure or dose 

equivalents, and outcomes for pregnant 

animals and offspring. The final rule 

also requires that when animal studies 

do not meet current standards for 

nonclinical developmental toxicity 

studies or when there are no animal 

data, the labeling must so state. 

(Comment 47) Two comments 

suggested that labeling should include 

language explaining the limitations of 

using animal data to predict the 

likelihood that the drug increases the 

risk of developmental abnormalities. 

(Response) FDA declines the 

suggestion to include language in 

labeling explaining the limitations of 

using animal data to predict the 

likelihood that the drug increases the 

risk of developmental abnormalities, 

because this is beyond the scope of this 

rule, and is discussed in guidance 

documents, such as FDA’s guidance for 

industry on ‘‘Reproductive and 

Developmental Toxicities—Integrating 

Study Results to Assess Concerns’’ 

(September 2011). 

(Comment 48) FDA proposed that the 

‘‘Risk Summary’’ contain ‘‘risk 

conclusions’’ based on animal data. One 

comment suggested that the term ‘‘risk 

conclusion’’ be replaced with the term 

‘‘risk statement’’ because it is difficult to 

reach any conclusions about fetal risk 

posed by drugs based solely on animal 

data. 

(Response) FDA agrees. As with 

human data, in the final rule, the 

Agency has replaced the term ‘‘risk 

conclusion’’ with the term ‘‘risk 

statement’’ when discussing risks based 

on animal data. 

(Comment 49) Risk statement based 

on pharmacology. One comment 

suggested that FDA consider whether a 

separate approach is appropriate for a 

group of drugs, such as oncology 

products, for which the pharmacological 

and toxicological mechanisms are 

similar. The comment suggested that for 

cytotoxic drugs, FDA could use the 

following standard risk statement: 

‘‘(Drug name) is indicated for (cancer 

type) and is generally used in terminally 

ill patients. There are very limited data 

on exposure in pregnant patients and, 

therefore, no assessment of fetal or 

maternal risk is available. The 

mechanism of action of this drug is to 

kill growing cells and it can be 

anticipated that there is a risk to the 

fetus at all stages of development.’’ 

(Response) FDA agrees that the 

‘‘Pregnancy’’ subsection of labeling 

should address situations in which a 

drug may result in an increased risk of 

adverse developmental outcomes based 

on a well-understood mechanism of 

action. The final rule requires that when 

the drug has a well-understood 

mechanism of action that may result in 

adverse developmental outcome(s), the 

‘‘Risk Summary’’ must explain the 

mechanism of action and the potential 

associated risks. 

Contraindications, warnings, and 

precautions. FDA proposed that the 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72085 

‘‘Fetal Risk Summary’’ refer to 

information that is included in the 

‘‘Contraindications’’ or ‘‘Warnings and 

Precautions’’ section of labeling 

regarding an increased risk to the fetus 

from exposure to the drug (proposed 

§ 201.57(c)(9)(i)(C)(5)). 

(Comment 50) One comment 

suggested that FDA specify that any 

contraindications or warnings or 

precautions that must be included in the 

‘‘Fetal Risk Summary’’ are those that 

relate to risk to the fetus. 

(Response) In the final rule, FDA 

removed the requirement that the ‘‘Risk 

Summary’’ refer to information that is 

included in the ‘‘Contraindications’’ or 

‘‘Warnings and Precautions’’ section of 

labeling regarding an increased risk to 

the fetus from exposure to the drug. As 

described in FDA’s draft guidance for 

industry implementing the PLR, when a 

topic is discussed in more than one 

section of labeling, the section 

containing the most important 

information relevant to prescribing 

should typically include a succinct 

description and should cross-reference 

sections that contain additional detail 

(FDA’s guidance for industry on 

‘‘Labeling for Human Prescription Drug 

and Biological Products—Implementing 

the PLR Content and Format 

Requirements’’ (February 2013)). 

Consistent with that principle, crossreferencing of information required 

under the final rule will typically 

appear in the section where the topic is 

briefly summarized, e.g., ‘‘Warnings and 

Precautions,’’ and will refer the reader 

to the place in labeling where it will be 

presented in greater detail, i.e., 

‘‘Pregnancy.’’ We note that because a 

contraindication is important 

information that needs to be 

communicated to the health care 

provider, the final rule requires that 

when use of a drug is contraindicated 

during pregnancy, this information must 

be stated first in the ‘‘Risk Summary.’’ 

iv. Clinical considerations. 

FDA proposed that the ‘‘Pregnancy’’ 

subsection of prescription drug labeling 

include a ‘‘Clinical Considerations’’ 

component to provide guidance and 

information to health care providers 

about the use of the drug in three 

distinct clinical situations: (1) 

Counseling women who were 

inadvertently exposed to the drug 

during pregnancy, (2) making 

prescribing decisions for pregnant 

women, and (3) making prescribing 

decisions during labor and delivery 

(proposed § 201.57(c)(9)(i)(D)). 

We received many comments on this 

proposal. Based on those comments, 

FDA has made some changes to the final 

rule. A description of each comment we 

received and our responses follow. 

(Comment 51) General comments. 

Comments expressed different opinions 

about the utility and appropriateness of 

the proposed ‘‘Clinical Considerations’’ 

component. Many comments expressed 

general support for including this 

information. One comment stated that 

‘‘Clinical Considerations’’ will help 

clinicians and patients to consider all 

aspects of the patient’s care when 

deciding when and how to prescribe 

drugs during pregnancy and in women 

of childbearing potential. Another 

comment stated that the title ‘‘Clinical 

Considerations’’ encourages 

professionals to make their own medical 

judgments. A separate comment noted 

that FDA refrained from interfering with 

the physician’s discretion by framing 

‘‘Clinical Considerations’’ as a practical 

guide that assists the provider in 

decisionmaking. 

Some comments cautioned that 

‘‘Clinical Considerations’’ was too 

directive in its advice and requiring this 

information intruded on the practice of 

medicine and could increase physician 

liability for failure to adhere to labeling 

instructions. One comment stated that 

‘‘Clinical Considerations’’ should not 

dictate prescribing by a physician for 

pregnant women. The comment 

requested that FDA revisit this 

provision to see whether the content can 

be made more useful without advising 

physicians how to practice medicine. In 

particular, the comment suggested that 

information about known alternative 

therapies should be included. 

Alternatively, the comment suggested 

that FDA consider the use of a general 

statement about clinical considerations 

rather than an extensive, clinically 

based discussion that may be unable to 

incorporate risk and benefit 

information. Another comment stated 

that it is the health care provider’s 

responsibility to keep abreast of the 

latest information about the disease 

state and its effect on pregnant women 

and to apply that knowledge to 

treatment of each individual patient, 

and the professional labeling is not the 

appropriate place for this information. 

(Response) FDA disagrees both that 

‘‘Clinical Considerations’’ is too 

directive and that professional labeling 

is not the appropriate place for this 

information. As a Public Health Agency 

with expertise in drug regulation and 

safety, FDA has a responsibility to issue 

regulations that facilitate the 

development of drug labeling that 

communicates how to safely and 

effectively prescribe drugs in the 

clinical setting. The Agency does not 

regard ‘‘Clinical Considerations’’ as 

dictating prescribing decisions. Rather, 

FDA views the ‘‘Clinical 

Considerations’’ component of 

‘‘Pregnancy’’ as providing information 

that supports health care providers’ 

understanding of drug product risks and 

benefits and facilitates informed 

prescribing decisions and patient 

counseling. 

Inadvertent exposure. FDA proposed 

that under the subheading ‘‘Clinical 

Considerations,’’ the ‘‘Pregnancy’’ 

subsection of labeling include 

information regarding known or 

predicted risks to the fetus from 

inadvertent exposure to the drug during 

pregnancy (proposed 

§ 201.57(c)(9)(i)(D)(1)). The proposed 

rule would have required that: The 

labeling must discuss the known or 

predicted risks to the fetus from 

inadvertent exposure to the drug 

(exposure in early pregnancy before a 

woman knows she is pregnant), 

including human or animal data on 

dose, timing, and duration of exposure. 

If there are no human or animal data to 

assess the risk from inadvertent 

exposure, the labeling must so state. 

(Comment 52) Comments expressed 

different opinions about the necessity 

and utility of including this 

information. 

Two comments supported including 

information about inadvertent exposure. 

One of these comments explained that 

the proposed section improves a 

physician’s ability to manage such 

cases. 

Two comments, however, suggested 

that FDA consider removing this 

requirement because it will be 

duplicative of the information contained 

in the ‘‘Fetal Risk Summary.’’ One of 

these comments explained that 

assuming equal exposure to the drug, 

the known or predicted risks to the fetus 

would be the same regardless of 

whether the exposure was intentional or 

not. This comment explained that 

because fetal risks are already fully 

described in the ‘‘Fetal Risk Summary,’’ 

including the same information under 

‘‘inadvertent exposure during 

pregnancy’’ would be redundant. The 

comment suggested that the 

‘‘inadvertent exposure during 

pregnancy’’ component instead include 

a cross-reference to the ‘‘Fetal Risk 

Summary’’ and describe only 

information not already described in the 

‘‘Fetal Risk Summary,’’ in particular, 

any information about ways to manage 

or mitigate the effects of inadvertent 

drug exposure. The other comment 

explained that the risk of drug exposure 

to the fetus early in pregnancy should 

not be different between women who 

mstockstill on DSK4VPTVN1PROD with RULES2

72086 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

choose to become pregnant and those 

whose pregnancies were unplanned. 

Another comment suggested that FDA 

either delete the statement ‘‘exposure in 

early pregnancy before a woman knows 

that she is pregnant’’ or retain it as an 

example. This comment explained that 

although inadvertent exposure is more 

likely in early pregnancy, it may occur 

at any time during pregnancy. 

One comment asked for clarification 

as to what is expected to be included in 

this section. Specifically, this comment 

questioned how the risk conclusions 

from animal data in the ‘‘Fetal Risk 

Summary’’ will be used to counsel 

clinicians on the risk of inadvertent 

exposure, and requested that FDA 

provide examples of this section in an 

Appendix. 

(Response) The Agency agrees that the 

proposed ‘‘inadvertent exposure during 

pregnancy’’ component would have 

required information about drug effects 

on the fetus that is largely redundant of 

the information that is required to be 

included in the ‘‘Risk Summary’’ in the 

‘‘Pregnancy’’ subsection of prescription 

drug labeling. FDA has removed the 

‘‘inadvertent exposure during 

pregnancy’’ component from the final 

rule. 

Prescribing decisions for pregnant 

women. FDA proposed that the 

‘‘Clinical Considerations’’ portion of the 

‘‘Pregnancy’’ subsection of prescription 

drug labeling contain information about 

prescribing decisions for pregnant 

women, including the following: (1) The 

risk, if known, to the pregnant woman 

and the fetus from the disease or 

condition the drug is indicated to treat; 

(2) information about dosing 

adjustments during pregnancy; (3) 

information about maternal adverse 

reactions associated with use of the 

drug; and (4) information about any 

known or anticipated complications in 

the neonate from treatment of the 

pregnant woman (proposed 

§ 201.57(c)(9)(i)(D)(2)). 

In the final rule, FDA removed the 

heading ‘‘Prescribing decisions for 

pregnant women.’’ FDA determined that 

because the ‘‘inadvertent exposure’’ 

component was removed from the final 

rule, the ‘‘Clinical Considerations’’ 

portion of the ‘‘Pregnancy’’ subsection 

was shortened such that having a 

separate heading for ‘‘Prescribing 

decisions for pregnant women’’ was 

unnecessary. 

FDA received comments about the 

information required in the proposed 

rule under the heading ‘‘Prescribing 

decisions for pregnant women.’’ A 

description of each comment and our 

responses follow. 

FDA proposed that the ‘‘Prescribing 

decisions for pregnant women’’ 

component under ‘‘Clinical 

Considerations’’ include information 

about the risk, if known, to the pregnant 

woman and the fetus from the disease 

or condition the drug is indicated to 

treat (proposed § 201.57(c)(9)(i)(D)(2)(i)). 

(Comment 53) Comments disagreed 

about whether the ‘‘Pregnancy’’ 

subsection of labeling should include 

information about the effects of not 

treating the woman’s underlying disease 

or condition. 

Two comments supported requiring 

the inclusion of information about the 

short- and long-term effects of not taking 

a necessary drug to treat a chronic 

disease or condition for the duration of 

a pregnancy, as well as information 

about the severity of the condition for 

which the drug might be prescribed. 

Two other comments, however, 

disagreed with including information in 

‘‘Clinical Considerations’’ about the 

risks of not treating the mother’s 

underlying disease or condition during 

pregnancy. These comments stated that 

prescription drug labeling is not the 

appropriate place for health care 

providers to learn about the risks of 

diseases that drugs are indicated to 

treat. 

(Response) FDA has determined that 

when relevant information is available 

about the serious effects of not treating 

conditions or diseases during 

pregnancy, it must be included in this 

section of labeling. In the final rule, this 

requirement appears first under 

‘‘Clinical Considerations’’ under the 

heading ‘‘Disease-associated maternal 

and/or embryo/fetal risk.’’ The wording 

of this portion of the final rule was 

revised to require that when there is a 

serious known or potential risk to the 

pregnant woman and/or the embryo/

fetus associated with the disease or 

condition for which the drug is 

indicated to be used, the labeling must 

describe the risk. 

(Comment 54) Other comments 

suggested that the ‘‘Clinical 

Considerations’’ component of the 

proposed rule be altered in various 

ways. 

Two comments expressed concern 

that descriptions of risks to the pregnant 

patient or fetus posed by diseases or 

conditions would vary among drugs that 

are indicated to treat the same disease 

or condition, thereby promoting 

confusion. One of these comments 

suggested that FDA develop diseasespecific text for developmental risks of 

major disease classes, such as asthma, 

hypertension, diabetes, and epilepsy, 

which sponsors can use in their 

prescription drug labeling. This 

comment also requested that the 

information be updated on a timely 

basis. 

(Response) FDA agrees that it is 

important that information provided in 

labeling is consistent and up-to-date, 

and we address this issue in our 

response to Comment 4. FDA is not 

mandating that labeling contain 

consistent disease-specific text, as 

knowledge of disease-associated risk 

may change over time as more data 

become available. 

(Comment 55) One comment 

suggested that FDA add a statement 

under ‘‘Clinical Considerations’’ 

explicitly stating that untreated or 

inadequately treated health conditions 

(such as infections; chronic diseases 

such as diabetes, hypertension, renal 

and thyroid diseases; and psychiatric 

disorders such as depression) can 

adversely affect the health of the woman 

and the outcomes of the pregnancy, and 

that decisions about medication usage 

must be balanced with the risks of 

untreated and/or poorly managed health 

conditions. 

(Response) FDA disagrees with this 

suggestion. We have determined that 

requiring a general standardized 

statement is less effective than 

providing drug-specific information 

about the risks of not treating the 

condition or disease for which the drug 

is indicated to be used. 

(Comment 56) One comment 

suggested that ‘‘Clinical Considerations’’ 

should provide information about how 

to discontinue or switch medications 

during pregnancy when necessary. 

(Response) FDA agrees that when 

such information is available, it may be 

appropriate to include it in ‘‘Clinical 

Considerations.’’ We note that this does 

not require a change to the final rule, 

because this is consistent with current 

labeling practices. 

(Comment 57) One comment 

suggested that ‘‘Clinical Considerations’’ 

take into account the severity of the 

disease, disorder, or condition to the 

mother, and the availability and the 

benefits and risks of alternative 

therapies for which greater or lesser 

knowledge may be known about their 

use in pregnant women. 

(Response) FDA disagrees with the 

suggestion that the labeling address the 

availability and the benefits and risks of 

alternative therapies during pregnancy. 

Because the comparative risks and 

benefits for different therapies may vary 

by patient, this determination must be 

made by the prescribing health care 

provider. FDA acknowledges, however, 

that under certain circumstances it may 

be appropriate to include a statement in 

the labeling that pregnant women 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72087 

should consider alternative drug 

therapies, and the appropriateness of 

this would be evaluated on a case-bycase basis during the labeling review 

process for a specific application. 

Dosing adjustments during 

pregnancy. FDA proposed that ‘‘Clinical 

Considerations’’ provide information 

about dosing adjustments during 

pregnancy (proposed 

§ 201.57(c)(9)(i)(D)(2)(ii)). The proposed 

rule stated that this information must 

also be included in the ‘‘Dosage and 

Administration’’ and ‘‘Clinical 

Pharmacology’’ sections of the labeling, 

and that if there are no data on dosing 

during pregnancy, the labeling must so 

state. 

(Comment 58) One comment 

suggested that dosing information 

should be restricted to the ‘‘Dosage and 

Administration’’ section of labeling and 

that ‘‘Clinical Considerations’’ should 

cross-reference the ‘‘Dosage and 

Administration’’ and ‘‘Clinical 

Pharmacology’’ sections of the labeling 

rather than repeat dosing adjustment 

information in the ‘‘Pregnancy’’ 

subsection of labeling. The comment 

also suggested replacing the phrase ‘‘no 

data’’ because it could become outdated 

and because, in some instances, there 

may be data but it might not be 

sufficient to support recommendations 

for dosing adjustments. 

(Response) We disagree with the 

suggestion that all information about 

dosing should be restricted to the 

‘‘Dosage and Administration’’ section of 

labeling. FDA has determined that it is 

important that labeling information 

relevant to the use of the drug during 

pregnancy be included in the 

‘‘Pregnancy’’ subsection. These issues 

are discussed in the draft guidance on 

pregnancy and lactation labeling, which 

is being published concurrently with 

the final rule. If there are 

pharmacokinetic data that support dose 

adjustment(s) during pregnancy and the 

postpartum period, this information 

must be provided under the heading, 

‘‘Dose adjustments during pregnancy 

and the postpartum period’’ in ‘‘Clinical 

Considerations,’’ and there should be a 

cross-reference to other sections of 

labeling that include more details (e.g., 

‘‘Dosage and Administration’’ or 

‘‘Clinical Pharmacology’’). Although in 

the proposed rule FDA had required a 

cross-reference to ‘‘Dosage and 

Administration’’ and ‘‘Clinical 

Pharmacology,’’ we have removed that 

requirement. We believe, however, that 

when appropriate, a cross-reference 

should be included. This approach is 

consistent with the regulations and 

guidance applicable to the ‘‘Dosage and 

Administration’’ section of labeling 

(§ 201.57(c)(3)) and FDA’s guidance for 

industry on ‘‘Dosage and 

Administration Section of Labeling for 

Human Prescription Drug and Biological 

Products—Content and Format’’ (March 

2012), which require that the labeling 

provide details on how to adjust or 

modify the dosage in the ‘‘Dosage and 

Administration’’ section of labeling, 

including for specific patient 

populations. 

FDA agrees with the suggestion to 

remove the phrase ‘‘no data’’ from the 

final rule. In the final rule, we have 

removed the requirement to state if 

there are no data available on dose 

adjustments during pregnancy and the 

postpartum period. In addition, as noted 

in the draft guidance on pregnancy and 

lactation labeling, which is being 

published concurrently with the final 

rule, headings under ‘‘Clinical 

Considerations’’ (including ’’Dose 

adjustments during pregnancy and the 

postpartum period’’) should be omitted 

if there are no data available or the 

available data are not relevant. 

Maternal adverse reactions. FDA 

proposed that ‘‘Clinical Considerations’’ 

contain information about maternal 

adverse reactions that are unique to 

pregnancy or adverse reactions that 

occur with increased frequency or 

severity in pregnant women. The 

proposed rule required that the labeling 

also describe any interventions that may 

be needed, such as monitoring blood 

glucose for a drug that causes 

hyperglycemia in pregnancy (proposed 

§ 201.57(c)(9)(i)(D)(2)(iii)). 

(Comment 59) One comment 

suggested that a cross-reference, ‘‘see 

Pregnancy,’’ be added to the ‘‘Adverse 

Reactions’’ section of labeling to ensure 

that health care providers refer to this 

section. 

(Response) FDA disagrees with this 

comment. The conventions for crossreferencing are explained in FDA’s 

guidance for industry on ‘‘Labeling for 

Human Prescription Drug and Biological 

Products—Implementing the PLR 

Content and Format Requirements’’ 

(February 2013). The suggestion that 

this rule require a cross-reference from 

the ‘‘Adverse Reactions’’ section to the 

‘‘Pregnancy’’ subsection of labeling is 

not consistent with the conventions set 

forth in that guidance. In addition, not 

every drug product will have 

pregnancy-related adverse reactions; 

thus, a required cross-reference is 

unnecessary. 

(Comment 60) One comment 

suggested that ‘‘Clinical Considerations’’ 

refer to ‘‘available’’ interventions rather 

than ‘‘needed’’ interventions to avoid 

interfering with the practice of 

medicine. 

(Response) FDA agrees with the 

suggestion to replace the phrase 

‘‘interventions that may be needed’’ 

with the phrase ‘‘available 

interventions.’’ In the final rule, FDA 

requires that if use of the drug is 

associated with a maternal adverse 

reaction that is unique to pregnancy or 

if a known adverse reaction occurs with 

increased frequency or severity in 

pregnant women, the labeling must 

describe the adverse reaction and 

available intervention(s) for monitoring 

or mitigating the reaction. This change 

also allows for differences that may 

exist in community standards of care 

and available services across the United 

States. We note that in the final rule we 

removed the following language from 

the codified: ‘‘e.g., monitoring blood 

glucose for a drug that causes 

hyperglycemia in pregnancy.’’ 

Fetal/Neonatal adverse reactions. 

FDA proposed that ‘‘Clinical 

Considerations’’ contain information 

about any known or anticipated 

complications in the neonate, including 

any interventions that might be needed 

(proposed § 201.57(c)(9)(i)(D)(2)(iv)). 

(Comment 61) Two comments asked 

FDA to clarify the meaning of the term 

‘‘complication.’’ One comment 

suggested that if FDA intended the term 

‘‘complication’’ to mean adverse 

reaction in the neonate, the Agency 

should use the term ‘‘adverse reaction.’’ 

This comment also suggested that if an 

adverse reaction/complication has been 

described in the ‘‘Fetal Risk Summary,’’ 

only a cross-reference to 

§ 201.57(c)(9)(i)(C) should be required to 

appear in § 201.57(c)(9)(i)(D)(2)(iv). 

Another comment suggested that FDA 

state that a ‘‘complication’’ could be an 

‘‘adverse drug reaction,’’ and suggested 

that FDA state that the term ‘‘adverse 

drug reaction’’ may be used when 

appropriate. 

(Response) FDA agrees that ‘‘adverse 

reaction’’ is a more appropriate term 

and that it is more consistent with the 

other portions of the final rule. In the 

final rule, the term ‘‘adverse reaction’’ 

(as defined in § 201.57(b)(7)) has 

replaced ‘‘complication.’’ Additionally, 

in the final rule FDA is requiring the 

inclusion of information regarding fetal 

adverse reactions in this section of 

labeling. Although the proposed rule 

only addressed adverse reactions 

(referred to there as ‘‘complications’’) in 

the neonate under what in the final rule 

is required in § 201.57(c)(9)(i)(C), FDA 

concludes that information intended to 

inform prescribing decisions for 

pregnant women appropriately includes 

information on fetal adverse reactions as 

well as neonatal adverse reactions. FDA 

does not believe that there is a 

mstockstill on DSK4VPTVN1PROD with RULES2

72088 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

principled distinction between the 

importance of such information with 

respect to the fetus and with respect to 

the neonate. The consistent location 

under ‘‘Clinical Considerations’’ of 

information about potential adverse 

reactions in the fetus as well as in the 

pregnant woman and the neonate, and 

about available interventions, will make 

the information in that subsection more 

useful, as well as easier to identify for 

prescribers and other health care 

providers. Accordingly, the final rule 

requires that if it is known or 

anticipated that maternal drug therapy 

increases the risk of an adverse reaction 

in the fetus or the neonate, the labeling 

must describe the adverse reaction, the 

potential severity and reversibility of 

the adverse reaction, and available 

intervention(s) for monitoring or 

mitigating the reaction. 

FDA disagrees with the suggestion 

that if an adverse reaction/complication 

has been described in the ‘‘Fetal Risk 

Summary,’’ only a cross-reference to 

§ 201.57(c)(9)(i)(C) should be required to 

appear in § 201.57(c)(9)(i)(D)(2)(iv). As 

discussed in the draft guidance on 

pregnancy and lactation labeling, which 

is being published concurrently with 

the final rule, the ‘‘Clinical 

Considerations’’ portion of the labeling 

is intended to describe fetal/neonatal 

adverse reactions that are not adverse 

developmental outcomes. Therefore, 

because the two portions of the labeling 

address different potential reactions/

outcomes, a cross-reference would not 

be appropriate. 

Additionally, in the final rule, FDA 

added the requirement that the labeling 

must describe, if known, the effect of 

dose, timing, and duration of exposure 

on the risk of an adverse reaction in the 

fetus or neonate as FDA has concluded 

that this information is important for 

informing prescribing decisions. 

Drug effects during labor or delivery. 

FDA proposed that the ‘‘Clinical 

Considerations’’ portion of pregnancy 

labeling contain information about drug 

effects during labor or delivery for drugs 

that have a recognized use during labor 

or delivery, whether or not the use is 

stated as an indication in the labeling, 

or are expected to affect labor or 

delivery (proposed 

§ 201.57(c)(9)(i)(D)(3)). 

(Comment 62) One comment 

supported the proposal to merge 

information about labor and delivery 

into the ‘‘Pregnancy’’ subsection of 

labeling. 

Another comment expressed concern 

that including information about drugs 

used during labor or delivery, including 

drugs that are used off-label during 

labor or delivery, conflicts with FDA’s 

long-standing position that off-label 

information is not to be included in 

labeling. 

(Response) We note that, as stated in 

the proposed rule (73 FR 30831 at 

30844), the language proposed for this 

heading contained only slight 

modifications from that in existing 

§ 201.57(c)(9)(ii). However, because 

important safety information, whether 

for an approved or unapproved use, may 

be required to be included in labeling 

(see, e.g., § 201.57(c)(6)(i)), we 

concluded that it is not necessary to 

include specific language regarding this 

issue. Therefore, FDA has removed the 

language regarding ‘‘drugs that have a 

recognized use during labor or delivery, 

whether or not the use is stated as an 

indication in the labeling.’’ In the final 

rule, FDA revised the heading ‘‘Drug 

effects during labor or delivery’’ to 

‘‘Labor or delivery,’’ which is consistent 

with the level of specificity used in the 

other headings under ‘‘Clinical 

Considerations.’’ 

v. Data. 

FDA proposed that the following 

information be included in the 

‘‘Pregnancy’’ subsection of labeling 

under the subheading ‘‘Data’’: 

(1) Under the subheading ‘‘Data,’’ the 

‘‘Pregnancy’’ subsection of the labeling 

must provide an overview of the data 

that were the basis for the fetal risk 

summary. 

(2) Human and animal data must be 

presented separately, and human data 

must be presented first. 

(3) The labeling must describe the 

studies, including study type(s) (e.g., 

controlled clinical or nonclinical, 

ongoing or completed pregnancy 

exposure registries, other 

epidemiological or surveillance studies), 

animal species used, exposure 

information (e.g., dose, duration, 

timing), if known, and the nature of any 

identified fetal developmental 

abnormalities or other adverse effect(s). 

Animal doses must be described in 

terms of human dose equivalents and 

the basis for those calculations must be 

included. 

(4) For human data, positive and 

negative experiences during pregnancy, 

including developmental abnormalities, 

must be described. To the extent 

applicable, the description must include 

the number of subjects and the duration 

of the study. 

(5) For animal data, the relationship 

of the exposure and mechanism of 

action in the animal species to the 

anticipated exposure and mechanism of 

action in humans must be described. If 

this relationship is not known, that 

should be stated (proposed 

§ 201.57(c)(9)(i)(E)). 

FDA received comments about the 

information required under ‘‘Data’’ in 

the proposed rule and made some 

changes to the final rule. The following 

discussion addresses these comments, 

our responses, and the changes to the 

final rule. 

(Comment 63) References. One 

comment suggested that under ‘‘Data,’’ 

the labeling should include references 

for the cited data. The comment 

explained that including references for 

the data would allow clinicians and 

other health care workers to further 

research pregnancy issues. 

(Response) We decline this 

suggestion. FDA has determined that 

prescription drug labeling is intended to 

facilitate prescribing decisions and is 

not intended as a research tool. We also 

note that this final rule is a part of 

labeling regulations, found at § 201.57, 

which address the inclusion of 

references in prescription drug labeling 

(see § 201.57(c)(16)). 

(Comment 64) Postmarketing 

reporting of adverse reactions. One 

comment stated that if specific numbers 

of adverse event reports are included in 

drug labeling, the labeling will need to 

be constantly updated. The comment 

suggested that the Agency instead 

consider using quantitative measures of 

frequency to produce a more stable 

label. 

(Response) FDA acknowledges that 

the inclusion in labeling of actual 

numbers of postmarketing reports for 

particular adverse reactions is often not 

appropriate. We agree that the number 

of postmarketing reports of adverse 

reactions changes over time and labeling 

may become rapidly outdated. In 

addition, postmarketing reports of 

adverse reactions generally do not 

establish an incidence or prevalence of 

a particular outcome or definitively 

demonstrate an association between 

prenatal exposure to the drug in 

question and the adverse developmental 

outcome. However, FDA also recognizes 

that there may be isolated situations in 

which reporting of adverse reactions 

corroborates other human data and, in 

these situations, it may be appropriate 

to list a specific number of cases with 

the date when the reporting was 

collected. FDA will consider whether 

the labeling for a drug product should 

include specific numbers of reports of 

adverse reactions on a case-by-case basis 

based on evaluating all available data 

and principles of epidemiology and data 

interpretation. 

In the final rule, FDA replaced the 

phrase ‘‘provide an overview of the 

data’’ with ‘‘describe the data.’’ FDA 

made this change to clarify our 

intention that under the subheading 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72089 

‘‘Data,’’ the labeling must include a 

more detailed description of the data 

than might be understood from use of 

the term ‘‘overview.’’ In the final rule, 

FDA also added the requirement that 

under ‘‘Data,’’ the labeling describe the 

data that are the basis for the ‘‘Clinical 

Considerations.’’ The proposed rule 

stated that ‘‘Data’’ must describe the 

data that were the basis for the fetal risk 

summary, and did not address the data 

that were the basis for ‘‘Clinical 

Considerations.’’ FDA has determined 

that there is no principled reason to 

distinguish between the data under the 

fetal risk summary and that underlying 

‘‘Clinical Considerations.’’ Accordingly, 

the final rule requires that under the 

subheading ‘‘Data,’’ the labeling 

describe the data that are the basis for 

both the ‘‘Risk Summary’’ and ‘‘Clinical 

Considerations.’’ This subheading, 

therefore, is only required to the extent 

that there are data that are the basis for 

these two subheadings and the headings 

under them. 

FDA has also determined that the 

information in labeling would be clearer 

if human data and animal data appeared 

separately under applicable headings. In 

the final rule, FDA requires that human 

and animal data be presented separately 

under the headings ‘‘Human Data’’ and 

‘‘Animal Data.’’ 

In the final rule, FDA requires that for 

human data, the labeling must describe 

adverse developmental outcomes, 

adverse reactions, and other adverse 

effects. To the extent applicable, the 

labeling must describe the types of 

studies or reports, number of subjects 

and the duration of each study, 

exposure information, and limitations of 

the data. The final rule requires that 

both positive and negative study 

findings be included. The proposed rule 

listed various types of studies. These 

were removed from the final rule 

because we determined that it is more 

appropriate to discuss these elements in 

guidance. 

Animal data. FDA proposed that 

human and animal data must be 

presented separately, and human data 

must be presented first. 

(Comment 65) One comment 

suggested that FDA omit the 

requirement that human data must be 

presented first. The comment explained 

that the most robust data should be 

presented first regardless of whether it 

is animal or human data. 

(Response) FDA declines this 

suggestion. We have determined that to 

promote consistency and to meet 

readers’ expectations that information 

will always be found in the same place, 

a fixed order of presentation must be 

maintained. Additionally, as discussed 

in the preamble to the proposed rule, 

the importance of human data in 

labeling was stressed by physicians who 

participated in focus group testing of the 

model labeling format and also by the 

FDA advisory committee that provided 

input on the proposed format (73 FR 

30831 at 30841). FDA has determined 

that human data should always be 

presented first because human data are 

often the most relevant to prescribers, 

and animal data may not always be 

applicable to humans. 

FDA also proposed that animal doses 

must be described in terms of human 

dose equivalents and the basis for those 

calculations must be included. 

(Comment 66) Two comments 

suggested that the final rule remove the 

requirement to use ‘‘administered dose’’ 

as a comparator between animal and 

human data and to replace it with 

comparisons based on systemic 

exposure, if available. One of these 

comments explained that basing the 

comparison on systemic exposure will 

provide greater consistency within the 

labeling and will also provide a way to 

more easily make comparisons between 

drugs. 

(Response) FDA declines this 

suggestion to restrict the comparison to 

only those based on systemic exposure. 

We agree that comparisons based on 

systemic exposure could provide 

consistency within labeling and 

therefore the final rule requires that they 

must be included when data are 

available, but the data are not always 

available for such a comparison. FDA 

believes that including the human dose 

equivalent may be more meaningful 

information for health care providers, 

particularly in the absence of data to 

make comparisons based on systemic 

exposure, and as such, in the final rule, 

a comparison of the animal to human 

doses must be included using the data 

available. 

The proposed rule required that for 

animal data under the ‘‘Data’’ 

component the relationship of the 

exposure and mechanism of action in 

the animal species to the anticipated 

exposure and mechanism of action in 

humans be described. In the final rule, 

we removed this requirement because 

often this relationship is not known. 

The final rule requires that animal doses 

or exposures be described in terms of 

human dose or exposure equivalents, 

and that the basis for those calculations 

be included. 

2. 8.2 Lactation 

FDA proposed that the ‘‘Nursing 

mothers’’ subsection of prescription 

drug labeling be replaced with the 

subsection ‘‘Lactation’’ (proposed 

§§ 201.56(d)(1) and 201.57(c)(9)(ii)). 

FDA proposed that the ‘‘Lactation’’ 

subsection of prescription drug labeling 

contain the following subheadings: 

‘‘Risk Summary,’’ ‘‘Clinical 

Considerations,’’ and ‘‘Data’’ (proposed 

§ 201.57(c)(9)(ii)). FDA received many 

comments about the proposed 

‘‘Lactation’’ subsection and made 

changes to the final rule based on these 

comments. The discussion that follows 

addresses these comments, our 

responses, and the changes FDA made 

to the final rule. 

a. General comments. 

i. Support for ‘‘Lactation’’ subsection 

(Comment 67) FDA received many 

comments expressing support for the 

proposed ‘‘Lactation’’ subsection. One 

of these comments explained that it is 

essential for drug labeling ‘‘to carry ’best 

science’ information that enables 

clinicians to efficiently and thoroughly 

review what is known about the drug 

and any reported health effects to the 

breast-fed infant.’’ The comment stated 

that the proposed rule would facilitate 

more efficient consideration of the data. 

(Response) We agree with these 

comments, and our final rule requires 

labeling to include a subsection on 

lactation with risk and benefit 

information related to breastfeeding and 

the breast-fed infant. 

ii. Drug alternatives 

(Comment 68) One comment 

suggested that a statement should be 

included that many drugs for which we 

may not have lactation data have a 

suitable alternative for which we do 

have data. 

(Response) We decline to adopt this 

comment. We do not believe it would be 

appropriate to include this type of 

statement in labeling. Because the 

comparative risks and benefits will vary 

among individual patients, a health care 

provider, in consultation with his or her 

patient, is in the best position to 

determine whether there is a ‘‘suitable 

alternative’’ for a particular drug. 

iii. Validating data 

(Comment 69) One comment 

expressed concern about the potential 

for bias or omissions with respect to 

which data the sponsor includes and the 

risk statements the sponsor uses to 

characterize such data. The comment 

encouraged FDA to employ all 

reasonable means to validate the 

sponsor’s collection, evaluation, and 

subsequent conclusions regarding 

lactation data. 

(Response) FDA agrees. FDA will 

review data available in literature and 

sponsor-submitted data used for 

developing the ‘‘Lactation’’ subsection 

of drug labeling. We note that this does 

not require a change to the final rule 

mstockstill on DSK4VPTVN1PROD with RULES2

72090 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

because FDA’s normal review process 

for prescription drug labeling includes 

validating the applicant’s collection, 

evaluation, and subsequent conclusions 

regarding data. 

b. Risk summary 

i. ‘‘Active metabolites’’ 

(Comment 70) Two comments 

suggested that FDA revise the ‘‘Risk 

Summary’’ so that it explicitly refers to 

active metabolites of the drug, in 

addition to the drug itself. 

(Response) FDA agrees with this 

comment. We also have determined that 

it is appropriate to include information 

about the effects of a drug and/or its 

active metabolite(s) not only in the 

‘‘Risk Summary,’’ but under other 

subheadings in the ‘‘Lactation’’ 

subsection of labeling. Therefore, the 

final rule has been revised to refer 

explicitly to drugs and/or their active 

metabolites. 

ii. ‘‘Compatible with breastfeeding’’ 

FDA proposed that under the 

subheading ‘‘Risk Summary,’’ if, as 

described under § 201.57(c)(9)(ii)(A)(1) 

through (c)(9)(ii)(A)(3) of the section, 

the data demonstrate that the drug does 

not affect the quantity and/or quality of 

human milk and there is reasonable 

certainty either that the drug is not 

detectable in human milk or that the 

amount of drug consumed via breast 

milk will not adversely affect the breastfed child, the labeling must state: The 

use of (name of drug) is compatible with 

breastfeeding. After this statement (if 

applicable), the risk summary must 

summarize the drug’s effect on milk 

production, what is known about the 

presence of the drug in human milk, 

and the effects on the breast-fed child 

(proposed § 201.57(c)(9)(ii)(A)). 

(Comment 71) Two comments 

suggested that FDA eliminate the 

statement, ‘‘The use of (name of drug) 

is compatible with breastfeeding’’ from 

the ‘‘Lactation’’ subsection of the final 

rule. One of the comments explained 

that it will be difficult to determine 

whether a drug is compatible with 

breastfeeding with such definitive 

certainty, especially since the term 

‘‘compatible’’ implies safety. Another 

comment suggested that in the final rule 

FDA should replace the statement 

‘‘compatible with breastfeeding’’ with a 

standardized statement that ‘‘sufficient’’ 

human data exist to indicate that the 

drug does or does not adversely affect 

the breast-fed child, followed by a 

supportive narrative. 

(Response) FDA agrees that the term 

‘‘compatible’’ is not clearly defined and 

implies that the use of a drug during 

lactation is ‘‘safe.’’ No drug is 

completely safe even in a person who is 

not pregnant or breastfeeding. In 

addition to offering potential 

therapeutic benefit(s), all drugs have 

potential side effects and risks involved 

with their use. The balance between 

those benefits and risks is taken into 

account not just at the approval stage, 

but also helps direct diagnostic and 

treatment recommendations for a 

particular patient in a particular clinical 

scenario. Accordingly, in the final rule 

FDA removed the statement ‘‘The use of 

(name of drug) is compatible with 

breastfeeding.’’ 

Breastfeeding offers significant health 

benefits to both the child and mother. 

Different drugs and/or their active 

metabolites pass into breast milk in 

different concentrations; they may or 

may not be orally bioavailable in the 

infant, and they may or may not result 

in significant adverse reactions in the 

short term or adverse outcomes in the 

long term. Often, all of the potential 

risks related to drug treatment during 

lactation are not known even though the 

benefits of breastfeeding are known and 

substantial. 

FDA declines the suggestion to 

include a standardized statement that 

‘‘sufficient’’ human data exist to 

indicate that the drug does or does not 

adversely affect the breast-fed child, 

followed by a supportive narrative. 

However, the final rule requires that if 

the drug is absorbed systemically, the 

labeling must include, under ‘‘Risk 

Summary,’’ available information, if 

relevant, on the known or predicted 

effects on the breast-fed child from 

exposure to the drug and/or its active 

metabolite(s), including systemic and/or 

local adverse reactions. If the available 

information is sufficient to determine 

that use of the drug is contraindicated 

during breastfeeding, this significant 

information is required at the beginning 

of the ‘‘Risk Summary.’’ The ‘‘Risk 

Summary’’ must state when there are no 

data to assess the effects of the drug on 

the child. 

FDA also revised the final rule to 

require that if studies demonstrate the 

presence of the drug and/or its active 

metabolite(s) in human milk but the 

drug and/or its active metabolite(s) are 

not expected to be systemically 

bioavailable to the breast-fed child, then 

the ‘‘Risk Summary’’ must describe the 

disposition of the drug and/or its active 

metabolite(s). FDA added this 

requirement to the final rule to identify 

situations in which a drug and/or its 

active metabolite(s) are present in 

human milk but the breast-fed child 

does not have any systemic exposure 

because of degradation in the 

gastrointestinal tract. 

iii. Not systemically absorbed 

FDA proposed that if data 

demonstrate that a drug is not 

systemically absorbed, the fetal risk 

summary must contain only the 

following statement: (Name of drug) is 

not absorbed systemically from (part of 

body) and cannot be detected in the 

mother’s blood. Therefore, detectable 

amounts of (name of drug) will not be 

present in milk. Breastfeeding is not 

expected to result in fetal exposure to 

the drug (proposed § 201.57(c)(9)(ii)(A)). 

(Comment 72) One comment 

suggested that the statement be revised 

to focus on the route of administration 

rather than on the part of the body 

where the drug is administered. The 

comment also suggested that the 

language ‘‘cannot be detected in blood’’ 

could be omitted because it is 

redundant with ‘‘not systemically 

absorbed.’’ 

(Response) FDA agrees with this 

comment and we removed the phrase 

‘‘cannot be detected in blood’’ from the 

final rule. 

We also agree with the suggestion to 

focus on the route of administration. 

FDA agrees that ‘‘part of the body’’ 

could be misconstrued and we have 

determined that the use of ‘‘route of 

administration’’ to describe how the 

drug enters the body is more consistent 

with labeling language that addresses 

dosing and administration. In the final 

rule, FDA has replaced ‘‘part of the 

body’’ with ‘‘route of administration.’’ 

(Comment 73) Another comment 

suggested revising the language 

‘‘systemically absorbed’’ to ‘‘has a 

systemic effect’’ to include the action of 

biological products (vaccines) that are 

immune stimulants rather than 

chemicals that are absorbed. 

(Response) FDA declines the 

suggestion to change the language 

‘‘systemically absorbed’’ to ‘‘has a 

systemic effect.’’ The terms 

‘‘systemically absorbed’’ and ‘‘absorbed 

systemically’’ refer to the absorption of 

the drug or biological product from its 

site of administration into serum and/or 

other body tissues where the drug or 

biological product, including a vaccine, 

can reach its receptor or target cell and 

exert its pharmacological or 

immunological effect. A drug or 

biological product that is not 

systemically absorbed will not be 

excreted into human milk and, 

therefore, breastfeeding should not 

result in the child’s exposure to the 

drug. In the final rule, FDA has deleted 

the sentence, ‘‘Therefore, detectable 

amounts of (name of drug) will not be 

present in breast milk.’’ The final rule 

also replaces the sentence, 

‘‘Breastfeeding is not expected to result 

in fetal exposure to the drug’’ with 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72091 

‘‘breastfeeding is not expected to result 

in exposure of the child to (name of 

drug).’’ 

(Comment 74) Two comments noted 

that the term ‘‘fetal’’ was used 

improperly in this section of the 

proposed rule. 

(Response) FDA agrees and has 

removed the term ‘‘fetal’’ from the 

‘‘Lactation’’ subsection and replaced it 

with the term ‘‘child.’’ 

iv. Presence of drug in human milk 

FDA proposed that under the heading 

‘‘Presence of drug in human milk’’: 

(1) The risk summary must describe 

the presence of the drug in human milk 

in one of the following ways: The drug 

is not detectable in human milk; the 

drug has been detected in human milk; 

the drug is predicted to be present in 

human milk; the drug is not predicted 

to be present in human milk; or the data 

are insufficient to know or predict 

whether the drug is present in human 

milk; 

(2) If studies demonstrate that the 

drug is not detectable in human milk, 

the risk summary must state the limits 

of the assay used; and 

(3) If the drug has been detected in 

human milk, the risk summary must 

give the concentration detected in milk 

in reference to a stated maternal dose 

(or, if the drug has been labeled for 

pediatric use, in reference to the labeled 

pediatric dose), an estimate of the 

amount of the drug consumed daily by 

the infant based on an average daily 

milk consumption of 150 milliliters per 

kilogram of infant weight per day, and 

an estimate of the [percentage] of the 

maternal dose excreted in human milk 

(proposed § 201.57(c)(9)(ii)(A)(2)(i)– 

(c)(9)(ii)(A)(2)(iii)). We received 

comments about this portion of the 

‘‘Lactation’’ subsection of the proposed 

rule. The discussion that follows 

addresses these comments, our 

responses, and the changes FDA made 

to this portion of the ‘‘Lactation’’ 

subsection of the final rule. 

(Comment 75) Predicting whether 

drug is present in human milk. Several 

comments objected to the proposal that 

the ‘‘Risk Summary’’ state that the drug 

is ‘‘predicted’’ or ‘‘not predicted’’ to be 

present in human milk. One of these 

comments stated that avoiding 

predictions and relying instead on 

clinical data would better assist 

providers. Two comments suggested 

that the statements about whether the 

drug is predicted or not predicted to be 

present in human milk should be 

omitted because the other proposed 

descriptions effectively cover the range 

of potential options. 

(Response) FDA agrees that the terms 

‘‘predicted’’ and ‘‘not predicted’’ should 

not be used in the ‘‘Risk Summary,’’ and 

that a description of available data, if 

relevant, on the presence of the drug 

and/or its active metabolite(s) in human 

milk should be used instead. In 

addition, FDA has determined that, in 

order to provide clarity in the ‘‘Risk 

Summary,’’ in situations where there are 

no data to assess whether the drug and/ 

or its active metabolite(s) are present in 

human milk, the ‘‘Risk Summary’’ must 

so state. 

(Comment 76) Limits of the assay 

used. Two comments suggested omitting 

assay information if the presence of 

drug in milk is not detectable. The 

comments stated that assay information 

is overly technical and unfamiliar for 

many health care providers. In addition, 

the comments explained that it would 

be presumed that during its review of 

the data, the review division at FDA 

would consider the validity of studies, 

including the assay’s reliability and 

sensitivity, before approving the 

inclusion in labeling of a statement that 

the drug is not detectable in human 

milk. 

(Response) FDA declines this 

comment. We have determined that the 

limit of the assay is critical to 

understanding the amount of the drug 

and/or its active metabolite(s) that may 

or may not be present in human milk. 

We also believe that most health care 

providers are capable of interpreting 

this data when presented in labeling 

and that health care providers are 

familiar with the importance of assay 

limits for all types of laboratory testing. 

In the final rule, FDA has retained the 

requirement from the proposed rule that 

if studies demonstrate that the drug 

and/or its active metabolite(s) are not 

detectable in human milk, the ‘‘Risk 

Summary’’ must state the limits of the 

assay used. 

(Comment 77) Concentration of the 

drug detected in human milk. Two 

comments expressed support for FDA’s 

proposal that the ‘‘Lactation’’ subsection 

of prescription drug labeling provide the 

concentration of the drug detected in 

human milk in reference to a stated 

adult or labeled pediatric dose. One of 

these comments suggested that the 

labeling should also include the 

milligrams per kilogram received per 

day and the percentage of the weightequivalent therapeutic dose 

administered to the mother. This 

comment requested that the doses be 

presented according to infant age ranges 

when possible. A separate comment 

suggested providing a calculation of the 

estimated infant daily dose consumed as 

compared to available pediatric dosing 

rather than to maternal dosing, but 

added that clinicians may have 

difficulty interpreting the calculations. 

One comment stated that the 

concentration of the drug detected in 

milk should not be made in reference to 

the maternal dose or the labeled 

pediatric dose. The comment explained 

that the concentration of a drug in milk 

may vary widely depending upon 

whether it reflects steady-state or a 

single dose, and could vary based on the 

timing between the ingestion of the drug 

and taking the sample. The comment 

suggested that an estimate of the amount 

of the drug consumed daily by the 

infant could be made in reference to the 

maximum maternal daily dose or the 

maximum labeled pediatric dose and 

that ‘‘an estimate of the [percentage] of 

the maternal dose excreted in human 

milk’’ could be omitted. 

One comment suggested that FDA 

standardize the approach to presenting 

drug concentrations in breast milk and 

stated that this would ensure that 

uniform data are presented by all 

manufacturers, allowing for easy 

comparisons between prescription 

products. The comment also suggested 

that FDA provide a guidance document 

highlighting the value of breast milk 

area under the curve (AUC) 

concentrations, explaining that 

providing standardized ways of 

calculating weight-normalized drug 

doses and average breast milk 

consumption could better guide 

manufacturers and help create a unified 

approach to describing drug 

concentrations in breast milk. 

(Response) FDA addresses these 

issues in the draft guidance for industry 

on ‘‘Clinical Lactation Studies—Study 

Design, Data Analysis, and 

Recommendations for Labeling’’ 

(February 2005) (the draft guidance on 

clinical lactation studies). 

FDA agrees that it would be helpful 

to clinicians to provide infant drug 

exposure dosing in milligrams per 

kilograms received per day so that a 

clinician may compare it to a labeled 

infant or pediatric dose if available. 

However, because of the technical 

considerations for calculating drug and/ 

or active metabolite levels in milk, FDA 

is not requiring this in the final rule. 

FDA has determined that the actual or 

calculated infant daily dose must be 

compared to the labeled infant or 

pediatric dose, when available, and to 

the maternal dose when pediatric 

dosing is not available. When infant or 

pediatric dosing is available for a drug 

and pediatric pharmacokinetic data are 

available for a drug and/or its active 

metabolite(s), these data provide an 

effective way to estimate comparative 

exposure (and potentially comparative 

mstockstill on DSK4VPTVN1PROD with RULES2

72092 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

safety) of a breast-fed child versus a 

child receiving a drug therapeutically. 

Although not required by the final 

rule, FDA agrees that data presented 

according to infant age groups could be 

useful given the changes in infant 

hepatic and renal function during the 

first few months of life, and infants’ 

increasing ability with age to metabolize 

and clear drugs and/or their active 

metabolites. These data may not always 

be available, but when they are, their 

presentation stratified by age would be 

clinically relevant and should be 

included in labeling. 

(Comment 78) ‘‘No data.’’ One 

comment suggested removing the phrase 

‘‘no data’’ from the ‘‘Risk Summary’’ in 

the ‘‘Lactation’’ subsection, because 

there are rarely no data for a drug. 

(Response) FDA disagrees with the 

suggestion to remove the phrase ‘‘no 

data’’ from the ‘‘Risk Summary.’’ Often, 

there are no lactation data (either 

human or animal) at the time of 

approval of NDAs and BLAs. 

v. Effects on milk production and 

quality 

FDA proposed that if the drug is 

absorbed systemically, the risk summary 

must describe the effect of the drug on 

the quality and quantity of milk, 

including milk composition, and the 

implications of these changes to the 

milk on the breast-fed child (proposed 

§ 201.57(c)(9)(ii)(A)(1)). 

(Comment 79) Several comments 

stated that it is seldom feasible to 

adequately study the effects of a drug on 

the quality and quantity of breast milk, 

and this information should only be 

provided when available. One comment 

explained that to be scientifically valid, 

such evaluation requires a study before, 

during, and after drug exposure. This 

comment explained that further 

complicating factors are substantial 

inter- and intra-individual variation and 

small study sample size. 

One comment requested that FDA 

include information about the effects of 

the drug on the woman’s milk supply 

and other issues that affect the process 

of breastfeeding. The comment stated 

that many women are advised against 

taking medications that affect milk 

supply while lactating but are not 

informed that this is the reason they 

should avoid these medications. 

(Response) Although FDA agrees that 

it is not always possible to determine 

the effects of a drug and/or its active 

metabolite(s) on milk production, we 

have determined that when the relevant 

data are available, this information must 

be included in the labeling. In the final 

rule, FDA requires that the ‘‘Risk 

Summary’’ describe the effects of the 

drug and/or its active metabolite(s) on 

milk production, and if there are no data 

to assess the effects of the drug and/or 

its active metabolite(s) on milk 

production, the ‘‘Risk Summary’’ must 

so state. 

With respect to milk quality and 

composition, there are currently no 

established standards or documented 

population variability for milk content. 

It is also not known how much change 

in various milk components would 

reduce the known benefits of 

breastfeeding relative to the risks of 

exposure to a drug and/or its active 

metabolite(s) through breast milk 

combined with any potential effects on 

milk composition and quality. 

Accordingly, in the final rule, FDA has 

removed the requirement that the ‘‘Risk 

Summary’’ describe the effect of the 

drug on the quality and composition of 

milk, and the implications of these 

changes to the milk on the breast-fed 

child. 

vi. Sufficient Data 

(Comment 80) One comment noted 

that the proposed rule does not require 

sufficient data to reach conclusions in 

the ‘‘Risk Summary’’ in the ‘‘Lactation’’ 

subsection, and suggested that FDA 

discuss what constitutes sufficient data, 

as it does in the ‘‘Pregnancy’’ 

subsection. 

(Response) As discussed previously, 

many comments disagreed with FDA’s 

proposed use of the term ‘‘sufficient’’ in 

the ‘‘Pregnancy’’ subsection of labeling. 

The comments stated that the term was 

not clearly defined in the proposed rule, 

and suggested that it would be difficult 

to apply the term consistently across 

drug labeling. Based on FDA’s 

consideration of these comments, the 

final rule does not refer to ‘‘sufficient’’ 

data in either the ‘‘Pregnancy’’ or the 

‘‘Lactation’’ subsection. 

vii. Risk and Benefit Statement 

(Comment 81) FDA received seven 

comments noting that the proposed 

‘‘Lactation’’ subsection did not require 

the inclusion in labeling of any 

information about the benefits of 

breastfeeding. Some of these comments 

recommended that FDA add such a 

statement to the final rule to prevent 

patients from unnecessarily foregoing or 

discontinuing breastfeeding. 

(Response) FDA acknowledges that 

the proposed rule did not require the 

inclusion of information about the 

benefits of breastfeeding. The Agency 

has determined that the inclusion in the 

‘‘Lactation’’ subsection of labeling of a 

risk and benefit statement will provide 

a useful framework for health care 

providers to use when making 

prescribing decisions for lactating 

patients. In the final rule, FDA requires 

that for drugs absorbed systemically, 

unless breastfeeding is contraindicated 

during drug therapy, a statement that 

the developmental and health benefits 

of breastfeeding should be considered 

along with the mother’s clinical need for 

the drug and any potential adverse 

effects on the breast-fed child from the 

drug or from the underlying maternal 

condition, must be included at the end 

of the ‘‘Risk Summary’’ in the 

‘‘Lactation’’ subsection of labeling. 

c. Clinical Considerations 

FDA proposed that under the 

subheading ‘‘Clinical Considerations,’’ 

the labeling must provide the following 

information to the extent it is available: 

(1) Information concerning ways to 

minimize the exposure of the breast-fed 

child to the drug, such as timing the 

dose relative to breastfeeding or 

pumping and discarding milk for a 

specified period; (2) information about 

potential drug effects in the breast-fed 

child that could be useful to caregivers, 

including recommendations for 

monitoring or responding to these 

effects; and (3) information about dosing 

adjustments during lactation. This 

information must also be included in 

the ‘Dosage and Administration’ and 

‘Clinical Pharmacology’ sections 

(proposed § 201.57(c)(9)(ii)(B)(1)– 

(c)(9)(ii)(B)(3)). FDA received comments 

about the proposed ‘‘Clinical 

Considerations’’ subheading. The 

discussion that follows addresses these 

comments, our responses, and FDA’s 

changes to the final rule. 

i. Other Therapies 

In the Proposed rule, FDA included 

sample labeling for several fictitious 

drugs. In the ‘‘Clinical Considerations’’ 

portion of the ‘‘Lactation’’ subsection, 

the ALPHAZINE sample stated that 

‘‘Other medical therapies are available 

for treatment of maternal hypertension.’’ 

(Comment 82) Two comments 

disagreed with the inclusion of this 

statement. The comments explained that 

the statement is confusing because 

although no comparator data are 

presented, clinicians may infer that 

other drugs in the class are safe and 

effective. 

(Response) We note that the language 

to which these comments refer was 

included in sample labeling included 

with the proposed rule, and not in the 

proposed rule itself. FDA included 

sample labeling with the proposed rule 

to serve as examples of how to apply the 

requirements of the proposed rule in 

different scenarios. We note that the 

final rule does not include sample 

labeling. FDA agrees, however, that 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72093 

statements such as, ‘‘Other medical 

therapies are available for treatment of 

maternal hypertension,’’ may be 

confusing, and should not be included 

in the ‘‘Pregnancy’’ or ‘‘Lactation’’ 

subsections of labeling. 

ii. Minimizing Exposure to the BreastFed Child 

(Comment 83) General comments. 

Four comments disagreed with the 

proposal to include information 

regarding minimizing exposure of the 

breast-fed child in the ‘‘Clinical 

Considerations’’ portion of the 

‘‘Lactation’’ subsection. These 

comments explained that inclusion of 

this information could discourage 

women from breastfeeding even when 

there is no reason for concern. One 

comment noted that this information 

should only be included when there is 

information that breastfeeding should be 

withheld during drug therapy and the 

timing of pumping and discarding of 

breast milk can be provided. 

Alternatively, the comment suggested 

stating when information regarding the 

timing of pumping and discarding 

breast milk cannot be provided. Another 

comment noted that this information 

should not be obligatory when data 

suggest that there is not sufficient 

excretion of the drug in milk to cause 

concern for the infant. The comment 

explained that including this 

information when the ‘‘Risk Summary’’ 

and ‘‘Data’’ components have already 

stated that the drug is compatible with 

breastfeeding could give the false 

impression that the drug is unsafe for 

the child and may encourage women to 

discontinue breastfeeding. One 

comment noted that in cases when the 

drug disappears from breast milk with a 

known half-life, it is possible to 

minimize infant exposure by 

recommending dosing occur at certain 

times related to feeding. 

(Response) FDA notes that 

information concerning minimizing 

exposure to the breast-fed child must be 

provided only to the extent it is 

available and relevant. In addition, the 

final rule was revised to clarify that 

information concerning minimizing 

drug exposure in the breast-fed child 

must be included only if the drug and/ 

or its active metabolite(s) are present in 

human milk in clinically relevant 

concentrations; the drug does not have 

an established safety profile in infants; 

and the drug is used either 

intermittently, in single doses, or for 

short courses of therapy. As discussed 

further in our response to Comment 84, 

the final rule also requires that, when 

applicable, the labeling describe ways to 

minimize a breast-fed child’s oral intake 

of topical drugs applied to the breast or 

nipple skin. 

(Comment 84) Topical products. In 

the proposed rule, FDA did not provide 

for inclusion of data regarding topical 

drugs that are not absorbed systemically 

by the mother but that may transfer to 

infants during breastfeeding. One 

comment requested that FDA include a 

standardized statement in the ‘‘Risk 

Summary’’ about such drug products. 

(Response) Situations in which a 

topical pharmaceutical product can 

result in infant exposure without 

systemic absorption of the product into 

maternal serum are limited to topicals 

applied to the skin of the breast, 

especially that of the nipple and areola. 

For prescription drug products, these 

topicals would most likely include 

corticosteroids and anti-infectives. FDA 

acknowledges that the proposed rule 

did not accommodate a situation in 

which a drug product does not result in 

maternal systemic exposure but could 

result in infant systemic exposure. In 

response to this comment, FDA revised 

the ‘‘Minimizing exposure’’ portion of 

‘‘Clinical Considerations’’ to 

accommodate the inclusion of 

information about such products. In the 

final rule, FDA added a requirement 

that, when applicable, the labeling must 

also describe ways to minimize a breastfed child’s oral intake of topical drugs 

applied to the breast or nipple skin. 

iii. Drug Effects in the Breast-Fed Child 

and Monitoring for Adverse Reactions 

FDA proposed that the ‘‘Clinical 

Considerations’’ portion of the 

‘‘Lactation’’ subsection of prescription 

drug labeling include information about 

potential drug effects in the breast-fed 

child that could be useful to caregivers, 

including recommendations for 

monitoring or responding to these 

effects (proposed 

§ 201.57(c)(9)(ii)(B)(2)). 

(Comment 85) FDA received one 

comment about this portion of the 

proposed ‘‘Clinical Considerations.’’ 

The comment suggested that FDA omit 

the first part of this provision— 

’’information about potential drug 

effects in the breast-fed child’’—because 

this information duplicates the 

information required to appear in the 

‘‘Risk Summary’’ under proposed 

§ 201.57(c)(9)(ii)(A)(3), ‘‘Effects of drug 

on the breast-fed child.’’ The comment 

also stated that the term 

‘‘recommendations’’ in the second part 

of this provision could interfere with 

the practice of medicine. The comment 

suggested the following language: 

‘‘Information about ways to monitor for, 

or respond to, potential drug effects in 

the breast-fed child that could be useful 

to caregivers.’’ 

(Response) FDA acknowledges that 

this portion of the proposed rule 

appeared to require information 

duplicative of information in the ‘‘Risk 

Summary.’’ We removed the language, 

‘‘information about potential drug 

effects in the breast-fed child,’’ from the 

‘‘Clinical Considerations’’ portion of the 

‘‘Lactation’’ subsection of the final rule. 

In the final rule, when relevant 

information is available about potential 

adverse effects in an infant due to 

exposure to the maternal drug and/or its 

active metabolite(s) through human 

milk, this information must be included 

in the ‘‘Risk Summary.’’ FDA also 

concluded that it was not necessary to 

characterize information about the 

potential effects of a drug and/or its 

active metabolite(s) on a breast-fed child 

as being useful to caregivers because, 

although caregivers sometimes read 

prescription drug labeling, it is not 

directed at them, and individual health 

care providers are in the best position to 

discuss with their patients information 

that may be useful for the patients to 

share with other caregivers. Therefore, 

the reference to information that may be 

useful to caregivers also has been 

removed. 

FDA acknowledges the comment 

concerning the use of the term 

‘‘recommendations’’ in the second part 

of this provision, and in the final rule 

has removed the term 

‘‘recommendations for monitoring’’ and 

replaced it with ‘‘available interventions 

for monitoring or mitigating.’’ The final 

rule requires that under ‘‘Clinical 

Considerations’’ the labeling describe 

information about available 

interventions for monitoring or 

mitigating the adverse reactions 

described in the ‘‘Risk Summary.’’ We 

note that this language is consistent 

with the language in the ‘‘Pregnancy’’ 

subsection. 

iv. Dose Adjustments 

(Comment 86) One comment stated 

that dose adjustment information 

should not be included in the 

‘‘Lactation’’ subsection. The comment 

suggested that dosing information 

generally should be restricted to the 

‘‘Dosage and Administration’’ section of 

labeling. 

(Response) FDA agrees with the 

suggestion that we omit information 

about dose adjustments from the 

‘‘Lactation’’ subsection of prescription 

drug labeling, although this decision is 

not based on a conclusion (as suggested 

in the comment) that dosing information 

generally should be restricted to the 

‘‘Dosage and Administration’’ section of 

mstockstill on DSK4VPTVN1PROD with RULES2

72094 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

labeling. FDA has determined that other 

than during the immediate postpartum 

period when a woman’s physiology is 

reverting from a pregnant to a 

nonpregnant state, a lactating woman is 

unlikely to require dose adjustments for 

drugs. The physiological changes 

associated with lactation are unlikely to 

result in pharmacokinetic changes 

significant enough to warrant maternal 

dose adjustments. Therefore, FDA has 

determined that all available and 

relevant information about dose 

adjustments during pregnancy and the 

postpartum period must be included in 

the ‘‘Pregnancy’’ subsection of labeling. 

In the final rule, FDA has removed the 

requirement that information about 

dosing adjustments during lactation be 

included in the ‘‘Lactation’’ subsection 

of labeling. 

d. Data 

FDA proposed that under the 

subheading ‘Data,’ the ‘Lactation’ 

subsection of the labeling must provide 

an overview of the data that are the 

basis for the risk summary and clinical 

considerations (proposed 

§ 201.57(c)(9)(ii)(C)). FDA received 

comments about this portion of the rule. 

One comment expressed support for 

presenting lactation data under ‘‘Data’’ 

when available. The other comments 

and changes we made in response to 

those comments are explained in this 

section of the document. 

(Comment 87) FDA received 

comments requesting that the Agency 

clarify when animal lactation data 

should be included in labeling. Several 

comments questioned the usefulness of 

animal lactation data in the absence of 

clinical data. One comment stated that 

extrapolation of animal data to humans 

may not be helpful without stating what 

is known about the correlation to 

humans. 

Several comments stated that only 

human data should be presented when 

it is available. Two comments requested 

that if, in cases where both human and 

animal data are available, FDA decides 

to retain the requirement that both kinds 

of data be presented, the ‘‘Lactation’’ 

subsection be revised to state that 

clinical data are to be presented before 

preclinical data. 

One comment requested additional 

clarification regarding the quantity and 

quality of animal data that would 

support inclusion of the data in 

labeling, and asked that FDA provide 

sample labeling for a drug for which 

only animal lactation data are available. 

Another comment suggested that the 

labeling state when there is an absence 

of available or sufficient human and/or 

animal data in the ‘‘Lactation’’ 

subsection. 

(Response) The preamble to the 

proposed rule did not include a 

discussion of animal lactation data, and 

the inclusion of animal lactation data 

was not addressed in the codified 

section of the proposed rule. In the final 

rule, under ‘‘Risk Summary,’’ FDA 

defines situations for which animal 

lactation data must and must not be 

included in the ‘‘Lactation’’ subsection. 

Animal lactation data can be helpful in 

predicting whether a drug and/or its 

active metabolite(s) will be present in 

human milk; however, because of 

species-specific differences in lactation 

physiology, animal lactation data 

typically do not reliably predict drug 

levels in human milk. FDA added a 

requirement to the final rule that when 

relevant human lactation data are 

available, animal data must not be 

included unless the animal model is 

specifically known to be predictive for 

humans. In addition, under ‘‘Risk 

Summary,’’ ‘‘Presence of drug in human 

milk,’’ FDA clarified that if only animal 

lactation data are available, the ‘‘Risk 

Summary’’ must state only whether or 

not the drug and/or its active 

metabolite(s) were detected in animal 

milk and specify the animal species. 

Although animal data do not reliably 

predict whether a drug and/or its active 

metabolite(s) will be present in human 

milk, in the absence of human data, 

FDA determined that the fact that a drug 

and/or its active metabolite(s) were or 

were not detected in animal milk may 

nevertheless be useful in informing 

prescribing decisions. 

In the final rule, FDA revised the 

‘‘Data’’ portion of the ‘‘Lactation’’ 

subsection to require that the labeling 

‘‘describe the data that are the basis for 

the Risk Summary and Clinical 

Considerations’’ and removed the 

requirement that the labeling ‘‘provide 

an overview of the data.’’ FDA made 

this change to clarify that under ‘‘Data,’’ 

the labeling must include a more 

detailed description of the data than 

might be understood from use of the 

term ‘‘overview,’’ as well as to maintain 

consistency between the ‘‘Data’’ 

portions of the ‘‘Lactation’’ and 

‘‘Pregnancy’’ subsections. Furthermore, 

this subheading is only required to the 

extent that there are data that are the 

basis for the Risk Summary and Clinical 

Considerations subheadings, and the 

headings under them. 

3. 8.3 Females and Males of 

Reproductive Potential 

In the final rule, FDA is adding a 

requirement that information regarding 

pregnancy testing, contraception, and 

infertility be relocated in labeling under 

subsection ‘‘8.3 Females and Males of 

Reproductive Potential.’’ FDA is adding 

this requirement to the final rule based 

on public comments regarding these 

issues, and based on the Agency’s 

conclusion that this information should 

be presented in labeling in a consistent 

location. Subsection ‘‘8.3 Females and 

Males of Reproductive Potential’’ 

includes three subheadings, ‘‘Pregnancy 

Testing,’’ ‘‘Contraception,’’ and 

‘‘Infertility.’’ Each subheading should 

only be included if it is applicable or if 

relevant information is available, and 

Section 8.3 should be omitted in its 

entirety if none of the subheadings are 

applicable. The comments are discussed 

in detail in our responses to Comments 

88, 89, and 90. 

Information concerning pregnancy 

testing, contraception, and infertility is 

important for informing decisions made 

by patients, in consultation with their 

health care providers, regarding the use 

of prescription drugs before or during 

pregnancy. This information is in many 

ways inherently linked to the scientific 

and medical rationale underpinning the 

Pregnancy subsection of prescription 

drug labeling. However, in the course of 

developing this final rule, and in 

particular in evaluating comments 88, 

89, and 90, FDA concluded that because 

there was no consistent placement in 

the labeling of information about 

pregnancy testing, contraception, and 

infertility, it was difficult for health care 

providers to find this important 

information. For example, clinical 

advice on infertility might be found 

with the discussion of animal data in 

the ‘‘Nonclinical Toxicology’’ section, in 

the ‘‘Adverse Reactions’’ section, or in 

the ‘‘Warnings and Precautions’’ 

section. Contraception and pregnancy 

testing recommendations for known or 

suspected teratogens might be found in 

the ‘‘Pregnancy’’ subsection or in the 

‘‘Warnings and Precautions’’ section. 

(Comment 88) FDA received one 

comment suggesting that the new 

labeling explicitly state that a woman 

taking drugs with potential or known 

adverse effects on pregnancy outcomes 

should (1) consider using reliable 

contraception if she does not intend to 

become pregnant or (2) if she does 

intend to become pregnant, seek 

consultation with her health care 

provider to discuss medical 

management of her health condition 

before becoming pregnant, if possible. 

(Response) FDA agrees that when a 

drug has a potential or known adverse 

effect on pregnancy outcomes (e.g., is a 

known or suspected human teratogen), 

information regarding recommendations 

or requirements regarding contraception 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72095 

use must be included in prescription 

drug labeling. In the final rule, FDA 

requires that when contraception is 

required or recommended before, 

during, or after drug therapy, this 

information must be included under the 

subheading ‘‘Contraception’’ in 

subsection ‘‘8.3 Females and Males of 

Reproductive Potential.’’ In addition, it 

may be appropriate to include in this 

subsection information concerning 

counseling females of reproductive 

potential about pregnancy planning. 

Furthermore, the concerns expressed 

in the comment regarding the inclusion 

of information about contraception use 

when taking a drug with potential or 

known adverse effects on pregnancy 

outcomes apply equally to information 

about pregnancy testing, particularly 

when a drug is a known or suspected 

human teratogen. Therefore, FDA has 

determined that information regarding 

recommendations or requirements 

concerning pregnancy testing before, 

during, or after drug therapy must also 

be included in prescription drug 

labeling. In the final rule, FDA requires 

that this information be included under 

the subheading ‘‘Pregnancy Testing’’ in 

subsection ‘‘8.3 Females and Males of 

Reproductive Potential.’’ 

(Comment 89) FDA received three 

comments noting that the ‘‘Pregnancy’’ 

subsection of the proposed rule only 

addresses risks to the fetus when the 

drug is administered to a pregnant 

woman, and it does not address the 

potential for manifestations of 

developmental toxicity associated with 

fetal drug exposure from transfer of drug 

through semen to the maternal and fetal 

circulations. One of the three comments 

noted that the proposed rule does not 

address the potential for manifestations 

of developmental toxicity associated 

with exposure resulting from transfer 

through the semen or the need for male 

contraception when a compound is 

determined to have a predicted risk of 

developmental toxicity and the transfer 

of semen is unknown. This comment 

suggested that statements addressing 

this issue be added when the 

information is required for the product. 

One of the comments suggested that 

FDA add a section to the final rule that 

addresses prescribing information for 

male patients with a partner of 

reproductive potential or a pregnant 

partner. Another comment suggested 

that the risk conclusion statement 

specify whether it is based on maternal 

or paternal exposure when that 

information is available. 

(Response) FDA agrees that when 

relevant information is available, this 

information should be included in 

labeling. In the final rule, FDA requires 

that information about recommended or 

required use of contraception by men be 

included under the subheading 

‘‘Contraception’’ in subsection ‘‘8.3 

Females and Males of Reproductive 

Potential.’’ 

(Comment 90) FDA received one 

comment requesting that the Agency 

clarify how and when animal data 

described in subsection 13.1 of labeling 

(‘‘Carcinogenesis, Mutagenesis, 

Impairment of Fertility’’) that raises 

concerns about mutagenesis, 

impairment of fertility, or preimplantation loss should be included in 

subsection ‘‘8.1 Pregnancy.’’ The 

comment also requested that FDA 

clarify when it would be appropriate to 

move information from subsection 13.1 

to subsection 8.1 or to cross-reference 

subsection 13.1 in subsection 8.1. 

(Response) As stated previously, FDA 

concluded that it is important to include 

information about drug-associated 

fertility effects in labeling in a 

consistent location and manner. In the 

final rule, animal data that raise 

concerns about drug-associated 

impairment of fertility and/or preimplantation loss effects must be 

included under ‘‘Infertility’’ in 

subsection ‘‘8.3. Females and Males of 

Reproductive Potential.’’ In addition, 

when there are contraception 

recommendations based on animal 

mutagenesis data, this information must 

be included in subsection 8.3 under the 

Contraception subheading. Because the 

same concerns about drug-associated 

fertility effects apply to human data, 

FDA has determined that human data 

that raise such concerns also must be 

included in the ‘‘Infertility’’ subsection. 

With respect to the question about 

cross-referencing, subsection 8.3 should 

cross-reference the applicable animal 

data included in subsection 13.1, 

consistent with FDA’s cross-referencing 

regulations (e.g., § 201.57(c)(1), 

(c)(6)(iv), and (c)(15)(ii)). The draft 

guidance on pregnancy and lactation 

labeling, which is being published 

concurrently with this final rule, 

addresses these issues. 

IV. Implementation 

FDA proposed that holders of 

applications (including an NDA, BLA, 

or efficacy supplement) approved before 

June 30, 2001, would be required to 

remove the pregnancy category from 

their labeling within 3 years after the 

effective date of this rule. These 

applications are those that are not 

subject to the requirements of the PLR. 

For drugs with applications (including 

an NDA, BLA, or efficacy supplement) 

approved on or after June 30, 2001, FDA 

proposed a phased-in implementation 

plan that would stagger the required 

dates these products would be required 

to replace the content and formatting of 

the pregnancy and lactation subsections 

of their labeling with the new content 

and formatting required by this rule. 

These applications are those that are 

subject to the requirements of the PLR. 

Table 1 contains the implementation 

plan that was included in the proposed 

rule. In table 1, ‘‘Applications’’ includes 

NDAs, BLAs, and efficacy supplements. 

TABLE 1—IMPLEMENTATION PLAN

Applications required to conform to new pregnancy/lactation 

content requirements 

Time by which labeling with new pregnancy/lactation content must be 

submitted to FDA for approval 

New or Pending Applications 

Applications submitted on or after the effective date of the pregnancy 

final rule.

Time of submission. 

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 approval, whichever is later. 

Approved Applications Subject to the Physician Labeling Rule 

Applications approved any time from June 30, 2001, up to and including June 29, 2002, and from June 30, 2005, up to and including 

June 29, 2007.

3 years after the effective date of pregnancy final rule. 

Applications approved any time from June 30, 2007, up to and including the effective date of the pregnancy final rule.4 years after the effective date of pregnancy final rule. 

mstockstill on DSK4VPTVN1PROD with RULES2

72096 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

TABLE 1—IMPLEMENTATION PLAN—Continued 

Applications required to conform to new pregnancy/lactation 

content requirements 

Time by which labeling with new pregnancy/lactation content must be 

submitted to FDA for approval 

Applications approved from June 30, 2002, up to and including June 

29, 2005.

5 years after the effective date of pregnancy final rule. 

(Comment 91) Two comments stated 

that the proposed implementation plan 

was confusing. One of these comments 

requested that FDA explain the rationale 

supporting the implementation 

schedule. Another comment stated the 

proposed phased-in approach for 

previously approved drugs may generate 

confusion. The comment explained that 

if drug labeling information and drug 

reference materials contain pregnancy 

information that is inconsistent between 

newly approved and previously 

approved drugs through a 3- to 5-year 

period, confusion may limit the 

understanding of the new labeling. 

Comments disagreed about whether 

the length of the implementation 

schedule was reasonable. One comment 

stated that the long implementation 

timeline will delay the delivery of 

complete information. Another 

comment stated that FDA should 

expedite the implementation schedule 

for licensed drugs that are necessary to 

maintain the health status of the mother 

and could harm the fetus if the mother 

is left untreated. This comment also 

suggested that the Agency should make 

supplemental information available in 

advance of the printed label. Another 

comment, however, expressed support 

for the proposal to give sponsors 3 years 

after the effective date of the rule to 

remove the pregnancy categories. 

(Response) The Agency has taken all 

of these comments into consideration, 

and has decided to maintain the 

implementation schedule that was 

published in the proposed rule. The 

implementation schedule follows the 

timetable used for implementation of 

the PLR and works to balance the 

anticipated workload for the review of 

labels. The purpose of having a 

staggered approach is to avoid 

overburdening both the Agency and 

industry. The implementation plan for 

the final rule (also referred to as the 

Pregnancy and Lactation Labeling Rule 

(PLLR)) is modeled from the 

implementation plan for the PLR and 

experience acquired from that plan. The 

PLLR implementation timeline also 

depends on the PLR implementation 

and the extent to which applications are 

subject to the PLR. 

(Comment 92) One comment 

expressed concern that under the 

proposed implementation schedule, the 

pregnancy categories will be removed 

from the labeling for some drugs before 

the new content required by the rule 

will be added to the labeling, and this 

could cause confusion among doctors 

and patients. 

(Response) We would like to clarify 

that a holder of an application that is 

not subject to the PLR, and thus, not 

subject to the new content and format 

requirements of this final rule, must 

remove the pregnancy category from its 

labeling within 3 years after the 

effective date of this rule. A holder of 

an application that is subject to the PLR 

and thus, subject to the new content and 

format requirements of this rule, is not 

required to remove the pregnancy 

category until such time that it is 

required to submit revised labeling with 

the new content and format, even if that 

occurs more than 3 years after the 

effective date of the final rule. FDA did 

not intend to suggest that application 

holders of previously approved 

applications subject to the PLR might, in 

some circumstances, be required to 

revise labeling twice as a part of 

implementation. Therefore, if a holder 

of an application is subject to the PLR, 

FDA does not anticipate that the 

pregnancy category will be removed 

from the labeling prior to submitting the 

revised labeling with the new content 

and format for that product under the 

PLLR implementation schedule. In 

conjunction with the publication of the 

final rule, the Agency is planning to 

launch an education campaign for all 

stakeholders, including health care 

providers and professional 

organizations, to ensure that they are 

well informed about the changes. 

V. Legal Authority 

A. Statutory Authority 

FDA is revising its regulations on the 

format and content of the ‘‘Pregnancy,’’ 

‘‘Labor and delivery,’’ and ‘‘Nursing 

mothers’’ subsections of the ‘‘Use in 

Specific Populations’’ section (under 

§ 201.57) and the ‘‘Precautions’’ section 

(under § 201.80) of the labeling for 

human prescription drugs (in addition 

to the list of headings and subheadings 

under § 201.56(d)(1)). 

FDA’s revisions to the content and 

format requirements for prescription 

drug labeling are authorized by the 

FD&C Act and by the PHS Act. Section 

502(a) of the FD&C Act deems a drug to 

be misbranded if its labeling is false or 

misleading ‘‘in any particular.’’ Under 

section 201(n) of the FD&C Act (21 

U.S.C. 321(n)), labeling is misleading if 

it fails to reveal facts that are material 

with respect to consequences that may 

result from the use of the drug under the 

conditions of use prescribed in the 

labeling or under customary or usual 

conditions of use. Section 502(f) of the 

FD&C Act deems a drug to be 

misbranded if its labeling lacks 

adequate directions for use and 

adequate warnings against use in those 

pathological conditions where its use 

may be dangerous to health, as well as 

adequate warnings against unsafe 

dosage or methods or duration of 

administration or application, in such 

manner and form, as are necessary for 

the protection of users. Section 502(j) of 

the FD&C Act deems a drug to be 

misbranded if it is dangerous to health 

when used in the dosage or manner, or 

with the frequency or duration, 

prescribed, recommended, or suggested 

in its labeling. 

In addition, the premarket approval 

provisions of the FD&C Act authorize 

FDA to require that prescription drug 

labeling provide the practitioner with 

adequate information to permit safe and 

effective use of the drug product. Under 

section 505 of the FD&C Act, FDA will 

approve an NDA only if the drug is 

shown to be both safe and effective for 

use under the conditions set forth in the 

drug’s labeling. Section 701(a) of the 

FD&C Act (21 U.S.C. 371(a)) authorizes 

FDA to issue regulations for the efficient 

enforcement of the FD&C Act. 

Under 21 CFR 314.125, FDA will not 

approve an NDA unless, among other 

things, there is adequate safety and 

effectiveness information for the labeled 

uses and the product labeling complies 

with the requirements of part 201. 

Under § 201.100(d) of FDA’s 

regulations, a prescription drug product 

must bear labeling that contains 

adequate information under which 

licensed practitioners can use the drug 

safely for their intended uses. This final 

rule amends the regulations specifying 

the format and content for such labeling. 

Section 351 of the PHS Act (42 U.S.C. 

262) provides legal authority for the 

Agency to regulate the labeling and 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72097 

shipment of biological products. 

Licenses for biological products are to 

be issued only upon a showing that they 

meet standards ‘‘designed to insure the 

continued safety, purity, and potency of 

such products’’ prescribed in 

regulations (section 351(d) of the PHS 

Act). The ‘‘potency’’ of a biological 

product includes its effectiveness (21 

CFR 600.3(s)). Section 351(b) of the PHS 

Act prohibits false labeling of a 

biological product. FDA’s regulations in 

part 201 apply to all prescription drug 

products, including biological products. 

B. First Amendment 

FDA’s requirements for the content 

and format of the ‘‘Pregnancy’’ and 

‘‘Lactation’’ subsections of labeling for 

prescription drug products are 

constitutionally permissible because 

they are reasonably related to the 

government’s interest in ensuring the 

safe and effective use of prescription 

drug products and because they do not 

impose unjustified or unduly 

burdensome disclosure requirements. In 

the PLR, FDA explained in greater depth 

why that rule passes muster under the 

First Amendment (see 71 FR 3922 at 

3964, January 24, 2006). That analysis is 

equally applicable to this final rule, and 

we hereby adopt that discussion by 

reference. 

VI. Environmental Impact 

The Agency has determined under 21 

CFR 25.30(h) that this action is of a type 

that does not individually or 

cumulatively have a significant effect on 

the human environment. Therefore, 

neither an environmental assessment 

nor an environmental impact statement 

is required. 

VII. Summary of Final Regulatory 

Impact Analysis 

A. Introduction 

FDA has examined the impacts of the 

final rule under Executive Order 12866, 

Executive Order 13563, the Regulatory 

Flexibility Act (5 U.S.C. 601–612), and 

the Unfunded Mandates Reform Act of 

1995 (Public Law 104–4). Executive 

Orders 12866 and 13563 direct Agencies 

to assess all costs and benefits of 

available regulatory alternatives and, 

when regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). The 

Agency believes that this final rule is 

not a significant regulatory action under 

Executive Order 12866. 

The Regulatory Flexibility Act 

requires Agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because our analysis suggests 

that some small prescription drug 

manufacturers and prescription drug 

repackagers and relabelers will incur 

costs that total more than 1 percent of 

their annual income in some years, the 

Agency finds that the final rule will 

have a significant economic impact on 

a substantial number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that Agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $141 

million, using the most current (2013) 

Implicit Price Deflator for the Gross 

Domestic Product. FDA does not expect 

this final rule to result in any 1-year 

expenditure that would meet or exceed 

this amount. 

The first regulations on the content 

and format of prescription drug labeling 

were established in 1979, including the 

requirement to assign drugs to one of 

five pregnancy categories. Over time, 

however, labeling became long, 

repetitive, and difficult to use. With the 

PLR in 2006, the Agency began to apply 

modern principles of effective 

communication to improve the quality 

of prescription drug labeling. However, 

the PLR left the content of the 

‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and 

‘‘Nursing mothers’’ subsections of the 

‘‘Use in Specific Populations’’ section 

untouched. This decision gave the 

Agency sufficient time to meet with 

experts and stakeholders to develop a 

regulatory framework that encourages 

applicants to prepare content that 

clearly communicates available 

information about prescription drug use 

during pregnancy and lactation, and in 

females and males of reproductive 

potential. With this final rule, the 

Agency specifically addresses the 

content and format of these subsections. 

B. Summary of Costs and Benefits 

The final regulatory impact analysis 

of the final rule (Ref. 2) is available at 

http://www.fda.gov/AboutFDA/ 

ReportsManualsForms/Reports/ 

EconomicAnalyses/default.htm. Table 2 

presents a summary of the annualized 

costs and benefits of the final rule over 

10 years. With a 7 percent discount rate, 

annualized costs equal about $9.5 

million; with a 3 percent discount rate, 

annualized costs equal about $9.2 

million. 

The final rule will require that 

applicants comply with new labeling 

content and format requirements for 

affected subsections for prescription 

drug and biological product labeling 

subject to the PLR under § 201.57(c)(9) 

(PLR labeling) and will require that 

applicants remove the pregnancy 

category from all prescription drug and 

biological product labeling subject to 

§ 201.80(f)(6)(i) (non-PLR labeling). The 

‘‘Pregnancy,’’ ‘‘Labor and delivery,’’ and 

‘‘Nursing mothers’’ subsections of the 

‘‘Use in Specific Populations’’ section 

will be replaced by the ‘‘Pregnancy,’’ 

‘‘Lactation,’’ and ‘‘Females and Males of 

Reproductive Potential’’ subsections. 

New information will be required to 

summarize the key information needed 

by health care providers treating females 

and males of reproductive potential. 

The information in these subsections 

will be presented in a narrative, 

following a standardized order and 

format with clear subheadings. 

The primary objectives of the final 

rule are to improve labeling by updating 

the content and format of these 

subsections of prescription drug product 

labeling, and to remove the pregnancy 

category system. The Agency concluded 

that following a standardized structure 

is essential for effective communication. 

The final rule is needed to ensure that 

these subsections contain the most upto-date information available and 

provide prescribers with clinically 

relevant data that they can use in their 

decisionmaking processes. Consistent 

with the approach taken by the PLR, the 

Agency intends to provide applicants 

with clear guidance about the required 

content and format. Concurrent with the 

publication of this final rule, FDA is 

issuing a draft guidance for industry on 

‘‘Pregnancy, Lactation, and 

Reproductive Potential: Labeling for 

Human Prescription Drug and Biological 

Products—Content and Format.’’ 

The level of effort needed to comply 

with the requirements of the final rule 

will depend on the type of labeling (PLR 

or non-PLR labeling) and the length of 

time the product has been marketed. 

Applicants and persons responsible for 

existing prescription drug and biological 

product labeling will incur one-time 

costs to revise existing labeling in years 

3, 4, and 5. Applicants submitting new 

BLAs, NDAs, and certain efficacy 

supplements will incur one-time costs 

to gather and organize new content 

required by the final rule at the time 

they prepare labeling for the application 

or supplement. In addition, we estimate 

the additional annual printing costs for 

mstockstill on DSK4VPTVN1PROD with RULES2

72098 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

longer PLR labeling that will include 

new content. 

We estimate that the total cost of the 

rule over 10 years will equal about $88.7 

million. The present value of the total 

costs will equal $78.2 million with a 3 

percent discount rate and $66.8 million 

with a 7 percent discount rate. Over 10 

years, the annualized present value will 

equal $9.2 million with a 3 percent 

discount rate and $9.5 million with a 7 

percent discount rate. 

TABLE 2—ECONOMIC DATA: COSTS AND BENEFITS ACCOUNTING STATEMENT

Category Primary 

estimate 

Low 

estimate 

High 

estimate 

Units 

Notes Year 

dollars 

Discount 

rate 

(percent) 

Period 

covered 

(years) 

Benefits: 

Annualized ............ ........................ ........................ ........................ ........................ 7 ........................ ........................

Monetized 

$millions/year .... ........................ ........................ ........................ ........................ 3 ........................ ........................

Annualized ............ ........................ ........................ ........................ ........................ 7 ........................ ........................

Quantified .............. ........................ ........................ ........................ ........................ 3 ........................ ........................

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

health care providers 

Costs: 

Annualized ............ $9.5 ........................ ........................ 2011 7 10 ........................

Monetized 

$millions/year .... 9.2 ........................ ........................ 2011 3 10 ........................

Annualized ............ ........................ ........................ ........................ ........................ 7 ........................ ........................

Quantified .............. ........................ ........................ ........................ ........................ 3 ........................ ........................

Qualitative ............. ........................ ........................ ........................ ........................ ........................ ........................ ........................

Transfers: 

Federal Annualized ........................ ........................ ........................ ........................ 7 ........................ ........................

Monetized 

$millions/year .... ........................ ........................ ........................ ........................ 3 ........................ ........................

From/To: From: To: 

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

Monetized 

$millions/year .... ........................ ........................ ........................ ........................ 3 ........................ ........................

From/To: From: To: 

Effects: 

State, Local or Tribal Government: No effect 

Small Business: The final rule will have significant impacts on some small pharmaceutical manufacturers and prescription 

drug repackagers and relabelers. 

Wages: No effect 

Growth: No effect 

VIII. Paperwork Reduction Act of 1995 

This final rule contains information 

collection requirements that are subject 

to review by the Office of Management 

and Budget (OMB) under the Paperwork 

Reduction Act of 1995 (the PRA) (44 

U.S.C. 3501–3520). The title, 

description, and respondent description 

of the information collection provisions 

are shown in the following paragraphs 

with an estimate of the total reporting 

and disclosure burdens. Included in the 

estimate is the time for reviewing 

instructions, searching existing data 

sources, gathering and maintaining the 

data needed, and completing and 

reviewing each collection of 

information. 

Title: Content and Format of Labeling 

for Human Prescription Drug and 

Biological Products; Requirements for 

Pregnancy and Lactation Labeling 

Description: The final rule amends 

FDA regulations concerning the content 

and format of the ‘‘Pregnancy,’’ ‘‘Labor 

and delivery,’’ and ‘‘Nursing mothers’’ 

subsections of the ‘‘Use in Specific 

Populations’’ section of the labeling for 

human prescription drugs. The final 

rule requires that labeling include, 

among other things, a summary of the 

risks of using a drug during pregnancy 

and lactation and a discussion of the 

data supporting that summary. The 

labeling also includes relevant 

information to help health care 

providers make prescribing decisions 

and counsel women about the use of 

drugs during pregnancy and lactation. 

The final rule eliminates the current 

pregnancy categories A, B, C, D, and X. 

In addition, the ‘‘Labor and delivery’’ 

subsection has been eliminated because 

information on labor and delivery is 

included in the ‘‘Pregnancy’’ subsection. 

The final rule also requires that the 

labeling include relevant information 

about pregnancy testing, contraception, 

and infertility for health care providers 

prescribing for females and males of 

reproductive potential. The final rule is 

intended to create a consistent format 

for providing information about the 

risks and benefits of prescription drug 

and/or biological product use during 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72099 

pregnancy and lactation and by females 

and males of reproductive potential. 

Under § 201.57(c)(9)(i) and (c)(9)(ii), 

holders of approved applications are 

required to provide new labeling 

content in a new format—that is, to 

rewrite the pregnancy and lactation 

portions of each drug’s labeling. Under 

§ 201.57(c)(9)(iii), these application 

holders are also required to include a 

new subsection 8.3, ‘‘Females and Males 

of Reproductive Potential,’’ which 

requires that when pregnancy testing or 

contraception is required or 

recommended before, during, or after 

drug therapy or when there are human 

or animal data that suggest drugassociated fertility effects, this 

subsection must contain this 

information. These application holders 

are required to submit supplements 

requiring prior approval by FDA before 

distribution of the new labeling, as 

required in § 314.70(b) or § 601.12(f)(1). 

Under § 201.80(f)(6)(i), holders of 

approved applications are required to 

remove the pregnancy category 

designation (e.g., ‘‘Pregnancy Category 

C’’) from the ‘‘Pregnancy’’ subsection of 

the ‘‘Precautions’’ section of the 

labeling. These application holders 

must report the labeling change in their 

annual reports, as required in 

§ 314.70(d) or § 601.12(f)(3). 

The new content and format 

requirements of the final rule apply to 

all applications that are required to 

comply with the PLR, including: (1) 

Applications submitted on or after the 

effective date of the final rule; (2) 

applications pending on the effective 

date of the final rule; and (3) 

applications approved from June 30, 

2001, to the effective date of the final 

rule. 

The following submissions under the 

final rule are subject to the PRA: 

• Applications submitted on or after 

the effective date of the final rule 

(§§ 314.50, 314.70(b), 601.2, 

601.12(f)(1)); 

• Amendments to applications 

pending on the effective date of the final 

rule (§§ 314.60, 601.2, 601.12(f)(1)); 

• Supplements to applications 

approved from June 30, 2001, to the 

effective date of the final rule 

(§§ 314.70(b), 601.12(f)(1)); 

• Annual reports for applications 

approved before June 30, 2001, that 

contain a pregnancy category, to report 

removal of the pregnancy category letter 

in their labeling (§§ 314.70(d), 

601.12(f)(3)). 

The information collection 

requirements and burden estimates are 

summarized in tables 3 and 4 of this 

document. The burden estimates are 

based on data and timeframes used for 

section VII of this document (Summary 

of Final Regulatory Impact Analysis) 

and for the final regulatory impact 

analysis of the final rule (available at 

http://www.fda.gov/AboutFDA/ 

ReportsManualsForms/Reports/ 

EconomicAnalyses/default.htm). FDA 

estimates that approximately 4,000 

applications containing labeling 

consistent with this rulemaking will be 

submitted to FDA during the 10-year 

period on or after the effective date of 

the final rule by approximately 390 

applicants and repackagers and 

relabelers. The estimate of 4,000 

applications includes labeling for 

approximately 800 applications 

submitted under section 505(b) of the 

FD&C Act or section 351 of the PHS Act, 

and 1,200 applications submitted under 

section 505(j) of the FD&C Act, and 

revised labeling from repackagers and 

relabelers for approximately 2,000 drug 

products. This estimate also includes 

labeling amendments submitted to FDA 

for applications pending on the effective 

date of the final rule. Based on data 

provided in section VII of this document 

and in the final regulatory impact 

analysis of the final rule, FDA estimates 

that for future approvals it will take 

applicants approximately 40 hours to 

prepare and submit labeling consistent 

with this rulemaking. The estimate of 40 

hours applies only to the requirements 

of this rulemaking and does not indicate 

the total hours required to prepare and 

submit complete labeling for these 

applications. The information collection 

burden to prepare and submit labeling 

in accordance with §§ 201.56, 201.57, 

and 201.80 is approved by OMB under 

control numbers 0910–0572 and 0910– 

0001. 

In addition, FDA estimates that 

approximately 10,150 supplements to 

applications approved from June 30, 

2001, to the effective date of the final 

rule, or pending on the effective date, 

will be submitted to FDA during the 

third, fourth, and fifth years after the 

effective date to update labeling in 

accordance with this final rule. This 

estimate includes approximately 1,080 

NDA, BLA, and efficacy supplements, 

approximately 1,320 ANDA 

supplements, and labeling supplements 

from repackagers and relabelers for 

approximately 7,750 drug products. 

FDA estimates that approximately 390 

application holders and repackagers and 

relabelers will submit these 

supplements, and that it will take 

approximately 120 hours to prepare and 

submit each supplement. 

FDA also estimates that 

approximately 5,500 annual reports will 

be submitted to FDA during the third 

year after the effective date for 

applications approved before June 30, 

2001, that contain a pregnancy category 

(5,500 includes annual reports for 

approximately 1,340 NDAs and BLAs 

and approximately 4,160 ANDAs 

containing labeling changes resulting 

from this rulemaking). FDA estimates 

that approximately 320 application 

holders will submit these annual 

reports, and that it will take 

approximately 40 hours for each 

submission. 

As indicated in tables 3 and 4 of this 

document, we estimate that the total 

hours resulting from the information 

collection in this rulemaking will be 

approximately 1,598,000 hours. The 

costs associated with this rulemaking, 

including labor costs, are discussed in 

section VII of this document and in the 

final regulatory impact analysis of the 

final rule. 

Description of Respondents: Persons 

and businesses, including small 

businesses and manufacturers. 

TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN 1

Type of submission 

(21 CFR section) 

Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total 

hours 

Supplements to applications approved 6/30/

01 to effective date (§§ 314.70(b), 

601.12(f)(1)).

390 26 10,150 (Submitted 3rd, 4th, 

and 5th years after effective date).

120 1,218,000 

Annual report submission of revised labeling 

for applications approved before 6/30/01 

that contain a pregnancy category 

(§§ 314.70(d), 601.12(f)(3)).

320 17 5,500 (Submitted 3rd year 

after effective date).

40 220,000 

mstockstill on DSK4VPTVN1PROD with RULES2

72100 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

TABLE 3—ESTIMATED ANNUAL REPORTING BURDEN 1—Continued 

Type of submission 

(21 CFR section) 

Number of 

respondents 

Number of 

responses per 

respondent 

Total annual 

responses 

Average 

burden per 

response 

Total 

hours 

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

1There are no capital costs or operating and maintenance costs associated with this information collection. 

TABLE 4—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1

Type of submission 

(21 CFR section) 

Number of 

respondents 

Number of 

disclosures 

per 

respondent 

Total annual 

disclosures 

Average 

burden per 

disclosure 

Total 

ours 

New NDAs/ANDAs/BLAs/efficacy supplements 

submitted on or after effective date, including 

amendments to applications pending on effective date (§§ 314.50, 314.60, 314.70(b), 601.2, 

601.12(f)(1)).

390 10 4,000 (Submitted during 

10-year period after 

effective date).

40 160,000 

1There are no capital costs or operating and maintenance costs associated with this information collection. 

The information collection provisions 

of this final rule have been submitted to 

OMB for review, as required by section 

3507(d) of the PRA. Prior to the effective 

date of this final rule, FDA will publish 

a notice in the Federal Register 

announcing OMB’s decision to approve, 

modify, or disapprove the information 

collection provisions in this final rule. 

An Agency may not conduct or sponsor, 

and a person is not required to respond 

to, a collection of information unless it 

displays a currently valid OMB control 

number. 

IX. Federalism 

FDA has analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that this final rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, the 

Agency has concluded that the rule does 

not contain policies that have 

federalism implications as defined in 

the Executive order and, consequently, 

a federalism summary impact statement 

is not required. 

X. References 

In addition to the references placed 

on display in the Division of Dockets 

Management for the proposed rule 

under Docket No. FDA–2006–N–0515 

(formerly Docket No. 2006N–0467), the 

following references are on display in 

the Division of Dockets Management 

under Docket No. FDA–2006–N–0515 

(formerly Docket No. 2006N–0467) and 

may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday, and are available 

electronically at http://

www.regulations.gov. (FDA has verified 

all Web site addresses in this reference 

section, but we are not responsible for 

any subsequent changes to the Web sites 

after this document publishes in the 

Federal Register.) 

1. Decision Partners, LLC, ‘‘Evaluation of 

How Best to Communicate to Healthcare 

Providers about the Risks and Benefits of 

Prescription Drug Use for Pregnant and 

Nursing Women: A Mental Models 

Research Report,’’ September 2009 

(available at http://www.fda.gov/

AboutFDA/ReportsManualsForms/

Reports/EconomicAnalyses/default.htm). 

2. Final Regulatory Impact Analysis for 

Docket No. FDA–2006–N–0515 (formerly 

Docket No. 2006N–0467) (available at 

http://www.fda.gov/AboutFDA/Reports

ManualsForms/Reports/Economic

Analyses/default.htm and at http:// 

www.regulations.gov). 

3. U.S. Food and Drug Administration, 

‘‘Guidance for Industry, Warnings and 

Precautions, Contraindications, and 

Boxed Warning Sections of Labeling for 

Human Prescription Drug and Biological 

Products—Content and Format,’’ 2011. 

4. Kweder, S.L., ‘‘Drugs and Biologics in 

Pregnancy and Breastfeeding: FDA in the 

21st Century.’’ Birth Defects Research 

Part A: Clinical and Molecular 

Teratology. 82(9):605–609, September 

2008. 

5. Adam, M.P., J.E. Polifka, and J.M. 

Friedman, ‘‘Evolving Knowledge of the 

Teratogenicity of Medications in Human 

Pregnancy.’’ American Journal of 

Medical Genetics Part C: Seminars in 

Medical Genetics. 157C(3):175–182, 

August 15, 2011. 

6. Law, R., P. Bozzo, G. Koren, et al. ‘‘FDA 

Pregnancy Risk Categories and the CPS. 

Do They Help or Are They a 

Hindrance?’’ Canadian Family 

Physician. 56:239–241, March 2010. 

7. U.S. Food and Drug Administration 

‘‘Guidance for industry, Establishing 

Pregnancy Exposure Registries,’’ 2002. 

8. U.S. Food and Drug Administration 

‘‘Guidance for Industry, Reproductive 

and Developmental Toxicities— 

Integrating Study Results to Assess 

Concerns,’’ 2011. 

9. Rynn, L., J. Cragan, and A. Correa, ‘‘Update 

on Overall Prevalence of Major Birth 

Defects—Atlanta, Georgia, 1978–2005.’’ 

Centers for Disease Control and 

Prevention Morbidity and Mortality 

Weekly Report. 57(01):1–5, January 11, 

2008. 

10. American College of Obstetricians and 

Gynecologists Frequently Asked 

Questions: Miscarriage and Molar 

Pregnancy, 2011 (available at http:// 

www.acog.org/∼/media/For%20Patients/ 

faq090.pdf?dmc=1&ts=20140130T

1655496642). 

11. U.S. Food and Drug Administration, 

‘‘Reviewer Guidance, Evaluating the 

Risks of Drug Exposure in Human 

Pregnancies,’’ 2005. 

12. U.S. Food and Drug Administration, 

‘‘Guidance for industry, Considerations 

for Developmental Toxicity Studies for 

Preventive and Therapeutic Vaccines for 

Infectious Disease Indications,’’ 2006. 

13. U.S. Food and Drug Administration, 

‘‘Guidance for industry, M3 (R2) 

Nonclinical Safety Studies for the 

Conduct of Human Clinical Trials and 

Marketing Authorization for 

Pharmaceuticals and the International 

Conference on Harmonisation S5 (R2) 

Guideline: Detection of Toxicity to 

Reproduction for Medicinal Products 

and Toxicity to Male Fertility,’’ 2010. 

14. Tracy, T.S., et al. ‘‘Temporal Changes in 

Drug Metabolism (CYP1A2, CYP2D6 and 

CYP3A Activity) During Pregnancy.’’ 

American Journal of Obstetrics and 

Gynecology. 192(2):633–639, February 

2005. 

15. Anderson, G.D., ‘‘Pregnancy-Induced 

Changes in Pharmacokinetics.’’ Clinical 

Pharmacokinetics. 44(10):989–1008, 

2005. 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72101 

16. American Academy of Pediatrics Policy 

Statement. ‘‘Breastfeeding and the Use of 

Human Milk.’’ Pediatrics. 129(3):e827– 

841, 2012. 

17. Sachs, H.C. and Committee on Drugs. 

‘‘The Transfer of Drugs and Therapeutics 

Into Human Breast Milk: An Update on 

Selected Topics.’’ Pediatrics. 

132(3):e796–809, September 2013. 

18. U.S. Food and Drug Administration, 

‘‘Draft Guidance for industry Clinical 

Lactation Studies—Study Design, Data 

Analysis, and Recommendations for 

Labeling,’’ 2005. 

19. Proposed Pregnancy and Lactation 

Labeling Rule (available at http:// 

www.fda.gov/Drugs/Development

ApprovalProcess/Development

Resources/Labeling/ucm093307.htm). 

20. Public Comments on Proposed Pregnancy 

and Lactation Labeling Rule (available at 

http://www.regulations.gov/#!docket

Detail;D=FDA-2006-N-0515). 

List of Subjects in 21 CFR Part 201 

Drugs, Labeling, Reporting and 

recordkeeping requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, 21 CFR part 201 is 

amended as follows: 

PART 201—LABELING 

■ 1. The authority citation for 21 CFR 

part 201 continues to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 358, 360, 360b, 360gg–360ss, 371, 

374, 379e; 42 U.S.C. 216, 241, 262, 264. 

§ 201.56 [Amended] 

■ 2. Amend § 201.56 in paragraph (d)(1) 

by removing from the list of headings 

and subheadings the subheadings ‘‘8.2 

Labor and delivery’’ and ‘‘8.3 Nursing 

mothers’’ and adding in their places the 

subheadings ‘‘8.2 Lactation’’ and ‘‘8.3 

Females and Males of Reproductive 

Potential’’, respectively. 

■ 3. Amend § 201.57 by revising 

paragraphs (c)(9)(i), (ii), and (iii) to read 

as follows: 

§ 201.57 Specific requirements on content 

and format of labeling for human 

prescription drug and biological products 

described in § 201.56(b)(1). 

* * * * * 

(c) * * * 

(9) * * * 

(i) 8.1 Pregnancy. This subsection of 

the labeling must contain the following 

information in the following order 

under the subheadings ‘‘Pregnancy 

Exposure Registry,’’ ‘‘Risk Summary,’’ 

‘‘Clinical Considerations,’’ and ‘‘Data’’: 

(A) Pregnancy exposure registry. If 

there is a scientifically acceptable 

pregnancy exposure registry for the 

drug, contact information needed to 

enroll in the registry or to obtain 

information about the registry must be 

provided following the statement: 

‘‘There is a pregnancy exposure registry 

that monitors pregnancy outcomes in 

women exposed to (name of drug) 

during pregnancy.’’ 

(B) Risk summary. The Risk Summary 

must contain risk statement(s) based on 

data from all relevant sources (human, 

animal, and/or pharmacologic) that 

describe, for the drug, the risk of 

adverse developmental outcomes (i.e., 

structural abnormalities, embryo-fetal 

and/or infant mortality, functional 

impairment, alterations to growth). 

When multiple data sources are 

available, the statements must be 

presented in the following order: 

Human, animal, pharmacologic. The 

source(s) of the data must be stated. The 

labeling must state the percentage range 

of live births in the United States with 

a major birth defect and the percentage 

range of pregnancies in the United 

States that end in miscarriage, 

regardless of drug exposure. If such 

information is available for the 

population(s) for which the drug is 

labeled, it must also be included. When 

use of a drug is contraindicated during 

pregnancy, this information must be 

stated first in the Risk Summary. When 

applicable, risk statements as described 

in paragraphs (c)(9)(i)(B)(1) and (2) of 

this section must include a crossreference to additional details in the 

relevant portion of the ‘‘Data’’ 

subheading in the ‘‘Pregnancy’’ 

subsection of the labeling. If data 

demonstrate that a drug is not 

systemically absorbed following a 

particular route of administration, the 

Risk Summary must contain only the 

following statement: ‘‘(Name of drug) is 

not absorbed systemically following 

(route of administration), and maternal 

use is not expected to result in fetal 

exposure to the drug.’’ 

(1) Risk statement based on human 

data. When human data are available 

that establish the presence or absence of 

any adverse developmental outcome(s) 

associated with maternal use of the 

drug, the Risk Summary must 

summarize the specific developmental 

outcome(s); their incidence; and the 

effects of dose, duration of exposure, 

and gestational timing of exposure. If 

human data indicate that there is an 

increased risk for a specific adverse 

developmental outcome in infants born 

to women exposed to the drug during 

pregnancy, this risk must be 

quantitatively compared to the risk for 

the same outcome in infants born to 

women who were not exposed to the 

drug but who have the disease or 

condition for which the drug is 

indicated to be used. When risk 

information is not available for women 

with the disease or condition for which 

the drug is indicated, the risk for the 

specific outcome must be compared to 

the rate at which the outcome occurs in 

the general population. The Risk 

Summary must state when there are no 

human data or when available human 

data do not establish the presence or 

absence of drug-associated risk. 

(2) Risk statement based on animal 

data. When animal data are available, 

the Risk Summary must summarize the 

findings in animals and based on these 

findings, describe, for the drug, the 

potential risk of any adverse 

developmental outcome(s) in humans. 

This statement must include: The 

number and type(s) of species affected, 

timing of exposure, animal doses 

expressed in terms of human dose or 

exposure equivalents, and outcomes for 

pregnant animals and offspring. When 

animal studies do not meet current 

standards for nonclinical developmental 

toxicity studies, the Risk Summary must 

so state. When there are no animal data, 

the Risk Summary must so state. 

(3) Risk statement based on 

pharmacology. When the drug has a 

well-understood mechanism of action 

that may result in adverse 

developmental outcome(s), the Risk 

Summary must explain the mechanism 

of action and the potential associated 

risks. 

(C) Clinical considerations. Under the 

subheading ‘‘Clinical Considerations,’’ 

the labeling must provide relevant 

information, to the extent it is available, 

under the headings ‘‘Disease-associated 

maternal and/or embryo/fetal risk,’’ 

‘‘Dose adjustments during pregnancy 

and the postpartum period,’’ ‘‘Maternal 

adverse reactions,’’ ‘‘Fetal/Neonatal 

adverse reactions,’’ and ‘‘Labor or 

delivery’’: 

(1) Disease-associated maternal and/ 

or embryo/fetal risk. If there is a serious 

known or potential risk to the pregnant 

woman and/or the embryo/fetus 

associated with the disease or condition 

for which the drug is indicated to be 

used, the labeling must describe the 

risk. 

(2) Dose adjustments during 

pregnancy and the postpartum period. If 

there are pharmacokinetic data that 

support dose adjustment(s) during 

pregnancy and the postpartum period, a 

summary of this information must be 

provided. 

(3) Maternal adverse reactions. If use 

of the drug is associated with a maternal 

adverse reaction that is unique to 

pregnancy or if a known adverse 

reaction occurs with increased 

frequency or severity in pregnant 

mstockstill on DSK4VPTVN1PROD with RULES2

72102 Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 

women, the labeling must describe the 

adverse reaction and available 

intervention(s) for monitoring or 

mitigating the reaction. The labeling 

must describe, if known, the effect of 

dose, timing, and duration of exposure 

on the risk to the pregnant woman of 

experiencing the adverse reaction. 

(4) Fetal/Neonatal adverse reactions. 

If it is known or anticipated that 

treatment of the pregnant woman 

increases or may increase the risk of an 

adverse reaction in the fetus or neonate, 

the labeling must describe the adverse 

reaction, the potential severity and 

reversibility of the adverse reaction, and 

available intervention(s) for monitoring 

or mitigating the reaction. The labeling 

must describe, if known, the effect of 

dose, timing, and duration of exposure 

on the risk. 

(5) Labor or delivery. If the drug is 

expected to affect labor or delivery, the 

labeling must provide information about 

the effect of the drug on the pregnant 

woman and the fetus or neonate; the 

effect of the drug on the duration of 

labor and delivery; any increased risk of 

adverse reactions, including their 

potential severity and reversibility; and 

must provide information about 

available intervention(s) that can 

mitigate these effects and/or adverse 

reactions. The information described 

under this heading is not required for 

drugs approved for use only during 

labor and delivery. 

(D) Data—(1) ‘‘Data’’ subheading. 

Under the subheading ‘‘Data,’’ the 

labeling must describe the data that are 

the basis for the Risk Summary and 

Clinical Considerations. 

(2) Human and animal data headings. 

Human and animal data must be 

presented separately, beneath the 

headings ‘‘Human Data’’ and ‘‘Animal 

Data,’’ and human data must be 

presented first. 

(3) Description of human data. For 

human data, the labeling must describe 

adverse developmental outcomes, 

adverse reactions, and other adverse 

effects. To the extent applicable, the 

labeling must describe the types of 

studies or reports, number of subjects 

and the duration of each study, 

exposure information, and limitations of 

the data. Both positive and negative 

study findings must be included. 

(4) Description of animal data. For 

animal data, the labeling must describe 

the following: Types of studies, animal 

species, dose, duration and timing of 

exposure, study findings, presence or 

absence of maternal toxicity, and 

limitations of the data. Description of 

maternal and offspring findings must 

include dose-response and severity of 

adverse developmental outcomes. 

Animal doses or exposures must be 

described in terms of human dose or 

exposure equivalents and the basis for 

those calculations must be included. 

(ii) 8.2 Lactation. This subsection of 

the labeling must contain the following 

information in the following order 

under the subheadings ‘‘Risk 

Summary,’’ ‘‘Clinical Considerations,’’ 

and ‘‘Data’’: 

(A) Risk summary. When relevant 

human and/or animal lactation data are 

available, the Risk Summary must 

include a cross-reference to the ‘‘Data’’ 

subheading in the ‘‘Lactation’’ 

subsection of the labeling. When human 

data are available, animal data must not 

be included unless the animal model is 

specifically known to be predictive for 

humans. When use of a drug is 

contraindicated during breastfeeding, 

this information must be stated first in 

the Risk Summary. 

(1) Drug not absorbed systemically. If 

data demonstrate that the drug is not 

systemically absorbed by the mother, 

the Risk Summary must contain only 

the following statement: ‘‘(Name of 

drug) is not absorbed systemically by 

the mother following (route of 

administration), and breastfeeding is not 

expected to result in exposure of the 

child to (name of drug).’’ 

(2) Drug absorbed systemically. If the 

drug is absorbed systemically, the Risk 

Summary must describe the following to 

the extent relevant information is 

available: 

(i) Presence of drug in human milk. 

The Risk Summary must state whether 

the drug and/or its active metabolite(s) 

are present in human milk. If there are 

no data to assess this, the Risk Summary 

must so state. If studies demonstrate 

that the drug and/or its active 

metabolite(s) are not detectable in 

human milk, the Risk Summary must 

state the limits of the assay used. If 

studies demonstrate the presence of the 

drug and/or its active metabolite(s) in 

human milk, the Risk Summary must 

state the concentration of the drug and/ 

or its active metabolite(s) in human milk 

and the actual or estimated daily dose 

for an infant fed exclusively with 

human milk. The actual or estimated 

amount of the drug and/or its active 

metabolite(s) ingested by the infant 

must be compared to the labeled infant 

or pediatric dose, if available, or to the 

maternal dose. If studies demonstrate 

the presence of the drug and/or its 

active metabolite(s) in human milk but 

the drug and/or its active metabolite(s) 

are not expected to be systemically 

bioavailable to the breast-fed child, the 

Risk Summary must describe the 

disposition of the drug and/or its active 

metabolite(s). If only animal lactation 

data are available, the Risk Summary 

must state only whether or not the drug 

and/or its active metabolite(s) were 

detected in animal milk and specify the 

animal species. 

(ii) Effects of drug on the breast-fed 

child. The Risk Summary must include 

information, on the known or predicted 

effects on the child from exposure to the 

drug and/or its active metabolite(s) 

through human milk or from contact 

with breast or nipple skin (for topical 

products). The Risk Summary also must 

include information on systemic and/or 

local adverse reactions. If there are no 

data to assess the effects of the drug 

and/or its active metabolite(s) on the 

breast-fed child, the Risk Summary 

must so state. 

(iii) Effects of drug on milk 

production. The Risk Summary must 

describe the effects of the drug and/or 

its active metabolite(s) on milk 

production. If there are no data to assess 

the effects of the drug and/or its active 

metabolite(s) on milk production, the 

Risk Summary must so state. 

(3) Risk and benefit statement. For 

drugs absorbed systemically, unless 

breastfeeding is contraindicated during 

drug therapy, the following risk and 

benefit statement must appear at the end 

of the Risk Summary: ‘‘The 

developmental and health benefits of 

breastfeeding should be considered 

along with the mother’s clinical need for 

(name of drug) and any potential 

adverse effects on the breast-fed child 

from (name of drug) or from the 

underlying maternal condition.’’ 

(B) Clinical considerations. Under 

‘‘Clinical Considerations,’’ the following 

information must be provided to the 

extent it is available and relevant: 

(1) Minimizing exposure. The labeling 

must describe ways to minimize 

exposure in the breast-fed child if: The 

drug and/or its active metabolite(s) are 

present in human milk in clinically 

relevant concentrations; the drug does 

not have an established safety profile in 

infants; and the drug is used either 

intermittently, in single doses, or for 

short courses of therapy. When 

applicable, the labeling must also 

describe ways to minimize a breast-fed 

child’s oral intake of topical drugs 

applied to the breast or nipple skin. 

(2) Monitoring for adverse reactions. 

The labeling must describe available 

intervention(s) for monitoring or 

mitigating the adverse reaction(s) 

presented in the Risk Summary. 

(C) Data. Under the subheading 

‘‘Data,’’ the labeling must describe the 

data that are the basis for the Risk 

Summary and Clinical Considerations. 

(iii) 8.3 Females and males of 

reproductive potential. When pregnancy 

mstockstill on DSK4VPTVN1PROD with RULES2

Federal Register / Vol. 79, No. 233 / Thursday, December 4, 2014 / Rules and Regulations 72103 

testing and/or contraception are 

required or recommended before, 

during, or after drug therapy and/or 

when there are human and/or animal 

data that suggest drug-associated 

fertility effects, this subsection of 

labeling must contain this information 

under the subheadings ‘‘Pregnancy 

Testing,’’ ‘‘Contraception,’’ and 

‘‘Infertility,’’ in that order. 

* * * * * 

§ 201.80 [Amended] 

■ 4. Amend § 201.80 as follows: 

■ a. Remove the paragraph heading 

‘‘Pregnancy category A.’’ and the words 

‘‘Pregnancy Category A.’’ from 

paragraph (f)(6)(i)(a); 

■ b. Remove the paragraph heading 

‘‘Pregnancy category B.’’ and the words 

‘‘Pregnancy Category B.’’ both times 

they appear from paragraph (f)(6)(i)(b); 

■ c. Remove the paragraph heading 

‘‘Pregnancy category C.’’ and the words 

‘‘Pregnancy Category C.’’ both times 

they appear from paragraph (f)(6)(i)(c); 

■ d. Remove the paragraph heading 

‘‘Pregnancy category D.’’ and the words 

‘‘Pregnancy Category D.’’ from 

paragraph (f)(6)(i)(d); and 

■ e. Remove the paragraph heading 

‘‘Pregnancy category X.’’ and the words 

‘‘Pregnancy Category X.’’ from 

paragraph (f)(6)(i)(e). 

Dated: November 25, 2014. 

Leslie Kux, 

Associate Commissioner for Policy. 

[FR Doc. 2014–28241 Filed 12–3–14; 8:45 am] 

BILLING CODE 4164–01–P 

mstockstill on DSK4VPTVN1PROD with RULES2