Ahead of Friday's deadline for comments, a number of biopharmaceutical companies are seeking further clarification from the US Food and Drug Administration (FDA) on various aspects of the draft biosimilar interchangeability guidance.
In January, FDA released its draft guidance on biosimilar interchangeability for consultation, noting that there is "no single data package that will work for all proposed interchangeable products."
The draft calls on companies to use so-called "switching studies" to determine whether alternating between a biosimilar and its reference product two or more times impacts the safety or efficacy of the treatment.
"Rather than being used only as a control, the comparator product is used in a switching study in both the active switching arm and the control non-switching arm," FDA writes. "Thus, using a non-US-licensed comparator product generally would not be appropriate."
FDA also says sponsors should consider the "totality of factors" for their product to determine the amount and type of data to demonstrate interchangeability.
Building off previously released comments, Pfizer noted: "Interchangeability is defined to mean that the biological product may be substituted for the reference product without the intervention of the prescriber. It is a prerequisite for substitution at the pharmacy level based on a growing body of state laws."
The company urges FDA to "directly address confusion related to physician-mediated switching and pharmacy-level substitution in order to ensure appropriate use of terminology such that it is clear that physician-mediated switching is part of usual medical practice and does not require an interchangeability designation."
Pfizer also takes issue with FDA's use of the term "fingerprint-like characterization," which it says "lacks a clear definition. Pfizer acknowledges the difficulties in defining the term when it is intended to apply broadly to a wide range of biological products. However, the lack of clear definition creates uncertainty for sponsors developing proposed interchangeable biological products and can be manipulated to undermine confidence in biosimilar products. The Draft Guidance states that 'a clinically relevant and thus meaningful fingerprint like characterization' may enable a more selective and targeted approach to clinical studies. However, sponsors will be unable to benefit from this in the absence of a clear definition of the term and a timely decision on what this means for their development program relative to the implementation of their clinical program."
Boehringer Ingelheim, meanwhile, said that the terms "totality of the data" and "residual uncertainty" are "still arbitrarily defined and burdensome. More importantly, 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 that the designation of interchangeability by FDA not be misinterpreted as designating a superior or higher quality product to an approved biosimilar that is not interchangeable."
The Biosimilars Forum said it is concerned that the draft guidance uses the terms "switching" and "substitution" without precise definitions.
Novartis' Sandoz took up the issue of postmarket changes to biosimilars, noting that if "sponsors provide comprehensive data and the Agency has carefully reviewed and approved the post-approval changes, there should be no expectation that a change in the safety or efficacy profile will occur. Accordingly, it is not necessary to re-establish either biosimilarity or interchangeability once it is initially established with comprehensive and convincing data package."
For indications licensed to a reference product after the approval of an interchangeable biosimilar, Sandoz said: "In the supplement submission, no new data or information should be required other than that supporting extrapolation and a revised label adopting the new indication(s) and associated supporting information from the reference biologic label."
In the draft, FDA also recommends that sponsors use a US-licensed reference product in a switching study (or studies), which several commenters noted.
"This recommendation has the potential to create practical challenges with regard to where the study can be conducted," Pfizer said.
Similarly, the biosimilars medical group, a group within Medicines for Europe, said the need to use a US reference product undermines the global nature of biosimilars development.
On the topic of labeling and naming biosimilars, which Genentech also took up, Pfizer said it "would not be advisable for an interchangeable product to carry the same suffix as designated in the proper name of the reference product" and recommended "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. It should be clear in labeling that a designation of interchangeability simply denotes that the product has met the statutory standard for substitution without the intervention of the health care provider who prescribed the reference product and does not relate to the quality, safety, or effectiveness of the product."