ABSTRACT
The progress made over the past 30 years in the international harmonization of safety testing guidance has provided the basis to inform toxicity testing paradigms. Expectations of what “to do” comes from our long history of translating traditional small molecules into the clinic where conformance to standardized approaches, “checklists,” has generally been sufficient to support clinical development. Strict adherence to guidance provides greater assurance that the studies that are conducted will be acceptable to the regulatory authorities. In contrast, preclinical safety assessment of biotechnology-derived pharmaceuticals has, by necessity, relied on consideration of product attributes to inform the design of preclinical programs, a more flexible “case-by-case approach.” Studies are designed to answer specific questions to inform clinical decision-making, rather than conforming to a more prescriptive number and/or types of studies “to do.” As a consequence, there is greater uncertainty as to whether what is done will be acceptable to regulatory authorities and thus an inextricable imperative to establish early dialogue.
The increasing knowledge base that is derived from preclinical studies and correlative clinical experiences should help better advise the type and extent of studies that are needed to inform safety. Departures from standardized testing paradigms have often been referred to as minimal, modified, streamlined, or platform approaches, all of which infer a sense of omission or inadequacy. While a case-by-case approach encompasses all of these variations, the objective is to do “the right amount” based on current knowledge to inform clinical decisions for the intended population. This will become increasingly important as newer modalities are being developed to treat rare diseases including individualized therapies. It is hoped that preclinical safety evaluation strategies and testing paradigms will continue to evolve through the application of scientific insight, historical and anecdotal experiences, and common sense.
