U. S. FOOD AND DRUG ADMINISTRATION REQUIREMENTS FOR TOXICITY TESTING OF CONTRACEPTIVE PRODUCTS

Abstract

ABSTRACT The evolution of toxicity testing of drugs in general, before and after the enactment of the Kefauver-Harris Amendments of 1962 to the Food, Drug and Cosmetic Act of 1938, and of the specialized requirements for test methodology to support the safety of systemic contraceptives are described, with comments on the organizational mechanisms for their implementation, for the interpretation of test results and for eventual regulatory actions and policies. The controversial long-range (life-time) studies in beagles and rhesus monkeys for hormonal contraceptives to predict their carcinogenic potentials are discussed. Results already obtained from these ongoing investigations suggest a hypothesis that in those hormonal contraceptives which are capable of inducing "atypical" nodules and/or malignant tumours in mammary glands of beagles it might be their chemical configurations that exert this reaction, along with their progestogenic potency. Since the contraceptive compounds exhibiting these adverse properties in beagles have not been used long enough clinically to determine their carcinogenic or tumorigenic potential in humans, it is not possible to correlate these effects in the beagle to that in the human for these compounds. On the other hand, for OC's which have been approved for marketing and have been in wide and long clinical usage in the United States, no hazard in terms of increased tumorigenic or carcinogenic potential has been identified to date for the human and the beagle. While metabolism studies with those contraceptive formulations that were incriminated by their adverse actions in beagles have disclosed metabolic patterns and endproducts to be different in the beagle and human, a causative relationship between their metabolic endproducts and a tumorigenie and carcinogenic effect, especially with prolonged administration of these contraceptive compounds, has not been investigated. With these considerations, and because the suitability of the rhesus monkey as an animal model for carcinogenicity testing is questioned, it would be contrary to the spirit and intent of the existing drug safety regulations in the United States to eliminate the canine species as a test animal in carcinogenicity investigations to support the safety of hormonal contraceptives. Tentative guidelines for toxicity tests on new and forthcoming principles for contraception such as the prostaglandins, and IUD's serving as carriers of pharmacologically active substances, have been drawn up in consultation with advisory committees and will be discussed.