Nonclinical development of a biosimilar: the current landscape.

Preclinical studies have always been a critical component in the development program of a biopharmaceutical. With the advent of biosimilars the traditional preclinical program has changed to a new paradigm that integrates the concept of comparability with existing knowledge of the biopharmaceutical reference drug. Recently, the recommended preclinical program espoused by the European Medicines Agency has been modified to an abbreviated one that now emphasizes in vitro studies in lieu of in vivo for monoclonal antibody biosimilars. Likewise, the US FDA guidance on biosimilars suggests a flexible approach rather than the 28-day comparative toxicology studies that have historically been conducted for worldwide marketing. For now, structure and function studies will continue to be the foundation of the overall analytical assessment of biosimilarity. Traditional, comparative animal safety assessments will have limited value in determination of biosimilarity and in an abbreviated design they may have most value in providing assurance of safety in first-in-human trials when structural attributes are not indistinguishable. Unless this value can be proven, particularly as analytical technology improves in sensitivity, accuracy and precision, the need for these animal safety studies will diminish. Thus, the future lies in the ever evolving and sophisticated analytical studies that will replace the current in vivo studies for biosimilar products.