Download FDA Issues Proposed Rule on Pregnancy and Lactation Labeling

FDA/Healthcare Practice Group
June 10, 2008
FDA Issues Proposed Rule on
Pregnancy and Lactation Labeling
Agency Requests Public Comments By August 27, 2008
On May 29th, FDA issued a proposed rule that would require major
revisions of both the format and content of prescription drug and
biological labeling with respect to pregnancy and lactation. The
FDA states that the revised labeling is intended to provide more
complete information for physicians and consumers on possible
effects of drugs used during pregnancy (including inadvertent
exposure before pregnancy is detected) and breast-feeding, in a
consistent format that will be useful for decision making by women
of childbearing age and their healthcare providers. See “Content
and Format of Labeling for Human Prescription Drug and
Biological Products; Requirements for Pregnancy and Lactation
Labeling,” 73 Fed. Reg. 30831 (May 29, 2008).
For more information, contact:
Christina M. Markus
(202) 626-2926
[email protected]
Beverly H. Lorell, M.D.
(202) 383-8937
[email protected]
King & Spalding
Washington, D.C.
1700 Pennsylvania Avenue, NW
Washington, DC 20006-4706
Tel: 202-737-0500
Fax: 202-626-3737
www.kslaw.com
The FDA proposes two major subsections of the new labeling:
“Pregnancy” and “Lactation.” These major subsections would
replace the existing “Pregnancy,” “Labor and Delivery,” and
“Nursing Mothers” sections of drug labeling. FDA’s current
regulations permit omission of the “Pregnancy” subsection if a drug
is not absorbed systemically and it is not known to have the
potential for indirect harm to the fetus; in contrast, the proposed rule
would require that the labeling for all prescription drugs contain a
“Pregnancy” subsection. The proposed rule also would eliminate
the current alphabetical (A, B, C, D, and X) categorization of risk.
Instead, each new subsection would contain three principal
components: a risk summary, clinical considerations, and a data
section that is intended to describe available animal and human data,
including data acquired in postmarket experience (such as via
postmarket pregnancy registries).
Because of the potential impact on pharmaceutical and biologics
manufacturers, we urge our clients to carefully review this proposed
rule. Comments concerning the proposed rule are due by August
27, 2008.
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FDA/Healthcare Practice Group
Background. FDA has developed the proposed revised labeling over the course of a decade, including the
use of a formal hearing, focus group and advisory committee input, and the issuance of guidance documents
during that time. The complex development history is described in detail in the preamble to FDA’s
proposed rule.
Key elements. Under FDA’s proposed rule, the new “Pregnancy” labeling subsection would be required to
contain the following elements:
Fetal Risk Summary
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Risk conclusions in standardized format that characterize the likelihood that a drug increases the
risk of specific types of developmental abnormalities (including structural abnormalities, fetal and
infant mortality, impaired physiologic function, and alterations to growth) and other relevant risks
(e.g., transplacental carcinogenesis);
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A statement as to whether the risk conclusion was based on animal data, human data, or both; and
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If human data are available, a statement describing (to the extent possible) the specific
developmental abnormality (e.g., neural tube defects); the incidence, seriousness, reversibility, and
correctability of the abnormality; and the effect on risk of dose, gestational timing of exposure, and
duration of exposure. When appropriate, the description would be required to include the risk
above background level attributable 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.
Clinical Considerations
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A section addressing inadvertent exposure of a fetus early in pregnancy before a woman knows
she is pregnant, including data on timing, dose, and duration of exposure;
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A section addressing prescribing decisions for pregnant woman including risks to mother and fetus
from the disease(s) the drug is intended to treat, dosing adjustments recommended during
pregnancy, adverse drug reactions unique to pregnancy, interventions (such as monitoring) that
may be needed, and any complications in the neonate that may be associated with use of the drug,
including severity, reversibility, and general types of interventions that may be needed; and
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A section addressing effects during labor or delivery including potential effect of the drug on the
mother and fetus/newborn, duration of labor and delivery, possible complications and associated
interventions, and growth development and maturation of the child. Note that the FDA has
retained existing regulatory language that this section should address “a recognized use during
labor or delivery, whether or not the use is stated as an indication in the labeling.”
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FDA/Healthcare Practice Group
Data Section
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Human data, such as that acquired in postmarket adverse event reports and pregnancy exposure
registries, would be presented before animal data;
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An animal data section including types of studies conducted, species, dose exposure information
described in terms of human equivalents, and specific nature of identified fetal abnormalities;
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A discussion of what is understood about the relationship between drug exposure and mechanism
of action in the animals studied versus humans;
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A statement regarding human pregnancy exposure registries, including telephone number and
enrollment information; and
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A general standardized statement about human background risk indicating that all pregnancies
have a background risk of birth defects, fetal loss, or other adverse outcome regardless of drug
exposure.
Under the proposed rule, the new “Lactation” subsection would require the following elements:
Risk Summary
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An affirmative statement that use of the drug is compatible with breast-feeding if data have
demonstrated that (1) the drug does not affect the quantity and/or quality of human milk and (2)
there is reasonable certainty that the drug is not detectable in human milk or the amount of drug
consumed will not adversely affect the breast-fed child;
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A lactation risk summary describing the drug’s effects on milk production, whether the drug is
present, and if so in what quantities, in human milk, and the effects of the drug on the breast-fed
child;
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The sources of the data that are the basis for the risk summary; and
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If insufficient data exist to assess drug effects on human milk and/or effects on the breast-fed child,
a statement of that fact in the risk summary.
We note that the proposed rule appears to contain an error regarding this proposed mandatory statement
regarding systemic absorption in nursing mothers because it cites “fetal exposure” rather than exposure
of the breast-fed child.
Clinical Considerations
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FDA/Healthcare Practice Group
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A description of ways to minimize exposure to the breast-fed child (e.g., alterations in timing of
feeding related to drug ingestion);
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A statement of potential drug effects in the child and suggestions for monitoring or responding to
such effects; and
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A description of recommended dosing adjustment during lactation.
Data Section
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Overview of the human data on which risk summary and clinical considerations are based; and
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Overview of the animal data on which risk summary and clinical considerations are based.
Applicability and timing of implementation. If implemented, FDA’s proposed rule would affect the
format and content of the labeling of all prescription drugs that are required to have a pregnancy category in
the labeling in compliance with the Physician Labeling Rule, which became effective on June 30, 2006.1
FDA has assumed that the proposed pregnancy rule will become effective no earlier than June 30, 2010. If
the proposed rule becomes effective earlier than this date, FDA plans to adjust the proposed implementation
schedule that is set forth in the proposed rule accordingly.
The timing for implementation of the revised pregnancy and lactation labeling will be phased. The most
immediate burden for potential new data collection and interpretation will be incurred for drugs that are
currently advanced in premarket development and for which marketing applications are likely to be
submitted shortly after the effective data of the pregnancy final rule. Applications submitted on or after the
effective date of the pregnancy final rule would be required to comply with the revised labeling format at
time of submission. Applications pending on the effective date of the pregnancy final rule must comply 4
years after the effective date or at time of approval, whichever is later.
For applications already approved and subject to the Physician Labeling Rule, three different deadlines
apply.
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For applications approved from June 30, 2001, up to and including June 29, 2002, and from June
30, 2005, up to and including June 29, 2007, revised labeling must be submitted to FDA for
approval 3 years after the effective date of the final rule;
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For applications approved from June 30, 2007, up to and including the effective date of the final
rule, revised labeling must be submitted to FDA for approval 4 years after the effective date of the
final rule;
1
See “Requirements on Content and Format of Labeling for Human Prescription Drug and Biologic Products,” 71 Fed. Reg. 3921
(January 24, 2006).
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FDA/Healthcare Practice Group
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For applications approved from June 30, 2002, up to and including June 29, 2005, revised labeling
must be submitted to FDA for approval 5 years after the effective date of the final rule.
It is important to recognize that products with applications approved prior to June 30, 2001 (i.e.,
applications not subject to the Physician Labeling Rule) would not be required to implement the new
content requirements of the revised label. However, if those products currently are labeled with an
alphabetic (A, B, C, D or X) pregnancy risk category, the application holder will be required to remove the
alphabetic pregnancy risk category designation by 3 years after the effective data of the pregnancy final
rule. This change would only be required to be reported to FDA in the annual report for the new drug or
biologics license application.
Important issues for consideration by manufacturers. The proposed change in pregnancy and lactation
labeling will provide new burdens on some manufacturers related to acquisition and analysis of data
necessary to meet new labeling content requirements. In addition, the mandatory discussion of pregnancy
exposure registries is likely to heighten interest in the acquisition of data using such postmarket registries.
In the full description of the proposed rule in the Federal Register, we also call attention to two additional
elements as manufacturers consider the potential impact of the proposed labeling changes. First, the
proposed rule contains a detailed discussion as to how risk descriptors regarding the magnitude of risk are to
be constructed, including the five risk designations: (1) not predicted to increase risk; (2) low likelihood of
increased risk; (3) moderate likelihood of increased risk; (4) high likelihood of increased risk; and (5)
insufficient data. Second, the full description of the proposed rule contains an appendix with multiple
sample labeling statements for hypothetical drugs that provide examples as to how the FDA anticipates the
proposed rule will be applied. These hypothetical examples may be very helpful as manufacturers consider
the potential implications of the proposed rule for their specific products.
As noted, public comments must be submitted by August 27, 2008. Please contact us if you have questions,
or if we can assist you in the preparation of comments.
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