Analytical studies to demonstrate that a biosimilar is highly similar to its reference product are central to the biosimilar development and approval process. For this reason, there have been calls from industry for more guidance from FDA on its expectations for evaluating and demonstrating analytical similarity.
In response to these calls, in September 2017, FDA issued the draft guidance “Statistical Approaches to Evaluate Analytical Similarity.” The draft guidance set forth general principles for evaluating analytical similarity; described the type of information a sponsor of a proposed biosimilar product should obtain about the structural/physicochemical and functional attributes of the reference product and how that information could be used in the development of an analytical similarity assessment plan for the proposed biosimilar; and recommended statistical approaches for evaluating analytical similarity.
After publishing the draft guidance, FDA received nineteen comments. Some came from biosimilar makers, who raised concerns that FDA’s approach would raise costs and increase the difficulty of developing biosimilars. The draft guidance’s recommendations on the use of reference product lots were a particular source of criticism from biosimilar makers. They argued that FDA’s guidance that sponsors should sample a minimum of ten reference product lots when possible and the agency’s preference for reference lots that come from a U.S.-sourced reference were particularly onerous. Some commenters also took issue with the specific statistical methods set forth in the draft guidance. These commenters criticized FDA’s guidance that biosimilar sponsors should choose from three different statistical methods based on which product quality attribute was being evaluated, which in their view would create confusion.
Innovator companies and the Biotechnology Innovation Organization (BIO) were also critical of the draft guidance. For instance, BIO commented that FDA’s recommended approach for statistical analysis of analytical similarity “can be a useful tool in supporting interpretation of data when applied appropriately,” but “should be considered complementary to the overall analytical similarity assessment and not used as a decision tool.” BIO also found fault with the guidance’s preference for pre-specified statistical analysis plans, as well as what BIO saw as a general lack of clarity in terminology. Genentech, for its part, criticized the draft guidance on the grounds that it called for biosimilar sponsors to develop “Analytical Similarity Assessment Plans” instead of more rigorous and detailed experimentation protocols. Genentech also requested that FDA limit the scope of the draft guidance to non-orphan drugs.
In response to these comments, on June 21, 2018, FDA announced that it was withdrawing the draft guidance to give “further consideration to the scientific and regulatory issues involved.” In the announcement, FDA stated that the agency intends to “issue future draft guidance that will reflect state-of-the-art techniques in the evaluation of analytical data,” and that will “address potential challenges faced by biosimilar sponsors in designing studies that are intended to demonstrate that a proposed biosimilar product is highly similar to a reference product, including consideration of appropriate methods to analyze analytical data to account for potential lot-to-lot variability of the reference product.” According to FDA, future draft guidance will provide “appropriate flexibility for sponsors in order to help spur the efficient development of biosimilars without compromising the agency’s rigorous scientific standards for evaluating marketing applications for biosimilars.”
FDA’s withdrawal of its draft guidance on statistical approaches for evaluating analytical similarity shows that FDA is weighing how to provide an efficient regulatory pathway for biosimilars while ensuring safety and biosimilarity.
