A biosimilar is a biological product that is similar to a reference biologic in efficacy, safety, and immunogenicity, albeit minor differences deemed clinically not important. The U.S. Food and Drug Administration (FDA) defines biosimilar as “a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product.” With several biologics fast approaching their patents expiration, many biosimilars are currently under development.
Generics of small-molecule drugs are chemically synthesized (i.e., made) using the same active ingredients as the reference drug. However, biologics, whether reference or biosimilar, are derived (i.e., grown) from living cells or organisms such as bacteria, animals, and even humans, frequently through the use of recombinant DNA technology. The generic is likely to behave almost the same way as the reference drug as long as bioequivalence is shown. However, even minor modifications in the manufacturing process can introduce unintended changes, often adversarial, to the final biological product. These changes may negatively affect the clinical safety and effectiveness of biosimilars.
Because manufacturing processes for biologics are inherently complex and complicated, it is still challenging to fully characterize structural and functional properties of biologics. Furthermore, it is even intricate to define similarity of two biologics d on physicochemical and biological attributes. Instead, clinical trials are playing a critical role to detect any clinically significant differences in efficacy, safety, and immunogenicity between the biosimilar and a reference biologic. Therefore, scientifically and clinically valid statistical methods are to be applied to the design, conduct, analysis, and report of clinical trials with biosimilars to assess their equivalence to and interchangeability with a reference product.
The equivalence margin is the largest difference that is clinically acceptable between the test (i.e., experimental) drug and the active control (i.e., reference) drug
(Lee, 2012). It is important to accurately set the equivalence margin because the consumer risk that mistakes biosimilars for erroneously declaring equivalence when in fact it is not should be minimized in the approval of any biosimilar products. Based on this understanding, CCADD has developed a new statistical methodology to appropriately derive the equivalence margin in hypothesis testing between the biosimilar and a reference biologic. The core principle is similar to the calculation of the non-inferiority margin recommended by the U.S. FDA and two-step fixed-margin approach. The first margin is estimated using the historical data obtained from mostly the placebo-controlled trials of the reference drug. The second margin is then set by narrowing the first margin d on clinical judgement.
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