Developing the Totality of Evidence for Biosimilarity

The development of biosimilars is focused on the minimization of potential differences between the proposed biosimilar and reference product, as well as the establishment of a robust manufacturing process to consistently produce a high-quality biosimilar.

“The goal of the biosimilar clinical development program is not to demonstrate efficacy and safety per se, but rather to confirm similarity with the reference product based on pharmacokinetic (PK) and pharmacodynamic (PD) equivalence and a confirmatory comparative pivotal clinical study in a representative indication evaluating safety, efficacy, and immunogenicity,” according to a review written by a team headed by Richard Markus, MD, PhD, Amgen’s vice president of global development and head of research and development for biosimilars. The review, published in BioDrugs, notes that biosimilar development presents unique challenges because of the complex structure and the specialized manufacturing processes involved, which affect efficacy, immunogenicity, and safety. The complexities of biosimilar development require a targeted approach, expertise, and rigorous standards to maintain high-quality options for patients.

For approval in the United States, a proposed biosimilar must be shown to be similar to the reference product approved in the United States; for approval in the European Union, a biosimilar must be shown to be similar to the reference product approved in the European Economic Area. The approach recommended by most regulatory agencies, including the FDA, is one of a totality of evidence, which focuses on stepwise development involving demonstration of structural similarity and functional equivalence, the authors explain.

The need to use living cells to manufacture biomolecules adds further variability to an already complicated process. Yet it is expected that biosimilar manufacturers will demonstrate consistency and control over the manufacturing process, just as innovator products must in order to avoid chemical, structural, and functional differences between lots. The objective of analytical testing is to establish similarity assessment criteria based on the reference product profile, followed by a comparative assessment of the biosimilar candidate and the reference product. These studies guide the creation of a proposed biosimilar product that has similar structural and functional characteristics.

If the biosimilar molecule demonstrates high structural and functional similarity, a targeted clinical program is then created in order to compare the PK, efficacy, safety, and immunogenicity of the proposed biosimilar with those of the reference product.

Clinical studies should be performed in a sensitive population, using appropriate endpoints to allow detection of any clinically meaningful differences between the biosimilar and the reference product. The clinical development program must demonstrate PK similarity of the 2 products. Comparative clinical studies of efficacy and safety must demonstrate that the biosimilar candidate has neither decreased nor increased efficacy and does not have an increased safety risk compared to the reference. Statistical equivalence margins and confidence limits are used to confirm these endpoints.

Immunogenicity is also a critical factor used by the FDA to assess biosimilarity. Establishing an immune response that is similar to that seen with the reference is key. Thus, clinical trials must be long enough to allow for potential development of immunogenicity, and adequate pharmacovigilance is needed to ensure that any adverse events are properly attributed.

In the United States, there exists additional concern about determining interchangeability. The FDA requires that for a biosimilar to be labeled interchangeable with the reference, switching studies must be undertaken to show that switching between the biosimilar and the reference is not associated with a greater risk than using the reference product without interruption.

Based on the totality of data provided, extrapolation of indications—allowing biosimilars potentially to be labeled for use in indications approved for reference drugs that were not studied as part of the biosimilar clinical development program—may or may not be appropriate. However, the FDA allows for extrapolation if scientific justification is available, and the authors note that extrapolation is important; if clinical trials were to be conducted in each indication, biosimilar development programs would take longer, and would negate the advantages of the abbreviated approval pathway.