Document ID: FDA-2006-N-0515-0001
Agency: fda
Document Type: Notice
Title: Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling
Posted Date: 2008-05-29T04:00Z

[Federal Register: May 29, 2008 (Volume 73, Number 104)]
[Proposed Rules]               
[Page 30831-30868]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29my08-33]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

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

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

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is proposing to amend 
its regulations concerning the format and content 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 agency is proposing to 
require that labeling include a summary of the risks of using a drug 
during pregnancy and lactation and a discussion of the data supporting 
that summary. The labeling would also include relevant clinical 
information to help health care providers make prescribing decisions 
and counsel women about the use of drugs during pregnancy and/or 
lactation. The proposal would eliminate the current pregnancy 
categories A, B, C, D, and X. The ``Labor and delivery'' subsection 
would be eliminated because information on labor and delivery is 
included in the proposed ``Pregnancy'' subsection. The proposed rule is 
intended to create a consistent format for providing information about 
the effects of a drug on pregnancy and lactation that will be useful 
for decisionmaking by women of childbearing age and their health care 
providers.

DATES:  Submit written or electronic comments on the proposed rule by 
August 27, 2008. Submit comments on information collection issues under 
the Paperwork Reduction Act of 1995 by June 30, 2008, (see the 
``Paperwork Reduction Act of 1995'' section of this document).

ADDRESSES:  You may submit comments, identified by Docket No. FDA-2006-
N-0515 and/or RIN number 0910-AF11, by any of the following methods, 
except that comments on information collection issues under the 
Paperwork Reduction Act of 1995 must be submitted to the Office of 
Regulatory Affairs, Office of Management and Budget (OMB) (see the 
``Paperwork Reduction Act of 1995'' section of this document).
Electronic Submissions
Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal, as described previously, in the ADDRESSES portion 
of this document under Electronic Submissions.
    Instructions: All submissions received must include the agency name 
and Docket No(s). and Regulatory Information Number (RIN) (if a RIN 
number has been assigned) for this rulemaking. All comments received 
may be posted without change to http://www.regulations.gov, including 
any personal information provided. For additional information on 
submitting comments, see the ``Comments'' heading of the SUPPLEMENTARY 
INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts, and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT:

     Christine F. Rogers, Center for Drug Evaluation and Research (HFD-
7), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, 301-594-2041, or
     Stephen Ripley, Center for Biologics Evaluation and Research (HFM-
17), Food and Drug Administration, 1401 Rockville Pike, suite 200N 
Rockville, MD 20856, 301-827-6210.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Current Pregnancy, Labor and Delivery, and Lactation Labeling

[[Page 30832]]

II. FDA's Examination of Pregnancy Labeling
    A. Part 15 Hearing on the Pregnancy Labeling Categories
    B. Development of a Model Pregnancy Labeling Format
    C. Focus Group Testing of Model Pregnancy Labeling Format
    D. Advisory Committee Assessment of Pregnancy Labeling Concepts
    E. Focus Group Testing of Pregnancy Risk Statements
III. FDA's Examination of Labeling on Lactation
    A. Recommendations on Lactation Labeling From Part 15 Hearing
    B. Advisory Committee on Lactation Labeling Issues
    C. The Need for Informative Lactation Labeling
IV. Description of the Proposed Rule
    A. General Description of the Format and Content of the Pregnancy 
and Lactation Subsections of Labeling
    B. Pregnancy Subsection
    C. Lactation Subsection
    D. Removing the Pregnancy Designation
V. Implementation Plan for the Proposed Rule
    A. General
    B. New Content (Proposed Sec.  201.57(c)(9)(i) and (c)(9)(ii))
    C. Removing the Pregnancy Category (Proposed Sec.  201.80(f)(6))
VI. Legal Authority
VII. Environmental Impact
VIII. Analysis of Impacts
    A. Need for the Proposed Rule
    B. Scope of the Proposed Rule
    C. Costs of the Proposed Rule
    D. Benefits of the Proposed Rule
    E. Impacts on Small Entities
    F. Alternatives Considered
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Request for Comments
XII. References
Appendix

I. Current Pregnancy, Labor and Delivery, and Lactation Labeling

    Under the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
352 and 355), FDA has responsibility for ensuring that prescription 
drug and biological products (both referred to as ``drugs'' in this 
proposed rule) are accompanied by labeling (including prescribing 
information) that summarizes scientific information concerning their 
safe and effective use. FDA regulations on labeling for use during 
pregnancy, during labor and delivery, and by nursing mothers were 
originally issued in 1979 as part of a rule prescribing the content and 
format for labeling for human prescription drugs (21 CFR part 201) (44 
FR 37434, June 26, 1979).\1\ The requirements on content and format of 
labeling for human prescription drug and biological products were 
revised on January 24, 2006 (71 FR 3922).\2\ As part of the 2006 
revision, the subsections of the labeling on pregnancy, labor and 
delivery, and nursing mothers were moved from the ``Precautions'' 
section under Sec.  201.57 to the ``Use in Specific Populations'' 
section. The content of these sections in part 201 (21 CFR part 201) 
was not revised, but they were redesignated as Sec. Sec.  
201.57(c)(9)(i) through (c)(9)(iii). The previous labeling regulation 
(adopted in 1979) was redesignated Sec.  201.80, and this regulation 
applies to products not affected by the January 24, 2006, revisions. In 
redesignated Sec.  201.80, the subsections on pregnancy, labor and 
delivery, and nursing mothers are Sec.  201.80(f)(6) through (f)(8)).
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    \1\ Thus, the labeling for drugs originally approved before 1979 
may not contain the information required by these regulations 
regarding pregnancy, labor and delivery, and nursing mothers.
    \2\ FDA's regulations governing the content and format of 
labeling for human prescription drug products are contained in 
Sec. Sec.  201.56, 201.57, and 201.80. Although those regulations do 
not specifically mention the term ``biologics,'' under the act most 
biologics are drugs that require a prescription and, thus, are 
subject to these regulations.
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    The current regulations provide that, unless a drug is not absorbed 
systemically and is not known to have a potential for indirect harm to 
a fetus, a ``Pregnancy'' subsection must be included within the ``Use 
in Specific Populations'' section of the labeling. The ``Pregnancy'' 
subsection must contain information on the drug's teratogenic effects 
and other effects on reproduction and pregnancy. 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 must 
also be included. The regulations require 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.
    Currently, Sec. Sec.  201.57(c)(9)(i)(A)(1) through (c)(9)(i)(A)(5) 
and 201.80(f)(6)(i)(a) specify the following pregnancy category 
designations and language:
     Pregnancy Category A
    For pregnancy category A, if adequate and well-controlled studies 
in pregnant women have failed to demonstrate a risk to the fetus in the 
first trimester of pregnancy (and there is no evidence of a risk in 
later trimesters), the labeling must state:
    Pregnancy Category A. Studies in pregnant women have not shown 
that (name of drug) increases the risk of fetal abnormalities if 
administered during the first (second, third, or all) trimester(s) 
of pregnancy. If this drug is used during pregnancy, the possibility 
of fetal harm appears remote. Because studies cannot rule out the 
possibility of harm, however, (name of drug) should be used during 
pregnancy only if clearly needed.
    If animal reproduction studies are also available and they fail to 
demonstrate a risk to the fetus, the labeling must also state:
    Reproduction studies have been performed in (kinds of animal(s)) 
at doses up to (x) times the human dose and have revealed no 
evidence of impaired fertility or harm to the fetus due to (name of 
drug).
     Pregnancy Category B
    For pregnancy category B, if animal reproduction studies have 
failed to demonstrate a risk to the fetus and there are no adequate and 
well-controlled studies in pregnant women, the labeling must state:
    Pregnancy Category B. Reproduction studies have been performed 
in (kind(s) of animal(s)) at doses up to (x) times the human dose 
and have revealed no evidence of impaired fertility or harm to the 
fetus due to (name of drug). There are, however, no adequate and 
well-controlled studies in pregnant women. Because animal 
reproduction studies are not always predictive of human response, 
this drug should be used in pregnancy only if clearly needed.
If animal reproduction studies have shown an adverse effect (other than 
decrease in fertility), but adequate and well-controlled studies in 
pregnant women have failed to demonstrate a risk to the fetus during 
the first trimester of pregnancy (and there is no evidence of a risk in 
later trimesters), the labeling must state:
    Pregnancy Category B. Reproduction studies in (kind(s) of 
animal(s)) have shown (describe findings) at (x) times the human 
dose. Studies in pregnant women, however, have not shown that (name 
of drug) increases the risk of abnormalities when administered 
during the first (second, third, or all) trimester(s) of pregnancy. 
Despite the animal findings, it would appear that the possibility of 
fetal harm is remote, if the drug is used during pregnancy. 
Nevertheless, because the studies in humans cannot rule out the 
possibility of harm, (name of drug) should be used during pregnancy 
only if clearly needed.
     Pregnancy Category C
    For pregnancy category C, if animal reproduction studies have shown 
an adverse effect on the fetus, if there are no adequate and well-
controlled studies in humans, and if the benefits from the use of the 
drug in pregnant women may be acceptable despite its potential risks, 
the labeling must state:
    Pregnancy Category C. (Name of drug) has been shown to be 
teratogenic (or to have an

[[Page 30833]]

embryocidal effect or other adverse effect) in (name(s) of species) 
when given in doses (x) times the human dose. There are no adequate 
and well-controlled studies in pregnant women. (Name of drug) should 
be used during pregnancy only if the potential benefit justifies the 
potential risk to the fetus.
    If there are no animal reproduction studies and no adequate and 
well-controlled studies in humans, the labeling must state:
    Pregnancy Category C. Animal reproduction studies have not been 
conducted with (name of drug). It is also not known whether (name of 
drug) can cause fetal harm when administered to a pregnant woman or 
can affect reproduction capacity. (Name of drug) should be given to 
a pregnant woman only if clearly needed.
     Pregnancy Category D
    For pregnancy category D, if there is positive evidence of human 
fetal risk based on adverse reaction data from investigational or 
marketing experience or studies in humans, but the potential benefits 
from the use of the drug in pregnant women may be acceptable despite 
its potential risks, the labeling must state: ``Pregnancy Category D. 
See `Warnings and Precautions' section'' (for Sec.  
201.57(c)(9)(i)(A)(4)) or ``Pregnancy Category D. See `Warnings' 
Section'' (for Sec.  201.80(f)(6)(i)(d)). Under the ``Warnings and 
Precautions'' or ``Warnings'' section, the labeling must state:
    (Name of drug) can cause fetal harm when administered to a 
pregnant woman. (Describe the human data and any pertinent animal 
data.) If this drug is used during pregnancy, or if the patient 
becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to a fetus.
     Pregnancy Category X
    For pregnancy category X, if studies in animals or humans have 
demonstrated fetal abnormalities or if there is positive evidence of 
fetal risk based on adverse reaction reports from investigational or 
marketing experience, or both, and the risk of the use of the drug in a 
pregnant woman clearly outweighs any possible benefit, the labeling 
must state: ``Pregnancy Category X. See `Contraindications' section.'' 
Under ``Contraindications,'' the labeling must state:
    (Name of drug) may (can) cause fetal harm when administered to a 
pregnant woman. (Describe the human data and any pertinent animal 
data.) (Name of drug) is contraindicated in women who are or may 
become pregnant. If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should 
be apprised of the potential hazard to a fetus.
    With regard to labor and delivery, the current regulations state at 
Sec.  201.57(c)(9)(ii) and Sec.  201.80(f)(7) that, under certain 
circumstances, the labeling must include information on the effects of 
the drug on, among other things, the mother and the fetus, the duration 
of labor and delivery, and the effect of the drug on the later growth, 
development, and functional maturation of the child.
    With regard to labeling on lactation, under current FDA 
regulations, a ``Nursing mothers'' subsection must be included in 
either the ``Use in Specific Populations'' section of the labeling 
(Sec.  201.57(c)(9)(iii)) or the ``Precautions'' section of the 
labeling (Sec.  201.80(f)(8)). The ``Nursing mothers'' subsections 
provide that if a drug is 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'' subsections require the use of certain standard statements.
    If the drug is known to be excreted in human milk and is associated 
with serious adverse reactions or has a known tumorigenic potential, 
the labeling must state: ``Because of the potential for serious adverse 
reactions in nursing infants from (name of drug) (or, ``Because of the 
potential for tumorigenicity shown for (name of drug) in (animal or 
human) studies), a decision should be made whether to discontinue 
nursing or to discontinue the drug, taking into account the importance 
of the drug to the mother.''
    If the drug is known to be excreted in human milk, but is not 
associated with serious adverse reactions and does not have a known 
tumorigenic potential, the labeling must state: ``Caution should be 
exercised when (name of drug) is administered to a nursing woman.''
    If information on excretion in human milk is unknown and the drug 
is associated with serious adverse reactions or has a known tumorigenic 
potential, the labeling must state: ``It is not known whether this drug 
is excreted in human milk. Because many drugs are excreted in human 
milk and because of the potential for serious adverse reactions in 
nursing infants from (name of drug) (or, ``Because of the potential for 
tumorigenicity shown for (name of drug) in (animal or human) studies), 
a decision should be made whether to discontinue nursing or to 
discontinue the drug, taking into account the importance of the drug to 
the mother.''
    If information on excretion in human milk is unknown, but the drug 
is not associated with serious adverse reactions and does not have a 
known tumorigenic potential, the labeling must state: ``It is not known 
whether this drug is excreted in human milk. Because many drugs are 
excreted in human milk, caution should be exercised when (name of drug) 
is administered to a nursing woman.''

II. FDA's Examination of Pregnancy Labeling

A. Part 15 Hearing on the Pregnancy Labeling Categories

    In September 1997, the agency held a part 15 hearing (21 CFR part 
15) on the current category requirements for pregnancy labeling (62 FR 
41061, July 31, 1997). The agency sought comment on the practical 
utility and effects of the pregnancy categories as well as on problems 
associated with the categories. The agency also sought input on ways to 
address problems with the categories, including suggestions for 
possible alternatives to the categories for communicating information 
on reproductive and developmental toxicity. The following are the 
specific issues the agency sought comment and data on, followed by a 
summary of the comments received and the discussion related to those 
comments:
    (1) The agency requested comment on the extent to which the 
category designations are relied upon in making decisions about drug 
therapy in pregnant women and women of childbearing potential and 
decisions about inadvertent fetal exposure, the extent to which such 
reliance may be misplaced, and the extent to which such reliance may 
have untoward public health consequences.
    Participants stated that because the categories appear to provide a 
simple, convenient measure of risk, they are routinely relied upon by 
health care providers and others in making decisions about drug therapy 
in pregnant women and women of childbearing age. There was concern 
that, because these decisions are more complex than the category 
designations suggest, such reliance may often be misplaced and could 
result in poorly informed clinical decisionmaking.
    (2) The agency requested comment on the extent to which current 
pregnancy labeling (category designation and accompanying narrative 
text) is effective in communicating risk of reproductive and 
developmental toxicity.
    Participants stated that the current categories are confusing and 
overly simplistic and, therefore, not adequate to effectively 
communicate risk of reproductive and developmental toxicity. A major 
problem identified by the participants is that the categories convey 
the incorrect impression that developmental risk increases from 
category A to B to C to D to X when, in fact, the criteria for 
inclusion in the categories are not based solely on

[[Page 30834]]

increasing risk. Categories C, D, and X also consider risk weighed 
against benefit. Thus, drugs in categories C or D may pose risks 
similar to a drug in Category X based on animal or human data, but may 
be categorized differently based on different risk-benefit 
considerations.
    Participants stated that the categories also create the incorrect 
impression that drugs within a given category have similar potential to 
cause developmental toxicity. In fact, because the descriptive criteria 
for the individual categories focus largely on whether the available 
data have identified a potential hazard, they permit assignment of 
drugs to the same category when the severity, incidence, and types of 
risk may be quite different. The criteria also permit drugs with known 
risks and drugs with no known risks to be placed in the same category. 
Specifically, category C (which includes more than 60 percent of all 
products with a pregnancy category)\3\ includes both drugs with 
demonstrated adverse reproductive effects in animals and drugs for 
which no animal studies have been performed.
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    \3\ Based on searches of the 2001 and 2002 electronic version of 
the Physicians' Desk Reference (Ref. 39).
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    Participants also expressed concern that current labeling can be 
confusing because the way risk is characterized does not readily 
discriminate among potential developmental adverse effects on the basis 
of severity, incidence, or type of adverse effects, nor does it make a 
distinction between the nature of the data (e.g., possible effects in 
humans based on animal data versus known effects that have been 
observed in humans) and the quality of the data (e.g., statistical 
significance, study design) that identified the effects. In addition, 
current labeling often does not indicate whether there are degrees of 
risk based on the dose, duration, frequency, route of exposure, and 
gestational timing of exposure to a given product.
    (3) The agency requested comment on the extent to which current 
pregnancy labeling may not adequately address the range of issues that 
may bear on decisions about drug therapy in pregnant women and women of 
childbearing potential and decisions about inadvertent fetal exposure 
(e.g., indication-specific concerns, pregnancy status, magnitude of 
exposure, incidental exposure, chronic exposure, timing of exposure).
    Participants stated that current pregnancy labeling does not 
adequately address the range of clinical situations in which 
information about drug exposure in pregnancy is needed. Specifically, 
current pregnancy labeling focuses almost entirely on prospective 
considerations of whether to prescribe a drug for a pregnant woman and 
rarely addresses inadvertent exposure. However, because approximately 
50 percent of pregnancies are unplanned (Ref. 1), there is significant 
potential for inadvertent exposure to a drug before a pregnancy is 
detected. Participants expressed strong support for addressing 
inadvertent exposure issues in pregnancy labeling because clinical 
decisions about inadvertent exposures often involve deciding whether to 
terminate pregnancies due to the exposure. It was also pointed out that 
a statement about the risk associated with use of a drug during 
pregnancy should be put in the context of the background risk of 
adverse fetal outcomes.
    (4) The agency requested comment on additional information (data or 
interpretation of data) that could be included in pregnancy labeling to 
better address the range of issues that bear on decisions about drug 
therapy in pregnant women and women of childbearing potential and 
decisions about inadvertent fetal exposure.
    Participants stated that current pregnancy labeling does not 
adequately address the full range of potential developmental 
toxicities--fetal death, structural malformations, perturbations of 
fetal growth, and functional deficits. There were also concerns that 
current labeling does not present enough of the evidentiary basis for 
the category designation or adequately discuss the potential relevance 
of animal data to humans. Participants urged FDA to implement a 
mechanism to routinely update the ``Pregnancy'' subsection of labeling 
after a drug is marketed to include human exposure information as it 
becomes available. Several participants spoke favorably about the 
utility of pregnancy exposure registries. FDA was also encouraged to 
expand its assessment of the adequacy of pregnancy labeling to include 
what was then called the ``Nursing mothers'' subsection and to 
incorporate discussions of a product's effects on fertility, pregnancy, 
and lactation into a single labeling subsection. Some participants also 
expressed concern that current pregnancy labeling fails to discuss the 
risks, sometimes serious, of foregoing medically necessary medication 
during pregnancy.
    (5) The agency requested comment on options to improve 
communication of reproductive and developmental risk in labeling, which 
could include alternatives to the categories (both content and format 
options) or efforts to make the current category scheme and 
accompanying narrative text more consistent and informative.
    Most participants stated that the current letter categories should 
be replaced with a concise narrative summarizing a product's risks to 
pregnant women and women of childbearing age, and the clinical 
implications of such risks. To aid comprehension and facilitate 
evaluation of therapeutic options, it was recommended that the 
narratives contain common core elements. Some comments also supported 
providing a conclusive statement or recommendation about clinical use. 
FDA also was encouraged to take steps to better understand how language 
used in pregnancy labeling to communicate risk is perceived by health 
care providers.

B. Development of a Model Pregnancy Labeling Format

    After the part 15 hearing testimony and comments, FDA decided to 
revise its pregnancy labeling regulations and began to develop a model 
format to address the concerns raised about the existing format. The 
model format was designed to prominently display important information 
relevant to managing the risks of fetal and maternal adverse effects in 
the clinical setting, provide a summary of the risks that are the basis 
for the clinical care recommendations, and provide an overview of the 
data that are the basis for the risk conclusions. Accordingly, the 
model format divided the ``Pregnancy'' subsection into three 
components: (1) Clinical management statement, (2) summary risk 
assessment, and (3) discussion of data. The model format replaced the 
letter categories with concise conclusions about risk presented in 
narrative form, in large part to address concerns that users of the 
labeling might misinterpret the categories as presenting gradations of 
risk and as indicating that drugs in a given category pose similar 
risks. The model format also separated clinical management information 
from the risk assessment. This separation was intended to address 
concerns that the current categories (category X, in particular) appear 
to represent only risk assessments, but, in some cases, actually 
represent risk-benefit considerations. The three distinct labeling 
components were intended to clearly differentiate between the clinical 
management information, the risk conclusions, and the data that 
underpin the risk conclusions.

[[Page 30835]]

C. Focus Group Testing of Model Pregnancy Labeling Format

    FDA sought practical feedback on the model format the agency had 
developed for the ``Pregnancy'' subsection at the 15th Annual Clinical 
Update in Obstetrics and Gynecology Conference in February 1999 
(February 1999 Conference). At this conference, FDA conducted two focus 
groups that included obstetrician-gynecologists and family 
practitioners. One of the groups also included a reproductive 
endocrinologist.
    Participants were provided with sample ``Pregnancy'' subsections of 
labeling for three fictitious drugs. One sample used the current 
pregnancy labeling format and the other two used the model format that 
FDA had developed based on recommendations from the part 15 hearing. 
The feedback the agency sought and the responses it received from the 
participants were as follows:
    (1) What factors did they take into account when prescribing for a 
pregnant woman and what information did they rely on?
    Focus group members indicated that they rely on the pregnancy 
categories as a guide for prescribing and that they also rely on 
colleagues for advice.
    (2) What was the availability and quality of data they relied on in 
making prescribing decisions for pregnant women?
    The major concern of focus group members was the absence of human 
data. They indicated a willingness to rely on animal data in the 
absence of human data if the labeling provided some correlation to 
human dosing. They also recommended that if human data were available, 
they should take precedence over animal data in making risk 
conclusions.
    (3) What were their overall impressions of the sample labeling 
formats, including their thoughts about the formats generally and the 
clinical management section in particular?
    Focus group members preferred the model pregnancy labeling formats 
that had been developed based on recommendations from the part 15 
hearing. They agreed that the clinical recommendations should appear 
first in the labeling, followed by the details. They favored a clinical 
management section, but there was some difference of opinion as to how 
directive the management advice should be. While some members said they 
appreciated the directive nature of the new labeling formats, other 
participants were uncomfortable with the directive management advice. 
The overall consensus was that the participants wanted as much 
information as possible without specific instructions pertaining to 
clinical management.
    (4) What were their recommendations for what should be in labeling 
and how it should be presented?
    Focus group members recommended that animal data be arranged by 
species and that the data be organized by effect in trimester of 
pregnancy. They also preferred a uniform labeling format for all drug 
products. Finally, participants stated that more information was better 
and that the most important information should be presented first. 
Specifically, they encouraged FDA to include relevant information about 
human exposures even if such information was limited (e.g., from a very 
limited number of case reports of exposures).

D. Advisory Committee Assessment of Pregnancy Labeling Concepts

    Based on the part 15 hearing and the feedback from the focus groups 
at the February 1999 Conference, the agency further developed the model 
pregnancy labeling format and presented the revised version for 
discussion and comment at a meeting of the Pregnancy Labeling 
Subcommittee of the FDA Reproductive Health Drugs Advisory Committee in 
June 1999 (64 FR 23340, April 30, 1999). The model labeling format was 
presented as a Concept Paper on Pregnancy Labeling (http://www.fda.gov/
ohrms/dockets/ac/99/transcpt/3516r1.doc).
    The agency asked the advisory committee for input on the following 
issues:
    (1) The committee was asked to provide comment on the usefulness of 
the proposed reorganization of information on pregnancy, fertility, and 
lactation in the labeling that separates information into three 
components: Clinical management, summary risk assessment, and 
discussion of data, including their suggestions to refine or improve 
the model.
    In general, committee members thought the proposed model with its 
standardized format was an improvement over the current labeling and 
that separating information into three components (clinical management 
statement, risk summary, and discussion of data) under the fertility, 
pregnancy, and lactation subsections would be beneficial. However, they 
felt that the summary risk information was the most important 
information in the pregnancy subsection; therefore, the risk statement 
should precede the clinical management information. One advisory 
committee member recommended against including fertility, saying that 
fertility is a very different issue and should be considered 
separately.
    (2) How specific and detailed should the recommendations be in the 
clinical management statements (e.g., should they address types and 
frequency of testing and monitoring)? Were there circumstances under 
which specific recommendations should not be provided?
    Committee members agreed that it was important to have information 
relevant to clinical management of pregnant women in the labeling. 
However, they advised against providing directive advice or 
instructions (e.g., specific instructions about the type of monitoring 
that should be done and when to do it). They were concerned that 
directive advice could intrude on the practice of medicine and, if not 
kept current, could become outdated and contrary to the standard of 
care. They were also concerned about the liability implications for 
prescribers of failing to adhere to instructions in labeling that are 
no longer the standard of care for the relevant clinical situation.
    Committee members also objected to the heading ``Clinical 
Management Statement'' because it suggested that the information is 
intended to dictate to health care providers how to manage their 
patients. They recommended that the heading be changed to ``Clinical 
Considerations'' to clarify that the information is intended to assist 
health care providers and patients in making their own decisions.
    (3) In the risk summary, how could appropriate context for the 
reader be provided, such as risks to pregnancy associated with the 
maternal disease state or baseline population rates of the adverse 
outcomes in question?
    Committee members agreed that the risk summary should be expressed 
in terms of an increased risk due to drug exposure compared to a 
background risk--either a background risk for a disease state or 
general background risk for the occurrence of the hazard in pregnancy. 
Some members advocated including a general statement in this section to 
remind readers of the inherent risks of developmental adverse effects 
independent of drug therapy. The committee also recommended that 
standardized risk statements be used and that the risk statement 
indicate gestational periods of higher and lower fetal vulnerability if 
that information is available. They felt that any description of risk 
should be portrayed as either ``potential'' or ``known'' depending on 
whether the information is based on animal studies or human experience.
    (4) Could the committee provide guidance on the relative merits of

[[Page 30836]]

quantitative (e.g., risk ratios) vs. qualitative (e.g., high/low) 
descriptions of risk for this section of the label?
    There was general agreement among the committee members that 
quantitative description of risks is more informative and less 
problematic than qualitative description. Some members also expressed 
the view that stating the absolute or attributable risk is preferable 
to stating a risk ratio. Others stated they would like to see 
confidence intervals around numbers used because they convey 
information on the quantity of data.
    (5) What should the goals be for the discussion of data component? 
How should information be selected for inclusion?
    Committee members stated that the discussion of data component 
should include human data to the extent available. There was some 
discussion about the utility of animal data in the absence of human 
data. However, there was consensus among committee members that the 
labeling should address the relevance of animal data for the doses 
generally prescribed for humans.
    In the model format provided to the committee members, the 
discussion of data component included six subheadings: Structural 
alteration (or dysmorphogenesis), embryo-fetal death, growth 
retardation (irreversible and reversible), functional toxicities, 
maternal toxicity, and labor and delivery. The agency's purpose in 
proposing these subheadings was to address the full range of possible 
reproductive and developmental toxicities that might be appropriate for 
discussion in the data component. The committee's discussion focused on 
animal data because most of the data in current labeling is animal 
data. Committee members thought that the subheadings were too detailed. 
Instead, it was suggested that the presentation of animal studies 
should focus on describing the toxicities and include dose response 
information. Committee members also thought it was important, with 
regard to animal data, to compare the level of systemic exposure in 
animals to the human level.
    (6) In the setting where little is known about risk, how should 
this lack of information be communicated in a manner that is optimally 
informative?
    Committee members agreed that situations where there are ``no 
data'' should be distinguished from those where there are ``limited 
data.'' They agreed that the labeling should clearly state when there 
are no data available. When there are some data available, but the data 
are not sufficient to draw a conclusion about the risk of developmental 
abnormality, it was suggested that the labeling should qualify the risk 
by saying that the risk is undetermined. Committee members also 
cautioned against making the assumption that all drugs within a 
pharmaceutical class are teratogenic just because one member of the 
class is.
    (7) How could uncertainty associated with the predictive value of 
animal studies, particularly in the absence of human data, best be 
communicated?
    Some committee members stated that the uncertainty of predicting 
human risk based on animal data should be clearly expressed in the 
labeling. Other committee members suggested that in the absence of 
human data, instead of focusing on the uncertainty of the predictive 
value of the available animal data, the labeling should focus on the 
weight of evidence provided by the animal data.
    (8) Is there risk or other descriptive language that has acquired 
sufficient unintended connotation that it should be avoided in 
providing advice or in summary risk statements? Were there examples and 
could they suggest alternatives?
    There was general agreement among committee members that labeling 
should describe the facts. Committee members cautioned against the use 
of phrases or terms such as ``use with caution,'' ``crosses the 
placental barrier,'' and ``probability'' because the lay public and 
scientists define the terms very differently. One member also pointed 
out that all of the terms used to describe animal findings can be 
alarming to patients and providers.

E. Focus Group Testing of Pregnancy Risk Statements

    Based on the recommendations of the advisory committee, the agency 
further refined the model pregnancy labeling format. FDA also developed 
a number of standard statements to use in pregnancy labeling to 
characterize the risk of developmental abnormality associated with a 
drug. In May 2000, FDA conducted four focus groups to evaluate these 
standard statements being considered by the agency. Two focus groups 
consisted of nurse-midwives attending the annual meeting of the 
American College of Nurse-Midwives and two focus groups consisted of 
obstetrician/gynecologists attending the annual meeting of the American 
College of Obstetricians and Gynecologists (ACOG).
    Participants in all four focus groups were asked to review the 
following series of risk statements:
    Risk Statement 1
    Drug X does not appear to increase the risk of (type of 
developmental toxicity). Data on a limited number of exposed 
pregnancies indicate no adverse effects on the health of the (fetus/
newborn child). While animal studies did show (specific adverse effect 
seen in animals), such effects in humans are unlikely.
    Risk Statement 2
    Drug X is not expected to increase the risk of (type of 
developmental toxicity) attributable to Drug X. Data on a large number 
of exposed pregnancies indicate no adverse effects on the health of the 
(fetus/newborn child). Animal studies show (specific adverse effect 
seen in animals) but the implications for humans are uncertain.
    Risk Statement 3
    Drug X does not appear to increase the risk of (type of 
developmental toxicity). Data on a limited number of exposed 
pregnancies indicate no adverse effects on the health of the (fetus/
newborn child). Animal studies show (specific adverse effect seen in 
animals) but the implications for humans are uncertain.
    Risk Statement 4
    Drug X may increase the risk of (type of developmental toxicity or 
adverse effect) based on animal studies and data on a limited number of 
exposed pregnancies.
    Risk Statement 5
    Drug X does not appear to increase the risk of (type of 
developmental toxicity). Data on a large number of exposed pregnancies 
indicate no adverse effect on the health of the (fetus/newborn child), 
although animal studies did show (specific adverse effect seen in 
animals).
    Risk Statement 6
    Drug X may increase the risk of (type of developmental toxicity). 
Data on a limited number of exposed pregnancies indicate no adverse 
effects on the health of the (fetus/newborn child). However, animal 
studies did show (specific adverse effect seen in animals).
    The focus groups were asked to consider a number of phrases for 
possible use in risk statements, including phrases used in the six 
model risk statements above. These phrases included ``does not appear 
to increase the risk,'' ``there is no known risk attributable to,'' 
``is not expected to increase the risk,'' ``may not increase the 
risk,'' and ``may increase the risk.'' In general, the participants did 
not like the use of terms such as ``may increase,'' ``may not 
increase,'' ``is uncertain,'' ``although,'' or ``however,'' saying they 
felt the words were too vague and not useful to them. They preferred a 
factual statement that would allow them to

[[Page 30837]]

make a clinical judgment based on the circumstances of their patient. 
Participants also believed that the degree of risk that certain 
statements attempted to convey overlapped with that conveyed by other 
statements.
    The physicians participating in the focus groups at the ACOG 
meeting also were asked to review a general statement about the risks 
inherent in pregnancy independent of drug therapy, the difficulty in 
determining whether a drug poses any additional risk of developmental 
abnormality above the background incidence, and the uncertain 
predictive value of animal studies. The physicians agreed that it would 
be useful to include the general statement in labeling and said it 
would be particularly useful when explaining the concept of background 
risk to their patients.
    Based on feedback from the four focus groups, FDA revised the 
standard risk statements in the model format and incorporated the 
general statement reviewed by the physician groups.

III. FDA's Examination of Labeling on Lactation

A. Recommendations on Lactation Labeling From Part 15 Hearing

    Participants in the September 1997 part 15 hearing on pregnancy 
labeling also recommended that the agency revise the requirements for 
the ``Nursing mothers'' subsection of the labeling. They were concerned 
that current labeling on lactation is not informative for a number of 
reasons, including lack of data and a tendency for clinicians to 
conclude, based on the current format of the labeling, that they should 
recommend to their patients that they choose between breast-feeding and 
taking a drug. Based in part on these concerns, FDA developed a new 
format for the lactation subsection of labeling, using the draft 
pregnancy labeling model as a guide.

B. Advisory Committee on Lactation Labeling Issues

    In September 2000, the agency held a joint advisory committee 
meeting of the Pregnancy Labeling Subcommittee of the Advisory 
Committee for Reproductive Health Drugs and the Pediatric Subcommittee 
of the Anti-Infective Drugs Advisory Committee to consider lactation 
labeling (65 FR 50995, August 22, 2000) (advisory committee on 
lactation). Committee members heard presentations on what was then 
called the ``Nursing mothers'' subsection of the labeling, the need for 
research and information on drug therapy during lactation, and the 
draft format developed by FDA for the lactation portion of the 
labeling.
    The committee members were specifically asked to address the 
following questions:
    (1) Is maternal drug therapy during lactation an important health 
issue for infants? If yes, how should fundamental data be derived to 
determine if a drug is expressed in breast milk; whether a drug found 
in breast milk is available to the infant; and, when the drug is 
available, what the risk or lack of risk is to the nursing infant?
    The advisory committee members agreed that maternal drug therapy 
during lactation is an important health issue for infants. They 
believed that the only type of studies that could be ethically 
conducted involving nursing infants would be those in which the mother 
had already independently made the decision to breast-feed during drug 
therapy. The committee agreed that serum levels in the child would 
provide valuable information and that it is most important to assess 
clinical effects on the child from drug exposure. Committee members 
indicated that, as a practical matter, only short-term effects could be 
detected. They recommended that, if there is a known pediatric dose and 
safety profile, the dose received via breast milk should be put in 
perspective by reference to the recommended pediatric dose.
    (2) What products or types of therapies are most important to 
study: Those for conditions common in young women; those for chronic 
conditions; those for life-threatening conditions? Are there 
characteristics that are common across products or groups of products 
that make them a high priority?
    After lengthy discussion of the various issues and classes of 
drugs, the committee recommended that studies in the following 
categories of drugs should be of higher priority: Drugs predicted to 
have high levels in breast milk; drugs commonly used by women of 
childbearing age; and drugs used to treat chronic illnesses.
    (3) What kinds of information should be included in the labeling to 
allow informed decisions as to the safety of breast-feeding while 
taking a medication?
    The advisory committee members recommended that labeling include 
the following information:
     The amount of drug in breast milk,
     The anticipated daily dose for a nursing infant,
     The effect of the drug on the infant taking into account 
the infant's age,
     Drug pharmacokinetics during lactation,
     The presence of metabolites in breast milk and their half-
lives,
     The effect of the drug on displacement of bilirubin from 
protein-binding, and
     The effect of the drug on the quantity and quality of 
breast milk produced.
    Committee members recommended against a general statement that a 
drug enters the breast milk without information on the quantity of drug 
in breast milk. The committee advised that labeling discussions about 
the need to discontinue breast-feeding should be put in the context of 
a particular drug, its importance to the mother, and any risk to the 
infant. One member questioned the value of including animal data in 
lactation labeling, saying the data can be confusing and not 
necessarily helpful. Committee members urged FDA to provide a mechanism 
to ensure that labeling is updated as new data become available.

C. The Need for Informative Lactation Labeling

    Breast milk is the most complete form of nutrition for infants and 
offers a range of health benefits for breast-feeding women and infants. 
Research in developed and developing countries provides strong evidence 
that breast-feeding decreases the incidence and/or severity of a wide 
range of infectious diseases including bacterial meningitis, 
bacteremia, diarrhea, respiratory tract infection, necrotizing 
enterocolitis, otitis media, urinary tract infection, and late-onset 
sepsis in preterm infants. Studies suggest that breast-feeding 
significantly reduces postneonatal infant mortality and rates of sudden 
infant death syndrome in the first year of life. In addition, data 
suggest that older children who were breast-fed have slightly enhanced 
cognitive performance and decreased rates of asthma, obesity and 
overweight, diabetes mellitus (insulin and non-insulin dependent), 
lymphoma, leukemia, and Hodgkin's disease. Maternal benefits of breast-
feeding include reduction in postpartum bleeding, earlier return to 
pre-pregnancy weight, reduced risk of premenopausal breast cancer, and 
reduced risk of osteoporosis (Ref. 2).
    A survey conducted in 2001 found that 69.5 percent of women 
initiated breast-feeding and 32.5 percent had continued to breast-feed 
when surveyed at 6 months postpartum (Ref. 3). Given these numbers, FDA 
believes that it is highly likely that a woman will need and take 
medications while she is breast-feeding and thereby potentially will 
expose her child to the effects of

[[Page 30838]]

these medications. Surveys in various countries indicate that 90 to 99 
percent of nursing mothers receive a medication during the first week 
postpartum. At 4 months postpartum, the percentage of nursing mothers 
taking medication was 17 to 25 percent. Five percent of nursing mothers 
receive long-term drug therapy (Ref. 4).
    Because lactation studies, including studies of the transfer of 
drug into milk (animal or human), are not usually conducted during drug 
development, for most drugs there is little scientific information 
available on the effects on milk production, the extent of passage into 
breast milk, and the effects on the infant. Therefore, breast-feeding 
women and their health care providers must make decisions about 
treatment of maternal medical conditions in the absence of data. FDA is 
aware that a decision often is made to stop breast-feeding in order to 
take needed drug therapy.
    FDA encourages sponsors to conduct lactation studies so that women 
and their health care providers will have the information they need to 
make decisions about breast-feeding during maternal drug use. On 
February 8, 2005, the agency issued a draft guidance for industry 
entitled ``Clinical Lactation Studies--Study Design, Data Analysis, and 
Recommendations for Labeling'' (70 FR 6697). The draft guidance 
provides advice and recommendations on the design, conduct, and 
analysis of clinical lactation studies, including advice about when to 
perform such studies. It sets out in detail the types of information on 
lactation that the agency believes should be available to breast-
feeding women and their health care providers. In addition to the 
public comments received on the draft guidance, the agency requested 
input from the Pediatric Advisory Committee at its November 29, 2007, 
meeting. FDA is currently working to finalize its guidance on Clinical 
Lactation Studies.

IV. Description of the Proposed Rule

A. General Description of the Format and Content of the Pregnancy and 
Lactation Subsections of Labeling

    The agency is proposing to revise the format and content of Sec.  
201.57 to change the requirements for the current ``Pregnancy,'' 
``Labor and delivery,'' and ``Nursing mothers'' subsections. The 
proposed rule would merge the current ``Pregnancy'' and ``Labor and 
delivery'' subsections into a single ``Pregnancy'' subsection and would 
modify the requirements for the format and content of that subsection. 
The proposed rule would modify the format and content of the ``Nursing 
mothers'' subsection. The agency is proposing to rename the subsection 
``Lactation'' because the focus of the subsection is primarily on the 
breast-fed child rather than on the lactating woman. In labeling, the 
identifying numbers for the subsections under the section ``8 Use in 
Specific Populations'' would be 8.1 for ``Pregnancy'' and 8.2 for 
``Lactation.'' The identifying number 8.3 would be available for future 
use.

B. Pregnancy Subsection

    The proposed rule would amend Sec.  201.57(c)(9)(i) by entirely 
replacing the format and content of the ``Pregnancy'' subsection. As 
discussed in section II.A of this document, the pregnancy category 
system has been criticized as being confusing and overly simplistic. 
The standardized statements required by current regulations do not 
distinguish information about risk alone from judgments based on both 
risk and benefit. In addition, the statements associated with the 
pregnancy categories do not take into account that a woman may already 
have been exposed to a drug before learning she is pregnant, and thus 
considerations for her may differ from those for a women who has not 
yet been exposed to a drug during pregnancy. The agency believes that 
advice and cautions about drug use should be clear and should 
specifically relate to the particular clinical situation, which 
includes whether exposure has already occurred or is being 
contemplated. The clinical situation also includes the risks presented 
if the woman has a condition or disease that remains untreated during 
her pregnancy.
    FDA's process for developing this model for the pregnancy and 
lactation subsections of labeling included establishing an internal 
working group to obtain extensive input from experts from multiple 
disciplines across the Center for Drug Evaluation and Research and the 
Center for Biologics Evaluation and Research. The working group 
carefully explored a multitude of models to determine whether a 
different pregnancy category system could accurately and consistently 
communicate differences in degrees of maternal and fetal risk. The 
working group considered systems employed by other countries, including 
the European Union and Australia, but concluded that these approaches 
either did not address degrees of risk, or that these approaches simply 
provided statements that directed clinicians whether or not to use a 
product without describing risk information in a clinically meaningful 
way. The working group also explored developing a new model using 
alpha-numeric symbols or character/graphics to represent a continuum of 
risk. This approach included building tables and matrices of evidence-
based criteria that might underlie each category along the risk 
continuum. When the working group 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.
    FDA concluded that using a category system to characterize the 
risks of drug use during pregnancy would not be appropriate because of 
the complexity of medical decisionmaking about drug use during 
pregnancy. Various combinations of reproductive toxicology data, human 
pregnancy exposure data, and information about the mother's condition 
define a risk/benefit equation for each individual patient and her 
circumstances. As for any drug in any patient, prescribing and drug use 
decisions that affect both mother and fetus require consideration of 
various clinical and individual factors including the effects of the 
drug on the mother, the severity of the mother's condition, maternal 
tolerance of the drug, coexisting maternal conditions, the impact of 
maternal illness on the fetus, and the available alternative therapies. 
These conclusions mirror and support feedback FDA obtained from the 
public through the 1997 part 15 hearing and in Advisory Committee 
meetings and focus groups with experts and other clinicians who care 
for pregnant women. The feedback from the participants in these 
activities made it clear that the explanation of what is meant by any 
determination of ``risk'' or ``hazard'' is equally, if not more, 
important than the risk determination itself. 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 
much more complex constructs in clinical medicine than in other areas, 
such as environmental exposure or consumer product ratings. For similar 
reasons, FDA does not apply symbol or letter designations of risk to 
other potential toxicities or adverse effects expected with medical 
product use. Accordingly, FDA believes 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.
    One of FDA's primary objectives in developing the model labeling 
format in response to the part 15 hearing and

[[Page 30839]]

early focus group testing was to make a clear distinction between risk 
information and clinical management information. The model format 
originally contained three components in the following order: Clinical 
management, summary risk assessment, and discussion of data. Committee 
members at the June 1999 advisory committee stated that the summary 
risk assessment was the most important information in pregnancy 
labeling and therefore should precede the clinical considerations 
component. FDA agrees that the risks should be presented first, 
followed by clinical considerations. Accordingly, under the proposed 
rule, pregnancy labeling would contain a fetal risk summary, clinical 
considerations, and data discussion, in that order. Since developing 
the model format, the agency has concluded that pregnancy labeling 
should contain two additional components: Pregnancy exposure registry 
information (if applicable) and a general statement about the 
background risk of fetal developmental abnormalities. These two 
components, as well as the reasons for including them, are discussed in 
detail below. Thus, the proposed ``Pregnancy'' subsection would require 
prescription drug labeling to contain, under the subheading ``8.1 
Pregnancy,'' the following information: (1) Pregnancy exposure registry 
information (if applicable), (2) a general statement about the 
background risk of fetal developmental abnormalities, (3) a fetal risk 
summary, (4) clinical considerations, and (5) data. Information on 
labor and delivery would be included under clinical considerations of 
the pregnancy subsection because, from a medical perspective, labor and 
delivery is the end phase of pregnancy. FDA seeks comment on how these 
elements should be ordered to optimize the clinical usefulness of this 
labeling subsection. Specifically, FDA is interested in comments on 
whether the fetal risk summary should precede the pregnancy registry 
contact information and the information on background risk.
    FDA's current regulations permit omission of the ``Pregnancy'' 
subsection of labeling if the drug is not absorbed systemically and is 
not known to have a potential for indirect harm to the fetus. In 
contrast, the proposed rule would require that the labeling for all 
drugs contain a ``Pregnancy'' subsection. The agency believes that 
labeling that omits the ``Pregnancy'' subsection is confusing because 
the reader has no way of knowing why that subsection has been omitted. 
It is unlikely that most health care providers are aware that the 
``Pregnancy'' subsection may be omitted when the drug is not absorbed 
systemically. Thus, the lack of a ``Pregnancy'' subsection does not 
necessarily signal to the reader that the drug is not absorbed 
systemically. Furthermore, in some cases, particularly with older 
labeling, there may be no ``Pregnancy'' subsection even when the drug 
is systemically absorbed. To correct this potential source of 
confusion, the proposed rule would require that the labeling of all 
drugs contain a ``Pregnancy'' subsection. However, when the drug is not 
systemically absorbed, the fetal risk summary would 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.''
1. Pregnancy Exposure Registry Information (Proposed Sec.  
201.57(c)(9)(i)(A))
    FDA believes that appropriately conducted pregnancy exposure 
registries are an important mechanism for the collection of clinically 
relevant data concerning the effects of exposure to drugs during human 
pregnancy. Because of its belief in the value of pregnancy exposure 
registries, the agency has taken a number of steps to facilitate the 
establishment of well-designed pregnancy exposure registries and to 
encourage participation in such registries. In August 2002, the agency 
published a guidance for industry on ``Establishing Pregnancy Exposure 
Registries'' to provide sponsors with recommendations on the design of 
pregnancy exposure registries (67 FR 59528, September 23, 2002). FDA's 
Office of Women's Health maintains a Web site (http://www.fda.gov/
womens/registries/default.htm) that explains what a pregnancy registry 
is and lists pregnancy registries currently enrolling pregnant women 
with specific medical conditions and women using specific drugs. 
Providing information about pregnancy exposure registries in 
prescription drug labeling is an additional step to encourage 
participation in registries.
    Data from pregnancy registries have been used to support important 
labeling changes for certain drugs. The agency anticipates that, under 
the proposed labeling format, data from pregnancy registries, among 
other types of data, would be used to update labeling that, in most 
cases, would otherwise contain only animal data, and thus labeling 
would provide more clinically useful information for health care 
providers and their patients.
    The proposed rule states that, 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 stated at the beginning of the ``Pregnancy'' subsection of 
labeling. FDA believes that placing this information in a position of 
prominence in prescription drug labeling may encourage participation in 
pregnancy registries by making it easier for health care providers and 
their patients to learn of pregnancy registries and the means to 
contact them. This information may also be appropriate for inclusion in 
a Medication Guide (patient labeling) under 21 CFR part 208.
    If there is no pregnancy registry for the drug, the labeling is not 
required to contain any statement about pregnancy registries.
2. General Statement About Background Risk (Proposed Sec.  
201.57(c)(9)(i)(B))
    In all pregnancies, there is a risk that there will be an adverse 
outcome, even if the mother takes no medications during her pregnancy. 
This risk is usually referred to as the background risk. Rates of 
adverse pregnancy outcomes vary with maternal age and underlying 
maternal medical conditions (Ref. 5). Fifteen to twenty percent of 
recognized pregnancies result in spontaneous abortion or miscarriage 
(loss prior to 20 weeks) (Ref. 6), and 1 in 200 known pregnancies 
results in fetal death or stillbirth (loss after 20 weeks) (Ref. 7). 
One out of 28 infants is born with serious birth defects (i.e., those 
resulting in physical or mental disability or death) (Ref. 1). Except 
for genetic syndromes and chromosomal abnormalities, most birth defects 
have no known cause. Minor birth defects may be 10 to 20 times more 
common than major ones, and 20 percent of infants with one or more 
minor birth defects also have a major birth defect (Ref. 8).
    Because many women of reproductive age are not aware that there is 
a background risk in all pregnancies, physicians on the advisory 
committee and those who participated in focus testing of the model 
format suggested that FDA include in pregnancy labeling a general 
statement about background risk. The physicians stated that including 
such a statement would help them when counseling their patients.
    FDA agrees that it is important to make clear that, when labeling 
characterizes the risk presented by a drug used during pregnancy, it is 
the

[[Page 30840]]

increase over the background risk that is being characterized. To 
emphasize this point, proposed Sec.  201.57(c)(9)(i)(B) would require 
pregnancy labeling to state that all pregnancies have a background risk 
of birth defect, loss, or other adverse outcome, regardless of drug 
exposure, and that the fetal risk summary describes the drug's 
potential to increase the risk of developmental abnormalities above the 
background risk.
3. Fetal Risk Summary (Proposed Sec.  201.57(c)(9)(i)(C))
    The proposed rule states that, under the subheading ``Fetal Risk 
Summary,'' the labeling must contain 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. The fetal risk summary must characterize the likelihood 
that the drug increases the risk of developmental abnormalities and 
other risks (e.g., transplacental carcinogenesis) in humans.
    a. Types of developmental abnormalities and other risks. 
Reproductive toxicologists refer to birth defects as developmental 
toxicities, and divide such toxicities into four types: (1) 
Dysmorphogenesis, (2) developmental mortality, (3) functional toxicity, 
and (4) alterations to growth (Ref. 9). Because some of this 
terminology is technical and unfamiliar to most health care providers, 
FDA is proposing to use simpler terms so that pregnancy labeling based 
on this proposed rule would be more easily understandable. Accordingly, 
FDA uses the following terms in this proposed rule:
     To describe developmental toxicities, the proposed rule 
uses ``developmental abnormalities.''
     To describe dysmorphogenesis, the proposed rule uses 
``structural anomalies,'' which includes malformations, deformations, 
and disruptions.
     To describe developmental mortality, the proposed rule 
uses ``fetal and infant mortality,'' which includes miscarriage, 
stillbirth, and neonatal death.
     To describe functional toxicity, the proposed rule uses 
``impaired physiologic function,'' which includes such outcomes as 
deafness, endocrinopathy, neurodevelopmental effects, and impairment of 
reproductive function.
     The proposed rule retains the term ``alterations to 
growth,'' which includes such outcomes as growth retardation, excessive 
growth, and early maturation because this term is not as technical as 
the others, and other terms do not adequately capture this range of 
outcomes.
    In addition to the four types of developmental abnormalities, there 
may be other risks that are appropriate for discussion in the fetal 
risk summary, such as transplacental carcinogenesis.
    FDA believes that it is important for pregnancy labeling to 
describe, to the extent possible, all recognized potential adverse 
outcomes to the fetus associated with drug use during pregnancy. This 
point was also made by participants at the part 15 hearing. Thus, the 
proposed rule provides that the fetal risk summary must characterize 
the likelihood that the drug increases the risk of developmental 
abnormalities (i.e., structural anomalies, fetal and infant mortality, 
impaired physiologic function, alterations to growth) or other risks 
(e.g., transplacental carcinogenesis) in humans.
    b. Conclusions about risk. The June 1999 advisory committee 
recommended that pregnancy labeling use standardized risk statements. 
Some participants at the part 15 hearing recommended that pregnancy 
labeling provide a conclusion statement as well as a narrative summary. 
Based on this feedback and its own internal deliberations, FDA believes 
that, to be most useful to health care providers, pregnancy labeling 
should draw conclusions about the likelihood that drug use during 
pregnancy increases the risk of developmental abnormalities, as well as 
describe the nature of the risk(s). Thus, the proposed rule would 
require that the fetal risk summary component of pregnancy labeling 
include language characterizing the likelihood that the drug increases 
the risk of developmental abnormalities or other risks in humans by 
using certain standardized risk conclusions that are provided in the 
proposed rule. More than one risk conclusion may be needed to 
characterize the likelihood of risk for different developmental 
abnormalities, doses, durations of exposure, or gestational ages at 
exposure. Examples of risk conclusions for varying types of data are 
provided in the sample fetal risk summaries in the appendix of this 
document.
    c. Data sources. In developing the fetal risk summary, 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 or other relevant risks must be 
considered. Participants in the part 15 hearing expressed concern that 
current pregnancy labeling does not clearly identify whether 
descriptions of, and conclusions about, risk are based on animal or 
human data. FDA agrees that it is critical to know the source of the 
information and conclusions in the fetal risk summary. Thus, the 
proposed rule would require that the source(s) of the data that are the 
basis for the fetal risk summary be stated. For example, the risk 
summary must state that it is based on human data or based on animal 
data. The proposed rule also states that the fetal risk summary must 
present human data before animal data.
    For the fetal risk summary, the agency is proposing different 
approaches for communicating the risks of drug use during pregnancy 
depending on whether the risk is based on human data or on animal data. 
Although FDA is proposing the use of standardized risk conclusions both 
for risks based on human data and those based on animal data, the risk 
conclusions based on human data would be followed by a narrative 
discussion of the risk. The agency believes that a narrative 
description of human data is the best approach for summarizing such 
data in a comprehensive manner because the types of human data 
contributing to the assessment are variable and complex. The assessment 
must also contribute constructively to the clinical decision to be made 
by the health care provider by helping her understand how the human 
data may or may not apply to the individual patient. In deciding 
whether to prescribe a drug during pregnancy, the clinician needs to 
consider the human data in combination with the maternal and fetal 
effects of not treating the maternal condition, other coexisting 
maternal conditions and/or medications, and whether exposure has 
already occurred. On the other hand, while the degree to which 
teratogenesis in animals predicts teratogenesis in humans varies, 
collective knowledge about the animal species used for reproductive 
toxicology studies and certain principles of reproductive toxicology 
provide a basis for more algorithmically characterizing expected risk 
in the context of animal data. It is important to emphasize that animal 
data can only predict that a risk exists. For this reason, and because 
most clinicians are not experts in reproductive toxicology, the 
proposed rule uses only standardized risk statements to convey risk 
based on animal findings, and does not include a narrative summary of 
the animal findings.
    d. Sources of human data. Except for the few products developed to 
treat conditions unique to pregnancy, prescription drugs are not tested 
in pregnant women prior to their approval. Therefore, human data 
concerning a

[[Page 30841]]

drug's effect(s) on pregnant women and their offspring almost never 
come from controlled clinical trials. When human data are available, 
they may come from a variety of other sources. Sources that may 
contribute to an evaluation of whether a drug increases the risk of 
developmental abnormalities include pregnancy exposure registries, 
cohort studies, case-control studies, case series, and case reports. An 
assessment of the quality and quantity of the available human data is 
critical in determining the probative value of that data.
    e. The importance of human data. FDA expects that revising our 
regulations on the content and format of pregnancy labeling will result 
in pregnancy labeling that includes much more information based on 
human data than does existing labeling. The importance of including 
human data in labeling was stressed by physicians who participated in 
focus group testing of the model format and also by the June 1999 
advisory committee.
    Participants at the part 15 hearing also emphasized that pregnancy 
labeling should be updated routinely to include human exposure 
information as it becomes available. The same principle was addressed 
by the Teratology Society in its comments on FDA's draft guidance for 
reviewers on ``Integration of Study Results to Assess Concerns About 
Human Reproductive and Developmental Toxicities,'' issued in October 
2001 (66 FR 56830, November 13, 2001):
    We recommend that assessment of the developmental and 
reproductive toxicity of every drug be seen as an ongoing process, 
not one that ends when the drug receives initial FDA approval. The 
process should encourage collection of human reproductive and 
developmental toxicity data after the drug has been approved and 
include provision for regular re-evaluation of all available data, 
and especially of relevant human data, as they become available.
Most health care providers are not able to translate animal 
reproductive toxicity data into an accurate assessment of human 
teratogenic risk. Thus, in the absence of human data, it is difficult 
for health care providers to adequately counsel patients about the 
risks of drug use in pregnancy. Without adequate counseling, women may 
decide to take steps to avoid becoming pregnant while on needed drug 
therapy, to forego needed drug therapy while pregnant, or to terminate 
pregnancies.
    Providing the most complete assessment of risk possible, including 
both human and animal data, is essential because complete avoidance of 
drug use by pregnant women is neither realistic nor beneficial to the 
overall wellbeing of mother and fetus. Women of reproductive age 
commonly use prescription drugs. A recent survey reported that 46 
percent of women 18 to 44 years old had used at least one prescription 
drug during the preceding week, while 3 percent had used five or more 
(Ref. 10). Approximately 10 percent of women between the ages of 15 and 
44 become pregnant annually (Ref. 11), and about half of these 
pregnancies are unplanned (Ref. 1). Thus, it is not uncommon for a 
fetus to be exposed to drugs before a woman knows she is pregnant. In 
many cases, such exposure would likely occur during the critical period 
of organogenesis (3 to 8 weeks postconception) (Ref. 12).
    Some women enter pregnancy with medical conditions that require 
ongoing or episodic treatment with prescription drugs (e.g., asthma, 
epilepsy, hypertension). In addition, new medical problems may develop, 
or old ones may be exacerbated by pregnancy (e.g., migraine headaches, 
depression). Studies show that most women who know they are pregnant 
use either prescribed or over-the-counter drugs during pregnancy (Refs. 
13 through 15).
    Because pregnant women do use prescription drugs, it is critical 
that health care providers have access in labeling to available 
information about the effects of drug exposure in human pregnancies. In 
the usual case, no human data are available at the time a drug is 
approved. Animal studies function as a screen for potential human 
teratogenicity and are a required part of the drug development process. 
However, the positive and negative predictive values of animal studies 
for humans are often uncertain (Ref. 16). In screening for drug-induced 
fetal effects, animal models can be misleading by suggesting 
associations that ultimately turn out to be false positive or false 
negative in humans (Ref. 17). That is, there may be a finding of a 
drug-associated developmental abnormality in an animal study when that 
abnormality, or indeed, any abnormality, is not associated with the 
drug in humans. On the other hand, animal studies may predict that a 
drug is not associated with any developmental abnormality, while human 
experience may later indicate that the drug is associated with some 
developmental abnormality.
    In some cases, drugs that are teratogenic in animals when given at 
high doses are not teratogenic to humans in therapeutic doses, which 
are typically much lower. In addition, certain animal species are 
especially disposed to develop a particular type of developmental 
abnormality (e.g., cleft palate in mice), making it difficult to 
determine whether drug exposure contributed to the effect or, if so, to 
what extent. The strongest concordance between animal findings and 
human effects is when there are positive findings from more than one 
species, although even in this case the results cannot always be used 
to predict specific human effects or the incidence in humans (Ref. 18).
    Inclusion of clinically relevant new human data in pregnancy 
labeling is necessary to ensure that labeling complies with the general 
requirements on content and format of labeling for human prescription 
drug and biological products (Sec.  201.56(a)(1) and (a)(2)). Section 
201.56(a)(1) provides that the labeling must contain a summary of the 
essential scientific information needed for the safe and effective use 
of the drug. Section 201.56(a)(2) provides, in part, that ``the 
labeling must be updated when new information becomes available that 
causes the labeling to become inaccurate, false, or misleading.''
    When 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. 
For example, animal data available at the time of approval might 
suggest that use of a particular drug during pregnancy is likely to be 
associated with a risk for the development of neural tube defects in 
the fetus. Under the proposed rule, that information would be included 
in the ``Pregnancy'' subsection of the labeling when the drug is 
approved. If data developed after the initial approval (perhaps from an 
appropriately designed and powered pregnancy registry) indicate that 
the drug may not be associated with neural tube defects in humans, the 
drug's original labeling--based only on animal data--would be 
inaccurate, false, and misleading. In such a situation, Sec.  201.56(a) 
would require that the labeling be updated to include the new 
information.
    f. Risk conclusions based on human data. The proposed rule states 
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. A risk conclusion based on human data

[[Page 30842]]

must be followed by a narrative description of the risk(s) as discussed 
in section IV.B.3.h of this document.
    The proposed rule addresses two different situations where human 
data are available: Those where human data are ``sufficient'' and those 
involving ``other human data.'' The proposed rule states that 
``sufficient human data'' are those that are sufficient to reasonably 
determine the likelihood that the drug increases the risk of fetal 
developmental abnormalities or specific developmental abnormalities. As 
explained in the proposed rule, sufficient human data may come from 
such sources as clinical trials, robust pregnancy exposure registries 
or other large scale, well-conducted epidemiologic studies, or case 
series reporting a rare event.
    The proposed rule provides the following two risk conclusions to be 
used when human data are sufficient:
     When sufficient human data do not show an increased risk, 
the risk conclusion must state: ``Human data do not indicate that (name 
of drug) increases the risk of (type of developmental abnormality or 
specific developmental abnormality).'' An example of a hypothetical 
risk conclusion using this statement is: ``Human data do not indicate 
that hypothezine increases the risk of structural malformations.'' 
Another example is: ``Human data do not indicate that hypothezine 
increases the risk of neural tube defects.''
     When sufficient human data show an increased risk, the 
risk conclusion must state: ``Human data indicate that (name of drug) 
increases the risk of (type of developmental abnormality or specific 
abnormality).'' An example of a hypothetical risk conclusion using this 
statement is: ``Human data indicate that theoretamine increases the 
risk of cardiac abnormalities.'' Another example is: ``Human data 
indicate that theoretamine increases the risk of hypospadias and 
clitoral anomalies.'' The proposed rule states that when human data are 
available but are not sufficient to require the use of one of the two 
preceding risk conclusions, the likelihood that the drug increases the 
risk of developmental abnormalities must be characterized as low, 
moderate, or high. Whether the likelihood of increased risk would be 
characterized as low, moderate, or high would require a scientific 
judgment about the quantity and quality of the available data. For 
example, if the human data consisted of a pregnancy registry examining 
the increased risk for a specific developmental abnormality, FDA would 
consider such factors as the duration of the registry, the number of 
patients enrolled, and the statistical power of the study to identify 
or rule out a specified level of risk.
    The proposed rule uses a slightly different approach for situations 
involving other human data,'' i.e., those where the human data are not 
sufficient to reasonably determine the likelihood that the drug 
increases the risk of fetal developmental abnormalities or specific 
developmental abnormalities. As discussed in section II.E of this 
document, FDA conducted four focus groups to evaluate standard 
statements being considered by the agency to characterize the increased 
risk of drug-associated developmental abnormalities in pregnancy 
labeling. After holding these focus groups, an agency working group 
further considered numerous possible wordings for standard statements. 
The working group also prepared many samples of fetal risk summaries to 
evaluate the concepts being discussed for this proposed rule. These 
risk summaries were based on varying types and amounts of data and 
described varying endpoints. The working group's experience in 
preparing these sample risk summaries indicated that using standardized 
risk conclusions about human data that were not sufficient to 
reasonably determine the drug's effect(s) on fetal developmental 
abnormalities presented difficulties. Using standardized risk 
conclusions often removed the flexibility needed to accurately convey 
the data. There were situations where the data did not fit into the 
format of the standardized risk conclusions. Rather than force the data 
to fit a standardized risk conclusion, the working group determined 
that labeling under the proposed rule should not be required to employ 
standardized statements when human data are not sufficient. Therefore, 
the proposed rule would not mandate the use of prescribed sentences 
when available human data are not sufficient to reasonably determine 
the drug's effects on fetal developmental abnormalities. Instead, the 
risk would be classified as either low, medium, or high. FDA seeks 
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).''
    g. Risk conclusions based on animal data. Section 201.56(a)(3) of 
FDA regulations states that labeling must be based whenever possible on 
data derived from human experience. Some of the limitations of animal 
data concerning the increased risk of developmental abnormalities 
because of drug exposure have been discussed in section IV.B.3.e of 
this document. There is an additional limitation that the agency 
considers to be particularly important in determining what conclusions 
can be drawn from animal data regarding human pregnancy outcomes. Toxic 
drug exposure may manifest as one type of developmental abnormality 
(e.g., embryolethality) in an animal species, but a different type of 
developmental abnormality (e.g., structural anomalies) in humans. Thus, 
the agency does not believe it is possible to draw a conclusion, based 
on animal data alone, that a drug is likely to cause an increased risk 
of a particular type of developmental abnormality (e.g., fetal and 
infant mortality), much less a specific developmental abnormality 
(e.g., cleft palate). However, it is more concerning when teratogenic 
effects occur in more than one animal species, especially if these 
effects were consistent across the different species. Accordingly, 
where the risk conclusion is based solely on animal data, the proposed 
rule would require that the fetal risk summary component consist only 
of a risk conclusion, and not, in addition, a description of the 
effects found in animals. The risk conclusion would be followed by a 
cross reference to the Data component of the ``Pregnancy'' subsection, 
and the effects found in animals would be described in the ``Data'' 
component.
    The proposed rule states 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 five risk 
conclusions.
     When animal data contain no findings for any developmental 
abnormality, the fetal risk summary must state, ``Based on animal data, 
(name of drug) is not predicted to increase the risk of developmental 
abnormalities.''
     When animal data contain findings of developmental 
abnormality but the weight of the evidence indicates that the findings 
are not relevant to humans (e.g., findings in a single animal species 
that are caused by unique drug metabolism or a mechanism of action

[[Page 30843]]

thought not to be relevant to humans; findings at high exposures 
compared with the maximum recommended human exposure), the fetal risk 
summary must state, ``Based on animal data, the likelihood that (name 
of drug) increases the risk of developmental abnormalities is predicted 
to be low.''
     When animal data contain findings of one or more fetal 
developmental abnormalities in one or more animal species, and those 
findings are thought to be relevant to humans, the fetal risk summary 
must state, ``Based on animal data, the likelihood that (name of drug) 
increases the risk of developmental abnormalities is predicted to be 
moderate.''
     When animal data contain robust findings of developmental 
abnormalities (e.g., multiple findings in multiple animal species, 
similar findings across species, findings at low exposures compared 
with the anticipated human exposure) thought to be relevant to humans, 
the fetal risk summary must state, ``Based on animal data, the 
likelihood that (name of drug) increases the risk of developmental 
abnormalities is predicted to be high.''
     When animal data are insufficient to assess the drug's 
potential to increase the risk of developmental abnormalities, the 
fetal risk summary must state that fact. When there are no animal data 
to assess the drug's potential to increase the risk of developmental 
abnormalities, the fetal risk summary must state that fact.
    FDA seeks 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 confusion among prescribers.
    h. Narrative description of the risks. The proposed rule states 
that when human data are available, in addition to the risk 
conclusion(s), the fetal risk summary must be followed by a brief 
description of the risks of developmental abnormalities as well as on 
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 
the dose, duration of exposure, or gestational timing of exposure. When 
appropriate, the description must include the risk above the background 
risk attributed to drug exposure. For example, the labeling might 
state: ``Exposure to Drug X during the first trimester increases the 
risk of neural tube defects 20-fold, from 10 to 25 defects in 10,000 
pregnancies to 200 to 500 defects in 10,000 pregnancies.'' When 
possible, the description must also communicate the level of certainty 
about the risk based on the power of the study and confidence limits. 
Thus, the proposed rule states that, when appropriate, the description 
must include confidence limits and power calculations to establish the 
statistical power of the study to identify or rule out a specified 
level of risk. For example, the labeling might state: ``Compared to a 
1.62% prevalence of major malformations in women with the same disease 
not exposed to the drug, the relative risk of having an affected 
offspring for Drug X-exposed women is 7.3 (95% CI: 4.4 to 12.2; 
p<0.001).''
    i. Contraindications, warnings, and precautions. The proposed rule 
states that if there is information on an increased risk to the fetus 
from exposure to the drug in the ``Contraindications'' or ``Warnings 
and Precautions'' sections of the labeling (Sec.  201.57(c)(5) or 
(c)(6)), the fetal risk summary must refer to the relevant section.
    Section 201.57(c)(5) of FDA's labeling regulations provides that 
the ``Contraindications'' section must describe ``any situations in 
which the drug should not be used because the risk of use * * * clearly 
outweighs any possible therapeutic benefit.'' This requirement applies 
to the use of a drug in pregnancy. FDA believes that pregnancy is 
different from other situations, however, in that the risk could be to 
the fetus as well as to the mother, and that in order to be 
contraindicated for use in pregnancy, the risk would have to clearly 
outweigh any possible therapeutic benefit either to the mother or to 
the fetus. Thus, the risk/benefit analysis would be somewhat different 
than for other situations because one would need to consider risk and 
benefit to both the mother and to the fetus. For example, a drug might 
have the potential to cause serious harm to the fetus, but be needed by 
the mother as treatment for an otherwise fatal disease or condition. 
Given that the mother's death would, depending on the gestational age 
of the fetus, result in the death of the fetus, the risk to the fetus 
from the drug would not necessarily outweigh the benefit to the mother.
    FDA's understanding is that existing practice has been to 
contraindicate a drug in its entirety for use in pregnancy if any 
indication is contraindicated for such use, despite the fact that the 
risk/benefit analysis might differ for different indications. FDA 
believes that when there is more than one labeled indication for a 
drug, a decision should be made separately for each indication as to 
whether the drug should be contraindicated for use in pregnancy. It may 
also be appropriate to contraindicate a drug for use in pregnancy only 
for a particular patient population (e.g., when there is coexisting 
renal disease). In this case, the labeling should describe specifically 
the population to which the contraindication applies.
    It may also be the case that a drug poses an increased risk to the 
fetus only during a particular time period, for example, the period of 
organogenesis or during the third trimester. Thus, the agency believes 
that if there is a specific known time period when the drug would pose 
an increased risk to the fetus, the contraindication should specify the 
time period (e.g., first trimester; after 30 weeks).
    Finally, current drug labeling has sometimes contraindicated a drug 
for use in pregnancy simply because it is reasonable to assume that a 
pregnant woman would not use or be prescribed that drug. For example, 
women who know they are pregnant do not use oral contraceptives or 
fertility drugs. However, participants at the part 15 hearing clearly 
emphasized that contraindicating a drug gives the impression that it 
has been shown to cause fetal developmental abnormalities, perhaps 
leading women to terminate otherwise wanted pregnancies because of drug 
exposure before they realized they were pregnant. As was also brought 
out in the part 15 hearing, health care providers may also recommend 
termination to pregnant patients when a drug is contraindicated for use 
in pregnancy. Thus, FDA believes it is not appropriate to 
contraindicate a drug for use in pregnancy for the sole reason that the 
drug is not usually prescribed for pregnant women. Rather, a 
contraindication for use in pregnancy should be based on a 
determination that the drug should not be used in pregnancy because the 
risk of use during pregnancy clearly outweighs any possible therapeutic 
benefit.
4. Clinical Considerations (Proposed Sec.  201.57(c)(9)(i)(D))
    The proposed clinical considerations component of pregnancy 
labeling is intended 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

[[Page 30844]]

women, and (3) making prescribing decisions during labor and delivery.
    a. Inadvertent exposure. The agency recognizes that many women are 
exposed to drugs before they know they are pregnant. Failure to address 
such inadvertent exposure has been identified as one of the key 
weaknesses of current pregnancy labeling. Participants in the part 15 
hearing advocated that labeling address issues relating to inadvertent 
exposure because clinical decisions about inadvertent exposures often 
involve deciding whether to terminate pregnancies. FDA agrees that it 
is critical to address inadvertent exposure in labeling. The population 
at risk for unnecessary terminations due to early drug exposure is 
large because approximately half of all pregnancies in the United 
States are unintended (Ref. 1). Thus, the proposed rule would require 
that the clinical considerations component of pregnancy labeling 
discuss the known or predicted risks to the fetus from inadvertent 
exposure, including human or animal data on dose, timing, and duration 
of exposure. If there are no data to assess the risk from inadvertent 
exposure, the labeling would be required to state this fact.
    b. Prescribing decisions for pregnant women. The discussion 
relating to prescribing decisions for pregnant women would be required 
to include the following four types of information:
    (1) The labeling would be required to describe 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.
    There is evidence that women of childbearing age and their health 
care providers overestimate the likelihood that drugs used in pregnancy 
will cause serious birth defects, probably because of the thalidomide 
tragedy in the early 1960s (Refs. 19 through 27). Because of this 
overestimation of risk, women may not be appropriately treated for 
serious and even life-threatening diseases or conditions during 
pregnancy (Refs. 22 and 27). Of the 62 million women of childbearing 
age (15 to 44) in the United States (Ref. 28), more than 9 million have 
chronic conditions such as asthma, epilepsy, and hypertension (Ref. 29) 
that require ongoing treatment with prescription medicines. Failure to 
treat these conditions properly can have serious consequences for 
mothers and fetuses (Refs. 25 and 30). The agency believes that 
including information about the risks to the pregnant woman and the 
fetus from the disease or condition to be treated will help health care 
providers to weigh the risks of drug treatment against the risks of not 
treating the disease or condition.
    (2) The labeling would be required to include information about 
dosing adjustments during pregnancy. Corresponding information would 
also be required in the ``Dosage and Administration'' and ``Clinical 
Pharmacology'' sections (Sec. Sec.  201.57(c)(3) and (c)(13)). For 
example, the pregnancy subsection of the labeling might state under 
``Clinical Considerations,'' ``Drug X is eliminated more rapidly in 
pregnant women than in nonpregnant women. Dosage adjustment is 
necessary for pregnant women. See `Dosage and Administration.''' If 
there are no data on dosing in pregnancy, a statement of that fact 
would be required in the labeling.
    Many physiologic changes occur during pregnancy, and these changes 
can affect drug pharmacokinetics. Assuming that the usual adult dose is 
appropriate during pregnancy can result in substantial underdosing or, 
in some cases, excessive dosages. FDA encourages sponsors to conduct 
studies to determine appropriate dosing during pregnancy. To this end, 
the agency published a draft guidance for industry on the design, 
conduct, and interpretation of pharmacokinetic studies in pregnant 
women. The availability of this guidance entitled ``Pharmacokinetics in 
Pregnancy--Study Design, Data Analysis, and Impact on Dosing and 
Labeling'' was announced in the Federal Register of November 1, 2004 
(69 FR 63402).
    (3) If use of the drug is associated with maternal adverse 
reactions that are unique to pregnancy or if known adverse reactions 
occur with increased frequency or severity in pregnant women, this 
portion of the labeling would be required to describe such adverse 
reactions. This description would include, if known, the effect of 
dose, timing, and duration of exposure on the risk to the pregnant 
woman of experiencing the adverse reaction(s). If information is 
available on interventions that might be needed, language to that 
effect would also be required. For example, the labeling might include 
the following statement: ``Drug X may cause hyperglycemia in pregnant 
women. Careful monitoring of blood glucose is recommended when using 
Drug X during pregnancy.''
    (4) If it is known or anticipated that treatment of the pregnant 
woman will cause a complication in the fetus or the neonate, the 
labeling would be required to describe the complication, the severity 
and reversibility of the complication, and general types of 
interventions, if any, that may be needed.
    c. Labor and delivery. 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 if the drug is expected to affect labor or 
delivery, the discussion of clinical considerations would be required 
to provide the 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. FDA believes, for products to which this provision 
applies, that including this information in the labeling is important 
to help ensure the safe use of the drug under what may be a common 
condition of its use. FDA notes that, although the proposed rule would 
modify slightly the language currently found at Sec.  201.57(c)(9)(ii), 
these changes are intended solely to update the language used in these 
sections and not to affect the information required by these provisions 
to be included in the labeling.
5. Data (Proposed Sec.  201.57(c)(9)(i)(E))
    The Data component of the proposed pregnancy labeling is intended 
to provide a brief overview of the data that are the basis for the 
fetal risk summary and the clinical considerations portion of the 
labeling. The discussion of the data is not intended to be all-
encompassing, but rather to explain and supplement the conclusions in 
the fetal risk summary and clinical considerations portions of the 
labeling.
    As in the fetal risk summary portion, the proposed rule states that 
human and animal data must be presented separately and human data must 
be presented first. The labeling would be required to describe the 
studies, including study type(s) (e.g., controlled clinical or 
nonclinical studies, 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).
    Isolated case reports generally would not be included in the Data 
component of the labeling unless the quality of the report(s) and other 
factors (e.g., consistency with animal findings; information on the 
dose, duration, and timing of gestational exposure) support their 
inclusion.
    The proposed rule states that, for human data included in the Data 
component, positive and negative

[[Page 30845]]

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.
    The proposed rule states that, for animal data included in 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 must be described. This proposed requirement addresses the 
concerns of focus group members and advisory committee members that 
pregnancy labeling should help health care providers understand the 
relationship between animal data and human exposures.
    FDA seeks comment on whether, in the Data component of labeling, 
when animal data is described, the rule should also require the 
inclusion of information on the findings that contribute to the 
designation of the risk from animal data as low, moderate, or high. For 
example, should there be information on the number of species with 
positive findings, the consistency of the findings, or the severity of 
findings?

C. Lactation Subsection

    Proposed Sec.  201.57(c)(9)(ii) would require prescription drug 
labeling to contain, under the subheading ``8.2 Lactation,'' the 
following three components: (1) A risk summary, (2) clinical 
considerations, and (3) data.
1. Risk Summary (Proposed Sec.  201.57(c)(9)(ii)(A))
    The proposed rule provides that a lactation risk summary must 
summarize the following information: (1) The drug's impact on milk 
production, (2) what is known about the presence of the drug in human 
milk, and (3) the effects on the breast-fed child. The proposed rule 
states that when, as discussed below, the data demonstrate that the 
drug does not affect the quantity and/or quality of human milk and 
there is reasonable certainty either that the drug is not detectable in 
human milk or that the amount of drug consumed via breast milk will not 
adversely affect the breast-fed child, the labeling must state that the 
use of the drug is compatible with breast-feeding. Requiring such a 
statement is supported by FDA's consultation with stakeholders. The 
discussion at the advisory committee on lactation included a 
recommendation that, if appropriate, labeling contain a statement 
indicating that it is safe for a nursing mother to take a drug. 
Participants in the September 1997 part 15 hearing also expressed 
concern that mothers who need to take prescription drugs after they 
give birth may be advised by their health care providers to choose 
between breast-feeding and taking a drug. FDA agrees that, if the data 
support the conclusion, it is important for lactation labeling to 
indicate that use of a drug is compatible with breast-feeding.
    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 impact on milk 
production, the presence of the drug in human milk, and/or the effects 
on the breast-fed child, the risk summary would be required to state 
that fact.
    Under FDA's current regulations, information is only required to be 
included in the ``Nursing mothers'' subsections of FDA's current 
regulations if a drug is absorbed systemically, in which case, 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. FDA believes 
that if a drug is not absorbed systemically, it is important for the 
health care provider and the nursing mother to be aware of this fact. 
Therefore, the proposed rule would require that the labeling of all 
drugs contain a ``Lactation'' subsection. The proposed rule would 
require that, when the drug is not systemically absorbed, the risk 
summary in the ``Lactation'' subsection contain 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 amount of (name of drug) will not be present in breast 
milk. Breast-feeding is not expected to result in fetal exposure to 
the drug.''
     The drug's impact on milk production. The proposed rule 
states that the description of the effects of the drug on milk 
production must include the effect of the drug on the quality and 
quantity of milk, including milk composition, and the implications of 
these changes to the milk for the breast-fed child. The advisory 
committee on lactation thought this information was important and 
recommended its inclusion in the labeling.
     The presence of the drug in human milk. The proposed rule 
states that the presence of the drug in human milk must be described in 
one of the following five 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.
If studies demonstrate that the drug is not detectable in human milk, 
the proposed rule would require that the risk summary state the limits 
of the assay used.
    The advisory committee on lactation recommended that lactation 
labeling include the amount of drug present in breast milk. Thus, the 
proposed rule also would require that, if the drug has been detected in 
human milk, the risk summary must give the concentration detected in 
milk in reference to a stated adult dose (or, if the drug has been 
labeled for use in pediatric populations, in reference to the labeled 
pediatric dose), an estimate of the amount consumed daily by the infant 
based on an average daily milk consumption of 150 milliliters (mL) per 
kilogram (kg) of infant weight per day (Ref. 31), and an estimate of 
the percent of the adult dose excreted in human milk.
     Effects on the breast-fed child. As recommended by the 
advisory committee on lactation, the proposed rule would require that 
the labeling contain information regarding the effects of the drug on 
the breast-fed child. This would include information on the likelihood 
and seriousness of known or predicted effects on the breast-fed child 
from exposure to the drug in human milk. As proposed, the risk summary 
must be based on the pharmacologic and toxicologic profile of the drug, 
the amount of drug detected or predicted to be found in human milk, and 
age-related differences in absorption, distribution, metabolism, and 
elimination. For example, the labeling might state: ``Based on its 
pharmacologic properties, Drug X has the potential to cause sedation in 
the breast-fed child. However, it is unlikely that sedation will occur 
because the estimated daily dose in human milk, based on the predicted 
presence of Drug X in human milk, is 2 percent of the daily pediatric 
dose for 6- to 12-month old infants.'' If the drug has not been labeled 
for pediatric use, the amount of the drug predicted to be present in 
human milk would be stated as a percentage of the maternal (i.e., 
adult) dose.
2. Clinical Considerations (Proposed Sec.  201.57(c)(9)(ii)(B))
    The clinical considerations component of the proposed ``Lactation'' 
subsection is intended to help health

[[Page 30846]]

care providers make informed decisions about prescribing drugs for 
lactating women. The proposed rule would require a discussion of three 
clinical issues to the extent information on them is available:
     Minimizing exposure of the breast-fed child. The proposed 
rule states that, when there are ways to minimize the exposure of the 
breast-fed child to the drug, such as timing the dose relative to 
breast-feeding or pumping and discarding milk for a specified period, 
the labeling must provide this information.
     Potential drug effects in the breast-fed child. The 
proposed rule states that the labeling must provide 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. For example, the labeling might state: ``Drug X may 
cause sedation in the breast-fed child.''
     Dosing adjustment during lactation. The proposed rule 
states that, to the extent it is available, information about dosing 
adjustments during lactation must be provided and that this information 
must also be included in the ``Dosage and Administration'' and 
``Clinical Pharmacology'' sections.
3. Data (Proposed Sec.  201.57(c)(9)(ii)(C))
    The proposed rule states that the Data component of the 
``Lactation'' subsection must provide an overview of the data that are 
the basis for the risk summary and the basis for the clinical 
considerations component.

D. Removing the Pregnancy Category Designation

    As discussed in section II.A and II.B of this document, the 
pregnancy categories currently found in Sec.  201.57(c)(9)(i)(A)(1) 
through (c)(9)(i)(A)(5) and Sec.  201.80(f)(6)(i)(a) through 
(f)(6)(i)(e) have been criticized for being overly simplistic and 
misleading about the degree of risk a drug presents to the fetus. 
Accordingly, FDA is not including pregnancy categories in its proposed 
revision to Sec.  201.57. However, the agency believes that it would be 
confusing to require category designations in the labeling for products 
subject to Sec.  201.80 while the labeling for products subject to 
Sec.  201.57 would not contain pregnancy categories. Therefore, the 
proposed rule would remove the pregnancy category designations (A, B, 
C, D, and X) from both the headings and text of Sec.  
201.80(f)(6)(i)(a) through (f)(6)(i)(e).

V. Implementation Plan for the Proposed Rule

A. General

    There are two components to this proposed rule. The first component 
would require that the labeling of new and recently approved products 
be revised to comply with the new pregnancy and lactation labeling 
content (new content) described in proposed Sec.  201.57(c)(9)(i) and 
(c)(9)(ii). The second component, affecting Sec.  201.80(f)(6)(i), 
would require products subject to that regulation to remove from 
existing labeling the pregnancy category designations (e.g., 
``Pregnancy Category C'') in both the headings and the text of that 
subsection of the labeling.
    For already approved products subject to the new content 
requirements, under Sec. Sec.  314.70(b) and 601.12(f)(1) (21 CFR 
314.70(b), 21 CFR 601.12(f)(1)), holders of approved applications would 
be required to submit a supplement and obtain FDA approval prior to 
distributing the new labeling. Already-approved products that only 
would be required to remove the pregnancy category designation would be 
required to report the change to FDA in an annual report (Sec. Sec.  
314.70(d) and 601.12(f)(3) (21 CFR 314.70(d) and 601.12(f)(3)).
    In the following discussion of the implementation plan, the term 
``application'' refers to new drug applications (NDAs), biologic 
licensing applications (BLAs), and efficacy supplements. Any final rule 
that becomes effective based on this proposed rule is referred to in 
the following discussion as ``the pregnancy final rule.''

B. New Content (Proposed Sec.  201.57(c)(9)(i) and (c)(9)(ii))

    The new content requirements of the proposed rule would apply to 
all applications required to comply with FDA's final rule on 
``Requirements on Content and Format of Labeling for Human Prescription 
Drug and Biological Products'' (71 FR 3921, January 24, 2006) (the 
physician labeling rule or the PLR). As stated in Sec.  201.56(b)(1), 
this includes:
     Prescription drug products for which an application was 
approved by FDA between June 30, 2001, and June 30, 2006;
     Prescription drug products for which an application was 
pending June 30, 2006;
     Prescription drug products for which an application was or 
is submitted anytime on or after June 30, 2006.
    The implementation schedule proposed in table 1 of this document 
would give all affected parties except those who submit an application 
on or after the date the pregnancy final rule becomes effective a 
minimum of 3 years after the effective date of the pregnancy final rule 
to submit labeling with the new content. FDA believes that this 3-year 
period would give industry sufficient time to use up existing labeling 
stocks and would avoid requiring manufacturers that have recently made 
the major labeling revision required by the physician labeling rule to 
make another significant labeling change in less than 3 years. In 
addition, the proposed implementation schedule would distribute the 
number of affected applications requiring review by the agency over a 
period of several years, thus assisting the agency in managing the 
workload associated with reviewing the new labeling.
    The effective date of the physician labeling rule was June 30, 
2006. For ease of coordinating the implementation of the pregnancy 
final rule with the implementation of the PLR, FDA proposes that the 
pregnancy final rule would become effective on the first June 30th that 
occurs at least 120 days after the date of publication of the pregnancy 
final rule. Thus, if the pregnancy final rule were to publish on 
January 14, 2010, the rule would become effective on June 30, 2010. Or, 
if the pregnancy final rule were to publish on June 1, 2010, the rule 
would become effective on June 30, 2011. For purposes of developing the 
proposed implementation schedule, FDA has assumed that the pregnancy 
rule will become effective no earlier than June 30, 2010. If it becomes 
effective earlier than that, FDA will adjust the implementation 
schedule accordingly.
    Table 1 of this document describes the implementation plan FDA is 
proposing for the pregnancy final rule.

[[Page 30847]]

                                          Table 1.--Implementation Plan
----------------------------------------------------------------------------------------------------------------
   Applications Required To Conform to New Pregnancy/      Time by Which Labeling with New Pregnancy/Lactation
             Lactation Content Requirements                   Content Must Be Submitted to FDA for Approval
----------------------------------------------------------------------------------------------------------------
New or Pending Applications:
----------------------------------------------------------------------------------------------------------------
  Applications submitted on or after the effective date  Time of submission
   of the pregnancy final rule
----------------------------------------------------------------------------------------------------------------
  Applications pending on the effective date of the      4 years after the effective date of pregnancy final
   pregnancy final rule                                   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  3 years after the effective date of pregnancy final
   to and including June 29, 2002, and from June 30,      rule
   2005, up to and including June 29, 2007
----------------------------------------------------------------------------------------------------------------
  Applications approved any time from June 30, 2007, up  4 years after the effective date of pregnancy final
   to and including the effective date of the pregnancy   rule
   final rule
----------------------------------------------------------------------------------------------------------------
  Applications approved from June 30, 2002, up to and    5 years after the effective date of pregnancy final
   including June 29, 2005                                rule
----------------------------------------------------------------------------------------------------------------

C. Removing the Pregnancy Category (Proposed Sec.  201.80(f)(6))

    Holders of applications approved prior to June 29, 2001 (i.e., 
applications not subject to the PLR), would not be required to 
implement the new content requirements. 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 pregnancy final rule. 
Because this is a relatively minor change, FDA believes it is not 
necessary to stagger its implementation.

VI. Legal Authority

A. Statutory Authority

    In this proposed rule, FDA is proposing to revise its regulations 
prescribing the format and content of the ``Pregnancy,'' ``Labor and 
delivery,'' and ``Nursing mothers'' subsections of the ``Use in 
Specific Populations'' section (under Sec.  201.57) and the 
``Precautions'' section (under Sec.  201.80) of the labeling for human 
prescription drugs.
    FDA's revisions to the content and format requirements for 
prescription drug labeling are authorized by the act and by the Public 
Health Service Act (the PHS Act). Section 502(a) of the act deems a 
drug to be misbranded if its labeling is false or misleading ``in any 
particular.'' Under section 201(n) of the act (21 U.S.C. 321(n)), 
labeling is misleading if it fails to reveal facts that are material 
with respect to consequences which 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 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 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 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 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 act 
(21 U.S.C. 371(a)) authorizes FDA to issue regulations for the 
efficient enforcement of the act.
    Under 21 CFR 314.125, FDA will not approve an NDA unless, among 
other things, there is adequate safety and effectiveness information 
for the labeled uses and the product labeling complies with the 
requirements of part 201. Under Sec.  201.100(d) of FDA's regulations, 
a prescription drug product must bear labeling that contains adequate 
information under which licensed practitioners can use the drug safely 
for their intended uses. This proposed rule amends the regulations 
specifying the format and content for such labeling.
    Section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 
262) provides legal authority for the agency to regulate the labeling 
and 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 proposed requirements for the content and format of the 
``Pregnancy'' and ``Lactation'' subsections of labeling for human 
prescription drug and biological 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. That analysis is equally applicable to this 
proposed rule, and we hereby adopt that discussion by reference.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or

[[Page 30848]]

cumulatively have a significant effect on the human environment. 
Therefore, neither an environmental assessment nor an environmental 
impact statement is required.

VIII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs agencies to assess all costs and benefits of 
available regulatory alternatives and, when regulation is necessary, to 
select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). The agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because so many prescription drug manufacturers 
would be affected by the proposed rule, the agency believes that this 
rule could have a significant impact on a substantial number of small 
entities. Consequently, the agency does not certify that the proposed 
rule will not have a significant economic impact on a substantial 
number of small entities. The following analysis, in conjunction with 
the preamble, constitutes the agency's initial regulatory flexibility 
analysis as required by the Regulatory Flexibility Act.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $127 million, using the most current (2006) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The proposed rule would amend the current requirements for the 
content of human prescription drug labeling related to use in specific 
populations. The primary benefit of the proposed rule would be improved 
communication of clinically relevant information on the safe and 
effective use of prescription drugs by pregnant or lactating women. 
Although the agency is unable to quantify these benefits, this proposed 
rule is the product of over 10 years of consultation with stakeholders. 
Direct costs of the proposed rule are projected to range from 
approximately $0.8 million to $17.6 million in any single year, and 
over 10 years have a total present value of approximately $50.3 million 
with a 7-percent discount rate or $61.7 million with a 3-percent 
discount rate. The annualized costs over 10 years would be $7.2 million 
with both a 7-percent discount rate and with a 3-percent discount rate. 
Although the agency is unable to quantify the net benefits of this 
proposed rule, the rule responds to problems with existing labeling 
identified by current users of drug product labeling. FDA therefore 
concludes that the potential benefit of better informed health care 
providers and patients would justify the costs of the rule. 
Furthermore, the agency has determined that the proposed rule is not an 
economically significant rule as defined by the Executive order.

A. Need for the Proposed Rule

    In response to concerns about the usefulness of the current 
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers'' 
subsections of prescription drug product labeling, FDA held a part 15 
hearing and two advisory committee meetings and consulted with focus 
groups and the public to solicit comment on how to improve these 
subsections. During these discussions, participants said that current 
prescription drug product labeling lacks clarity and often fails to 
provide meaningful clinical information about drug exposure during 
pregnancy and lactation. Of equal concern, current prescription drug 
product labeling is not designed to address either inadvertent drug 
exposure in early pregnancy or the potential consequences of 
discontinuing during pregnancy a drug prescribed to the mother to treat 
a chronic condition. Moreover, the current system of pregnancy 
categories can be ambiguous, give a false impression of the comparative 
risks of different prescription drug products, and fail to adequately 
provide meaningful information that health care providers can use to 
advise their patients on the safe and effective use of prescription 
drugs during pregnancy.
    This rule, therefore, proposes to improve the quality of 
prescription drug labeling. Providing up-to-date information on the 
safe and effective use of prescription drugs during pregnancy and 
lactation in a standardized format would make labeling a more reliable 
resource that health care providers could consult when they seek 
prescription drug information for their pregnant and lactating 
patients.

B. Scope of the Proposed Rule

    This proposed rule would affect human prescription drugs that would 
be required to have labeling with a ``Pregnancy'' or ``Lactation'' 
subsection. Some manufacturers with multiple dosage forms, dosage 
strengths, and package sizes of the same active ingredients may produce 
a single version of the labeling to use with all products. 
Nevertheless, for this analysis, FDA assumes that manufacturers will 
produce separate labeling for each dosage form, but will use the same 
version for all package sizes and dosage strengths of the same dosage 
form. This assumption may lead to an overestimation of the costs of the 
proposed rule.

C. Costs of the Proposed Rule

    The extent to which the proposed rule might affect labeling depends 
on whether an affected application is subject to the PLR. The labeling 
for applications subject to the PLR would need to conform to the 
proposed content requirements for the ``Pregnancy'' and ``Lactation'' 
subsections of the ``Use in Specific Populations'' section of the full 
prescribing information (proposed Sec. Sec.  201.57(c)(9)(i)-
(c)(9)(ii)). The labeling of applications not subject to the PLR would 
only need to conform to the proposed requirement to remove the 
pregnancy category if it exists. The level of effort required to comply 
with the proposed changes, therefore, would depend on whether the 
affected application is subject to the requirements of the PLR. In the 
analysis of costs, multiple applications for the same prescription drug 
product are counted only once.
1. Affected Applications
    a. Future applications. NDAs, BLAs, and efficacy supplements 
submitted on or after the effective date of the pregnancy labeling 
final rule are future applications. Even though the number of future 
applications is unknown, for the analysis of impacts for the PLR (71 FR 
3922 at 3969), FDA examined approvals from 1997 to 2001 to estimate the 
average annual number of applications that might be submitted in the 
future (i.e., after the effective date of the PLR). An updated analysis 
of the FDA approval data suggests that these estimates remain 
representative of current activity. Thus, FDA continues to

[[Page 30849]]

use the numbers derived for the PLR analysis as the agency's best 
estimate of future activity. Table 2 of this document shows that 
manufacturers might submit an estimated 1,580 applications in the 10 
years following the effective date of the pregnancy labeling final 
rule, with approximately 75 percent of these submissions being for 
innovator products.
    b. Approved or pending applications subject to the PLR. Any 
approved or pending application subject to the requirements of the PLR 
would also need to conform to the requirements of this proposed rule. 
This includes applications pending on the effective date of the 
pregnancy labeling final rule and those applications approved between 
June 30, 2001, and the effective date of the pregnancy labeling final 
rule. For the purposes of this analysis, FDA assumes that the pregnancy 
labeling final rule would become effective on June 30, 2010, and affect 
some applications counted as future applications in the PLR analysis.
    This analysis uses FDA's approval data to tally the number of 
affected approvals between June 30, 2001, and June 30, 2006. This 
number provides a partial estimate of the number of approved or pending 
applications that might be affected by the proposed rule. Because the 
number of applications that would be submitted between June 30, 2006, 
and the effective date of the pregnancy labeling rule is unknown, FDA 
uses the estimate of the number of future applications in years 5 to 10 
from the PLR analysis to complete the estimate of the number of 
approved or pending applications subject to the PLR that might be 
affected by this proposed rule.
    To minimize the burden on industry, FDA proposes that manufacturers 
with labeling that already conforms to the PLR requirements on the 
effective date of the pregnancy labeling final rule would have from 3 
to 5 years to revise labeling to conform to the requirements of the 
rule. Table 2 of this document shows that the existing labeling of an 
estimated 1,300 innovator applications and 600 generic applications 
would need to be revised to add the new content that would be required 
by the pregnancy labeling final rule.

                                            Table 2.--Estimated Number of Applications Subject to the PLR\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                           Future Applications           Pending or Recently Approved Applications                  Total
              Year               -----------------------------------------------------------------------------------------------------------------------
                                   Innovator Drugs     Generic Drugs       Innovator Drugs        Generic Drugs      Innovator Drugs     Generic Drugs
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                               140                 40                     0                     0                140                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                               130                 40                     0                     0                130                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                               120                 40                   380                   260                500                300
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                               120                 40                   480                   130                600                170
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                               120                 40                   440                   210                560                250
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                               110                 40                     0                     0                110                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                               110                 40                     0                     0                110                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                               110                 40                     0                     0                110                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                               110                 40                     0                     0                110                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                              110                 40                     0                     0                110                 40
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                         1,180                400                 1,300                   600              2,480              1,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Numbers include an estimated 1,613 pending or future applications (Source: See ANDAs, efficacy supplements, new NDAs and BLAs for years 5 to 10 of
  table 14 in 71 FR 3922 at 3977 through 3978), and 1,900 approved applications when the pregnancy labeling final rule becomes effective (Source:
  Analysis of approvals from June 29, 2001, to June 30, 2006, using FDA's approval data). Numbers may not sum due to rounding.

    c. Approved applications not subject to the PLR. The proposed rule 
would require that manufacturers responsible for the labeling of 
approved applications not subject to the requirements of the PLR make 
minor revisions to remove the pregnancy category from the existing 
``Pregnancy'' subsection of the ``Precautions'' section of the 
labeling. Manufacturers would have 3 years after the effective date of 
the pregnancy labeling final rule to make this change. This provision 
of the proposed rule would affect any approved application not subject 
to the PLR that currently has labeling that contains a pregnancy 
category. Although the actual number of applications that would be 
affected by this provision of the proposed rule is uncertain, the 
recent analysis of FDA's approval data suggests that the labeling of up 
to 4,720 existing prescription drug products could be affected in year 
3 of the rule. Because the labeling of many older products initially 
approved before 1979 might not contain a pregnancy category, this 
estimate is an upper bound. Moreover, it should be noted that 
manufacturers sometimes voluntarily discontinue marketing older 
products and might do so before they would be required to remove the 
pregnancy category. Although the magnitude is uncertain, this natural 
attrition would likely reduce the number of products that would be 
affected by the pregnancy labeling final rule.
2. One-Time and Annual Labeling Costs
    a. One-time costs. The actions required under this proposed rule to 
create drug product labeling can be divided into two major categories: 
(1) Collecting and organizing the additional information required by 
this proposed rule and (2) revising existing labeling to add or remove 
information. FDA notes that designing the labeling is a routine cost of 
a new application and would not be attributable to this proposed rule. 
To conform to the requirements of the proposed rule, manufacturers 
might spend more time on these actions than

[[Page 30850]]

they currently spend preparing the ``Pregnancy,'' ``Labor and 
delivery,'' and ``Nursing mothers'' subsections of the labeling, thus 
incurring additional labeling costs. Which costs would be incurred by a 
manufacturer will depend on when in the product's life cycle the 
labeling subject to the pregnancy labeling final rule would be required 
and whether the application is subject to the PLR. For example, 
manufacturers with future innovator applications would only incur costs 
to collect and organize the required information because designing 
labeling is a routine cost of a new application. In contrast, 
manufacturers required to change existing product labeling would incur 
both types of costs (i.e., collecting and organizing required 
information, and revising existing labeling).
    i. One-time costs to collect and organize the new content. 
Manufacturers responsible for applications subject to the new content 
requirements would need to collect and organize the information 
required for the appropriate subsections of the ``Use in Specific 
Populations'' section of the labeling. Specifically, the proposed rule 
would merge the information in the ``Pregnancy'' and ``Labor and 
delivery'' subsections and revise the ``Nursing mothers'' subsection. 
The merged subsection would be called the ``Pregnancy'' subsection and 
would require the following: (1) Information about pregnancy exposure 
registries, (2) a general risk statement, (3) a fetal risk summary, (4) 
clinical considerations, and (5) a discussion of data. The proposed 
rule would rename the ``Nursing mothers'' subsection the ``Lactation'' 
subsection and require the following: (1) A risk summary, (2) clinical 
considerations, and (3) a discussion of data.
    Under the current system, applicants and FDA review any existing 
animal and human data and determine the appropriate pregnancy category. 
Although the proposed rule would no longer require that a drug be 
assigned to a pregnancy category, preparing the new labeling content 
might require more time than manufacturers currently spend preparing 
this part of the product labeling. FDA personnel have worked with 
manufacturers on a case-by-case basis to update certain prescription 
drug labeling to include content similar to the content that would be 
required by the proposed rule. This experience suggests that for 
innovator products, a physician or other health care professional might 
spend up to 10 hours collecting the new information. In addition, 
regulatory affairs and legal personnel might spend up to 10 hours 
organizing the information and discussing the new content with FDA. At 
hourly wage costs of $100 for medical personnel and $50 for regulatory 
and legal personnel, manufacturers would incur about $1,500 in 
additional costs (10 hours x $100 per hour + 10 hours x $50 per hour). 
Because labeling of generic drug products duplicates the labeling of 
reference listed drugs, FDA anticipates that manufacturers of generic 
products would not incur these incremental costs.
    Furthermore, under Sec.  314.50(l)(1)(i), all manufacturers 
submitting new or revised prescription drug labeling must prepare an 
electronic version of the labeling for submission to the agency. Some 
manufacturers may incur incremental costs to prepare and transmit an 
electronic version that is consistent with the XML (Extensible Markup 
Language)-based Structured Product Labeling (SPL) standard. Because FDA 
has little information on the impact of this step, FDA requests 
detailed comment from industry on these costs.
    ii. One-time costs to revise existing prescription drug labeling. 
The agency has previously estimated that the cost of revising 
prescription drug labeling varies with the size of the manufacturer (68 
FR 6062 at 6074, February 6, 2003). Product labeling involves many 
departments in a manufacturer, including legal, drug safety, regulatory 
affairs, layout, and production personnel. Larger manufacturers with 
several administrative layers may require more time to change labeling 
than smaller manufacturers with fewer layers. In addition to labor 
costs, manufacturers incur material costs for each change to drug 
product labeling, including artwork and labeling scrap. If the rule 
were to require a labeling revision without allowing sufficient time to 
deplete existing inventories of labeling, manufacturers might also lose 
the value of labeling that they must throw away.
    Using 2004 wages, table 3 of this document shows the estimated 
labor and material costs for generic drug manufacturers and three sizes 
of innovator manufacturers to revise labeling. Because the proposed 
implementation schedule would allow manufacturers with approved or 
pending applications subject to the PLR a minimum of 3 years to revise 
product labeling to conform to the requirements of the pregnancy final 
rule, manufacturers are not expected to incur any additional inventory 
costs beyond scrap. Material costs, therefore, include only the average 
cost of artwork and scrap.

                       Table 3.--Labeling Revision Costs by Size and Type of Manufacturer
----------------------------------------------------------------------------------------------------------------
                  Type of manufacturer                     Labor Cost ($)   Material Cost ($)    Total Cost ($)
----------------------------------------------------------------------------------------------------------------
Generic:                                                             1,000                500              1,500
Innovator (estimated share of products):                 .................  .................  .................
  Small (5 percent)                                                  1,000                500              1,500
  Medium (5 percent)                                                 1,500              1,420              2,920
  Large (90 percent)                                                 2,180              2,020              4,200
----------------------------------------------------------------------------------------------------------------
Source: 68 FR 6062 at 6074, updating for 2004 costs and excluding excess inventory loss from the material costs.

    FDA's approval data suggests that large manufacturers with 1,000 or 
more employees produce about 90 percent of the affected innovator 
prescription drug products. Assuming a uniform distribution of the 
other 10 percent of innovator prescription drug products among small 
and medium-size manufacturers, manufacturers of innovator prescription 
drug products may incur a weighted average cost of about $4,000 per 
product to revise existing product labeling ((5 percent small innovator 
manufacturers x $1,500) + (5 percent medium-size innovator 
manufacturers x $2,920) + (90 percent large innovator manufacturers x 
$4,200)). Generic drug manufacturers may incur about $1,500 per product 
to revise labeling.
    iii. One-time cost to prepare artwork for prescription drug 
labeling other than trade labeling. The PLR requires that trade 
labeling (labeling on or within the package from which the drug is to 
be dispensed) be printed in a minimum of 6-point type size and that 
labeling

[[Page 30851]]

disseminated in other contexts (nontrade labeling) be printed in a 
minimum of 8-point type size (Sec.  201.57(d)(6)). In the analysis of 
impacts for the PLR, FDA assumed that manufacturers would incur 
additional costs for nontrade labeling because the 8-point type size 
requirement would require that manufacturers revise nontrade labeling 
to accommodate the larger type size. FDA makes the same assumption for 
prescription drug labeling incorporating the new pregnancy and 
lactation content: that affected manufacturers would incur additional 
one-time costs to revise nontrade labeling to accommodate the new 
pregnancy and lactation content in the 8-point type size. The agency 
previously estimated it would cost manufacturers about $810 per product 
to revise and proofread the layout, and to prepare artwork (71 FR 3922 
at 3981). Updating for current material and labor costs, on average, 
FDA estimates that, on average, manufacturers might spend $1,000 for 
each affected innovator product.
    b. Annual incremental costs to print longer labeling. Longer 
labeling increases the cost of paper, ink, and other ongoing 
incremental printing costs. Some requirements of the proposed rule 
would increase the length of labeling. The incremental increase will 
depend on many factors, including the number of animal and human 
studies that have been conducted and their findings, the known risks of 
the drug, and whether a pregnancy registry exists. Based on the 
agency's experience with recent labeling changes incorporating content 
similar to that proposed in this rule, labeling conforming to both the 
PLR and the proposed requirements might increase by approximately 15 
square inches in 6-point type size and 24 square inches in 8-point type 
size.\4\ Although the estimate is based on a small number of labeling 
changes, FDA concludes it reasonably approximates the additional amount 
of paper that would be needed. Nevertheless, FDA requests comment from 
industry on these assumptions.
---------------------------------------------------------------------------

    \4\ This estimate is based on the agency's sample labeling in 
the appendix, experience with recent case-by-case labeling changes, 
and the results of a study on new approvals between January 1, 1997, 
and December 31, 2002. The net increase in the number of characters 
was tallied for each case and for the hypothetical samples in the 
appendix. Using the average increase in the number of characters and 
the proportion of drug products for each pregnancy category, we 
estimate that prescription drug labeling could increase by a 
weighted average of 3,200 characters. Labeling can accommodate 
approximately 200 characters per square inch in 6-point type size 
and about 130 characters per square inch in 8-point type size. 
Therefore, 3,200 additional characters would require about 15-square 
inches of paper in 6-point type size and 24-square inches of paper 
in 8-point type size.
---------------------------------------------------------------------------

    i. Trade labeling. Manufacturers must send trade labeling with all 
shipments of prescription drugs and with any samples distributed to 
health care providers. The PLR requires that trade labeling be printed 
in a minimum of 6-point type size. The proposed new content 
requirements would increase the size of trade labeling by an estimated 
15-square inches. To conserve space, trade labeling is normally printed 
on both sides of the paper. The proposed new content, therefore, would 
add about 7.5-square inches of paper to the overall size of trade 
labeling. The agency previously estimated that manufacturers would 
spend about $0.0086 to produce 100-square inches of labeling (65 FR 
81082 at 81107). Updating for inflation, FDA estimates that 
manufacturers might spend $0.01 for each additional 100-square inches 
of labeling they produce.
    The agency has also previously estimated that, on average, 
manufacturers annually send up to 650,000 pieces of trade labeling with 
each innovator product and up to 370,000 pieces of trade labeling with 
each generic product. In addition, industry wide, a total of 90 million 
pieces of trade labeling are distributed with drug samples each year 
(71 FR 3922 at 3979). Because the new content provisions of this 
proposed rule would only add about 7.5-square inches to the overall 
size of trade labeling, the cost of labeling for an affected innovator 
product would increase by approximately $470 each year (650,000 pieces 
per product x $0.000096 per square inch x 7.5-square inches per piece). 
Generic drug manufacturers would incur annual incremental printing 
costs of about $280 for each generic product affected by the proposed 
rule (370,000 pieces per product x $0.000102 per square inch x 7.5-
square inches per product).
    FDA assumes that almost all samples are innovator products. 
Although it is unlikely that all samples would be affected by the 
proposed rule, the annual cost of longer trade labeling accompanying 
all samples of innovator products could equal about $65,000 (90 million 
samples x $0.000096 per square inch x 7.5-square inches per piece).
    ii. Nontrade labeling. The PLR requires that any nontrade labeling 
be printed in a minimum of 8-point type size. For applications subject 
to the PLR, the new content requirements of the proposed rule would 
increase the size of the paper needed to print nontrade labeling by 
approximately 24 square inches. FDA assumes that only innovator 
products would incur these costs because almost all nontrade labeling 
is for innovator products. The agency previously estimated that 
manufacturers might distribute to health care providers and consumers 
an annual average of 730,000 pieces of labeling during the first 3 
years of the life of an innovator product (71 FR 3922 at 3981). FDA 
assumes that this estimate is also a reasonable estimate of the number 
of pieces of labeling that would be distributed in the first 3 years 
after a product is relabeled under this rule. Thus, a manufacturer 
might spend up to $5,100 per innovator product to print labeling in 8-
point type size.\5\
---------------------------------------------------------------------------

    \5\ For the PLR, the agency estimated that manufacturers would 
print and distribute 775,000 pieces of labeling in 8-point type size 
in the first year of the life cycle of an innovator drug product and 
710,000 pieces in years 2 and 3. Compared to the 6-point type size, 
about 59 percent more paper would be needed to print the new content 
in 8-point type size. Printing on one side of the paper, 
manufacturers would need about 24 square inches more paper to 
accommodate the new content. For this analysis, manufacturers would 
spend about $5,100 per product to print longer labeling ((775,000 + 
710,000 + 710,000) x $0.000096 per sq inch x 24 sq inches = $5,083).
---------------------------------------------------------------------------

    iii. Physicians' Desk Reference (PDR) costs. The new content 
requirements of this proposed rule would add about 0.2 page to labeling 
printed in the PDR and would cost manufacturers an additional $2,350 
annually for each affected product.\6\ FDA assumes that these costs 
would be incurred by the pharmaceutical industry as fees paid to the 
publisher of the PDR. The total cost for a manufacturer to print longer 
labeling in the PDR depends on how many years the labeling remains in 
the PDR. In the economic analysis of the PLR, FDA assumed that only 75 
percent of the affected innovator products would have labeling 
published in the PDR (some smaller manufacturers do not publish 
labeling in the PDR) and would continue to include the labeling in the 
PDR in subsequent years (71 FR 3922 at 3976). FDA makes the same 
assumptions for this analysis.
---------------------------------------------------------------------------

    \6\ There are approximately 15,850 characters on an average page 
of the PDR. The new content adds, on average, 3,200 more characters, 
requiring an additional 0.2 page. Using the lowest per page cost 
shown on the 2006 PDR rate card, manufacturers might spend up to 
$2,350 per product to add the new content ($11,730 per page x 0.2 
page).
---------------------------------------------------------------------------

3. Summary of Industry Compliance Costs for the Proposed Rule
    a. One-time costs for applications subject to the PLR. 
Manufacturers with future innovator applications or those with 
innovator applications pending on the effective date of the pregnancy 
labeling rule would incur one-time costs to collect and organize the 
information required for prescription drug labeling

[[Page 30852]]

conforming to the rule, but would not incur one-time costs to revise 
existing labeling. As explained in section VIII.C.2.a.i of this 
document, FDA estimates that manufacturers would spend approximately 
$1,500 to collect and organize the information for the new pregnancy 
and lactation content. In contrast, manufacturers with future generic 
applications would incur no additional costs.
    Manufacturers with applications approved on or after June 30, 2001, 
up to and including the effective date of the pregnancy labeling final 
rule, would incur costs to collect and organize the new content 
information and to revise existing prescription drug labeling. As 
described in section VIII.C.2.a.ii of this document, the estimated 
average cost to revise existing labeling equals $1,500 for generic 
drugs and $4,000 for innovator drugs. Moreover, manufacturers with 
innovator products might incur another $1,000 to prepare the artwork 
for labeling not accompanying the prescription drug product. Therefore, 
manufacturers might spend a total of $6,500 for existing innovator 
labeling ($1,500 to gather and organize information for the new content 
+ $4,000 to revise trade labeling + $1,000 to prepare artwork for 
labeling not accompanying the prescription drug product) and a total of 
$1,500 for existing generic labeling.
    Table 4 of this document shows that total one-time labeling costs 
would be $11.1 million and range from $0.2 million to $3.5 million in 
any single year. As shown in table 2 of this document, after 10 years, 
the labeling of approximately 2,480 innovator drug products and about 
1,000 generic drug products would include the new pregnancy and 
lactation content.

   Table 4.--One-Time Costs to Prepare New Content and Revise Existing
             Labeling for Applications Subject to the PLR\1\
------------------------------------------------------------------------
                               One-Time Costs ($ million)
     Year     ----------------------------------------------------------
                   Innovators            Generic             Total
------------------------------------------------------------------------
1              0.2                 0.0                 0.2
2              0.2                 0.0                 0.2
3              2.7                 0.4                 3.0
4              3.3                 0.2                 3.5
5              3.0                 0.3                 3.4
6              0.2                 0.0                 0.2
7              0.2                 0.0                 0.2
8              0.2                 0.0                 0.2
9              0.2                 0.0                 0.2
10             0.2                 0.0                 0.2
------------------------------------------------------------------------
Total          10.2                0.9                 11.1
------------------------------------------------------------------------
\1\ Costs may not sum due to rounding. See table 2 of this document for
  details on the number and distribution of affected products.

    b. Annual incremental printing costs for applications subject to 
the PLR.
    i. Trade labeling. As described in section VIII.C.2.b.i of this 
document, the agency estimates that each year manufacturers print an 
average of about 650,000 pieces of trade labeling for each innovator 
product and an average of about 370,000 pieces of trade labeling for 
each generic product. Based on the average number of pieces of trade 
labeling and the estimated number of affected applications subject to 
the PLR from table 2 of this document, table 5 of this document shows 
the cumulative number of pieces of trade labeling that would be 
affected by this proposed rule.

    Table 5.--Cumulative Number of Pieces of Prescription Drug Trade
   Labeling by Type of Product for Applications Subject to the PLR\1\
------------------------------------------------------------------------
                         Cumulative Number of Pieces (million)
    Year     -----------------------------------------------------------
                   Innovator            Generic             Samples
------------------------------------------------------------------------
1             90                  10                  90
2             180                 30                  90
3             500                 140                 90
4             890                 200                 90
5             1,250               300                 90
6             1,330               310                 90
7             1,400               330                 90
8             1,470               340                 90
9             1,540               360                 90
10            1,610               370                 90
------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding. The cumulative calculation
  assumes that manufacturers print 650,000 pieces for each innovator
  product and 370,000 pieces for each generic product, and once a
  product is approved, it remains on the market for the entire analysis.

    Printing longer trade labeling would cost manufacturers a total of 
$9.9 million over 10 years, including $7.4 million for innovator trade 
labeling, $1.8 million for generic trade labeling, and $0.7 million for 
trade labeling accompanying samples. As shown in table 6 of this 
document, annual costs to print the additional information that would 
be required by this proposed rule range from $0.1 million in year 1 to 
$1.5 million in year 10. However, if at some point in the future, 
manufacturers can supply trade labeling electronically, the rule will 
cease to impose these annual incremental printing costs.

Table 6.--Annual Incremental Printing Costs for Longer Trade Labeling\1\
------------------------------------------------------------------------
                            Costs by Type\2\ ($ million)
   Year    -------------------------------------------------------------
               Innovator        Generic         Samples         Total
------------------------------------------------------------------------
1           0.1             0.0             0.1             0.1
2           0.1             0.0             0.1             0.2
3           0.4             0.1             0.1             0.5
4           0.6             0.2             0.1             0.9
5           0.9             0.2             0.1             1.2
6           1.0             0.2             0.1             1.3
7           1.0             0.2             0.1             1.3
8           1.1             0.3             0.1             1.4
9           1.1             0.3             0.1             1.5
10          1.2             0.3             0.1             1.5
------------------------------------------------------------------------
Total       7.4             1.8             0.7             9.9
------------------------------------------------------------------------
\1\ Costs may not sum due to rounding.
\2\ Manufacturers would incur printing costs of about $72.37 for every
  100,000 pieces of innovator trade labeling and about $76.58 for every
  100,000 pieces of generic trade labeling. Trade labeling accompanying
  prescription drug samples would cost industry about $65,132 annually.
  See section IX.C.2.b.i of this document for details.

    ii. Nontrade labeling. As discussed in section VIII.C.2.b.ii of 
this document, the new content requirements of the pregnancy labeling 
final rule likely would require manufacturers to print longer nontrade 
labeling in 8-point type size during the first 3 years after adding the 
new content to labeling. FDA assumes that only innovator products would 
incur these costs because almost all nontrade labeling is for innovator 
products. Thus, over 10 years, manufacturers of innovator products 
might spend up to $12.6 million ($5,100 per innovator product x 2,480 
innovator products) to print labeling in 8-point type size.
    iii. Physicians' Desk Reference. As discussed in section 
VIII.C.2.b.iii of this document, manufacturers of innovator products 
may pay an additional $2,350 annually to include longer prescription 
drug labeling in the PDR. Because FDA assumes that, after the first 
year, labeling would remain in the PDR for all subsequent years, PDR 
printing costs are cumulative. As illustrated in table 7 of this 
document, in 10 years industry might incur a cumulative total of $27.8 
million to print longer labeling in the PDR.

     Table 7.--Cumulative Number of Affected Applications and Annual
        Incremental Cost of Longer Labeling Printed in the PDR\1\
------------------------------------------------------------------------
                         Cumulative Number of
        Year              Affected Innovator     Annual Incremental Cost
                           Applications\2\               ($ mil)
------------------------------------------------------------------------
1                     110                        0.2
2                     210                        0.5
3                     590                        1.4
4                     1,040                      2.4
5                     1,460                      3.4
6                     1,540                      3.6
7                     1,620                      3.8
8                     1,700                      4.0
9                     1,780                      4.2
10                    1,860                      4.4
------------------------------------------------------------------------

[[Page 30853]]

Total Cost            27.8
------------------------------------------------------------------------
\1\ Costs may not sum due to rounding.
\2\ Seventy-five percent of innovator products adding new content (see
  table 2 of this document) would be included in the PDR.

    c. One-time costs for applications not subject to the PLR. The 
proposed rule would require that manufacturers with approved 
prescription drugs not subject to the PLR remove the pregnancy category 
from labeling if a category exists. To minimize the impact on industry, 
the agency proposes to give manufacturers 3 years after the effective 
date of the pregnancy labeling final rule to make these changes. The 
proposed implementation schedule would give manufacturers sufficient 
time to deplete their stocks of labeling. Because removing the 
pregnancy category is a minor labeling change, manufacturers not 
subject to the PLR would only need to submit revised labeling with 
their annual reports. In most cases, the burden on manufacturers would 
be less than the average standard costs to revise existing labeling 
(see table 3 of this document). However, some manufacturers with 
multiple applications not subject to the PLR may need to revise 
simultaneously the labeling of many products, creating other costs than 
those estimated for standard labeling revisions. FDA requests detailed 
comment from industry about the potential burden of the implementation 
schedule for this provision of the proposed rule.
    Based on an analysis of FDA's approval data, an estimated 4,720 
prescription drug products would be affected by this provision of the 
proposed rule. The agency estimates that in year 3, manufacturers would 
remove the pregnancy category from labeling of 1,700 innovator 
prescription drug products and 3,020 generic prescription drug 
products, at a total cost of $11.3 million ((1,700 innovator products x 
$4,000 per innovator product) + (3,020 generic products x $1,500 per 
generic product)). This estimate likely overstates the direct 
compliance costs because many companies would remove the pregnancy 
category at the same time they voluntarily revise product labeling for 
other reasons.
    d. Summary of compliance costs. The industry compliance costs of 
the proposed rule include the following: (1) One-time cost to prepare 
the new ``Pregnancy'' and ``Lactation'' subsections of trade labeling 
and labeling not accompanying prescription drug products, and (2) 
annual incremental costs to print longer labeling.
    Similar to the rollout for PLR, FDA would provide training to 
medical reviewers on the requirements of the final pregnancy labeling 
rule. Nevertheless, reviewing the new labeling, including the longer 
content, would increase the review times and workloads of medical 
reviewers in the review divisions. Because the long-term impact of the 
rule depends on a number of uncertain factors, we are unable to 
quantify this burden on the agency.
    As shown in table 8 of this document, the total present value of 
all costs equals $50.3 million with a 7-percent discount rate or $61.7 
million with a 3-percent discount rate. The annualized cost would be 
$7.2 million with both a 7-percent discount rate and a 3-percent 
discount rate.

                                                        Table 8.--Summary of Compliance Costs\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                            Present Value ($ mil)
                     Year                        One-time Costs ($     Annual Costs ($ mil)   Total Costs ($ mil)  -------------------------------------
                                                        mil)                                                                3%                 7%
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                                                0.2                    0.6                    0.8                0.8                0.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                                                0.2                    1.2                    1.3                1.3                1.2
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                                               14.4                    3.2                   17.6               16.1               14.4
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                                                3.5                    5.4                    8.9                7.9                6.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                                                3.4                    7.4                   10.8                9.3                7.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                                                0.2                    7.0                    7.1                6.0                4.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                                                0.2                    6.4                    6.6                5.3                4.1
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                                                0.2                    5.9                    6.1                4.8                3.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                                                0.2                    6.2                    6.3                4.9                3.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                                               0.2                    7.0                    7.1                5.3                3.6
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
Total                                                           22.5                   50.3                   72.7               61.7               50.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Costs may not sum due to rounding.

D. Benefits

    This proposed rule is part of the agency's ongoing efforts to 
improve the quality of prescription drug labeling. To effectively 
communicate information about a drug, labeling should be easily 
accessible, understandable, accurate, reliable, and up-to-date. The 
agency's public health initiative to provide labeling in an electronic 
format is intended to make labeling accessible. This proposed rule 
would address the other aspects of effective communication and result 
in better quality prescription drug labeling. Once a prescription drug 
is approved, information starts to become available regarding clinical 
experience on the use of the drug during pregnancy or lactation. The 
purpose of this proposed rule is to ensure that prescription drug

[[Page 30854]]

labeling includes any available clinical information that can inform 
health care providers about the safe and effective use of prescription 
drugs during pregnancy and lactation. By requiring that manufacturers 
update prescription drug labeling with clinically relevant information, 
the proposed rule would improve the quality of labeling and could lead 
to better informed health care providers. The agency is unable to 
quantify the potential benefits of the proposed rule, but expects that 
better quality information in prescription drug labeling has the 
potential to improve the advice that health care providers give women 
about the safe and effective use of prescription drugs during pregnancy 
and lactation.
1. Current Use of Prescription Drugs.
    a. Women of reproductive age. Many women between 15 and 44 years of 
age take prescription drugs. Data from the Medical Expenditure Panel 
Survey (MEPS) show that, in 2003, almost 70 percent of the women of 
reproductive age were prescribed at least one prescription drug (Ref. 
32). Moreover, in a recent survey of medication use in adults, 82 
percent of the women between 18 and 44 years of age reported using some 
type of medication in the week preceding the survey and 46 percent of 
these women reported using at least one prescription drug (Ref. 9).
    b. Pregnant women. A recent retrospective study of over 150,000 
pregnant women enrolled in 8 health maintenance organizations located 
throughout the United States found that within 270 days before 
delivery, over 60 percent of the women included in the study were 
dispensed a prescription drug other than a vitamin or mineral 
supplement (Ref. 33). Oral anti-infective drugs were the most commonly 
dispensed prescription drugs, accounting for about 40 percent of all 
dispensed drugs. Even though almost half of the pregnant women in this 
study received prescription drugs with pregnancy category A or B, over 
30 percent received prescription drugs with pregnancy category C, and 2 
percent received category D or X drugs (excluding female reproductive 
hormones). Similarly, a smaller study of rural obstetric patients in 
West Virginia found that, excluding prenatal vitamins and minerals, 
about 60 percent of the pregnant women in the study were prescribed a 
prescription drug (Ref. 34). Although this study did not examine the 
pregnancy category of the prescribed drugs, antibiotics were the most 
frequently prescribed type of drug.
    These newer findings support findings reported in a 1994 Institute 
of Medicine report on women in clinical trials (Ref. 35). The report 
cited two studies from the 1980s on prescription drug use by pregnant 
women. One study found that pregnant women took an average of 3.8 
medications and the other found that over 75 percent of pregnant women 
took 3 to 10 drugs during their pregnancy. Studies of pregnant women in 
several developed countries have found similar results for prescription 
drug use during pregnancy (Refs. 14, 36, and 37).
    c. Lactating women. There is less information about the effect of 
prescription drugs on lactation than about effects on pregnancy. The 
percentage of new mothers who breast-feed their newborns continues to 
grow. A recent study found that the percent of mothers who breast-feed 
their newborns at some time increased from about 50 percent in 1990 to 
about 70 percent in 2003 (Ref. 38). With improved labeling, health care 
providers would have more concise clinical information about the use of 
prescription drugs during lactation, allowing women to make more 
informed choices about continuing to nurse their newborns while taking 
prescription drugs.
2. Current Pregnancy Labeling Is Not Adequate
    Since 1979, most human prescription drug product labeling includes 
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers'' 
subsections. Besides providing information about a prescription drug's 
effect on reproduction, pregnancy, and the development of the fetus, 
each ``Pregnancy'' subsection must include a letter category (A, B, C, 
D, or X) intended to: (1) Communicate the prescription drug's 
reproductive and developmental risks or (2) weigh the risks and 
potential benefits of the prescription drug. The pregnancy letter 
category suggests increased risk as the letters ascend and equivalent 
risk for drugs with the same letter. This is a particular problem with 
category C because a prescription drug can be assigned this category 
when sponsors: (1) Lack both animal and human data or (2) have adverse 
animal data, but lack human data.
    Pregnant women are rarely included in premarket clinical trials 
unless a drug is being developed to treat a condition unique to 
pregnancy. Consequently, few sponsors have any premarket data from 
pregnant women. Because human data on use during pregnancy are rarely 
available when a prescription drug is initially approved, category C is 
the most frequently assigned category. For example, a survey in the 
early 1990s found that about two-thirds of all prescription drugs in 
the hardcopy version of the PDR were in category C (Ref. 39). A recent 
search of the electronic PDR supports this observation. The study also 
found that over 60 percent of the prescription drugs with a pregnancy 
category were in category C (Ref. 40). Furthermore, once approved, 
prescription drugs tend to retain their initial pregnancy category.
    Current labeling fails to provide up-to-date information about 
prescription drug use by pregnant or lactating women. Since the 1990s, 
the Teratology Society and health care providers have called for the 
agency to replace the current pregnancy categories with narrative 
statements that summarize and interpret all available human data.
3. Potential Benefits From Better Quality Labeling
    As described in sections II and III of this document, FDA has 
consulted extensively with stakeholders interested in the use of 
prescription drugs during pregnancy and lactation. This proposed rule 
is in part a result of those consultations and would ensure that 
labeling contains clinically relevant information about prescription 
drug use during pregnancy and lactation to help health care providers 
and their patients make informed decisions about their treatment 
options. Although FDA has little information about adverse outcomes 
related to incomplete labeling information, better informed decisions 
about treatment options would likely lead to better outcomes.
    a. Treatment of chronic diseases during pregnancy or while 
lactating. Improved information about the safe and effective use of 
prescription drugs during pregnancy would benefit health care providers 
and their patients who are pregnant and require medication to treat 
chronic diseases. The number of women who may benefit from better 
informed health care providers depends on many factors, including the 
prevalence of chronic diseases in pregnant women. Some chronic diseases 
(such as asthma, diabetes, hypertension, mental illness, and epilepsy) 
may result in negative health outcomes if left uncontrolled during 
pregnancy and lactation. Without adequate information, women with 
chronic medical conditions may receive suboptimal treatment, and 
suboptimal treatment may lead to poor health outcomes for the woman and 
her fetus. By requiring that manufacturers include human data, labeling 
will become a reliable source of up-to-date information on prescription 
drug use during pregnancy. Without complete

[[Page 30855]]

information about the benefits and risks of continuing medications 
during pregnancy, women with chronic medical conditions cannot make 
informed decisions about whether to stop taking their prescription 
drugs during pregnancy, and could take actions that might jeopardize 
their health or the health of their fetuses (Ref. 41).
    i. Pregnancy and asthma. An estimated 6 million women of 
reproductive age have asthma. Previous studies have found that from 4 
to 7 percent of pregnant women have asthma (Ref. 42); a recent study 
that used data from national health surveys conducted from 1997 to 2001 
found that the annual prevalence of current asthma in pregnant women 
ranged from 3.7 to 8.4 percent (Ref. 43). Uncontrolled asthma has been 
associated with negative outcomes for both the pregnant women and the 
fetus.
    ii. Other chronic conditions. The Centers for Disease Control and 
Prevention (CDC) tracks live births for women with several medical risk 
factors, including some chronic conditions requiring prescription drug 
therapy. For example, in 2003, of the approximately 4 million live 
births, some of the most frequent maternal risk factors included 
diabetes (3.3 percent), cardiac disease (0.5 percent), chronic (not 
pregnancy-related) hypertension (0.9 percent), and pregnancy-related 
hypertension (3.7 percent) (Ref. 44). Moreover, it has been reported 
that about 1 million women of reproductive age have epilepsy (Ref. 45) 
and up to 9 percent of pregnant women may experience depression (Ref. 
46).
    b. Managing inadvertent exposure to drugs. Improved information 
about the effects of inadvertent exposure to prescription drugs before 
women know they are pregnant would help health care providers to advise 
these women about the consequences of their inadvertent exposure. 
Because about one-half of the pregnancies in the United States are 
unintended, many women are taking prescription drugs before they are 
aware of the pregnancy (Ref. 41). Inadvertent exposure to prescription 
drugs during pregnancy may be of particular concern for women taking 
prescription drugs for chronic conditions. Fears about possible fetal 
harm from early exposure to prescription drugs can create anxiety for 
pregnant women and their families.
    c. Use of OTC drugs and dietary supplements by pregnant women. Some 
studies in the United States have found that pregnant women often take 
over-the-counter (OTC) drugs and dietary supplements (Refs. 34, 47, and 
48). It is possible that women are substituting these products for 
prescription drugs because OTC drugs and dietary supplements are 
perceived as being safer for use during pregnancy than prescription 
drugs. However, information on the safety of many of these products 
during pregnancy is as limited, if it is available at all, as that for 
prescription drugs. Furthermore, unlike prescription and OTC drugs, 
dietary supplements can be marketed without FDA premarket approval. 
Providing up-to-date information on the risks and benefits of 
prescription drugs may encourage more pregnant and lactating women to 
use safe and effective products that they might otherwise avoid.
4. Potential Benefits for Companies in the International Market
    Besides the potential public health benefit of better informed 
health care providers, the proposed rule may benefit individual 
manufacturers operating on a global scale. In 1979, the United States 
began requiring that prescription drug manufacturers include a 
pregnancy category in the labeling of any systemically absorbed 
prescription drug. Although many European countries adopted similar 
category systems, recent guidance from the European Medicines Agency 
(EMEA) requires that prescription drug labeling include a narrative 
risk statement rather than a pregnancy category (Ref. 49). FDA's 
proposed rule would require narrative risk statements similar to those 
required by the EMEA. More consistent labeling at an international 
level may create some efficiency gains for global manufacturers 
marketing prescription drugs in both the United States and the European 
Union. FDA does not attempt to quantify these potential gains in 
efficiency.

E. Impacts on Small Entities

1. The Need for, and the Objectives of, the Proposed Rule
    The current labeling for pregnant and lactating women provides 
limited clinical information for health care providers and their 
patients. The use of pregnancy categories is confusing and can be 
misinterpreted. The primary objective of the proposed rule is to 
modernize the content of the ``Pregnancy,'' ``Labor and delivery,'' and 
``Lactation'' subsections of prescription drug product labeling and 
replace the category system with a narrative summary of potential risk. 
Narrative information can provide a valuable resource to clinicians and 
their patients about the relative risks and benefits of prescription 
drug use during pregnancy and lactation.
2. Description and Estimate of the Number of Small Entities Affected
    This proposed rule would affect all small entities with 
applications required to include ``Pregnancy'' and ``Lactation'' 
subsections in the labeling. The Small Business Administration (SBA) 
considers Pharmaceutical Preparation Manufacturing firms (NAICS (North 
American Industry Classification System) 325412) with fewer than 750 
employees and Biological Product Manufacturing firms (NAICS 325414) 
with fewer than 500 employees to be small entities. The U.S. Census 
Bureau reports that in 2002 there were 296 biological product 
manufacturing establishments (Ref. 50) and 901 pharmaceutical 
preparation manufacturing establishments (Ref. 51). However, Census 
employment size classes for pharmaceutical preparation manufacturing do 
not correspond to SBA size categories. For this analysis, any 
pharmaceutical preparation manufacturing establishment with less than 
1,000 employees would be considered a small entity. Census data suggest 
that approximately 96 percent of biological product manufacturing 
establishments and no more than 97 percent of the pharmaceutical 
preparation manufacturing establishments could be considered small 
entities. Despite the large number of small entities, large companies 
manufacture most prescription drug products.
    Because the labeling of all prescription drugs required to have a 
pregnancy category would be affected by the pregnancy labeling final 
rule, the agency expects this rule to have an impact on a substantial 
number of small entities. An analysis of FDA's approval data shows that 
about 60 small or privately held entities would be required to revise 
existing prescription drug labeling to conform to the content 
requirements between year 3 and year 5 of the proposed rule. An 
additional 180 small or privately held entities would be required to 
remove the pregnancy category from existing prescription drug labeling 
within 3 years of the effective date of the pregnancy labeling final 
rule, and many of these small entities would be required to remove the 
pregnancy category from more than 10 existing products. Because some of 
these entities would be required to make several labeling changes in 
the same year, the agency requests detailed comment from affected small 
entities on the potential burden of the proposed rule.

[[Page 30856]]

    The compliance requirements for small entities under this proposed 
rule are the same as those described above for other affected entities. 
Compliance primarily involves revising subsections of prescription drug 
labeling to conform to the requirements of the proposed rule. Because 
manufacturers already submit labeling to FDA, no additional skills 
would be required to comply with the proposed rule. The small entities 
likely to bear the highest total costs under this proposed rule are 
those entities that would need to simultaneously revise the 
prescription drug labeling of several high-volume products. Because 
these small entities would likely have the highest sales volumes of 
affected products manufactured by small entities, the incremental cost 
per unit sold is likely to be relatively low. In contrast, small 
entities with a single, low-volume product would have a higher 
incremental cost per unit sold. The following examples illustrate 
possible impacts on small entities with different production volumes. 
Prescription drug labeling costs are estimated for a small entity that 
must revise labeling of an innovator product. Table 9 of this document 
outlines the projected per-unit and total costs to the entity with 
three different levels of production: 1,000, 10,000, and 100,000 units 
produced per year.

Table 9.--Estimated Costs for Hypothetical Small Entity with a Single Innovator Product, Under Three Alternative
                                             Levels of Production\1\
----------------------------------------------------------------------------------------------------------------
                                                               Number of Units Produced and Sold Each Year
                     Cost Category                      --------------------------------------------------------
                                                              100,000             10,000             1,000
----------------------------------------------------------------------------------------------------------------
One-Time Costs:\2\
----------------------------------------------------------------------------------------------------------------
  Add new content to existing trade labeling                        $5,420             $5,420             $5,420
  Prepare labeling not accompanying prescription drug               $5,100             $5,100             $5,100
   products
  Total One-Time Costs                                             $10,520            $10,520            $10,520
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
Annual Incremental Costs:
----------------------------------------------------------------------------------------------------------------
  Printing longer trade labeling\3\                                    $80                 $8                 $1
  Printing longer PDR\4\                                            $2,350             $2,350                N/A
  Total Annual Incremental Costs                                    $2,430             $2,358                 $1
¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤¤
Annualized Costs:\5\
----------------------------------------------------------------------------------------------------------------
  Total Annualized Costs at 3 percent                               $3,660             $3,590             $1,230
  Additional annualized cost per unit sold at 3 percent              $0.04              $0.36              $1.23
  Total Annualized Costs at 7 percent                               $3,920             $3,850             $1,500
  Additional annualized cost per unit sold at 7 percent              $0.04              $0.39              $1.50
----------------------------------------------------------------------------------------------------------------
\1\ Numbers may not sum due to rounding.
\2\ Includes one-time costs to collect and organize information for the new content ($1,500), revise trade
  labeling ($2,920; see Medium firm in table 6 of this document), prepare artwork for labeling in 8-point type
  size ($1,000), and print labeling in 8-point type size to distribute directly to health care providers.
\3\ Number of pieces of trade labeling printed is calculated as units produced/year plus 10 percent wastage
  factor, at an incremental printing cost of $0.0005 per piece.
\4\ Assumes that products with less than 10,000 units per year will not have labeling in the PDR.
\5\ One-time costs are annualized over 10 years.

    Although this is an illustrative example, because the scope of the 
proposed rule would likely include most small entities, FDA uses the 
example of 100,000 units annualized over 10 years at a 7-percent 
discount rate to estimate the compliance costs as a proportion of 
average annual revenue. FDA calculated the average annual value of 
shipments for each employment category from data from the 2002 Economic 
Census. Because the agency's analysis of FDA's approval data found that 
at least one small entity might be required to revise the content of 
labeling for five innovator products in a single year, tables 10 and 11 
of this document show the potential lower and upper bound impact on 
small manufacturing entities. Even with five affected products in a 
single year, annualized compliance costs would be less than 1.1 percent 
of average annual shipments for all establishment sizes.

   Table 10.--Annualized Compliance Costs as a Percentage of the Value of Average Annual Shipments for Small Pharmaceutical Preparation Manufacturing
                                                              Establishments (NAICS 325412)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                     Hypothetical Annualized Costs as a
                                                                                                                     Percentage of Average Annual Value
                                                      Number of        Annual Value of   Average Per Establishment             of Shipments\1\
              Number of Employees                   Establishments    Shipments ($ mil)  Annual Value of Shipments -------------------------------------
                                                                                                  ($ mil)               1 Affected         5 Affected
                                                                                                                         Product            Products
--------------------------------------------------------------------------------------------------------------------------------------------------------
1-19                                                             436            1,101.9                        2.5               0.2%               0.8%
--------------------------------------------------------------------------------------------------------------------------------------------------------
20-49                                                            109              978.5                        9.0               0.0%               0.2%
--------------------------------------------------------------------------------------------------------------------------------------------------------
50-99                                                             93            2,804.7                       30.2               0.0%               0.1%
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 30857]]

100-499                                                          184           23,773.2                      129.2               0.0%               0.0%
--------------------------------------------------------------------------------------------------------------------------------------------------------
500-999                                                           48           35,262.7                      734.6               0.0%               0.0%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Table 4 in Ref. 50.
\1\ One time compliance costs annualized at 7 percent for 10 years. Total annualized costs for this example total $3,920 per affected innovator product.

    In the year that a small entity revises innovator labeling, the 
entity might spend up to $13,000 on one-time design costs, one-time 
printing costs for longer labeling in 8-point type size, and the annual 
incremental costs of printing longer trade labeling and a PDR listing 
conforming to the new content requirements. With five affected 
innovator products in a single year, compliance costs could total up to 
$65,000. However, FDA approval data suggest that it is unlikely that 
entities in the smallest category of establishments (i.e., less than 20 
employees) would have 5 innovator products requiring revision in a 
single year. Nevertheless, $65,000 in compliance costs would total less 
than 4 percent of average annual revenues for an entity with less than 
20 employees and less than 1 percent of average annual revenues for 
small entities with 20 or more employees.

       Table 11.--Annualized Compliance Costs as a Percentage of the Value of Average Annual Shipments for Small Biological Product Manufacturing
                                                              Establishments (NAICS 325414)
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                     Hypothetical Annualized Costs as a
                                                                                                                     Percentage of Average Annual Value
                                                      Number of        Annual Value of   Average Per Establishment             of Shipments\1\
              Number of Employees                   Establishments    Shipments ($ mil)  Annual Value of Shipments -------------------------------------
                                                                                                  ($ mil)               1 Affected         5 Affected
                                                                                                                         Product            Products
--------------------------------------------------------------------------------------------------------------------------------------------------------
1-19                                                             166              302.4                        1.8               0.2%               1.1%
--------------------------------------------------------------------------------------------------------------------------------------------------------
20-49                                                             58              378.5                        6.5               0.1%               0.3%
--------------------------------------------------------------------------------------------------------------------------------------------------------
50-99                                                             26              366.5                       14.1               0.0%               0.1%
--------------------------------------------------------------------------------------------------------------------------------------------------------
100-499                                                           35            2,719.7                       77.7               0.0%               0.0%
--------------------------------------------------------------------------------------------------------------------------------------------------------
Source: Table 4 in Ref. 49.
\1\ One time compliance costs annualized at 7 percent for 10 years. Total annualized costs for this example total $3,920 per affected innovator product.

F. Alternatives Considered

1. No New Regulatory Action
    This alternative is the baseline against which FDA measures the 
costs and benefits of the other regulatory alternatives. The current 
``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers'' 
subsections of the labeling, including the pregnancy categories, fail 
to provide relevant clinical information to health care providers and 
their patients about the safe and effective use of drug products during 
pregnancy and lactation. Current labeling also provides no information 
about the effects of inadvertent exposure before a woman knows she is 
pregnant.
2. Require the Labeling of Applications Submitted After the Effective 
Date of the Pregnancy Labeling Final Rule To Conform to the New Content 
Requirements; Remove the Pregnancy Category From the Labeling of All 
Other Approved Products (``Prospective Alternative'')
    This alternative would require that the new content be added only 
to the labeling for applications submitted after the effective date of 
the pregnancy final labeling rule. The scope of this alternative would 
be narrower than that of the proposed rule. Consequently, FDA estimates 
that 10 years after the effective date, 1,200 innovator products and 
400 generic products would contain the new content. The estimated 
costs, therefore, would be less than those of the proposed rule. 
Because the labeling of fewer products would include the new pregnancy 
labeling content, the potential benefits of this alternative, although 
uncertain, might be less than those of the proposed rule.
    This alternative would also require that, within 3 years of the 
effective date, manufacturers remove the pregnancy category (if it 
exists) from all labeling for products approved before the effective 
date of the pregnancy labeling final rule. FDA's approval data suggests 
that this requirement would affect about 2,990 innovator products and 
3,630 generic products. Like the proposed rule, these changes to 
labeling would not require a separate labeling supplement, but would be 
submitted in an annual report.
    FDA assumes that most cost components for this alternative are the 
same as for the proposed rule (see section VIII.C.2 of this document 
for details). However, because this alternative would only require new 
content prospectively, FDA anticipates

[[Page 30858]]

that no additional agency resources would be needed.
    Table 12 of this document shows the estimated costs of this 
alternative. The estimated one-time costs to add the new content and 
remove the pregnancy category are $19.2 million. The annual incremental 
costs to print longer labeling that contains the new content are 
estimated at $22.3 million. The present value of the total compliance 
costs of this option would be approximately $29.9 million with a 7-
percent discount rate or about $35.8 million with a 3-percent discount 
rate. The estimated annualized compliance costs for this alternative 
are $4.2 million with a 3-percent discount rate and $4.3 million with a 
7-percent discount rate. Moreover, any overlap of the implementation 
schedules of the PLR and the pregnancy labeling final rule would reduce 
these costs because firms could make all labeling changes at the same 
time. However, any potential cost savings depend on the effective date 
of the pregnancy labeling final rule.

                                                Table 12.--Estimated Costs of the Prospective Alternative
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                                           Present Value  ($ mil)
                      Year                        One-Time Revision    Annual Printing      Total Costs  ($ mil)   -------------------------------------
                                                     Cost ($ mil)       Costs ($ mil)                                       3%                 7%
--------------------------------------------------------------------------------------------------------------------------------------------------------
1                                                                0.2                0.6                        0.8                0.8                0.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
2                                                                0.2                1.2                        1.3                1.3                1.2
--------------------------------------------------------------------------------------------------------------------------------------------------------
3                                                               17.6                1.6                       19.2               17.6               15.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
4                                                                0.2                1.9                        2.1                1.8                1.6
--------------------------------------------------------------------------------------------------------------------------------------------------------
5                                                                0.2                2.1                        2.3                2.0                1.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
6                                                                0.2                2.4                        2.5                2.1                1.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
7                                                                0.2                2.6                        2.8                2.3                1.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
8                                                                0.2                2.9                        3.0                2.4                1.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
9                                                                0.2                3.1                        3.3                2.5                1.8
--------------------------------------------------------------------------------------------------------------------------------------------------------
10                                                               0.2                3.9                        4.1                3.0                2.1
========================================================================================================================================================
Total                                                           19.2               22.3                       41.5               35.8               29.9
--------------------------------------------------------------------------------------------------------------------------------------------------------

3. Require the Labeling of Categories of Drugs That Are Most Widely 
Used by Pregnant Women and Women of Reproductive Age To Conform to the 
Content Requirements
    The scope of this alternative would be greater than that of the 
proposed rule. In the agency's efforts to develop this proposed rule, 
it consulted with outside experts concerning what drugs should be 
covered by this rule. FDA asked the American College of Obstetrics and 
Gynecology, the American Academy of Pediatrics, and the Association of 
Women's Health, Obstetric and Neonatal Nurses were asked about which 
drugs each thought were important to the clinical care of pregnant 
women and for which drugs more information is needed. FDA asked the 
Organization of Teratology Information Services and Motherisk, two 
organizations that counsel pregnant women about exposure to drugs 
during pregnancy, to list the drugs about which they received the most 
questions from pregnant women. FDA also consulted the March of Dimes 
and the Canadian Pediatric Society. In addition, FDA asked the 
Pregnancy Labeling Subcommittee of the Advisory Committee for 
Reproductive Health Drugs to consider how to determine which drugs 
merited priority implementation of the new content and format for 
pregnancy labeling. Consultation with these experts resulted in 
numerous lists of drugs for which revised pregnancy labeling was 
considered a priority. However, no clear core set of drugs or drug 
classes emerged from this process. The agency compiled a list of drug 
classes from those suggested by the various sources. The list included 
analgesics, anti-infective drugs, anticoagulants, antidepressants, 
antiemetics, anticonvulsants, antifungals, antihypertensives, 
antimigraine drugs, antivirals, respiratory agents, thyroid drugs, 
tranquilizers, oral contraceptives, glucocorticoids, estrogens, 
gastrointestinal drugs, and antihistamines. Changing the content and 
format of pregnancy labeling for such a large universe of drugs would 
be a large burden for both industry and FDA. Because of the 
difficulties of identifying the products affected by this alternative, 
FDA did not estimate the costs of this alternative, but expects that 
they would fall somewhere between those of the proposed rule and the 
highest cost alternative described below.
4. Require the Labeling of All Approved Products To Conform to the New 
Content Requirements
    In contrast to the proposed rule, this alternative has the broadest 
scope and would require that new content be added to the labeling of 
about 4,170 innovator products and 4,030 generic products. Consequently 
the estimated costs and potential benefits would be greatest with this 
alternative.
    The implementation schedule and estimated costs for future 
applications and for approved applications subject to the PLR would be 
the same as for the proposed rule. Approved applications not subject to 
the PLR would follow a staggered implementation schedule in which 
manufacturers would be given from 6 to 10 years to revise product 
labeling, depending on the approval date. Under this staggered 
schedule, manufacturers with applications approved before June 30, 
1975, would have 6 years to revise labeling; manufacturers with 
applications approved between June 30, 1975, and June 29, 1984, would 
have 7 years to revise labeling; manufacturers with

[[Page 30859]]

applications approved between June 30, 1984, and June 29, 1990, would 
have 8 years to revise labeling; manufacturers with applications 
approved between June 30, 1990, and June 29, 1996, would have 9 years 
to revise labeling; and manufacturers with applications approved 
between June 30, 1996, to June 29, 2001, would have 10 years to revise 
labeling.
    The length of time since a product's approval determines the amount 
of information available for the new content. In general, more 
information about clinical experience is available for older products 
than for newly approved products. Thus, FDA expects that manufacturers 
with applications not subject to the PLR might spend more time 
collecting and organizing the new content and that the costs to print 
longer labeling may exceed those estimated for applications subject to 
the PLR. Because the new content for older products could be longer 
than that for newly approved products, additional FDA personnel might 
be needed to review the labeling supplements for older products.
    To account for these potential differences in the costs for the 
labeling of older products, this analysis uses a range of costs for 
products not subject to the PLR. One-time costs to collect and organize 
information range from $3,000 to $6,000 for innovator products. The 
length of trade labeling might increase by 12-square inches at a cost 
of $750 for innovator products and $450 for generic products. If the 
labeling of older products is longer than that of newly approved 
products, manufacturers with older innovator products might incur costs 
for labeling distributed directly to consumers and health care 
providers and costs to print longer labeling in the PDR. For this 
alternative, FDA estimates that, on average, labeling printed in 8-
point type size would increase by 38 square inches at a cost of $8,050, 
and the PDR would be about 0.3 page longer at a cost of $3,950. 
Finally, to account for a potential increase in FDA resources for this 
alternative, the number of additional FTEs would double from two to 
four for the last 5 years of the analysis.
    Over 10 years, the one-time costs to revise labeling to add the new 
content could range from $29.2 million to $34.3 million. Annual 
incremental printing costs might total about $91.5 million over 10 
years. The present value of the total compliance costs range from about 
$75.3 million to about $78.2 million with a 7-percent discount rate and 
from about 97.9 million to about $101.9 million with a 3-percent 
discount rate. The estimated annualized compliance costs for this 
alternative, therefore, range from $11.5 million to $11.9 million with 
a 3-percent discount rate and range from $10.7 million to $11.1 million 
with a 7-percent discount rate. Table 13 shows the upper bound estimate 
for this alternative.

                      Table 13.--Upper Bound Estimated Costs of Highest Impact Alternative
----------------------------------------------------------------------------------------------------------------
                    Number of Approved Applications by                              Present Value ($ mil)
                              Type of Product              Total Costs ($  -------------------------------------
       Year       --------------------------------------        mil)
                       Innovator           Generic                                  3%                 7%
----------------------------------------------------------------------------------------------------------------
1                                140                 40                1.3                1.2                1.2
----------------------------------------------------------------------------------------------------------------
2                                130                 40                1.8                1.7                1.5
----------------------------------------------------------------------------------------------------------------
3                                500                300                6.7                6.1                5.5
----------------------------------------------------------------------------------------------------------------
4                                600                170                9.3                8.3                7.1
----------------------------------------------------------------------------------------------------------------
5                                560                250               11.2                9.7                8.0
----------------------------------------------------------------------------------------------------------------
6                                480                630               15.5               13.0               10.3
----------------------------------------------------------------------------------------------------------------
7                                430                720               16.7               13.6               10.4
----------------------------------------------------------------------------------------------------------------
8                                390                650               17.7               13.9               10.3
----------------------------------------------------------------------------------------------------------------
9                                450                670               20.0               15.3               10.9
----------------------------------------------------------------------------------------------------------------
10                               490                560               25.6               19.1               13.0
================================================================================================================
Total                          4,170              4,030              125.8              101.9               78.2
----------------------------------------------------------------------------------------------------------------

5. Summary of Regulatory Options
    Table 14 of this document shows the total and incremental costs of 
the proposed rule and regulatory alternatives. The total benefits of 
the regulatory alternatives would be directly related to the costs, 
because the more costly the alternative the more products that would be 
covered. It should be noted that although the total benefits would 
correspond to the total costs, the marginal benefits of these 
alternatives may not correspond directly to marginal costs. FDA is 
unable, however, to quantify the total or incremental benefits of these 
regulatory alternatives.
    The requirements of this proposed rule are the result of the 
agency's efforts to revise the regulations concerning the content and 
format of the ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing 
mothers'' subsections of prescription drug labeling. Although the 
prospective alternative has lower costs than the proposed rule, it 
would result in two types of PLR labeling--one with the revised 
pregnancy and lactation content and one without the revised content. To 
ensure the consistent quality of labeling subject to the PLR, the 
agency, therefore, proposes that the pregnancy labeling rule apply to 
all labeling subject to the PLR.

[[Page 30860]]

 Table 14.--Comparison of the Estimated Compliance Costs of the Proposed
                 Rule and the Regulatory Alternatives\1\
------------------------------------------------------------------------
                         Annualized costs ($      Incremental costs ($
                              million)                  million)
    Alternatives     ---------------------------------------------------
                       3 percent    7 percent    3 percent    7 percent
------------------------------------------------------------------------
No new regulatory     0            0            N/A          N/A
 action
------------------------------------------------------------------------
Content required for  4.2          4.3          4.2          4.3
 labeling
 prospectively
------------------------------------------------------------------------
Proposed rule         7.7          7.6          3.5          3.3
------------------------------------------------------------------------
Content required for  7.7 < x <    7.6 < x <    0 < x < 4.2  0 < x < 3.5
 labeling of most      11.9         11.1
 widely used drugs
------------------------------------------------------------------------
Content required for  11.5 to      10.7 to      3.8 to 4.2   3.1 to 3.5
 labeling of all       11.9         11.1
 approved drugs
------------------------------------------------------------------------
\1\ The present value of the total estimated compliance costs are
  annualized over 10 years at a 3-percent discount rate or a 7-percent
  discount rate. Compliance costs include the costs to remove the
  pregnancy categories from labeling not subject to the content
  requirements of each alternative.

IX. Paperwork Reduction Act of 1995

    This proposed 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). A description of these requirements is given below, along with 
an estimate of the annual reporting burden. Included in the estimate is 
the time for reviewing instructions, searching existing data sources, 
gathering and maintaining the data needed, and completing and reviewing 
the collection of information.
    FDA invites comments on: (1) Whether the collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Content and Format of Labeling for Human Prescription Drug 
and Biological Products; Requirements for Pregnancy and Lactation 
Labeling
    Description: The proposed rule would amend FDA regulations 
concerning the format and content 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 proposal would require that labeling include a summary of 
the risks of using a drug during pregnancy and lactation and a 
discussion of the data supporting that summary. The labeling would also 
include relevant clinical information to help health care professionals 
make prescribing decisions and counsel women about the use of drugs 
during pregnancy and lactation. The proposal would eliminate the 
current pregnancy categories A, B, C, D, and X. The ``Labor and 
delivery'' subsection would be eliminated because information on labor 
and delivery would be included in the ``Pregnancy'' subsection. The 
proposed rule is intended to create a consistent format for providing 
information about the effects of a drug on pregnancy and lactation that 
will be useful for decisionmaking by women of childbearing age and 
their health care providers.
    Under proposed Sec. Sec.  201.57(c)(9)(i) and 201.57(c)(9)(ii), 
holders of approved applications\7\ would be required to provide new 
labeling content in a new format--that is, to completely rewrite the 
pregnancy and lactation portions of each drug's labeling. These 
application holders would be required to submit supplements requiring 
prior approval by FDA before distribution of the new labeling, as 
required in Sec.  314.70(b) or Sec.  601.12(f)(1).
---------------------------------------------------------------------------

    \7\ As discussed previously, the term ``application'' refers to 
NDAs, BLAs, and efficacy supplements.
---------------------------------------------------------------------------

    Under proposed Sec.  201.80(f)(6)(i), holders of approved 
applications would be 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 would report the labeling change in their annual 
reports, as required in Sec.  314.70(d) or Sec.  601.12(f)(3).
    The new content and format requirements of the proposed rule would 
apply to all applications that are required to comply with the PLR, 
including: (1) Applications submitted on or after the date the proposed 
rule becomes final; (2) applications pending on the date the proposed 
rule becomes final; and (3) applications approved from June 30, 2001, 
to the effective date of the pregnancy labeling rule.
    Information collection subject to the PRA would consist of the 
following submissions under the proposed rule:
    (1) Applications submitted on or after the effective date of the 
proposed rule (Sec. Sec.  314.50; 314.70(b); 601.2; 601.12(f)(1));
    (2) Amendments to applications pending on the effective date of the 
final rule (Sec.  314.60);
    (3) Supplements to applications approved from June 30, 2001, to the 
effective date of the final rule (Sec.  314.70(b); 601.12(f)(1));
    (4) Holders of applications approved before June 29, 2001, that 
contain a pregnancy category would be required to remove the pregnancy 
category designation by 3 years after the effective date of the final 
rule and include this labeling change in their annual report (Sec.  
314.70(d), 601.12(f)(3)).
    The information collection requirements and burden estimates are 
summarized in table 12 of this document. Based on data provided in 
section VIII of this document, FDA estimates that approximately 
1,613\8\ applications containing labeling consistent with this 
rulemaking would be submitted to FDA by approximately 885 applicants. 
Based on data provided in section VIII of this document, FDA estimates 
that it would take applicants approximately 20 hours to prepare and 
submit labeling consistent with this rulemaking. The estimate of 20 
hours is

[[Page 30861]]

incremental, in that it applies only to the requirements for this 
rulemaking and does not indicate the total hours required to prepare 
and submit complete labeling for these applications. The information 
collection burden to prepare and submit labeling in accordance with 
Sec. Sec.  201.56, 201.57, and 201.80 is approved by OMB under Control 
Number 0910-0572.
---------------------------------------------------------------------------

    \8\ 1,613 includes approximately 1,197 innovator and 416 generic 
drug products.
---------------------------------------------------------------------------

    FDA also estimates that approximately 111 amendments to 
applications pending on the effective date of the pregnancy labeling 
final rule would be submitted to FDA as a result of this proposal, by 
approximately 81 applicants, and that it would take those applicants 
approximately 20 hours (incremental) to prepare and submit each 
amendment.
    In addition, FDA estimates that approximately 1,789 supplements to 
approved applications would be submitted to FDA to update labeling in 
accordance with this proposal, that approximately 210 application 
holders would submit these supplements, and that it would take those 
application holders approximately 85 hours\9\ (incremental) to prepare 
and submit each supplement.
---------------------------------------------------------------------------

    \9\ The estimate for innovator companies is approximately 85 
hours, and the estimate for generic companies is approximately 22 
hours. For purposes of this information collection analysis, FDA 
used the higher estimate and invites comment on the time needed to 
prepare and submit these supplements.
---------------------------------------------------------------------------

    FDA also estimates that approximately 4,720\10\ annual reports 
containing labeling changes resulting from this rulemaking would be 
submitted to FDA by approximately 300 application holders, and that it 
would take application holders approximately 50 hours\11\ to prepare 
and submit each revision.
---------------------------------------------------------------------------

    \10\ 4,720 includes approximately 1,697 innovator and 3,023 
generic drug products.
    \11\ The estimate for innovator companies is approximately 50 
hours, and the estimate for generic companies is approximately 22 
hours. For purposes of this information collection analysis, FDA 
used the higher estimate and invites comment on the time needed to 
prepare and submit these supplements.
---------------------------------------------------------------------------

    FDA must request an extension of approval of this information 
collection every 3 years. For purposes of OMB approval for the first 3-
year period, FDA divided the total hours in table 15 of this document 
(422,545 hours) by 3 to provide OMB an annualized estimate of burdens 
associated with this rulemaking (i.e., 140,848 hours).
    Description of Respondents: Persons and businesses, including small 
businesses and manufacturers.
    Burden Estimate: Table 15 of this document provides an estimate of 
the annual reporting burden for the proposed pregnancy and lactation 
labeling requirements. FDA specifically requests comments on these 
estimates.

                                                     Table 15.--Estimated Annual Reporting Burden\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                            Number of       Number of Responses                         Hours per
               Category (21 CFR section)                   Respondents        per Respondent      Total  Responses       Response         Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
New NDAs/ANDAs/BLAs/efficacy supplements submitted on                 885                  1.82              1,613                 20             32,260
 or after effective date (Sec.  Sec.   314.50;
 314.70(b); 601.2; 601.12(f)(1))
--------------------------------------------------------------------------------------------------------------------------------------------------------
Amendments to applications pending on effective date                   81                  1.37                111                 20              2,220
 (Sec.   314.60)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Supplements to applications approved 6/30/01 to                       210                  8.52              1,789                 85            152,065
 effective date (Sec.   314.70(b); 601.12(f)(1))
--------------------------------------------------------------------------------------------------------------------------------------------------------
Annual report submission of revised labeling for                      300                 15.73              4,720                 50            236,000
 applications approved before 6/29/01 that contain a
 pregnancy category (Sec.   314.70(d); 601.12(f)(3))
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total                                                                                                                                            422,545
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    In compliance with section 3507(d) of the PRA, the agency has 
submitted the information collection requirements of this proposed rule 
to OMB for review. The information collection provisions of this 
proposed rule have been submitted to OMB for review. Interested persons 
are requested to fax comments regarding information collection by June 
30, 2008, to the Office of Information and Regulatory Affairs, OMB. To 
ensure that comments on information collection are received, OMB 
recommends that written comments be faxed to the Office of Information 
and Regulatory Affairs, OMB, Attn: FDA Desk Officer, FAX: 202-395-6974, 
or e-mailed to: baguilar@omb.eop.gov.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' In this proposed rule, FDA is proposing to 
revise its existing requirements concerning the format and content of 
the ``Pregnancy,'' ``Labor and delivery,'' and ``Nursing mothers'' 
subsections of labeling for human prescription drug and biological 
products. To the extent that a State requires labeling that conflicts 
with these requirements, the State required labeling would be subject 
to implied conflict preemption.
    As stated in the preamble, this proposed rule would amend portions 
of FDA's regulations that were recently revised by the PLR. When FDA 
finalized

[[Page 30862]]

the PLR, the agency responded to comments regarding the product 
liability implications of revising the labeling for prescription drugs. 
Several comments on the proposed PLR had raised concerns about State 
requirements on drug labeling, often as a result of product liability 
lawsuits, that conflict with federal requirements. As a result of those 
comments, and in discussing federalism issues, FDA restated its 
longstanding views on preemption. For further discussion of this issue, 
see 71 FR 3922 at 3933 through 3936 and 3967 through 3969. FDA's 
statements in this regard are applicable to this proposed rule as well, 
and reflect the agency's current position on this issue. Section 4(c) 
of Executive Order 13132 instructs us to restrict any Federal 
preemption of State law to the ``minimum level necessary to achieve the 
objectives of the statute pursuant to which the regulations are 
promulgated.'' This proposed rule meets the preceding requirement 
because as discussed above, it would preempt State laws that conflict 
with these Federal requirements. Section 4(d) of Executive Order 13132 
states that when an agency foresees the possibility of a conflict 
between State law and federally protected interests within the agency's 
area of regulatory responsibility, the agency ``shall consult, to the 
extent practicable, with appropriate State and local officials in an 
effort to avoid such a conflict.'' In this case, FDA foresees the 
possibility of a conflict between State law and federally protected 
interests within the agency's area of regulatory responsibility. 
Section 4(e) of Executive Order 13132 adds that ``when an agency 
proposes to act through adjudication or rulemaking to preempt State 
law, the agency ``shall provide all affected State and local officials 
notice and an opportunity for appropriate participation in the 
proceedings.''
    FDA is seeking input from all stakeholders on the proposed 
requirements for the content and format of pregnancy labeling through 
publication of the proposed rule in the Federal Register and will 
consult with State and local officials in an effort to avoid conflict 
between State law and federal protected interests.

XI. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.
    Please note that on January 15, 2008, the FDA Division of Dockets 
Management Web site transitioned to the Federal Dockets Management 
System (FDMS). FDMS is a Government-wide, electronic docket management 
system. Electronic comments or submissions will be accepted by FDA only 
through FDMS at http://www.regulations.gov.

XII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but FDA is not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)
    1. ``PRAMS and . . . Unintended Pregnancy,'' Centers for Disease 
Control and Prevention, National Center for Chronic Disease 
Prevention and Health Promotion, http://www.cdc.gov/PRAMS/PDFs/
PRAMSUnintendPreg.pdf (last viewed 4/23/08).
    2. American Academy of Pediatrics, ``Policy Statement: 
Breastfeeding and the Use of Human Milk, Pediatrics, vol. 115, pp. 
496-506, 2005.
    3. Ryan, A. S., Z. Wenjun, and A. Acosta, ``Breast-feeding 
Continues to Increase Into the New Millenium,'' Pediatrics, vol. 
110, pp. 1103-1109, 2002.
    4. Drugs and Human Lactation, edited by P. N. Bennett, Elsevier, 
Amsterdam, 1988.
    5. Williams Obstetrics, 21st ed., edited by F. G. Cunningham et 
al., McGraw-Hill, New York, pp. 201-219, 2001.
    6. March of Dimes, Fact Sheet: Miscarriage, http:/
www.marchofdimes.com/professionals/14332_1192.asp (last viewed 4/
23/08).
    7. March of Dimes, Fact Sheet: Stillbirth, http:/
www.marchofdimes.com/professionals/14332_1198.asp (last viewed 4/
23/08).
    8. Leppig, K. A. et al., ``Predictive Value of Minor 
Anomalies,'' The Journal of Pediatrics, vol. 110, pp. 531-537, 1987.
    9. Christian, M. S., ``Test Methods for Assessing Female 
Reproductive and Developmental Toxicology,'' Principles and Methods 
of Toxicology, 4th ed., edited by A. W. Hayes, Taylor & Francis, 
Philadelphia, p. 1301-1381, 2001.
    10. Kaufman, D. W. et al., ``Recent Patterns of Medication Use 
in the Ambulatory Adult Population of the United States: the Sloane 
Survey,'' Journal of the American Medical Association, vol. 287, pp. 
337-344, 2002.
    11. Ventura, S. J. et al., ``Trends in Pregnancies and Pregnancy 
Rates by Outcome: United States, 1976-96,'' National Center for 
Health Statistics, Vital and Health Statistics, 21(56), p. 1, http:/
/www.cdc.gov/nchs/data/series/sr_21/sr21_056.pdf (last viewed 4/
23/08).
    12. Schardein, J. L., Chemically Induced Birth Defects, 3rd ed., 
Marcel Dekker, Inc., New York, pp. 5-7, 2000.
    13. De Vigan, C. et al., ``Therapeutic Drug Use During 
Pregnancy: A Comparison in Four European Countries,'' Journal of 
Clinical Epidemiology, vol. 52, pp. 977-982, 1999.
    14. Lacroix, I. et al., ``Prescription of Drugs During Pregnancy 
in France,'' The Lancet, vol. 356, pp. 1735-1736, 2000.
    15. Mitchell, A. A. et al., ``Medication Use in Pregnancy 1976-
2000,'' Pharmacoepidemiology and Drug Safety, vol. 10, Supplement 1, 
pp. S146-S147, 2001.
    16. Mitchell, A. A., ``Special Considerations in Studies of 
Drug-Induced Birth Defects,'' in Pharmacoepidemiology, 3rd ed., 
edited by B. L. Strom, John Wiley & Sons, Ltd., England, pp. 749-
763, 2000.
    17. Ward, R. M., ``Difficulties in the Study of Adverse Fetal 
and Neonatal Effects of Drug Therapy During Pregnancy,'' in Seminars 
in Perinatology: Proceedings from the NIH Workshop to Label Drugs 
During Pregnancy, vol. 25, pp. 191-195, 2001.
    18. Rogers, J. M., and R. J. Kavlock, ``Developmental 
Toxicity,'' in Toxicology: The Basic Science of Poisons, 5th ed., 
edited by C. D. Klaassen, McGraw-Hill, New York, pp. 301-332, 1996.
    19. Matsui, D. et al., ``Drugs and Chemicals Most Commonly Used 
by Pregnant Women,'' in Maternal-Fetal Toxicology, edited by G. 
Koren, Marcel Dekker, Inc., New York, pp. 115-135, 2001.
    20. Jasper, J. D. et al., ``Effects of Framing on Teratogenic 
Risk Perception in Pregnant Women,'' The Lancet, vol. 358, pp. 1237-
1238, 2001.
    21. Kallen, B., ``Drugs in Pregnancy--The Dilemma of Labeling,'' 
Drug Information Journal, vol. 33, pp. 1135-1143, 1999.
    22. Koren, G., ``Misrepresentation and Miscommunication of 
Teratogenic Risk of Drugs; Analysis of Three Highly Publicized 
International Cases,'' Reproductive Toxicology, vol. 15, pp. 1-3, 
2000.
    23. Pole, M. et al., ``Drug Labeling and Risk Perceptions of 
Teratogenicity: A Survey of Pregnant Canadian Women and Their Health 
Professionals,'' Journal of Clinical Pharmacology, vol. 40, pp. 573-
577, 2000.
    24. Sanz, E., T. Gomez-Lopez, and M. J. Martinez-Quintas, 
``Perception of Teratogenic Risk of Common Medicines,'' European 
Journal of Obstetrics & Gynecology and Reproductive Biology, vol. 
95, pp. 127-131, 2001.
    25. Thurmann, P. A., and A. Steioff, ``Drug Treatment in 
Pregnancy,'' International Journal of Clinical Pharmacology and 
Therapeutics, vol. 39, pp. 185-191, 2001.
    26. Webster, W. S., and J. A. D. Freeman, ``Is This Drug Safe in 
Pregnancy?'' Reproductive Toxicology, vol. 15, pp. 619-629, 2001.
    27. Doering, P. L., L. A. Boothby, and M. Cheok, ``Review of 
Pregnancy Labeling of Prescription Drugs: Is the Current System 
Adequate to Inform of Risks?'' American Journal of Obstetrics and 
Gynecology, vol. 187, pp. 333-339, 2002.
    28. Alan Guttmacher Institute, ``Facts in Brief: Contraceptive 
Use,'' 1999, http://www.guttmacher.org/pubs/fb_contr_use.html 
(last viewed 4/23/08).

[[Page 30863]]

    29. Centers for Disease Control and Prevention, ``Current 
Estimates from the National Health Interview Survey, 1996,'' Vital 
and Health Statistics, 1999, http://www.cdc.gov/nchs/data/series/
sr_10/sr10_200.pdf (last viewed 4/23/08).
    30. Meadows, M., ``Pregnancy and the Drug Dilemma,'' FDA 
Consumer, May-June 2001.
    31. Drugs and Human Lactation, 2nd ed., edited by P. N. Bennett, 
Elsevier, Amsterdam, 1996.
    32. Agency for Healthcare Research and Quality, Medical 
Expenditure Panel Survey Household Component Data for 2003, 
generated using MEPSnet/HC, http://www.meps.ahrq.gov/mepsweb under 
``Database of Household Component (HC) Files'' housed in the on-line 
PUF (public use file) database (last viewed 4/23/08).
    33. Andrade, S. E. et al., ``Prescription Drug Use in 
Pregnancy,'' American Journal of Obstetrics and Gynecology, vol. 
191, pp. 398-407, 2004.
    34. Glover, D. D. et al., ``Prescription, Over-the-Counter, and 
Herbal Medicine use in a Rural, Obstetric Population,'' American 
Journal of Obstetrics and Gynecology, vol. 188, pp. 1039-1045, 2003.
    35. Mastroianni, A. C., R. Faden, and D. Federman, Editors, 
Women and Health Research: Ethical and Legal Issues of Including 
Women in Clinical Studies, Volume 1; Committee on Ethical and Legal 
Issues Relating to the Inclusion of Women in Clinical Studies, 
Institute of Medicine, p. 188, 1994.
    36. Donati, S. et al., ``Drug Use in Pregnancy Among Italian 
Women,'' European Journal of Clinical Pharmacology, vol. 56, pp. 
323-328, 2000.
    37. Irl, C., P. Kipferler, and J. Hasford, ``Drug Use Assessment 
and Risk Evaluation in Pregnancy--The PEGASUS-Project,'' 
Pharmacoepidemiology and Drug Safety, vol. 6, suppl. 3, pp. S37-S42, 
1997.
    38. Centers for Disease Control and Prevention, Department of 
Health and Human Services ``2004 National Immunization Survey, Table 
3: Any and Exclusive Breastfeeding Rates by Age, 2004.'' http://
www.cdc.gov/breastfeeding/data/NIS_data/2004/age.htm (last viewed 
4/23/08).
    39. Friedman, J. M., ``Report of the Teratology Society Public 
Affairs Committee Symposium on FDA Classification of Drugs,'' 
Teratology, vol. 48, pp. 5-6, 1993.
    40. Uhl, K., D. L. Kennedy, and S. L. Kweder, ``Risk Management 
Strategies in the Physicians' Desk Reference Product Labels for 
Pregnancy Category X Drugs,'' Drug Safety, vol. 25, pp. 885-892, 
2002.
    41. Lagoy, C. T. et al., ``Medication Use during Pregnancy and 
Lactation: an Urgent Call for Public Health Action,'' Journal of 
Women's Health, vol. 14, pp. 104-109, 2005.
    42. Namazy, J. A., and M. Schatz, ``Treatment of Asthma During 
Pregnancy and Perinatal Outcomes,'' Current Opinions Allergy 
Clinical Immunology, vol. 5, pp. 229-233, 2005.
    43. Kwon, H. L., K. Belanger, and M. B. Bracken, ``Asthma 
Prevalence among Pregnant and Childbearing-aged Women in the United 
States: Estimates from National Health Surveys,'' Annals of 
Epidemiology, vol. 13, pp. 317-24, 2003.
    44. Martin, J. A. et al., Births: Final data for 2003. National 
Vital Statistics Reports, vol. 54, no. 2, Hyattsville, MD, National 
Center for Health Statistics, 2005.
    45. The North American Pregnancy and Epilepsy Registry, ``A 
North American Registry for Epilepsy and Pregnancy, a Unique Public/
Private Partnership of Health Surveillance,'' Epilepsia, vol. 39, 
pp. 793-799, 1998.
    46. Wisner, K. L., ``Risk-Benefit Decision Making for Treatment 
of Depression During Pregnancy,'' American Journal of Psychiatry, 
vol. 157, pp. 1933-1940, 2000.
    47. Refuerzo, J. S. et al., ``Use of Over-the-Counter 
Medications and Herbal Remedies in Pregnancy,'' American Journal of 
Perinatology, vol. 22, pp. 321-4, 2005.
    48. Werler, M. M. et al., and the National Birth Defects 
Prevention Study, ``Use of Over-the-Counter Medications During 
Pregnancy,'' American Journal of Obstetrics and Gynecology, vol. 
193, pp. 771-7, 2005.
    49. Committee for Medicinal Products for Human Use (CHMP), 
``Guideline on Risk Assessment of Medicinal Products on Human 
Reproduction and Lactation: From Data to Labelling, Annex I'' 
European Medicines Agency, Evaluation of Medicines for Human Use, 
Doc Reference EMEA/CHMP/203927/2005, London, 23 March 2006 http://
www.emea.europa.eu/htms/human/qrd/qrdtemplate.htm (last viewed 4/23/
08).
    50. U.S. Department of Commerce, Economics and Statistics 
Administration, U.S. Census Bureau, ``Biological Product (Except 
Diagnostic) Manufacturing: 2002,'' 2002 Economic Census 
Manufacturing Industry Series, EC02-31I-325414, December 2004.
    51. U.S. Department of Commerce, Economics and Statistics 
Administration, U.S. Census Bureau, ``Pharmaceutical Preparation 
Manufacturing: 2002,'' 2002 Economic Census Manufacturing Industry 
Series, EC02-31I-325412, December 2004.

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, it is 
proposed that 21 CFR part 201 be 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.

Sec.  201.56   [Amended]

    2. Amend Sec.  201.56 in paragraph (d)(1) by removing from the list 
of headings and subheadings the subheadings ``8.2 Labor and delivery'' 
and ``8.3 Nursing mothers'' and adding in their place the subheading 
``8.2 Lactation''.
    3. Section 201.57 is amended by removing and reserving paragraph 
(c)(9)(iii) and by revising paragraphs (c)(9)(i) and (c)(9)(ii) to read 
as follows:

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

* * * * *
    (c) * * *
    (9) * * *
    (i) 8.1 Pregnancy. This subsection of the labeling must contain the 
following information in the following order:
    (A) Pregnancy exposure registry. 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 stated at the beginning of the ``Pregnancy'' subsection of the 
labeling.
    (B) General statement about background risk. The following 
statement must be included:
    ``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.''
    (C) Fetal risk summary. Under the subheading ``Fetal Risk 
Summary,'' the labeling must contain 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.
    (1) Using the risk conclusions provided in paragraphs 
(c)(9)(i)(C)(2) and (c)(9)(i)(C)(3) of this section, 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). More than one risk conclusion may be needed to 
characterize the likelihood of risk for different developmental 
abnormalities, doses, durations of exposure, or gestational ages at 
exposure. 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. The source(s) of the data that are 
the basis for the fetal risk summary must be stated. If data 
demonstrate that a drug is not systemically absorbed, the fetal risk 
summary must contain only the following statement, without any other 
risk conclusion:
    ``(Name of drug) is not absorbed systemically from (part of body) 
and cannot be detected in the blood.

[[Page 30864]]

Maternal use is not expected to result in fetal exposure to the drug.''
    (2) Risk conclusions based on human data. When both human and 
animal data are available, risk conclusions based on human data must be 
presented before risk conclusions based on animal data. A risk 
conclusion based on human data must be followed by a narrative 
description of the risks as described in paragraph (c)(9)(i)(C)(4) of 
this section.
    (i) Risk conclusions based on sufficient human data. Sufficient 
human data may come from such sources as clinical trials, pregnancy 
exposure registries or other large scale epidemiologic studies, or case 
series reporting a rare event. 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).''
    (ii) Risk conclusions based on other human data. When human data 
are available but are not sufficient to use one of the risk conclusions 
listed in paragraph (c)(9)(i)(C)(2)(i) of this section, the likelihood 
that the drug increases the risk of developmental abnormalities must be 
characterized as low, moderate, or high.
    (3) Risk conclusions based on animal data. 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:
    (i) Not predicted to increase the risk. When animal data contain no 
findings for any developmental abnormality, the fetal risk summary must 
state: ``Based on animal data, (name of drug) is not predicted to 
increase the risk of developmental abnormalities (see Data).''
    (ii) Low likelihood of increased risk. When animal data contain 
findings of developmental abnormality but the weight of the evidence 
indicates that the findings are not relevant to humans (e.g., findings 
in a single animal species that are caused by unique drug metabolism or 
a mechanism of action thought not to be relevant to humans; findings at 
high exposures compared with the maximum recommended human exposure), 
the fetal risk summary must state: ``Based on animal data, the 
likelihood that (name of drug) increases the risk of developmental 
abnormalities is predicted to be low (see Data).''
    (iii) Moderate likelihood of increased risk. When animal data 
contain findings of one or more fetal developmental abnormalities in 
one or more animal species, and those findings are thought to be 
relevant to humans, the fetal risk summary must state: ``Based on 
animal data, the likelihood that (name of drug) increases the risk of 
developmental abnormalities is predicted to be moderate (see Data).''
    (iv) High likelihood of increased risk. When animal data contain 
robust findings of developmental abnormalities (e.g., multiple findings 
in multiple animal species, similar findings across species, findings 
at low exposures compared with the anticipated human exposure) thought 
to be relevant for humans, the fetal risk summary must state: ``Based 
on animal data, the likelihood that (name of drug) increases the risk 
of developmental abnormalities is predicted to be high (see Data).''
    (v) Insufficient data. When there are insufficient animal data or 
no animal data on which to assess the drug's potential to increase the 
risk of developmental abnormalities, the fetal risk summary must so 
state (see Data).
    (4) Narrative description of risk(s). 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 or rule out a 
specified level of risk.
    (5) Contraindications, warnings, and precautions. If there is 
information in the ``Contraindications'' or ``Warnings and 
Precautions'' section of the labeling on an increased risk to the fetus 
from exposure to the drug, the fetal risk summary must refer to the 
relevant section.
    (D) Clinical considerations. Under the subheading ``Clinical 
Considerations,'' the ``Pregnancy'' subsection of the labeling must 
provide the following information:
    (1) Inadvertent exposure during pregnancy. 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.
    (2) Prescribing decisions for pregnant women. The labeling must 
provide the following information:
    (i) The labeling must describe the risk, if known, to the pregnant 
woman and the fetus from the disease or condition the drug is indicated 
to treat.
    (ii) Information about dosing adjustments during pregnancy must be 
provided. This information must also be included in the ``Dosage and 
Administration'' and ``Clinical Pharmacology'' sections of the 
labeling. If there are no data on dosing in pregnancy, the labeling 
must so state.
    (iii) If use of the drug is associated with maternal adverse 
reactions that are unique to pregnancy or if known adverse reactions 
occur with increased frequency or severity in pregnant women, the 
labeling must describe the adverse reactions. 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(s). The labeling must describe any interventions that may be 
needed (e.g., monitoring blood glucose for a drug that causes 
hyperglycemia in pregnancy).
    (iv) If it is known or anticipated that treatment of the pregnant 
woman will cause a complication in the neonate, the labeling must 
describe the complication, the severity and reversibility of the 
complication, and general types of interventions, if any, that may be 
needed.
    (3) Drug effects during labor or delivery. If 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, the labeling must provide the 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.
    (E) Data. (1) Under the subheading ``Data,'' the ``Pregnancy'' 
subsection of the labeling must provide an overview

[[Page 30865]]

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.
    (ii) 8.2 Lactation. This subsection of the labeling must contain 
the following information in the following order:
    (A) Risk summary. Under the subheading ``Risk Summary,'' if, as 
described under Sec.  201.57(c)(9)(ii)(A)(1) through (c)(9)(ii)(A)(3) 
of this section, the data demonstrate that the drug does not affect the 
quantity and/or quality of human milk and there is reasonable certainty 
either that the drug is not detectable in human milk or that the amount 
of drug consumed via breast milk will not adversely affect the breast-
fed child, the labeling must state: ``The use of (name of drug) is 
compatible with breast-feeding.'' 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. 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. 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 breast milk. Breast-feeding is 
not expected to result in fetal exposure to the drug.'' If the drug is 
absorbed systemically, the risk summary must describe the following to 
the extent information is available:
    (1) Effects of drug on milk production. 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.
    (2) Presence of drug in human milk.
    (i) 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.
    (ii) If studies demonstrate that the drug is not detectable in 
human milk, the risk summary must state the limits of the assay used.
    (iii) 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 percent of the maternal dose excreted in human 
milk.
    (3) Effects of drug on the breast-fed child. The risk summary must 
contain information on the likelihood and seriousness of known or 
predicted effects on the breast-fed child from exposure to the drug in 
human milk. The risk summary must be based on the pharmacologic and 
toxicologic profile of the drug, the amount of drug detected or 
predicted to be found in human milk, and age-related differences in 
absorption, distribution, metabolism, and elimination.
    (B) Clinical considerations. 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 
breast-feeding 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.
    (3) Information about dosing adjustments during lactation. This 
information must also be included in the ``Dosage and Administration'' 
and ``Clinical Pharmacology'' sections.
    (C) Data. 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.
* * * * *

Sec.  201.80   [Amended]

    4. Amend Sec.  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).
    [This appendix will not appear in the Code of Federal Regulations.]

APPENDIX

    This appendix contains examples of how to apply the proposed rule 
depending on the type of data available. All examples use hypothetical 
drugs.

SAMPLE PREGNANCY SUBSECTION LABELING

1. Drug for which only animal data are available; with developmental 
toxicity findings:
All pregnancies have a background risk of birth defect, loss, or other 
adverse outcome regardless of drug exposure. The fetal risk summary 
below describes ALPHATHON's potential to increase the risk of 
developmental abnormalities above the background risk.
Fetal Risk Summary
Based on animal data, the likelihood that ALPHATHON increases the risk 
of developmental abnormalities is predicted to be high (see Data).
Clinical Considerations

[[Page 30866]]

Asthma complicates approximately 1 percent of all pregnancies resulting 
in higher perinatal mortality, low birth weight infants, preterm 
births, and pregnancy-induced hypertension compared to outcomes for 
nonasthmatic women. Because of the risks of even mild maternal hypoxia 
to the developing fetus, asthma should be clinically well-controlled 
during pregnancy. There are no human studies evaluating ALPHATHON use 
in pregnant women. The time of gestation at which risk may be greatest 
is unknown; therefore, risks of inadvertent exposure in early gestation 
cannot be evaluated. Animal data suggest that ALPHATHON exposure may 
result in early fetal loss and anomalies of major organ systems. There 
are no data regarding dose adjustment needs in pregnancy. Given the 
lack of human data and the risks suggested by animal data, prescribers 
should consider alternative treatments for asthma for pregnant women 
when possible (especially during the first trimester) and women 
planning pregnancy.
Data
Human data.
     There are no data on human pregnancies exposed to 
ALPHATHON.
Animal Data.
     Reproductive studies performed during early pregnancy in 
rats at oral doses 0.75 to 1.0 times the recommended human dose 
(adjusted for body surface area) showed implantation loss, fetal 
resorptions, and major congenital anomalies of the cardiac, skeletal 
and renal systems without signs of maternal toxicity.
     Reproductive studies performed in early pregnancy in 
rabbits at doses approximately 0.33 to 1.0 times the recommended human 
dose (adjusted for body surface area) showed increased post-
implantation loss. Studies at 3 times the human dose showed significant 
fetal loss without signs of maternal toxicity.
     The effects of ALPHATHON on fetal growth, labor, or post-
natal complications were not evaluated in the animal studies.
2. Drug for which only animal data are available; lack of developmental 
toxicity findings:
    All pregnancies have a background risk of birth defect, loss, or 
other adverse outcome regardless of drug exposure. The fetal risk 
summary below describes GAMMAZINE's potential to increase the risk of 
developmental abnormalities above the background risk.
Fetal Risk Summary
Based on animal data, GAMMAZINE is not predicted to increase the risk 
of developmental abnormalities.
Clinical Considerations
Infection of the urinary tract in pregnant women carries a higher risk 
of morbidity than in the general population and is associated with an 
increased incidence of preterm delivery, low birth weight, and 
progression to pyelonephritis. It is not known whether the dose of 
GAMMAZINE requires adjustment during pregnancy.
Data
Human Data.
     There are no data on human pregnancies exposed to 
GAMMAZINE.
Animal Data.
     No teratogenic effects were seen when pregnant rats and 
rabbits were treated throughout pregnancy with doses equivalent to 1.5 
times the maximum recommended human dose adjusted for body surface 
area. There were no findings of increased fetal loss, mortality or 
resorptions, reductions in body weights in fetuses, or other 
developmental abnormalities.
3. Drug for which animal and some human (insufficient) data are 
available:
All pregnancies have a background risk of birth defect, loss, or other 
adverse outcome regardless of drug exposure. The fetal risk summary 
below describes KAPPAATE's potential to increase the risk of 
developmental abnormalities above the background risk.
Fetal Risk Summary
Based on limited human data from one retrospective cohort study and 
postmarketing adverse event reporting, the likelihood that KAPPAATE 
increases the risk of major congenital abnormalities or spontaneous 
abortions is low. Short term (less than 3 weeks), first trimester 
exposure to 5 to 10 milligrams per (mg/) day of KAPPAATE did not result 
in an increase in major congenital abnormalities or spontaneous 
abortions over the background rate. The limited number of pregnant 
women that were exposed to KAPPAATE during the second and third 
trimesters delivered infants with no major congenital abnormalities. 
Based on animal data, the likelihood that KAPPAATE increases the risk 
of developmental abnormalities is predicted to be moderate.
Clinical Considerations
Symptoms of heartburn and gastroesophageal reflux disease (GERD) are 
common during pregnancy, occurring in about 50 percent of women in the 
third trimester. During pregnancy, untreated GERD can lead to reflux 
esophagitis and can increase nausea and asthma exacerbations in 
asthmatics. Based on limited human data, inadvertent exposure to 
KAPPAATE in early pregnancy is unlikely to be associated with major 
congenital abnormalities or spontaneous abortions; however, animal data 
suggest that early fetal loss may result from KAPPAATE exposure. 
Pharmacokinetic studies have shown that no dose adjustment of KAPPAATE 
is needed for pregnant women in the third trimester (see DOSAGE AND 
ADMINISTRATION and CLINICAL PHARMACOLOGY). Pharmacologically similar 
drugs have demonstrated delayed parturition in animal studies, but the 
relevance of this finding in humans is not known.
Data
Human Data.
     A retrospective cohort study reported on 400 pregnant 
women who used 5 to 10 mg/day of KAPPAATE in the first trimester.\1\ 
The majority of use (90 percent) was short term (less than 3 weeks). 
The overall malformation rate for first trimester exposure to KAPPAATE 
was 3.4 percent (95 percent CI 1.3-7.2) compared to 4.1 percent (95 
percent CI 1.6-6.2) in the comparator group. The study could 
effectively rule out a relative risk greater than 2.0 for overall 
malformations. Rates of spontaneous abortions did not differ between 
the groups.
---------------------------------------------------------------------------

    \1\ Smith J.D., M.R. Perkins, ``Retrospective study on pregnant 
women exposed to Kappaate,'' Some Medical Journal, 121(55):123-134, 
2002.
---------------------------------------------------------------------------

     Postmarketing reports on 125 women exposed to 5 to 10 mg/
day of KAPPAATE during pregnancy did not suggest an increased risk of 
major congenital malformations compared to the background rate in the 
general population. However, gestational ages and durations of exposure 
were not available for all cases. Interpretation of these results are 
limited by the voluntary nature of postmarketing adverse event 
reporting and underreporting.
     No change in pharmacokinetics were seen in pregnant women 
at 32 to 36 weeks gestation given a single dose of KAPPAATE (see 
CLINICAL PHARMACOLOGY).
Animal Data.
     In rats, no teratogenic or embryocidal effects were 
observed when KAPPAATE was administered at doses up to 7 times the 
human dose on a body surface area basis).
     In rabbits, KAPPAATE at maternal doses about 5 to 50 times 
the human dose on a body surface area basis produced dose-related 
increases in embryo-lethality, fetal resorptions,

[[Page 30867]]

pregnancy disruptions, and fetal growth impairment.
     No effects were seen on parturition.
4. Drug for which sufficient human data are available:
All pregnancies have a background risk of birth defect, loss, or other 
adverse outcome regardless of drug exposure. The fetal risk summary 
below describes Deltaman's potential to increase the risk of 
developmental abnormalities above the background risk.
Fetal Risk Summary
Human data do not indicate that DELTAMAN increases the overall risk of 
congenital malformations or neural tube defects. The majority of 
reported human exposures to DELTAMAN are first trimester exposures. 
Epidemiology studies adequate to detect a 2.5-fold increase in the rate 
of major malformations and a 10-fold increase in the rate of neural 
tube defects did not detect a risk. Based on animal data, the 
likelihood that DELTAMAN increases the risk of other developmental 
abnormalities is predicted to be low.
Clinical Considerations
About 1 in 100 women of childbearing age has diabetes. During 
pregnancy, diabetic women have increased risks of miscarriage, preterm 
labor, stillbirth, macrosomia, and congenital malformations, including 
heart defects and neural tube defects. Neonates born to women with 
poorly controlled diabetes are at increased risk of breathing 
difficulties, low blood sugar levels and jaundice. Based on human data, 
inadvertent exposure to DELTAMAN in early pregnancy is not associated 
with an increased risk of major congenital abnormalities or neural tube 
defects. There are no data regarding whether dosing adjustments are 
needed when DELTAMAN is used in pregnancy.
Data
Human Data.
     The DELTAMAN Pregnancy Exposure Registry, a population-
based prospective cohort epidemiological study, has collected data 
since January 2000. As of December 2007, the registry documented 
outcomes on 1,055 infants exposed to DELTAMAN during pregnancy (997 
exposed during the first trimester and 58 exposed after the first 
trimester) have been documented. In utero exposure to DELTAMAN was not 
associated with an increased risk of major congenital malformations at 
birth (odds ratio 0.93, 95 percent CI 0.52-1.39). The number of infants 
born with neural tube defects was similar in the DELTAMAN exposed 
infants and controls. The sample size in this study had 90 percent 
power to detect a 2.5-fold increase in the rate of major malformation 
and 80 percent power to detect a 10-fold increase in the rate of neural 
tube defects.
     A retrospective cohort study reported on 869 pregnant 
women exposed to either DELTAMAN or pharmacologically similar drugs in 
the first trimester (245 exposed to DELTAMAN).\2\ The overall major 
malformation rate was 4.1 percent (95 percent CI 3.2-5.1) and the 
malformation rate for first trimester exposure to DELTAMAN was 3.4 
percent (95 percent CI 1.3-7.8). The relative risk of major 
malformations associated with first trimester exposure to DELTAMAN 
compared with nonexposed women was 0.92 (95 percent CI 0.34-2.3). The 
sample size in this study had 80 percent power to detect a 4-fold 
increase in the rate of major malformations.
---------------------------------------------------------------------------

    \2\ Jones A.B. and C.D. Smith, ``Exposure to Deltaman during 
pregnancy,'' Medical Journal, 98:56-68, 2000.
---------------------------------------------------------------------------

Animal Data.
     Exposure of pregnant rats or mice to DELTAMAN at doses 
comparable to the maximum recommended human dose (based on body surface 
area) resulted in embryonic death and malformations in the offspring. 
Skeletal abnormalities were the most common malformations observed in 
rats and cardiac, skeletal and urinary tract abnormalities were seen 
most often in mice. Neural tube defects were observed in pregnant mice 
and rats at doses of 15 to 25 and 5 to 20 times the human dose (based 
on body surface area), respectively. Behavioral alterations and poor 
weight gain were seen among the offspring of rats treated with DELTAMAN 
during pregnancy at doses greater than 15 times the maximum human dose 
(based on body surface area).
     Studies in cynomolgus monkeys at 1 to 10 times the maximum 
recommended human dose (based on a body surface area) demonstrated a 
dose dependent increase in neural tube and skeletal anomalies.

SAMPLE LACTATION SUBSECTION LABELING

1. Drug for which no data are available:
Risk Summary
No studies have been conducted to assess ALPHAZINE's impact on milk 
production, its presence in breast milk or its effects on the breast-
fed child.
Clinical Considerations
Other medical therapies are available for the treatment of maternal 
hypertension.
Data
No data available.
2. Drug for which pharmacologic class information is available, but no 
human data are available:
Risk Summary
    No studies have been conducted to assess THETAM's effect on milk 
production, its presence in breast milk, or its effects on the breast-
fed child. Based on experience with other products in this class, 
maternal THETAM use has the potential to cause neutropenia in the 
breast-fed child. Because of the potential for neutropenia in the 
breast-fed child, a decision should be made whether to discontinue 
breast-feeding or discontinue using THETAM.
Clinical Considerations
Other medical therapies are available for the treatment of maternal 
fungal infection.
Data
No data available.
3. Drug for which human data are available:
Risk Summary
GAMMATOL is secreted in human milk. At a maternal dose of 400 mg daily, 
the average milk concentration, collected over 24 hours after dosing, 
was 10 mcg/milliliter (mL) which is lower than maternal serum drug 
concentrations at steady state. Based on an average milk consumption of 
150 mL/kilogram (kg)/day, a 2-month-old infant would consume 
approximately 6 mg/day of GAMMATOL via breast milk, which is 
approximately 1.3 percent of the maternal dose. No studies have been 
performed to assess infant absorption and exposure to GAMMATOL from 
breast milk. No studies have been performed to assess the impact of 
GAMMATOL on milk production or its effects on the breast-fed child.
Clinical Considerations
Because GAMMATOL is taken once daily, mothers can reduce infant 
exposure by taking their GAMMATOL dose immediately after breast-feeding 
at the time of day when feedings are less frequent.
Data
     A lactation study was performed in 30 women who were 2 
months postpartum and exclusively breast-feeding their infants. All 
women enrolled in the study were taking a 400 mg single dose of 
GAMMATOL daily. Breast milk samples were collected from each breast at 
the beginning and end of each feeding for 24 hours after a GAMMATOL 
dose. An average

[[Page 30868]]

maximum milk concentration of 20 mcg/mL occurred 3 hours after dosing 
and drug concentrations in milk rapidly declined over the next 12 
hours. The average milk concentration was 10 mcg/mL. No drug was 
detectable in milk samples obtained 36 hours or later after dosing. No 
data are available to assess the impact of GAMMATOL on milk production 
or its effects on the breast-fed child.

    Dated: May 16, 2008.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E8-11806 Filed 5-28-08; 8:45 am]

BILLING CODE 4160-01-S