[Federal Register Volume 62, Number 147 (Thursday, July 31, 1997)]
[Notices]
[Pages 41061-41063]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-20247]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 97N-0289]


Content and Format of Labeling for Human Prescription Drugs; 
Pregnancy Labeling; Public Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of public hearing; request for comments.

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SUMMARY: The Food and Drug Administration (FDA) is announcing a public 
hearing regarding requirements for the content and format of the 
pregnancy subsection of labeling for human prescription drugs. The 
public hearing will focus on the requirement that each drug product be 
classified in one of five pregnancy categories intended to aid 
clinicians and patients with decisions about drug therapy. Public 
comments and FDA's preliminary review of the pregnancy category 
designations for marketed drugs suggest that the categories may be 
misleading and confusing, may not accurately reflect reproductive and 
developmental risk, and may be used inappropriately by clinicians in 
making decisions about drug therapy in pregnant women and women of 
childbearing potential and also in making decisions about how to 
respond to inadvertent fetal exposure. The hearing is intended to 
elicit comments on the practical utility, effects, and limitations of 
the current pregnancy labeling categories in order to help the agency 
identify the range of problems associated with the categories and to 
identify and evaluate options that might address identified problems, 
and to hear the views of groups most affected.

DATES: The public hearing will be held on Friday, September 12, 1997, 
from 9 a.m. to 5 p.m. Submit written notices of participation and 
comments for consideration at the hearing by August 28, 1997. Written 
comments will be accepted after the hearing until November 12, 1997.

ADDRESSES: The hearing will be held at the Holiday Inn Bethesda, 8120 
Wisconsin Ave.,Versailles I and II, Bethesda, MD 20814. Submit written 
notices of participation and comments to the Advisors and Consultants 
Staff, Center for Drug Evaluation and Research (HFD-21), ATTN: 
Pregnancy Labeling Hearing--Robin M. Spencer or Kimberly L. Topper, 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 
FAX 301-443-0699. Federal Express deliveries need to use the following 
street address: 1901 Chapman Ave., rm. 200, Rockville, MD 20852.
    Transcripts of the hearing will be available from the Freedom of 
Information Office (HFI-35), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, FAX 301-443-1726, approximately 15 business 
days after the hearing at a cost of 10 cents per page. Requests can 
also be made for microfiche or computer disk copies in place of paper 
copies.

FOR FURTHER INFORMATION CONTACT: Rose E. Cunningham, Center for Drug 
Evaluation and Research (HFD-6), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-594-6779, or FAX 301-594-5493; 
or Kimberly L. Topper, Advisors and

[[Page 41062]]

Consultants Staff (address above), 301-443-5455, or FAX 301-443-0699.

SUPPLEMENTARY INFORMATION:

I. Background

    Under the Federal Food, Drug, and Cosmetic Act (the act), FDA has 
responsibility for ensuring that prescription drug and biological 
products are accompanied by labeling (prescribing information) that 
summarizes essential scientific information needed for their safe and 
effective use. Unless a drug is not absorbed systemically and is not 
known to have a potential for indirect harm to a fetus, its labeling 
must include a ``Pregnancy subsection'' containing narrative 
information on the drug's teratogenic effects and other effects on 
reproduction and pregnancy, and, when relevant, effects on later 
growth, development, and functional maturation of the child (21 CFR 
201.57(f)(6)). The regulation also requires 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. A drug's pregnancy category is identified at the 
beginning of its pregnancy labeling subsection.
    Clinicians who treat pregnant women and women of childbearing 
potential, academic and specialty medical organizations, women's health 
organizations and others have expressed to FDA concern that the 
information contained in the typical pregnancy labeling subsection, and 
the manner in which such information is presented, are not sufficient 
to adequately inform decisions about drug therapy in pregnant women and 
women of childbearing potential, or decisions about how to respond to 
inadvertent fetal drug exposure.
    In response to these concerns and FDA's growing awareness of the 
limitations of the pregnancy subsection of the labeling, FDA is 
currently engaged in a comprehensive evaluation of the way the agency 
assesses reproductive and developmental toxicities associated with 
human drugs and biologics, and the way the agency communicates this 
information to clinicians and patients. This evaluation is focused on 
assessing the adequacy of animal and human exposure data currently 
developed or maintained, developing consistency in interpretation of 
reproductive and developmental risk from animal and human exposure 
data, and identifying means to optimize communication of this risk 
information.
    FDA has created a multidisciplinary task force to explore these 
issues. This group intends to develop, for use by FDA reviewers and 
industry, a guidance document on interpretation of reproductive and 
developmental toxicity data from animals and a guidance document on 
interpretation of human exposure data. The task force will also 
consider other possible actions that may be necessary to make pregnancy 
labeling content more consistent, informative, and accessible 
including: (1) Changing, or creating alternatives to, the pregnancy 
labeling categories; (2) clearly distinguishing in labeling between 
information that addresses whether to prescribe a therapeutic option 
during pregnancy, whether to prescribe a therapeutic option in a woman 
of childbearing potential, and the potential consequences of 
inadvertent fetal exposure; and (3) attempting to better delineate the 
different types of reproductive and developmental risks associated with 
a product. This hearing is intended to gather information to inform 
future task force recommendations.

II. The Pregnancy Categories

    FDA's information gathering and evaluation to date have identified 
the pregnancy categories as a source of concern for those who use or 
are affected by pregnancy labeling. The categories have been criticized 
for being confusing and misleading because they convey the impression 
that there is a gradation of reproductive risk from drug exposure 
across categories (i.e., that risk increases from A to B to C to D to 
X) and that there is similar risk within any given category, but the 
criteria for designating drugs in particular categories are not 
consistent with these impressions.
    The confusion concerning gradation of risk across categories is 
believed to be due, in part, to the fact that the criteria for 
inclusion in categories A, B, and to a certain extent C, are based 
primarily on risk with risk increasing from A to C, while criteria for 
inclusion in categories D, X, and to a certain extent C, are based on 
risk weighed against potential benefit. Thus, while it is intended that 
there be gradation of risk for categories A through C, drugs designated 
D, X, and in some cases C, may pose a very similar risk, but be 
categorized differently on the basis of potential benefit.
    The impression that there is similar risk for drugs within the same 
category is undercut by inclusion criteria that permit a broad range of 
risk within certain categories. For example, category C (the largest 
category) is intended to include both drugs with demonstrated adverse 
reproductive effects in animals and drugs for which there are no animal 
studies at all, situations that may be quite different in terms of 
risk. For the category C drugs that were tested in animals, moreover, 
there is a wide range of severity of adverse effects and often no 
distinction between teratogenic and other toxic effects.
    The confusion inherent in the current category designations may be 
exacerbated by inconsistent application of category classifications in 
certain instances, such that drugs with similar risk, or with similar 
risk-benefit assessments, may be found in different categories.
    Some who expressed concern to the agency about pregnancy labeling 
argue that failure of the category designations to accurately reflect 
reproductive and developmental risk, either across categories or within 
a category, presents potentially serious public health consequences. 
They maintain that many clinicians assume the categories reflect 
gradation of risk from category A through X, that any given category is 
homogenous in terms of risk, and based on those assumptions make 
decisions based largely or entirely on category designation rather than 
on careful evaluation of the available data. They also argue that, in 
addition to the potential for category designations to be misleading, 
the mere presence of category designations affords an overly simplistic 
evaluation of a complex problem that can deter the clinician from 
seeking additional information that could lead to a better informed 
decision. They maintain that clinicians making decisions based on 
category designation alone are more likely to overestimate risk, with 
potentially profound consequences. For example, decisions based on an 
overestimation of teratogenic risk may result in unnecessary 
withholding of beneficial therapy or in termination of wanted 
pregnancies.

III. Scope of the Hearing

    Because of the breadth and complexity of issues involved in 
assessing, interpreting, and communicating information that bears on 
therapeutic use and exposure to drugs in pregnancy and in women of 
childbearing potential, this part 15 (21 CFR part 15) hearing will 
focus on the pregnancy categories. To guide its future decision making, 
the agency is seeking public comment and data on the practical utility 
and effects of the pregnancy categories, problems associated with the 
categories, and the

[[Page 41063]]

means to address problems associated with the categories, including 
possible alternatives to the categories for communicating information 
on reproductive and developmental toxicity. The agency is specifically 
seeking comment and data on the following:
    (1) 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;
    (2) The extent to which current pregnancy labeling (category 
designation and accompanying narrative text) is effective in 
communicating risk of reproductive and developmental toxicity;
    (3) 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);
    (4) 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; and
    (5) 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.
    The agency encourages individuals, industry, consumer groups, 
health care professionals, and researchers with particular expertise in 
this area, as well as other interested persons, to respond to this 
notice. The agency strongly encourages persons who cannot attend the 
hearing to send information relevant to the topics and questions listed 
above to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 12420 Parklawn Dr., rm 1-23, Rockville, MD 20857. Two 
copies of any comments are to be submitted, except that individuals may 
submit one copy. Comments are to be identified with Docket No. 97N-
0289. Received comments may be seen in the office above between 9 a.m. 
and 4 p.m., Monday through Friday.

IV. Notice Of Hearing Under Part 15

    The Commissioner of Food and Drugs (the Commissioner) is announcing 
that the public hearing will be held in accordance with part 15. The 
presiding officer will be the Commissioner or his designee. The 
presiding officer will be accompanied by a panel of Public Health 
Service employees with relevant expertise.
    Persons who wish to participate in the part 15 hearing must file a 
written or facsimile notice of participation with the Advisors and 
Consultants Staff by August 28, 1997. To ensure timely handling, the 
outer envelope or facsimile cover sheet should be clearly marked with 
Docket No. 97N-0289 and the statement ``Pregnancy Labeling Hearing.'' 
Groups should submit two copies. The notice of participation should 
contain the speaker's name, address, telephone number, FAX number, 
title, business affiliation, if any, a brief summary of the 
presentation, and approximate amount of time requested for the 
presentation.
    The agency requests that persons or groups having similar interests 
consolidate their presentations and present them through a single 
representative. FDA will allocate the time available for the hearing 
among the persons who properly file notices of participation. If time 
permits, FDA may allow participation at the conclusion of the hearing 
from interested persons attending the hearing who did not submit a 
written notice of participation.
    After reviewing the notices of participation and accompanying 
information, FDA will schedule each appearance and notify each 
participant by mail, telephone, or FAX, of the time allotted to the 
person and the approximate time the person's presentation is scheduled 
to begin. The hearing schedule will be available at the hearing. After 
the hearing the schedule will be placed on file in the Dockets 
Management Branch (address above) under Docket Number 97N-0289.
    Under Sec. 15.30(f), the hearing is informal and the rules of 
evidence do not apply. The presiding officer and any panel members may 
question any person during or at the conclusion of their presentation. 
No other person attending the hearing may question a person making a 
presentation or interrupt the presentation of a participant.
    Public hearings under part 15 are subject to FDA's guideline (part 
10, subpart C (21 CFR part 10, subpart C)) concerning the policy and 
procedures for electronic media coverage of FDA's public administrative 
proceedings. Under Sec. 10.205, representatives of the electronic media 
may be permitted, subject, to certain limitations, to videotape, film, 
or otherwise record FDA's public administrative proceedings, including 
presentations by participants. Representatives of the electronic media 
are urged to provide advance notice of their planned attendance, to the 
identified contact person for the hearing, so that their needs for 
space and technical assistance can be anticipated and accommodated. The 
hearing will be transcribed as required in Sec. 15.30(b). Orders for 
copies of the transcript can be placed through the Dockets Management 
Branch (address above).
    Any disabled persons requiring special accommodations in order to 
attend the hearing should direct those needs to the contact person 
listed above.
    To the extent that the conditions for the hearing, as described in 
this notice, conflict with any provisions set out in part 15, this 
notice acts as a waiver of those provisions as specified in 
Sec. 15.30(h).
    To permit time for all interested persons to submit data, 
information, or views on this subject, the administrative record will 
remain open following the hearing until November 12, 1997.

    Dated: July 23, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-20247 Filed 7-30-97; 8:45 am]
BILLING CODE 4160-01-F