International Conference on Harmonisation; Guidance on the Duration of Chronic Toxicity Testing in Animals (Rodent and Nonrodent Toxicity Testing); Availability

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.

---------------------------------------------------------------------------

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