[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