A Proposal for the Use of an Innovative Two-Stage PK-Clinical Adaptive Trial in Biosimilar Product Development.

For approval of biosimilar drug products, the United States Food and Drug Administration (FDA) recommends a stepwise approach for obtaining the totality-of-the evidence for demonstration of the biosimilarity between a proposed biosimilar product and its reference (innovative) product. The stepwise approach consists of the assessment of analytical similarity, pharmacokinetics (PK) similarity or pharmacodynamics (PD) similarity, and clinical similarity, which may be conducted either sequentially or at the same time. Although the stepwise totality-of-evidence framework is scientifically rigorous, it may impose substantial time, cost, and operational burden on companies and may prolong the overall development and regulatory review timeline. These challenges can delay patient access to lower-cost biologic therapies. To improve efficiency while maintaining evidentiary rigor, under the Fundamental Biosimilarity Assumption that PK similarity is predictive of clinical similarity, we propose a biosimilar study utilizing an innovative two-stage adaptive trial design by combining a PK study and a clinical study. The proposed two-stage PK-clinical adaptive trial is efficient in the sense that (i) it allows decision-making at end of the first stage, (ii) it can avoid duplicated effort in demonstration of biosimilarity, (iii) it will shorten the development process, and most importantly (iv) it may reduce the development cost and may increase the probability of success in biosimilar drug development. Under the proposed two-stage PK-clinical adaptive trial design, a biosimilarity index based on the concept of reproducibility probability was derived for demonstration of biosimilarity. The biosimilarity index can also be applied for assessment of drug interchangeability under FDA's recommended switching designs.