Draft 2 (ICH Step 2 Sign-off, 29 March 1995)
NB: The texts supplied have been prepared in such a way as to replace the respective sections of the S5A guideline
. Introduction
1.1 Objective
Addendum to ICH - S5A Tripartite Guideline
1.2 Male fertility investigation, as included in the currently harmonised guideline, was accepted to require scientific and regulatory improvement and optimisation of test designs.
1.3 Better description of the testing concept and recommendations, especially those addressing:
flexibility premating treatment duration observations
1.4 The general principle and background is contained in two papers accepted for publication to:
J. Amer. Coll. Toxicol.
These papers contain the necessary experimental data (prospective and retrospective) for reaching consensus, and have been commentated. The “raw data” from the Japanese study will also be published.
1.5 The projected time-frame proposes
- Step 2 in March ‘95 (Washington)
- Step 3 in Brussels, July ‘95
- Step 4 Yokohama, Nov. ‘95
. The guideline draft texts is attached.
. For glossary see the harmonised S5 - A guideline
S5B Explanatory Note for the Steering Committee of the ICH Washington, D.C. 29 March 1995
Explanation to the current Activities concerning the ICH Guideline on Detection of Toxicity to Reproduction for Medicinal Products
Additional data on the duration of the premating treatment and on the parameters suited for the detection of effects on the male reproductive system and on fertility are presented in two papers that have been submitted to J. Amer. Coll. Toxicol. in February/March 1995. A collaborative study conducted came to the conclusion that histopathology of reproductive organs is the most sensitive method for detecting effects on spermatogenesis. Sperm analysis gives similar information and could be used as an alternative where histopathology is not feasible, as well as for confirmative purposes and further characterization. mating trails were found to be sensitive for the detection of effects of sperm maturation, sperm motility and of behavioural changes (e.g. libido).
The Japanese group compared premating treatments of 4 and 9 weeks duration and found no differences in detection rate. Data from the European literature survey show equal detection efficiency with premating treatments of 2 and 4 weeks duration.
. Takayama S, Akiake M, Kawashima K, Takahashi M, Kurokawa Y; A Collaborative Study in Japan on Optimal Treatment Period and parameters for Detection of Male Fertility Disorders in Rats Induced by Medical Drugs.
. Ulbrich B, Palmer AK; Detection of Effects on male Reproduction - A Literature Survey
. Jpn. J. Tox. Sci (Data details)
NB: This is only an explanation and no original part of the 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 (4.1.1) Premating treatment REVISED
The design of the fertility study, especially the reduction in the premating period for males, is based on evidence accumulated and re-appraisal of the basic research on the process of spermatogenesis. Compounds inducing selective effects on male reproduction are rare; compounds affecting spermatogenesis almost invariable affect post meiotic 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 2-4 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 behaviour) 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 characterise 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 of 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 behaviour 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:
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.
sperm analysis as an optional procedure for confirmation or better charaterization of an effect observed (Note 12).
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE