In the United States, the Food and Drug Administration (FDA) approval of a biosimilar is based on the ‘totality of the evidence’ from comparative analytical and functional assessments and comparative clinical (pharmacology, immunogenicity, safety and efficacy) assessments that support a conclusion of biosimilarity [1]. An approved biosimilar can also be designated as ‘interchangeable’ if it can be concluded that the biosimilar is expected to produce the ‘same clinical result as the reference product in any given patient’ and there is no increased risk in terms of safety or diminished efficacy associated with switching or alternating between the biosimilar and reference product (RP) [2]. With such designation, an interchangeable biosimilar could be substituted for its RP at the pharmacy level where state law allows [2].
To evaluate interchangeability, FDA guidance recommends conducting switching studies in patients where one group is switched multiple times between the proposed interchangeable product and the RP; and compared with a separate group that continues to receive the RP only [2, 3]. Such studies should be designed primarily to determine whether switching will result in differences in pharmacokinetic (PK) or immunogenicity profiles [2, 3]. Accordingly, it is recommended that PK parameters (area under the concentration-vs-time curve in the dosing period [AUCτ] and maximum concentration [Cmax]) are used as primary endpoints, rather than efficacy or safety outcomes, and these parameters are analysed using an equivalence approach with symmetric equivalence margins of 80%−125% [2, 3].
In a recent article, Alvarez et al. consider FDA guidance for demonstrating interchangeability and some of the challenges in conducting clinical studies to support a designation of interchangeability [3]. One aspect discussed is that the application of symmetric equivalence margins of 80%−125% for PK endpoints of AUCτ and Cmax does not consider biological plausibility. For example, for some biologicals, the known effect of immunogenicity only affects PK in one direction, potentially leading to reduced plasma concentrations. In these cases, the use of asymmetric margins, or even non-inferiority designs, might be appropriate. Also, differences of >25% in certain PK parameters between products may not necessarily have a clinical impact on efficacy or safety [3]. Moreover, owing to the typically high coefficient of variation for PK parameters in patients, relatively larger sample sizes may be required for such studies compared with those conducted in healthy subjects [3]. Determination of AUCτ and Cmax in patients also requires intense sampling with multiple blood draws, adding to the patient burden, with the potential to negatively affect study enrolment and to increase the dropout rate of non-evaluable subjects [3].
The FDA guidance on interchangeability recommends that immunogenicity is included as a secondary endpoint and analysed descriptively only [2, 3]. The authors agree that a descriptive analysis is appropriate since there are currently no recognized equivalence margins for the differences in immunogenicity that are expected to have a clinically meaningful impact [3]. Likewise, the interchangeability guidelines recommend that efficacy endpoints are analysed descriptively in a clinical interchangeability study, as they are measured with less precision than PK parameters and subject to the nocebo effect [2, 3].
While there is a regulatory expectation to conduct multiple-switch trials to support an interchangeability designation, the authors perceive that FDA should take a flexible view when considering the most appropriate statistical approaches and designs for such studies [3]. It is anticipated that over time, and through experience, FDA may deem switching studies to be unnecessary to support an interchangeability designation, once results have emerged from both clinical trials and real-world observational studies showing that PK, immunogenicity and efficacy are not affected by multiple switches between a RP and its biosimilar [3].
Conflict of interest
The authors of the research paper [3] reported conflict of interest, including being an employee of Pfizer, receiving research support, consulting fees or fees for participation in data monitoring boards from pharmaceutical companies. For full details of the authors’ conflict of interest, see the research paper [3].
Abstracted by Daniel F Alverez, MD, Medicine Team Lead Inflammation and Immunology, Global Product Development, Pfizer Inc.
Editor’s comment
Readers interested to learn more about interchangeability of biosimilars in the US are invited to visit www.gabi-journal.net to view the following manuscripts published in GaBI Journal:
Interchangeability of biosimilars in the US and around the world
Interchangeability. An insurmountable fifth hurdle?
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References
1. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. Guidance for industry. April 2015 [cited 2021 Jan 29]. Available from: www.fda.gov/regulatory-information/search-fda-guidance-documents/scientific-considerations-demonstrating-biosimilarity-reference-product
2. U.S. Food and Drug Administration. Considerations in demonstrating interchangeability with a reference product. Guidance for industry. May 2019 [cited 2021 Jan 29]. Available from: www.fda.gov/regulatory-information/search-fda-guidance-documents/considerations-demonstrating-interchangeability-reference-product-guidance-industry
3. Alvarez DF, Wolbink G, Cronenberger C, et al. Interchangeability of biosimilars: what level of clinical evidence is needed to support the interchangeability designation in the United States? BioDrugs. 2020;34(6):723-32.
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