Biopharma Companies Seek Greater Clarification About FDA's Interchangeability Guidance

Several biopharmaceutical companies are seeking further clarification from the FDA on the draft biosimilar interchangeability guidance the agency released in January 2017. The draft, which called on companies to use “switching studies” to determine the safety and efficacy of a biosimilar with respect to its reference product, has a deadline of today for submission of public comments.

The draft FDA guidance says that the comparator product, rather than only being used as a control, should be used in both the active switching arm and the control non-switching arm of switching studies, and notes that using a non-US-licensed comparator product generally would not be appropriate. The guidance also says there is no single data package that will work for all proposed interchangeable products.

In their comments, biopharmaceutical companies and the Biosimilars Forum took issue with the definition of interchangeability in the guidance and the confusion surrounding the terminology used to describe physician-mediated switching and pharmacy-level substitution.

Pfizer noted that interchangeability is defined to mean that the biological product may be substituted for the reference product without prescriber intervention. “It is a prerequisite for substitution at the pharmacy level based on a growing body of state laws,” the company countered. Pfizer urged the FDA to address the confusion related to physician-mediated switching and pharmacy-level substitution to ensure the appropriate use of terminology so it is clear that physician-mediated switching is part of usual medical practice and does not require an interchangeability designation. The company also disagreed with the FDA’s use of the phrase “fingerprint-like characterization” because it lacks a clear definition, creates uncertainty for sponsors developing proposed interchangeable biologics, and can be manipulated to undermine confidence in biosimilars.

Pfizer also disagreed with the draft guidance’s recommendation that US sponsors use US-licensed reference product in a switching study, saying the recommendation has the potential to create practical challenges regarding where the study can be conducted. The Biosimilars Forum believes this aspect of the guidance could undermine the global nature of biosimilar development.

Pfizer and Genentech were concerned with the guidance’s discussion of labeling and naming of biosimilars. It would not be advisable for an interchangeable product to carry the same suffix as designated in the proper name of the reference product, Pfizer said, and recommended that labeling of biosimilar and interchangeable biological products include an interchangeability statement that identifies whether or not interchangeability has been evaluated and outlines what is meant by interchangeability.

Boehringer Ingelheim said in its comments that the guidance’s use of the terms “totality of the data” and “residual uncertainty” were arbitrarily defined and burdensome. “More importantly,” the company wrote, “an approved biosimilar product will have already met the criteria for biosimilarity, including an assessment by FDA that it is ‘highly similar’ to the reference product, and is not of inferior quality to any biosimilar product that is also interchangeable.” It is critical to the designation of interchangeability, the company continued, that it not be misinterpreted as designating a superior or higher-quality product to an approved biosimilar that is not interchangeable.

Novartis/Sandoz’s comments focused on post-market changes to biosimilars, noting that if sponsors provide comprehensive data and the FDA carefully reviewed and approved post-approval changes, there should be no expectation that a change in safety or efficacy profile will occur, and accordingly, it is not necessary to re-establish either biosimilarity or interchangeability once it is initially established with a comprehensive and convincing data package.

Expressing strong support to the FDA’s proposal to require robust switching studies, the president of the American College of Rheumatology (ACR), Sharad Lakhanpal, MBBS, MD, said in a statement. “Such studies are vital to achieve a clear understanding of what patients are likely to experience with changing formularies in a multi payer, multi state, and ever changing market.” He further emphasized the need for open access to data from these switching studies, for both physicians and outside investigators.

“While the ACR does not support automatic extrapolation, we do believe that extrapolation should be rigorously studied and fully utilized to help reduce the cost of these drugs,” he added. Additionally, ACR supports the use of distinct suffixes for each biosimilar and believes the choice of treatment should be left to the physician and patient. To that effect, Lakhanpal urged the FDA to ensure product labels clearly state interchangeability with the reference product.