FDA Finalizes Guidance on Clinical Pharmacology Data to Support Biosimilars

Regulatory NewsRegulatory News | 03 January 2017 |  By 

Between Christmas and the beginning of 2017, the US Food and Drug Administration (FDA) finalized guidance from 2014 to help biosimilar sponsors understand what clinical pharmacology data is necessary to support a proposed biosimilar.

The 18-page guidance is one in a series implementing the Biologics Price Competition and Innovation Act of 2009 (BPCIA) that established a pathway for the approval of such follow-on biologics. Four other final guidance documents and two other draft guidances have been released by FDA so far, and guidance on interchangeability is expected this year (to read more about biosimilars see the Focus explainer from last year).

This guidance provides recommendations on how clinical pharmacology studies that assess the presence or absence of clinically meaningful differences between the proposed biosimilar and the reference product should be conducted and analyzed.

In terms of changes between the draft and final guidance, FDA said on 29 December 2016 in the Federal Register that the “changes are for clarity, however, and are not substantive.

“Clinical pharmacology studies are part of a stepwise approach for developing the data and information needed to support a demonstration of biosimilarity,” FDA added. “These studies can reduce the residual uncertainty in assessing the biosimilarity between a proposed biosimilar product and reference product and inform the design of subsequent clinical trials to assess clinically meaningful differences.”


The guidance includes four main sections: The role of clinical pharmacology studies in the demonstration of biosimilarity, critical considerations in the use of clinical pharmacology studies to support biosimilarity  (with subsections on safety and immunogenicity, among others), developing clinical pharmacology data for supporting a demonstration of biosimilarity (with subsections on study design, pharmacokinetic (PK) and pharmacodynamic (PD) measures, among others) and the utility of simulation tools in study design and data analysis.

In terms of immunogenicity, which has been a hot-button topic particularly in terms of safety, FDA says: “When immunogenicity results in, for example, either loss of PD effect or efficacy (e.g., neutralizing antibodies) or immune-mediated toxicity, the incidence and severity of the response should be assessed…The overall immunogenicity assessment should include relevant patient populations that are not immunocompromised and thus are able to mount an immune response.”

And since clinical pharmacology studies can “sometimes suggest that there are clinically meaningful differences between” the biosimilar and reference product that can inform the design and the details of additional investigations and/or clinical studies, FDA says, “The extent of such potential differences will determine whether or not further development of the proposed biosimilar product should continue, and if so, what studies should be conducted. Publicly available information on the safety and immunogenicity profile of the reference product should be considered when incorporating safety and immunogenicity measurements in the clinical pharmacology studies.”

As far as when modeling and simulation tools can be useful for designing a PK and/or a PD study, FDA says, “Sponsors should provide data to support the claim that the selected dose is on the steep part of the dose-response curve and not on the plateau of the dose-response curve where it is not likely to detect differences between the two products. Publicly available data for the dose (or exposure)-response relationship of the reference product can be analyzed using model-based simulations to justify the dose selected for the PK and/or PD study or studies.”

Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product: FDA Guidance for Industry



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