[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International Conference on Harmonisation; Draft Guidance on the 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SUMMARY: The Food and Drug Administration (FDA) is publishing a draft 
guidance entitled ``S4A Duration of Chronic Toxicity Testing in Animals 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 The draft guidance was 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 The draft guidance is intended to 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ADDRESSES: Submit written comments on the draft guidance to the Dockets 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 Copies of the draft 
guidance are available from the Drug Information Branch (HFD-210), 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)            
------------------------------------------------------------------------

    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]
BILLING CODE 4160-01-F