The assessment of biosimilarity with SABE and IBE criteria under a switching/alternating design

Category: Original Research
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Abstract:
The development of biosimilars has become one of the most rapidly evolving areas in recent years as key biological drug products are losing their patent protection. Unlike small molecule drug products, biosimilars are not exact copies of their brandname counterpart, and they are usually highly variable. The large variabilities of biosimilars render the average bioequivalence (ABE) criteria used in current bioequivalence (BE) studies inappropriate to address biosimilarity. Two other criteria were considered: scaled ABE (SABE) criterion that adjusts for variability of the reference product and individual bioequivalence (IBE) criterion that takes into account the inter-, intra-subject variability and the variability due to subject-by-formulation. Another important feature regarding biosimilars is interchangeability which includes switching and alternating between an innovative biologic product and its follow-on biologics. In this work, we propose a study design, Switching/Alternating design, to assess switching and alternating simultaneously. Furthermore, according to Biologics Price Competition and Innovation (BPCI) Act, biosimilarity needs to be established before interchangeability. Therefore in this paper we present a statistical procedure under the propsoed design to evaluate biosimilarity using SABE and IBE criteria. For statistical testing, the criteria are linearized and decomposed into independent components in order to construct the approximate upper condence bounds. The estimate for each component of the IBE criteria under the Switching/Alternating design is derived. Numerical studies are conducted to demonstrate expected type I errors and improved power for test drugs with less variabilities than the reference drugs. Interchangeability can be further studied based upon the results from this paper.

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