[Federal Register Volume 66, Number 219 (Tuesday, November 13, 2001)]
[Notices]
[Pages 56830-56831]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-28258]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 99N-2079]


Draft Guidance for Reviewers on the Integration of Study Results 
To Assess Concerns About Human Reproductive and Developmental 
Toxicities; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a draft guidance for reviewers entitled ``Integration 
of Study Results to Assess Concerns About Human Reproductive and 
Developmental Toxicities.'' This draft guidance describes a process for 
estimating human developmental and reproductive risks as a result of 
drug exposure when definitive human data are unavailable. The 
integration process is intended to estimate the likelihood a drug will 
increase the risk of adverse human developmental or reproductive 
effects.

DATES: Submit written or electronic comments on the draft guidance by 
March 13, 2002. General comments on agency guidance documents are 
welcome at any time.

ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Division of Drug Information (HFD-240), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857. Send one self-addressed adhesive label to 
assist that office in processing your requests. See

[[Page 56831]]

the SUPPLEMENTARY INFORMATION section for electronic access to the 
draft guidance document. Submit written comments on the draft guidance 
to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. 
Submit electronic comments to http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Joseph J. DeGeorge, Center for Drug 
Evaluation and Research (HFD-24), Food and Drug Administration,1451 
Rockville Pike, Rockville, MD 20852, 301-594-5476.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance for 
reviewers entitled ``Integration of Study Results to Assess Concerns 
About Human Reproductive and Developmental Toxicities.'' This draft 
guidance describes a process for estimating human reproductive and 
development risks as a result of drug exposure. The integration process 
is intended to estimate the likelihood a drug will increase the risk of 
adverse human reproductive or developmental effects. The process is 
based on the evaluation of a complete set of reproductive and general 
toxicology studies conducted in animals, pharmacokinetics, and the 
absorption and distribution of metabolic elimination (ADME) studies 
conducted in animals and humans. The evaluation also compares animal 
and human drug-induced pharmacodynamic responses, drug metabolism and 
disposition, drug-induced pharmacologic and toxic effects, and drug 
exposures in animal studies versus those at the highest recommended 
dose in humans.
    An earlier version of this integration tool was presented in a 
public meeting announced on May 4, 1999 (64 FR 23844), and held on June 
24, 1999. The draft integration tool, slides from the presentations at 
the meeting, and comments received subsequent to the meeting were 
placed on the FDA Web site and in docket number 99N-2079. This draft 
guidance incorporates modifications as a result of the public meeting 
and comments submitted to the public docket.
    The type and extent of the available toxicology data may vary 
depending on the biologic actions of the product, test systems 
available for studying the compound, and other factors. In some 
instances, the data may not include all desirable reproductive 
toxicology, general toxicology, pharmacokinetics, and ADME studies. 
Such limitations of the available data may preclude use of the 
integration process (e.g., often the case for biologic products). 
However, even if the integration process cannot be used, the product 
should be evaluated to the greatest extent possible in accordance with 
sound scientific principles and the considerations described in this 
document.
    For purposes of this draft guidance, all reproductive risks are 
divided into one of two broad categories of toxicity--reproductive and 
developmental toxicity, which are further subdivided into seven classes 
of toxicity. The three classes of reproductive toxicity include: 
Effects on fertility, parturition, and lactation. The four classes of 
developmental toxicity include: Mortality, dysmorphogenesis (structural 
alterations), alterations to growth, and functional toxicities. For a 
given drug, each class of toxicity should ordinarily be assessed 
individually.
    The criteria presented in the draft guidance are derived from a 
limited sample of pharmaceuticals where the clinical outcomes are 
reasonably well defined. The Center for Drug Evaluation and Research 
(CDER) believes that using specific criteria and benchmark values to 
assess the potential to increase risk to humans for adverse 
reproductive and developmental outcomes will result in a more unbiased 
and uniform evaluation. CDER also believes this approach will help 
identify specific areas of additional information about a 
pharmaceutical that would be useful in more fully defining risk and 
allow specific analysis of areas of disagreement that influence the 
risk evaluation. CDER is particularly interested in comment on the 
appropriateness of the values used to define levels of increased risk 
for products with positive signals for reproductive or developmental 
toxicity and on experience in applying the outlined evaluation approach 
using information that may exist in public and commercial domains.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the agency's current thinking on 
``Integration of Study Results to Assess Concerns About Human 
Reproductive and Developmental Toxicities.'' It does not create or 
confer any rights for or on any person and does not operate to bind FDA 
or the public. An alternative approach may be used if such approach 
satisfies the requirements of the applicable statutes and regulations.

II. Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments on the draft guidance. Two copies of 
any comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. The draft guidance and 
received comments are available for public examination in the Dockets 
Management Branch between 9 a.m. and 4 p.m., Monday through Friday.

III. Electronic Access

    Persons with access to the Internet may obtain the document at 
either http://www.fda.gov/cder/guidance/index.htm or http://www.fda.gov/ohrms/dockets/default.htm.

    Dated: November 1, 2001.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 01-28258 Filed 11-9-01; 8:45 am]
BILLING CODE 4160-01-S