[Federal Register Volume 64, Number 122 (Friday, June 25, 1999)]
[Notices]
[Pages 34259-34260]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16189]
[[Page 34259]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0444]
International Conference on Harmonisation; Guidance on the
Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent
Toxicity Testing); Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing a
guidance entitled ``S4A Duration of Chronic Toxicity Testing in Animals
(Rodent and Nonrodent Toxicity Testing).'' The guidance was prepared
under the auspices of the International Conference on Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human
Use (ICH) and is intended to provide guidance on the duration of
chronic toxicity testing in rodents and nonrodents as part of the
safety evaluation of a drug product. FDA is also noting circumstances
in which it may accept durations of chronic toxicity testing in
nonrodents that differ from the duration generally recommended by ICH.
DATES: Effective June 25, 1999. Submit written comments at any time.
ADDRESSES: Submit written comments on the guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Copies of the guidance are
available from the Drug Information Branch (HFD-210), Center for Drug
Evaluation and Research, Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857, 301-827-4573. Single copies of the guidance
may be obtained by mail from the Office of Communication, Training and
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and
Research (CBER), 1401 Rockville Pike, Rockville, MD 20852-1448, or by
calling the CBER Voice Information System at 1-800-835-4709 or 301-827-
1800. Copies may be obtained from CBER's FAX Information System at 1-
888-CBER-FAX or 301-827-3844.
FOR FURTHER INFORMATION CONTACT:
Regarding the guidance: Joseph J. DeGeorge, Center for Drug
Evaluation and Research (HFD-24), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-6758.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
SUPPLEMENTARY INFORMATION: In recent years, many important initiatives
have been undertaken by regulatory authorities and industry
associations to promote international harmonization of regulatory
requirements. FDA has participated in many meetings designed to enhance
harmonization and is committed to seeking scientifically based
harmonized technical procedures for pharmaceutical development. One of
the goals of harmonization is to identify and then reduce differences
in technical requirements for drug development among regulatory
agencies.
ICH was organized to provide an opportunity for tripartite
harmonization initiatives to be developed with input from both
regulatory and industry representatives. FDA also seeks input from
consumer representatives and others. ICH is concerned with
harmonization of technical requirements for the registration of
pharmaceutical products among three regions: The European Union, Japan,
and the United States. The six ICH sponsors are the European
Commission, the European Federation of Pharmaceutical Industries
Associations, the Japanese Ministry of Health and Welfare, the Japanese
Pharmaceutical Manufacturers Association, the Centers for Drug
Evaluation and Research and Biologics Evaluation and Research, FDA, and
the Pharmaceutical Research and Manufacturers of America. The ICH
Secretariat, which coordinates the preparation of documentation, is
provided by the International Federation of Pharmaceutical
Manufacturers Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the IFPMA, as well as observers from the World
Health Organization, the Canadian Health Protection Branch, and the
European Free Trade Area.
In the Federal Register of November 18, 1997 (62 FR 61513), FDA
published a draft tripartite guidance entitled ``S4A Duration of
Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity
Testing).'' The notice gave interested persons an opportunity to submit
comments by January 20, 1998.
There were no comments received and no revisions to the guidance. A
final draft of the guidance was submitted to the ICH Steering Committee
and endorsed by the three participating regulatory agencies on
September 2, 1998.
In accordance with FDA's Good Guidance Practices (62 FR 8961,
February 27, 1997), this document has been designated a guidance,
rather than a guideline.
The document provides guidance on the duration of chronic toxicity
testing in rodents and nonrodents as part of the safety evaluation of a
drug product. The guidance is intended to help eliminate or reduce the
need for pharmaceutical companies to duplicate testing in animals
during the development of new drug products. The guidance is based on
information currently available to the agency, and this information is
available to the public in Docket No. 97D-0444.
This guidance represents the agency's current thinking on the
duration of chronic toxicity testing in animals (rodent and nonrodent
toxicity testing). 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 statute, regulations, or both.
For guidance on biotechnology-derived pharmaceuticals, interested
parties are advised to consult the ICH guidance ``S6 Preclinical Safety
Evaluation of Biotechnology-Derived Pharmaceuticals'' (62 FR 61515,
November 18, 1997).
FDA note on duration of chronic toxicity testing in nonrodents: The
ICH guidance recommends 9-month chronic toxicity studies in nonrodents.
FDA considers 9-month studies in nonrodents acceptable for most drug
development programs, shorter studies may be equally acceptable in some
circumstances and longer studies may be more appropriate in others, as
follows:
Six-month studies may be acceptable for indications of
chronic conditions associated with short-term, intermittent drug
exposure, such as bacterial infections, migraine, erectile dysfunction,
and herpes.
Six-month studies may be acceptable for drugs intended for
indications for life-threatening diseases for which substantial long-
term human clinical data are available, such as cancer chemotherapy in
advanced disease or in adjuvant use.
Twelve-month studies may be more appropriate for
chronically used drugs to be approved on the basis of short-term
clinical trials employing efficacy surrogate markers where safety data
from humans are limited to short-term exposure, such as some acquired
immunodeficiency syndrome (AIDS) therapies.
[[Page 34260]]
Twelve-month studies may be more appropriate for new
molecular entities acting at new molecular targets where postmarketing
experience is not available for the pharmacological class. Thus, the
therapeutic is the first in a pharmacological class for which there is
limited human or animal experience on its long-term toxic potential.
As with all of FDA's guidances, the public is encouraged to submit
written comments with new data or other new information pertinent to
this guidance. The comments in the docket will be periodically
reviewed, and, where appropriate, the guidance will be amended. The
public will be notified of any such amendments through a notice in the
Federal Register.
Interested persons may, at any time, submit written comments on the
guidance to the Dockets Management Branch (address above). 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 guidance and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this guidance is
available on the Internet at ``http://www.fda.gov/cder/guidance/
index.htm'' or at CBER's World Wide Web site at ``http://www.fda.gov/
cber/publications.htm''.
The text of the guidance follows:
S4A Duration of Chronic Toxicity Testing in Animals (Rodent and
Nonrodent Toxicity Testing)\1\
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This guidance represents the agency's current thinking on the
duration of chronic toxicity testing in animals (rodent and
nonrodent toxicity testing). 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 satisifes the
requirements of the applicable statute, regulations, or both.
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1. Objective
The objective of this guidance is to set out the considerations
that apply to chronic toxicity testing in rodents and nonrodents as
part of the safety evaluation of a medicinal product. Since guidance
is not legally binding, an applicant may submit justification for an
alternative approach.
2. Scope
This guidance has been prepared for the development of medicinal
products with the exception of those already covered by the ICH
guidance ``S6 Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals'' (62 FR 61515, November 18, 1997), e.g., monoclonal
antibodies, recombinant DNA proteins.
3. Background
During the first International Conference on Harmonisation in
1991, the practices for the testing of chronic toxicity in the three
regions (the European Union, Japan, and the United States) were
reviewed. Arising from this, it emerged that there was a scientific
consensus on the approach for chronic testing in rodents, supporting
the harmonized duration of testing of 6 months. However, for chronic
toxicity testing in nonrodents, there were different approaches to
the duration of testing.
The lack of harmonized duration led to the need for
pharmaceutical companies to perform partially duplicative studies
for both 6 and 12 months' duration when developing new medicinal
products. As the objective of ICH is to reduce or eliminate the need
to duplicate testing during development of medicinal products and to
ensure a more economical use of material, animal, and human
resources, while at the same time maintaining safeguards to protect
public health, further scientific evaluation was undertaken.
Each of the regulatory authorities in the European Union, Japan,
and the United States undertook a review to determine whether a
single duration for chronic toxicity testing in nonrodents could be
identified. From this analysis, it emerged that in 16 cases a more
detailed evaluation of 6 versus 12 months' data should be
undertaken.
This evaluation was conducted as a joint exercise by the
competent authorities in the three regions.
In some of the cases analyzed at the tripartite meetings, there
were no additional findings at 12 months. For some other cases,
there was not complete agreement among the regulators with respect
to the comparability in study design and conduct to allow assessment
of whether there were differences in the findings at 6 and 12 months
due to duration of treatment alone.
In a number of cases there were findings observed by 12 months,
but not by 6 months. It was concluded that these would, or could,
have been detected in a study of 9 months' duration. Varying degrees
of concern for the differences in findings detected between the
studies of different durations were expressed. An agreement on the
clinical relevance of these findings could not be reached.
Studies of 12 months' duration are usually not necessary, and
studies of shorter than 9 months' duration may be sufficient.
In the European Union, studies of 6 months' duration in
nonrodents are acceptable according to Council Directive 75/318/EEC,
as amended. To avoid duplication, where studies with a longer
duration have been conducted, it would not be necessary to conduct a
study of 6 months.
4. Guidance on Duration of Chronic Toxicity Testing for Tripartite
Development Plan
Arising from the extensive analysis and review of the above
mentioned data in nonrodents and based upon the achievements of ICH
1 for testing in rodents, and so as to avoid duplication and follow
a single development plan for chronic toxicity testing of new
medicinal products, the following studies are considered acceptable
for submission in the three regions:
(1) Rodents:A study of 6 months' duration;
(2) Nonrodents: A study of 9 months' duration.
Dated: June 17, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy Coordination.
[FR Doc. 99-16189 Filed 6-24-99; 8:45 am]
BILLING CODE 4160-01-F
