[Federal Register Volume 62, Number 222 (Tuesday, November 18, 1997)]
[Notices]
[Pages 61513-61515]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30273]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 97D-0444]
International Conference on Harmonisation; Draft Guidance on the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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft
guidance entitled ``S4A Duration of Chronic Toxicity Testing in Animals
(Rodent and Nonrodent Toxicity Testing).'' The draft guidance was
prepared under the auspices of the International Conference on
Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use (ICH). The draft guidance is intended to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.
DATES: Written comments by January 20, 1998.
ADDRESSES: Submit written comments on the draft guidance to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 12420
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Copies of the draft
guidance are available from the Drug Information Branch (HFD-210),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.
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 July 1997, the ICH Steering Committee agreed that a draft
guidance entitled ``S4A Duration of Chronic
[[Page 61514]]
Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing)''
should be made available for public comment. The draft guidance is the
product of the Safety Expert Working Group of the ICH. Comments about
this draft will be considered by FDA and the Safety Expert Working
Group.
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 draft 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 draft guidance is intended to help
eliminate or reduce the need for pharmaceutical companies to duplicate
testing during the development of new drug products.
FDA has proposed draft guidance before on chronic toxicity testing.
In the Federal Register of April 15, 1992 (57 FR 13105), FDA announced
the availability of a proposed approach to toxicity testing, including
long-term toxicity studies. The new ICH draft guidance published here
reflects a change in recommended testing in nonrodents based on an
evaluation of findings from chronic toxicity studies. The evaluation
report is available in Docket No. 97D-0444. The agency requests
comments on the draft guidance and on specific classes of
pharmaceuticals for which either shorter or longer durations of testing
in nonrodents should be considered as general exceptions to the
duration recommended in the draft guidance. It would be helpful if the
scientific basis for comments addressing ``general exceptions'' were
also provided. Once this guidance is finalized, it will supersede the
1992 proposed guidance (57 FR 13105).
Other portions of the proposed approach to toxicity testing
announced in the Federal Register of April 15, 1992, have been
superseded by draft and finalized FDA and ICH guidances as follows:
Table 1.--1992 Draft Proposed Guidance
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Topic Superseded by
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Single Dose (Acute) Toxicity Guidance for Industry on Single
Studies Dose Acute Toxicity Testing for
Pharmaceuticals, PT 1, (61 FR
43934, August 26, 1996)
Reproductive and Developmental Detection of Toxicity to
Studies Reproduction for Medicinal
Products, ICH S5A, (59 FR 48746,
September 22, 1994)
Detection of Toxicity to
Reproduction for Medicinal
Products: Addendum on Toxicity to
Male Fertility, ICH S5B (61 FR
15360, April 5, 1996)
Carcinogenicity Studies (Dose Dose Selection for Carcinogenicity
Selection) Studies of Pharmaceuticals, ICH
S1C, (60 FR 11278, March 1, 1995)
Dose Selection for Carcinogenicity
Studies of Pharmaceuticals--
Addition of the Limit Dose and
Related Notes, Draft ICH S1C(R)
(62 FR 15715, April 2, 1997)
Timing and Duration Nonclinical Studies for the Conduct
of Human Clinical Trials for
Pharmaceuticals, Draft ICH M3 (62
FR 24320, May 2, 1997)
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This draft 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.
Interested persons may, on or before January 20, 1998, 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 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 using
the World Wide Web (WWW) ``http://www.fda.gov/cder/guidance.htm''.
The text of the draft guidance follows:
S4A Duration of Chronic Toxicity Testing in Animals (Rodent and
Nonrodent Toxicity Testing)
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.
Scope:
This guidance has been prepared for the development of medicinal
products with the exception of those already covered by ``Safety
Studies for Biotechnological Products,'' e.g., monoclonal
antibodies, recombinant DNA proteins.
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.
[[Page 61515]]
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.
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 to
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: November 12, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-30273 Filed 11-17-97; 8:45 am]
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