Title:Regulatory Approaches to Nonclinical Reproductive Toxicity Testing of Anti-Cancer Drugs
VOLUME: 17 ISSUE: 9
Author(s):Paul Barrow* and Georg Schmitt
Affiliation:Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, 124 Grenzacherstrasse, Basel, CH 4070, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, 124 Grenzacherstrasse, Basel, CH 4070
Keywords:Anti-cancer drugs, EMA, embryotoxicity, FDA, nonclinical safety testing, reproductive toxicity, teratogenicity.
Abstract: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.
