On December 28, 2016, the U.S. Food and Drug Administration (FDA) released a Guidance for Industry, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, as part of the Agency's ongoing efforts to implement the Biologics Price Competition and Innovation Act (BPCIA) of 2009. The Guidance "is intended to assist sponsors in designing clinical pharmacology studies that can support an [abbreviated BLA submission] to support a demonstration of biosimilarity."

The Guidance notes the "critical role" that clinical pharmacology studies play in the development of biosimilar products and addresses particular considerations in the use of these studies in supporting biosimilarity. In addressing the bioanalytical methods used in these pharmacology studies, the Guidance cautions that "[b]ecause of the generally complex molecular structure of biological products, conventional analytical methods might not be suitable for biological products." For example, the Guidance provides that "ligand-binding assays" are of particular importance for biosimilar product development. In this regard, it would appear that, for biological products that are antibodies, a higher level of characterization than that which is readily available for many of such products could be required for a complete biosimilarity analysis. Indeed, "assays that rely upon antibody reagents and epitopes involved in pharmacological/biochemical interactions with targets are most likely to produce concentration data that are meaningful for target binding activity." (Emphasis added.) Antibody characterization by epitope binding is not always available.

The Guidance also provides a list of critical topics that the biosimilar applicant should discuss with the FDA in designing their clinical pharmacology development program, including study design, use of nonlicensed comparator products, study populations, dose selections, routes of administration, pharmacokinetic and pharmacodynamic measures, defining appropriate pharmacodynamics time profiles, and statistical comparisons of results.

In addition to providing specific guidance related to pharmacology studies, the Guidance expands the FDA’s prior guidance regarding the general stepwise approach that should be used in designing a biosimilar development program. The FDA states that the "result of the comparative analytical characterization during product development can lead to one of the following four assessments within a development-phase continuum:" (1) insufficient analytical similarity, (2) analytical similarity with residual uncertainty, (3) tentative analytical similarity, and (4) fingerprint-like analytical similarity.

The FDA describes the fingerprint-like analytical similarity outcome as follows:

The results of integrated, multi-parameter approaches that are extremely sensitive in identifying analytical differences (i.e., fingerprint-like analyses) permit a very high level of confidence in the analytical similarity of the proposed biosimilar product 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 to support a demonstration of biosimilarity. (Emphasis added).

In cases where such a fingerprint-like level of analytical characterization demonstrates a high level of similarity, the FDA’s reference to "a more targeted and selective approach to conducting animal and/or clinical studies" may signal the possibility of demonstrating biosimilarity in the absence of clinical studies beyond clinical pharmacology studies.

Indeed, the Guidance notes that these clinical pharmacology studies "can guide both the need for and design of subsequent clinical testing to support a demonstration of no clinically meaningful differences in the overall demonstration of biosimilarity." (Emphasis added.) The Guidance concludes by stating that these studies "may also support a selective and targeted approach to the design of any recommended subsequent clinical studies to support a demonstration of biosimilarity." (Emphasis added).