Reproductive toxicology guidelines: comparison and application

Reproductive toxicity studies currently recommended by the three principal regulatory agencies, the United States Food and Drug Administration (FDA), the Committee for Proprietary Medicinal Products (CPMP) of the European Economic Community and the Japanese Ministry of Health and Welfare (MHW), have a three-segment design, with essentially similar objectives in identifying any possible adverse effects of medicinal products on all stages of the reproductive process in animals, in order to evaluate the potential risk in man. However, differences exist between the various guidelines which give rise to considerable difficulties in amalgamating experimental designs to comply with all three agencies. The main differences are between Western and Japanese recommendations and can be identified in two points which are cause for debate and form an obstacle to the mutual acceptance of studies: a) the treatment periods during pregnancy and b) the extent of studies on the progeny reared to maturity. Both points concern solely studies in rodents and are based on a different approach to the subject. Advantages and disadvantages of the differences in each study segment are considered in relation to practical applications. In comparing recommendations from different agencies, shortcomings in the instructions and nebulous or questionable requirements, but also valuable directives, are highlighted, in the hope that regulatory authorities can be encouraged to provide exhaustive information and instructions and more explicit policies in the new coordinated guidelines which are expected as a result of international harmonization. To this end, the need for greater flexibility is stressed, since the conventional designs of the segments often prove inapplicable or are deemed inadequate or unnecessary in the case of drugs whose pharmacological activity interferes with the reproductive process or which are intended for particular therapeutic modalities or purposes. In particular, regulatory authorities are urged to provide specific, coordinated guidelines for antitumor agents, taking into account that their technical application in animals should reflect treatment modalities and therapeutic uses in humans.