Preclinical Safety Testing of Species-specific Proteins Produced with Recombinant DNA-techniques. An Attempt to Transfer Current Experience into Future Testing Strategies

Preclinical toxicity studies in animals with species-specific recombinant DNA products have now been performed for several years. An interim statement on the significance of these animal tests and their ability to predict adverse effects in humans therefore appears indicated, with the aim of deducing future testing strategies. The experience accumulated so far shows that the animal models have failed to predict adverse effects subsequently observed in man. Immunogenicity of these proteins further restricted the usefulness of standard toxicity tests. There is also increasing evidence that animal tests on the toxic potential of impurities contained in the products are markedly inferior in sensitivity to analytical and quality control methods. Thus, modified testing programs are proposed to demonstrate safety rather than target organ toxicity using rodents and small non-rodent species and restricted dosing; furthermore the study duration should be limited by the detection of immunogenic responses.