Reproductive toxicity testing of pharmaceutical compounds to support the inclusion of women in clinical trials

Abstract

1 The potential for toxicity to reproduction and the developing fetus is an important concern requiring attention during the development of new medicines. However, there are differences in the opinions of the regulatory authorities in Europe, Japan and the USA regarding the nature and amount of data from reproductive toxicity tests that should be available at the various stages of clinical development.

2 Forty-one companies or their subsidiaries from Eur ope, Japan and the USA provided data for a ques tionnaire-based study, carried out in 1994, to ascertain the practices of pharmaceutical companies and their views on an ideal approach to the timing of reproduc tion and development toxicity studies in relation to clinical investigation.

3 Differences were identified in the stage of drug development at which animal studies were completed, the sequence of completion of specific studies, and the extent of reproduction testing completed to support the inclusion of women in clinical trials.

4 A harmonised, but flexible, guideline, encompassing the timing of reproductive toxicity studies in relation to clinical trials, would permit better integration between clinical and non-clinical studies in an international drug development programme.

Keywords

female reproductive toxicity female fertility embryo- fetal peri- and post-natal non-clinical testing strategy inclusion of women pharmaceuticals

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References

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guideline on detection of toxicity to reproduction for medicinal products. Draft #17, June 1993.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Toxicity to male fertility: An addendum to the ICH tripartite guideline on detection of toxicity to reproduction for medicinal products. Step 4 Draft #2, Revised 28 November 1995.

Food and Drug Administration, Department of Health and Human Services. Guideline for the study and evaluation of gender differences in clinical evaluation of drugs. Federal Register July 22, 1993; 58: 39406-39416.

Scales Mdc , Mahoney K. Animal toxicology studies on new medicines and their relationship to clinical exposure: a review of international recommendations. Adverse Drug Reactions and Toxicological Reviews 1991; 10: 155-168.

Parkinson C. , Thomas KE , Lumley CE The timing of preclinical toxicological studies: pharmaceutical company approaches to toxicity testing in support of initial clinical investigations. Regulatory Toxicology and Pharmacology 1996; 23: 162-172.

Scales D. , Usui T. Review of international recommendations on animal toxicity studies and their relation to exposure. In: The Timing of Toxicological Studies to Support Clinical Trials, Parkinson C, McAuslane N, Lumley C and Walker S (eds,) pp. 17-25. Kluwer Academic Publishers, Dordrecht, 1994.

Chen M-L. , Williams R. Women in bioavailability/ bioequivalence trials - a regulatory perspective . Drug Information Journal 1995; 29: 813-820.

Dupin-Spriet T. , Spriet A. Women in clinical trials. Journal of Pharmaceutical Medicine 1994; 4: 207-217.

Parkinson C. , McAuslane N, Lumley C, Walker S. The Timing of Toxicological Studies to Support Clinical Trials. Kluwer Academic Publishers , Dordrecht, 1994.

10.

Manson J. , Bühler F. The timing of reproductive toxicity studies in relation to clinical trials . In: The Timing of Toxicological Studies to Support Clinical Trials, Parkinson C , McAuslane N , Lumley C and Walker S (eds,) pp. 115-125. Kluwer Academic Publishers, Dordrecht, 1994.

11.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Guidelines for the timing of non-clinical safety studies for the conduct of human clinical trials for pharmaceuticals. Draft #7, March 1996.

12.

Bagley GP Informed consent: the Food and Drug Administration perspective. Drug Information Journal 1993; 27: 1247-1252.

13.

Bass R. , Günzel P. Preclinical testing strategy. In: International Pharmaceutical Product Registration, Cartwright AC and Matthews BR (eds,) pp.411-429. Ellis Horwood Ltd., Chichester, 1994.