US FDA unveils long-awaited biosimilar guidance

The draft guidance​ is intended to assist sponsors with the design and use of clinical pharmacology studies to support a decision that a proposed therapeutic biological product is biosimilar to its reference product. This guidance pertains to products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required to help demonstrate biosimilarity.

The FDA begins by defining the term biosimilarity to mean that the biological product is “highly similar to the reference product notwithstanding minor differences in clinically inactive components​” and that there are “no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product​.”

Clinical pharmacology studies often include PD endpoints (both therapeutic and toxic) and pharmacometric analysis to assess whether or not there are clinically meaningful differences between the proposed biosimilar and the reference product. If done well, they can add to the totality of the evidence, reduce residual uncertainty, and potentially reduce subsequent clinical testing.

A comparative analytical characterization by the agency may lead to one of four assessments, including:

• Not similar​: Further development through the 351(k) regulatory pathway is not recommended unless modifications are made to the manufacturing process for the proposed biosimilar;

• Similar​: Further information is needed to determine if the product is highly similar to the reference product. Additional analytical data or other studies are necessary to determine if observed differences are within an acceptable range to consider the proposed biosimilar. For example, the agency says that “glycosylation plays an important role in the PK of certain protein products. Manufacturing process conditions may impact glycosylation. Comparative PK and PD studies of the proposed biosimilar product and the reference product help resolve that some differences in glycosylation identified in the analytical studies would be within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product​”;

• Highly similar​: The proposed biosimilar product meets the statutory standard for analytical similarity and the results of the comparative analytical characterization permit high confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to conduct targeted and selective animal and/or clinical studies to resolve residual uncertainty; and

• Highly similar with fingerprint-like similarity​, which seems to be the gold standard of similarities: The proposed biosimilar product meets the statutory standard for analytical similarity based on integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences. The results of these fingerprint-like analyses permit a very high level of confidence in the analytical similarity of the proposed biosimilar and the reference product, and it would be appropriate for the sponsor to use a more targeted and selective approach to conducting animal and/or clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity.

The FDA adds that three key concepts: “exposure and response assessment, evaluation of residual uncertainty, and assumptions about analytical quality and similarity, are especially relevant to development of proposed biosimilar products​.”

If these criteria are addressed, through the submission of convincing PK and PD results, the FDA says, then “the extent of the clinical development program can be refined in both the design and extent of additional clinical trials necessary to assess whether there are clinically meaningful differences between the proposed biosimilar product and the reference product​.”