The Draft Guidance on Clinical Pharmacology Studies for Biosimilars – Is FDA Moving Forward, Sideways or Backwards by Retracing Steps Covered in the 2012 Draft Guidances?

By James C. Shehan –

As previously reported here, in February 2012, FDA released three highly-anticipated guidances on biosimilars.  Those of us interested in biosimilars have naturally been eagerly awaiting the next usual step in the process, the issuance of final guidances and perhaps the first approval of a biosimilar product under the 2010 BPCIA.  Dashing these expectations, however, FDA has instead issued another draft guidance, one that expands upon some previously-covered topics but also repeats much of what was said in 2012.  Forgive us for wondering whether the guidance moves us one step closer to approval of the first BPCIA biosimilar or moves the date further out into the future.  Put another way, will the stepwise process FDA first unveiled in 2012 be a walk in the park for sponsors or an ultra-marathon?

On May 13, 2014, FDA released a draft guidance entitled Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product.  It lays out an elaborate step-by-step process for demonstrating that the hoped-for biosimilar and the reference product are “highly similar” and pegs clinical pharmacology studies as a likely piece of the “totality of evidence” needed to meet the statutory standard of  “no clinically meaningful differences … in terms of “safety, purity, and potency.” 

Similar to what is laid out in the 2012 draft guidance, the step-by-step process is described as a risk-based approach under which FDA will consider the totality of the data submitted.  Sponsors are encouraged to collect data in the following order: structural and functional characterization, nonclinical evaluations, human pharmacokinetic and pharmacodynamic studies, clinical immunogenicity studies, clinical safety studies and when necessary clinical effectiveness studies.  The criterion for sponsors to use in determining whether the next step in this process is necessary is the amount of “residual uncertainty” that remains regarding similarity of the products.

In keeping with the step-by-step process envisioned by FDA but actually exceeding the “clinical pharmacology” scope implied by its title, the draft guidance, again echoing the 2012 draft guidance, recommends that “extensive and robust comparative structural and functional studies” precede clinical pharmacology studies.  This “extensive analytical characterization” should include “state-of-the-art” analytical assays that assess, for example “the molecular weight of the protein, its higher order structure and post-translational modifications, heterogeneity, functional properties, impurity profiles, and degradation profiles denoting stability.”   Intriguingly, FDA recommends that the attributes of the biosimilar and the reference product be compared through use of a “meaningful fingerprint-like analysis algorithm.”  FDA expects that this comparative analytical characterization will lead sponsors to one of four conclusions about their biosimilar product: not similar, similar, highly similar or highly similar with fingerprint-like similarity. “Not similar” products are not recommended to follow the biosimilar pathway; “similar” products require additional data and studies; and products in the “highly similar” and “highly similar with fingerprint-like similarity” categories are directed to “conduct targeted and selective animal and/or clinical studies” to support biosimilarity, with studies for the last category being more targeted and selective than those for the highly similar category. 

Moving on to the next step in the process, the draft guidance states that clinical pharmacology studies are “normally a critical part of demonstrating biosimilarity.”  Such studies are required to contain pharmacokinetic and pharmacodynamic elements, which are viewed as necessary to allow assessment of exposure and response.  One clue to FDA’s mentality in drafting the guidance is perhaps found in this section – the statement that determining exposure to a biological product is “particularly challenging” because biological products are “mixture[s] of closely related, complex biological substances that, in aggregate, make up the active component.”  Some may question whether this statement accurately describes all biologics.

The guidance contains detailed requirements for the pharmacokinetic and pharmacodynamic data types to be collected, specifying, for example, that all pharmacokinetic parameters should be collected for both products.  FDA also stresses that the integrity of the bioanalytical methods (assays) used in theses studies is critical, and it specifies that ligand binding assays, concentration and activity assays, and pharmacodynamic assays must be included.   There is also a recommendation that safety and immunogenicity data be collected from the clinical pharmacology studies and be used to determine whether the next step in the process, e.g., clinical studies, is required.

The guidance also includes a section that gives guidance on nine critical study design issues, for example, a recommendation that statistical comparisons of the biosimilar and the reference product include a valid criterion to allow the comparison, a confidence interval and an acceptable limit.  FDA notes that simulation tools can be useful in designing pharmacology studies and in data analysis.  Sponsors are encouraged to meet with FDA in the early stages of development to discuss their clinical pharmacology plan.   

Left unsaid in the guidance is what FDA will issue next relevant to the biosimilar approval process.  FDA recently received a letter from four senators that, among other things, asked for an update on FDA activities to implement best practices to make the finalization of guidances more efficient and expeditious (reported on here).  Perhaps a final guidance is not too much to wish for.