Regulatory Approaches to Nonclinical Reproductive Toxicity Testing of Anti-Cancer Drugs

This paper reviews the nonclinical reproductive toxicity testing of 15 drugs currently approved in the USA or Europe for the treatment of cancer. The list includes cytotoxic anti-tumour agents, small molecule inhibitors of pathways involved in neoplastic proliferation, monoclonal antibodies that target specific antigens expressed by neoplastic cells and supportive therapies used to counter the effects of chemotherapy. Most, but not all, drugs were tested for developmental or reproductive toxicity in animals prior to marketing and most were found to be embryotoxic or teratogenic. Because of the unmet need for comparative safety data on available cancer therapies for use by physicians when treating pregnant patients, at least embryofetal toxicity studies are now usually requested prior to marketing of new anti-cancer drugs, even when the pharmacological profile suggests likely side-effects on the embryo or fetus. Rats and rabbits are the preferred experimental species, but non-human primates have to be used for some biopharmaceuticals. Nonclinical study designs for anti-cancer drugs should be designed to allow the possibility of terminating the study once adverse effects have been demonstrated, without using the full number of animals specified in regulatory guidelines. All 15 drugs are currently labelled as being harmful to pregnancy, ether on the basis of animal data or documented hazards in humans. It is hoped that the forthcoming revision of the FDA drug labelling legislation will allow a better graduation of the relative risk between available anti-cancer therapies. Keywords: Anti-cancer drugs, EMA, embryotoxicity, FDA, nonclinical safety testing, reproductive toxicity, teratogenicity.