FDA's Latest Biosimilars Guidance: How to Show Biosimilarity Using Pharmacological Testing

The US Food and Drug Administration (FDA) has unveiled a new guidance document on biosimilars, this time explaining how to use clinical pharmacology data to show similarity to a reference product.

Background

The guidance, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, is one of several under development by FDA to establish a thorough biosimilar pathway. While the Patient Protection and Affordable Care Act (PPACA) vested FDA with the legal authority to regulate biosimilar products in 2010, the agency has been slow to issue and finalize guidance documents regarding its expectations for biosimilar applications.

The latest guidance follows the publication of five other biosimilar draft guidance documents:

• Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
• Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product
• Biosimilars:  Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
• Guidance for Industry: Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants
• Guidance for Industry on Biosimilars: Q & As Regarding Implementation of the BPCI Act of 2009

The Clinical Pharmacology guidance document is intended to assist in the development of therapeutic biological products for which pharmacokinetic (PK) and pharmacodynamic (PD) data are required as part of a so-called "stepwise" approach, FDA explained.

While PK and PD data are most commonly used to establish bioequivalence between two chemical drugs, biological drugs differ in that it is nearly impossible for them to be identical in structure. Rather, FDA defines biosimilarity as being "highly similar to the reference product notwithstanding minor differences in clinically inactive components" and lacking "clinically meaningful differences" with respect to safety, efficacy and potency.

A Critical Part of Showing Biosimilarity

Still, though, pharmacology data are often a "critical part of demonstrating biosimilarity by supporting a demonstration that there are no clinically meaningful differences between the proposed biosimilar and the reference products," FDA explains in its guidance.

FDA continues: "These studies provide the data that describe the degree of similarity in drug exposure between the proposed biosimilar and the reference product. In addition, 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 thus guide the need for and design of subsequent clinical testing to successfully support a demonstration of no clinically meaningful differences in the overall demonstration of biosimilarity."

Key Concepts

FDA's guidance goes on to note that there are three "key" concepts to keep in mind when conducting clinical pharmacology studies between biosimilar products and reference biologics:

• exposure and response assessment
• evaluation of residual uncertainty
• assumptions about analytical quality and similarity

For example, FDA explains that in regard to testing exposure, sponsors should consider:

• the time of onset of the PD marker relative to dosing
• the dynamic range of the PD marker over the exposure range to the biological product
• the sensitivity of the PD marker to differences between the proposed biosimilar product and the reference product
• the relevance of the PD marker to the mechanism of action of the drug
• the relationship between changes in the PD marker and clinical outcomes

These data are critical to refining and designing subsequent clinical trials, the agency said.

Sponsors will also need to determine which uncertainties exist after each step in order to guide future testing. Further, FDA advises that sponsors utilize extensive and state-of-the-art testing to determine physical differences between the proposed biosimilar and the reference product. "The type, nature, and extent of any differences between the two products should be clearly identified, and the potential effect of these differences should be addressed and supported by appropriate data," FDA wrote.

Types of Similarity

Some differences may be acceptable to regulators, while others may present a barrier to approval through the 351(k) biosimilar pathway.

FDA's guidance presents a four-part characterization assessment, similar to FDA's Orange Book assessments for chemical drugs:

• not similar
• similar
• highly similar
• highly similar with a fingerprint-like similarity

The latter indicates a level of similarity that presents almost no differences and has been validated by methods of analysis permitting a very high level of confidence, FDA explained.

The use of particular assays and analytical methods is explained at length in the guidance. The design of pharmacological studies is also explained extensively.

Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (FR)