Statistical considerations for the development of biosimilar products

Abstract

As the patents of a growing number of biological medicines have already expired or are due to expire, it has led to an increased interest from both the biopharmaceutical industry and the regulatory agencies in the development and approval of biosimilars. With the high urgency, European Medicines Agency released the first general guideline on similar biological medicinal products in 2005 and specific guidelines for different drug classes subsequently and US Food and Drug Administration issued three draft guidelines in 2012 on biosimilar product development. A synthesized message from these guidance documents is due to the fundamental differences between small molecule drug products and biological products which are made of living cells, the generic versions of biological products are viewed as similar, instead of identical as the innovative drug product. Thus, more stringent requirement is needed to show no clinically meaningful differences between the biosimilar product and the reference product in terms of the safety, purity, and potency. In this article, we will briefly review statistical issues and challenges in development of biosimilars, including criteria for biosimilarity and interchangeability; selection of endpoints and determination of equivalence margins; equivalence versus non-inferiority; bridging and regional effect; and how to quantify totality-of-the-evidence.