Abstract
Analytical similarity assessment of critical quality attributes (CQAs) serves as a foundation for the development of biosimilar products and facilitates an abbreviated subsequent clinical evaluation. In this study, we establish a statistical evaluation roadmap with statistical approaches for some selected CQAs from Tier 1, because they are most relevant to clinical outcomes and require the most rigorous statistical methods. In the roadmap, we incorporate 3 methods—ranking and tier assignment of quality attributes, the equivalence test, and the Mann–Whitney test for equivalence—that are important to determine analytical similarity between the reference and biosimilar products. For the equivalence test, we develop a power calculation formula based on the two one-sided tests procedure. Exact sample sizes can be numerically calculated. Then, we propose a flexible idea for selecting the number of reference lots (nR) and the number of biosimilar lots (nT) to adjust for serious unbalanced sample sizes. From results of extensive simulations under various parameter settings, we obtain a workable strategy to determine the optimum sample size combination (nT, nR) for the equivalence test of CQAs from Tier 1. R codes are provided to facilitate implementation of the roadmap and corresponding methods in practice.
Highlights
Biosimilars are biological products that are highly similar but not identical to their reference products, notwithstanding minor differences in clinically inactive components
We propose a statistical evaluation roadmap using feasible statistical methods for analytical similarity assessment of critical quality attributes (CQAs) from Tier 1
The statistical evaluation roadmap has 3 advantages: (i) there is a very flexible relationship between number of reference lots (nR) and number of biosimilar lots (nT), as nR = nT + k in the equivalence test; (ii) there is much more flexibility in choosing parameters such as equivalence margins and the true underlying mean difference as well as in obtaining optimum sample sizes; and (iii) the Mann–Whitney test is used for analytical data that follow a skewed distribution
Summary
Biosimilars are biological products that are highly similar but not identical to their reference products, notwithstanding minor differences in clinically inactive components. Considering that there may be a large number of CQAs in practice, Chow [9] and Tsong et al [10] proposed a statistical approach for demonstrating analytical similarity based on a tiered system that accounts for their criticality, for example, most (Tier 1), mild to moderate (Tier 2), and least (Tier 3) relevant to clinical outcomes. They recommended the equivalence test of means for CQAs from Tier 1, the quality range approach for CQAs from Tier 2, and visual displays for CQAs from Tier 3.
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