The Scientific Value of Non-Clinical Animal Studies in Drug Development

Abstract

Animal studies are considered needed as predictive models to evaluate safety and efficacy of new pharmaceuticals and are required by law. However, the scientific basis of the current paradigm on the predictability of animal studies for the effects of drugs in man is under discussion. Therefore, in this thesis we evaluated the scientific basis of the current practices and guidelines for the use of animal studies in pharmaceutical development and assessed the consequences and implications for the regulatory guidelines when animal studies are not informative. Marketing authorization applications (MAA) were used to study whether new post marketing adverse effects of small molecule therapeutics could have been detected from non-clinical studies. Less than 20% of SARs had a true positive corollary in animal studies. For biopharmaceuticals, 50% of post marketing adverse effects had an animal counterpart, which were related to target pharmacology or immune responses. Biopharmaceutical drug development increasingly uses non-human primate (NHP) as the primary species because they are often the only species available that are pharmacologically responsive. Safety studies with monoclonal antibodies in NHP show most adverse effects are either related to the pharmacology of the mAb or an immune response. The quality and interpretability of NHP data could be reduced by methodological issues and immunogenicity, which could be severe. Animal studies submitted for biosimilar applications did not show relevant differences compared to the reference product unless quality issues were previously identified. This further stresses the use of a step-wise approach to demonstrating biosimilarity. Full characterization and similarity to the reference product should be demonstrated in terms of quality, manufacture and control, which should be the starting point for any subsequent studies. To study the value of non-clinical drug development, the use of the MAA has been invaluable. Making these data available for unrestricted and serious study is needed but increased transparency of regulatory authorities and the pharmaceutical industry by disclosing proprietary data is essential for future studies. More informative non-clinical animal studies can be achieved by introducing reporting guidelines and registries for non-clinical animal studies. A thorough revision of regulatory guidelines on non-clinical issues could identify unnecessary animal studies and quickly improve the efficiency of non-clinical drug development. Earlier dialogue with regulatory authorities through scientific advice may increase regulatory intelligence, leading to smaller but more informative study packages. Where no relevant model exists, a slow and cautious entry into fist-in-man studies, preceded by informative in vitro and in silico assays and micro-dosing studies, is the only scientifically relevant option. While regulatory authorities should rethink their reliance on the precautionary principle, the pharmaceutical industries should to invest in alternative technologies to provide informative data on the safety of new drugs. Governments have an important role in incentivizing these activities, which includes the use of political leverage as well as economic incentives, and promoting further research. This takes considerable effort and trust by pharmaceutical companies and regulatory authorities alike but the trade-off is an efficient non-clinical drug development process which is based on science.