Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance?

Introduction: The first biopharmaceuticals were developed 30 years ago. Biopharmaceuticals differ significantly from small molecule therapeutics (SMTs). Because of such differences, it was expected that classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse effects of biopharmaceuticals. Therefore, until sufficient experience was gained, the preclinical safety evaluation of biopharmaceuticals was carried out on a case-by-case basis. 30 years of experience has since expanded the knowledge base in this area, in the hope to design a preclinical safety evaluation procedure suited to biopharmaceuticals. Areas covered: This review describes how the preclinical safety evaluation of biopharmaceuticals has evolved. It shows that, as result of the risk-averse behavior of regulators and industry, classical procedures were taken as starting point although state-of-the-art knowledge on biopharmaceuticals was directed towards creating a new procedure, driven by the specific properties of biopharmaceuticals. Expert opinion: Current preclinical safety evaluation guidance of biopharmaceuticals is criticized because it employs a checkbox approach. The adverse effects induced by biopharmaceuticals are on-target or immune system-- induced, therefore, the preclinical safety evaluation should not be standardized, but rather driven by product specific safety concern