Comments on FDA Draft Guidance for Industry on Statistical Approaches for Assessing Bioequivalence published

In December 2022, the U.S. Food and Drug Administration (FDA) has announced the availability of a draft guidance for industry entitled "Statistical Approaches to Establishing Bioequivalence". When finalized, the new document will replace the previous version, which was issued in February 2001.

The draft document can be downloaded on the FDA's website. Comments and suggestions could be submitted within 60 days after publication in the Federal Register (until 04 February 2023). After this deadline, the comments received have now been published.

Comments Submitted

Comments from the following companies/organizations and persons were published in the Federal Register:

• Takeda
• Biotechnology Innovation Organization (BIO)
• Stan Altan
• Association for Accessible Medicines (AAM)
• Bayer
• Novartis
• Humane Society of the U.S. (HSUS), Humane Society Legislative Fund (HSLF)
• International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS)
• Bristol Myers Squibb (BMS)
• Cipla Limited
• Statisticians in Pharmaceutical Industry (PSI) & European Federation of Statisticians in Pharmaceutical Industry (EFSPI)
• Daria Zhuravleva

Requests for Clarification

Some stakeholders, like the Association for Accessible Medicines (AAM) have several requests for clarification. Bristol Myers Squibb (BMS) "requests that clarification be provided in the ability to use replacement subjects in the BE analysis" and that "clarification be added on what the agency would consider highly variable." Novartis suggests "clarifying which part this guideline would be applicable to biosimilar developments." Bayer writes that "there seems to be a contradictory statement regarding whether replacements of dropouts are allowed or not." Furthermore, it is "unclear what is meant by highly variable drug product." Takeda says, that "in general, more clarity on what are relevant estimands in the BE setting would be valuable information to support product development."

The comments from the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) contain a detailed feedback on the Similarity Index (f₂).

Biotechnology Innovation Organization (BIO) writes that "this updated version of the guidance provides useful examples that will assist sponsors/applicants. In particular, the section on adaptive study designs is beneficial. At a high level, BIO suggests that for some newer treatment modalities with limited or no systemic pharmacokinetic exposure, Comparative Clinical Endpoint Bioequivalence Studies may not be the most appropriate choice."

The Humane Society of the U.S. (HSUS) and the Humane Society Legislative Fund (HSLF) point out that "the draft guidance does not address the Biopharmaceutics Classification System (BCS) based biowaiver."