ABSTRACT
As indicated in Chapter 2, current regulatory requirements for assessment of bioequivalence focus on average bioavailability, which ignore the associated variability of bioavailability (FDA, 2003; Chen et al., 1996; Chow and Liu, 2008). It is a concern that standard methods for evaluation of small-molecule drug products may not be suitable for biological products due to some fundamental differences between small-molecule drug products and biological products (see, e.g., Fox, 2010). These fundamental differences include that (1) the biological products are made of living cells; (2) the biological products have heterogeneous structures, which are difficult to characterize; (3) the biological products are variable and sensitive to certain conditions such as pH, light, and temperature; and (4) the biological products are usually injected and prescribed by specialists. In practice, large variability is often more likely to occur during the manufacturing process of biological products than that of the traditional small-molecules due to variability in the biologic mechanisms, inputs, and relatively large number of complex steps in the process. Variability in the products could lead to lower efficacy or potential safety risks for some patients, and have a significant impact on clinical outcomes of follow-on biologics (FOBs). Therefore, incorporating variance equivalence assessments should be an important part of determining biosimilarity between biological products.
