[Federal Register Volume 60, Number 161 (Monday, August 21, 1995)]
[Notices]
[Pages 43500-43501]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20609]



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[Docket No. 93D-0140]


International Conference on Harmonisation; Draft Guideline on 
Detection of Toxicity to Reproduction: Addendum on Toxicity to Male 
Fertility; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing portions 
of a revised draft guideline entitled ``Detection of Toxicity to 
Reproduction: Addendum on Toxicity to Male Fertility.'' This draft 
guideline was prepared under the auspices of the International 
Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use (ICH). The draft guideline is intended 
to reflect sound scientific principles for reproductive toxicity 
testing concerning male fertility, and is an addendum to an earlier ICH 
guideline on the detection of toxicity to reproduction for medicinal 
products.

DATES: Written comments by October 5, 1995.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857. Copies of the draft 
guideline are available from the CDER Executive Secretariat Staff (HFD-
8), Center for Drug Evaluation and Research, Food and Drug 
Administration, 7500 Standish Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:
    Regarding the guideline: Joy A. Cavagnaro, Center for Biologics 
Evaluation and Research (HFM-2), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852, 301-827-0379.
    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.
    At a meeting held on March 29, 1995, the ICH Steering Committee 
agreed that a draft guideline entitled ``Detection of Toxicity to 
Reproduction: Addendum on Toxicity to Male Fertility'' should be made 
available for public comment. The draft guideline is the product of the 
Safety Expert Working Group of the ICH. Comments about this draft will 
be considered by FDA and the Expert Working Group. Ultimately, FDA 
intends to adopt the ICH Steering Committee's final guideline.
    This draft guideline is an addendum to an ICH final guideline 
published in the Federal Register of September 22, 1994 (59 FR 48746) 
entitled ``Guideline on Detection of Toxicity to Reproduction for 
Medicinal Products.'' This draft guideline is intended to reflect sound 
scientific principles for reproductive toxicity testing concerning male 
fertility.
    In the past, guidelines have generally been issued under 
Sec. 10.90(b) (21 CFR 10.90(b)), which provides for the use of 
guidelines to state procedures or standards of general applicability 
that are not legal requirements but are acceptable to FDA. The agency 
is now in the process of revising Sec. 10.90(b). Therefore, this 
guideline is not being issued under the authority of Sec. 10.90(b), 

[[Page 43501]]
and it does not create or confer any rights, privileges, or benefits 
for or on any person, nor does it operate to bind FDA in any way.
    Interested persons may, on or before October 5, 1995, submit to the 
Dockets Management Branch (address above) written comments on the draft 
guideline. 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 guideline and received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.
    The text of the draft guideline follows:

Detection of Toxicity to Reproduction: Addendum on Toxicity to Male 
Fertility

1. Introduction

1.1 Objective

Addendum to ICH--S5A Tripartite Guideline
    1.2 Male fertility investigation, as included in the currently 
harmonized guideline, was accepted to recommend scientific and 
regulatory improvement and optimization of test designs.
    1.3 Better description is needed of the testing concept and 
recommendations with regard to male fertility assessment, especially 
those addressing:

     Flexibility
     Premating treatment duration
     Observation

    1.4 The general principles and background are contained in two 
papers accepted for publication to the Journal of American College 
of Toxicology.
    These papers contain necessary experimental data (prospective 
and retrospective) for reaching consensus, and have been discussed 
among the expert working group. The ``raw data'' from the Japanese 
study will also be published.
    1.5 The projected timeframe proposed:

--Step 2 in Washington, March 1995
--Step 3 in Brussels, July 1995
--Step 4 in Yokohama, November 1995

    2. The guideline draft texts are attached.
    3. For glossary see the harmonized S5--A guideline

Introduction

(Last paragraph revised)

    To employ this concept successfully, flexibility is needed (Note 
1). No guideline can provide sufficient information to cover all 
possible cases. All persons involved should be willing to discuss 
and consider variations in test strategy according to the state-of-
the-art and ethical standards in human and animal experimentation. 
(Delete next sentence)

Note 12 (4.1.l) Premating Treatment

(Revised)

    The design of the fertility study, especially the reduction in 
the premating period for males, is based on evidence accumulated and 
reappraisal of the basic research on the process of spermatogenesis. 
Compounds inducing selective effects on male reproduction are rare; 
compounds affecting spermatogenesis almost invariably affect 
postmeiotic stages; mating with females is an insensitive means of 
detecting effects on spermatogenesis. Histopathology of the testis 
has been shown to be the most sensitive method for the detection of 
effects on spermatogenesis. Good pathological and histopathological 
examination (e.g., by employing Bouin's fixation, paraffin 
embedding, transverse section of 2 to 4 microns for testes, 
longitudinal section for epididymides, PAS, and haematoxylin 
staining) of the male reproductive organs provides a quick direct 
means of detection. Sperm analysis (sperm counts and optionally 
sperm motility, sperm morphology) can be used as a method to confirm 
findings by other methods and to characterize effects further. Sperm 
are derived from the more mature stages. Samples from ejaculates, 
from vas deferens, or from cauda epididymis should be used. 
Information on potential effects on spermatogenesis (and female 
reproductive organs) can be derived from repeated dose toxicity 
studies.
    For detection of effects unrelated to spermatogenesis (sperm 
abnormalities, mating behavior), mating with females after a 
premating treatment of 2 and 4 weeks has been shown to be at least 
as efficient as mating after a longer duration of treatment. When 
the available evidence suggests that the scope of investigations in 
the fertility study should be increased, appropriate studies should 
be designed to characterize the effects further.

Administration Period

(Revised)

    The design assumes that, especially for effects on 
spermatogenesis, use will be made of data (e.g., histopathology and 
weight of reproductive organs, hormone assays, and genotoxicity 
data) from repeated dose toxicity studies. Provided no effects have 
been found that preclude this, a premating treatment interval of 2 
weeks for females and 4 weeks for males (2 weeks may be acceptable 
in some cases) can be used (Note 12). Selection of the length of the 
premating administration period should be stated and justified (see 
also chapter 1.1, pointing out the need for research). Treatment 
should continue throughout mating to termination for males and at 
least through implantation for females. This will permit evaluation 
of functional effects on male fertility that cannot be detected by 
histologic examination in repeated dose toxicity studies and effects 
on mating behavior in both sexes. If data from other studies show 
there are effects on weight or histologic appearance of reproductive 
organs in males or females, or if the quality of examinations is 
dubious, or if there are no data from other studies, then a more 
comprehensive study should be designed (Note 12).

4.1.1 Study of Fertility and Early Embryonic Development to 
Implantation

Observations

(Revised)

    At terminal examination, the following observations should be 
made:

 Necropsy (macroscopic examination) of all adults;
 Preserve organs with macroscopic findings for possible 
histological evaluation; keep corresponding organs of sufficient 
controls for comparison;
 Preserve testes, epididymides, ovaries, and uteri from all 
animals for possible histological examination and evaluation on a 
case-by-case basis;
 Count corpora lutea, implantation sites (Note 16);
 Live and dead conceptuses; and
 Sperm analysis as an optional procedure for confirmation or 
better characterization of an effect observed (Note 12).

    Dated: August 14, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20609 Filed 8-18-95; 8:45 am]
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