[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]
-----------------------------------------------------------------------
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Draft Guidance for Reviewers on the Integration of Study Results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.
-----------------------------------------------------------------------
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availability of a draft guidance for reviewers entitled ``Integration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 This draft guidance describes a process for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DATES: Submit written or electronic comments on the draft guidance by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ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information (HFD-240), Center for Drug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draft guidance document. Submit written comments on the draft guidance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FDA is announcing the availability of a draft guidance for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 This draft
guidance describes a process for estimating human reproductive and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