Interchangeability of Biosimilars: What Level of Clinical Evidence is Needed to Support the Interchangeability Designation in the United States?

Abstract

A biosimilar is a biologic drug that is "highly similar to a reference (originator) product, with no clinically meaningful differences between the two products in safety, purity, and potency". Regulatory approval of a biosimilar is based on analytical, structural, and functional comparisons with the reference product, comparative nonclinical (in vivo) studies, clinical pharmacokinetics and/or pharmacodynamics, and immunogenicity. In addition, comparative clinical efficacy and safety assessments are usually conducted and, taken together, comprise the "totality of the evidence" supporting biosimilarity. For a biosimilar to meet the additional designation of interchangeability in the United States (US), the applicant must demonstrate that the biological drug can be expected to produce the "same clinical result as the reference product in any given patient" and "if the biological drug is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological drug and the reference product is no greater than the risk of using the reference product without such alternation or switch". The challenges faced in conducting clinical studies to support a designation of interchangeability, as defined in the final interchangeability guidance from the US Food and Drug Administration, are considered. Potential alternative approaches to generating adequate and sufficient clinical data to support a designation of interchangeability are also presented.

Safety, Immunogenicity and Interchangeability of Biosimilar Monoclonal Antibodies and Fusion Proteins: A Regulatory Perspective

“…However, immunogenicity is often presented as the main and unpredictable risk of biosimilars in spite of the questionable theoretical basis and lack of any supporting clinical evidence for this hypothesis [13,38,41]. Furthermore, much of the discussion on interchangeability has been focused on the requirement for extensive studies with multiple switches, as well as switches between biosimilars of the same reference product [39][40][41][42][43][44][45][46][47][48][49][50][51]. Such studies would require hundreds of patients per study, which will discourage the development of biosimilars [32,41].…”

“…Furthermore, much of the discussion on interchangeability has been focused on the requirement for extensive studies with multiple switches, as well as switches between biosimilars of the same reference product [39][40][41][42][43][44][45][46][47][48][49][50][51]. Such studies would require hundreds of patients per study, which will discourage the development of biosimilars [32,41]. Not surprisingly, most publications advocating for systematic switch studies were sponsored by innovator pharmaceutical companies.…”

Progress in oncology biosimilars till 2020: Scrutinizing comparative studies of biosimilar monoclonal antibodies

“…2,29 Recently, prospective substitute approaches for the generation of ample and adequate clinical data to aid a nomination of interchangeability has also been presented. 30 Other most frequent obstacles faced in acquiring education regarding biosimilars include restricted financial aid for education on products which are biosimilar the percentage of which was 38.4%, extensive amount of work already done the percentage of which was 31.4% and insufficient educational assets the percentage of which was 27.9% according to the study conducted which included 86 respondents from both international and non-international Society of Oncology Pharmacy Practitioners. 31 Some of the key issues that should be considered by oncologists when they are prescribing biosimilars are 1) availability of safety data which includes the immunogenicity in which they play a vital role by documentation of any post-approval adverse drug reaction, 2) indications already approved including the extrapolation, 3) practice of substitution within their country or state, 4) status of interchangeability for biosimilars approved by FDA and 5) information on approval from regulatory agencies.…”

Is There Any Research Evidence Beyond Surveys and Opinion Polls on Automatic Substitution of Biological Medicines? A Systematic Review

“…While the EU remits the decision on interchangeability and its practical execution to each Member State, in the US, automatic substitution is only possible for interchangeable biosimilars. To gain the interchangeability designation, additional clinical data to demonstrate stability in clinical performance, pharmacokinetics and immunogenicity profile during multiple switches is needed for a biosimilar [68]. Thus, although the US has the legal framework to implement automatic substitution of biological drugs, it is possible that the first efficient substitution implementations will be seen through national decision making in the EU.…”