[Federal Register Volume 73, Number 104 (Thursday, May 29, 2008)]
[Proposed Rules]
[Pages 30831-30868]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E8-11806]
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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: [email protected].
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.
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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.
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\1\ Smith J.D., M.R. Perkins, ``Retrospective study on pregnant
women exposed to Kappaate,'' Some Medical Journal, 121(55):123-134,
2002.
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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,
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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.
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\2\ Jones A.B. and C.D. Smith, ``Exposure to Deltaman during
pregnancy,'' Medical Journal, 98:56-68, 2000.
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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
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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