Issues in selecting, standardizing and assessing efficacy models of immunopathology for biopharmaceutical development

摘要

Proof-of-principle experiments using models of in vivo efficacy in animals are an important step between discovery and preclinical phases in the development of biologies and pharmaceuticals. Advanced development programs may also require nonclinicalefficacy or mechanistic studies to help define polytherapy, adverse events, surrogate markers, chronicity and reversibility concerns that arise in the clinical program. In the event of discontinuation of the initial clinical trials because of unacceptable toxicities, access to a predictable and acceptable animal model of disease may be pivotal to defining the next lead molecule and reducing special clinical monitoring requirements for related or next generation biologies. Unfortunately, many commonly used efficacy models were developed to address specific research questions in basic biology or pharmacology and they may lack absolute robustness and transferability to efficacy testing in biopharmaceutical testing. The physical and pathophysiologic constraints of these models are many and varied. Furthermore, preconceived assumptions of clinical relevance and regulatory acceptance, poor experimental design, ill-defined endpoints and lack of consensus on required qualitative and quantitative histopathological assessment also contributes to inter-study variation, unexpected study outcome and costly repeated studies. Finally, investigator knowledge base, personal preference, and management or company culture may drive inappropriate model selection. This discussion will focus on commonly used animal models of immunopathology as a framework to discuss issues in the selection, standardization and evaluation of efficacy testing of biopharmaceuticals. The judicious use of, and a balanced interpretation ofthe results from animal models of human disease are important to providing a rational and cost-effective biopharmaceutical development program.