FDA rethinks need for comparative efficacy studies for certain biosimilars

The draft guidance follows recent FDA developments in the biosimilar space, which we wrote about here, including the first reported waiver of the CES requirement for a biosimilar version of a complex monoclonal antibody biological product. On that occasion we noted FDA’s “growing confidence in advanced analytical and other methods, short of additional clinical investigations, as reliable tools for establishing biosimilarity.” That confidence is apparent in the draft guidance.

Key themes

FDA explains that, since it issued the 2015 final guidance, Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, it has gained “significant experience in evaluating data from comparative analytical and clinical studies” and that current analytical technologies can now “structurally characterize highly purified therapeutic proteins and model in vivo functional effects with a high degree of specificity and sensitivity.” As a result, FDA says, “a comparative analytical assessment (CAA) is generally more sensitive than a CES to detect differences between two products, should any exist, that may preclude a demonstration of biosimilarity.”

Under the “streamlined approach” outlined in the draft guidance, FDA says that a CES “may not be necessary” for “therapeutic protein products” (TPPs) in the following circumstances:

• The biosimilar and reference product “are manufactured from clonal cell lines, are highly purified, and can be well-characterized analytically.”
• The relationship between “quality attributes and clinical efficacy is generally well understood for the reference product” and “can be evaluated by assays included in the CAA.”
• An appropriately designed human pharmacokinetic (PK) similarity study and immunogenicity assessment can address residual uncertainty.

A CES may therefore still be necessary for biologics with limited structural understanding or where analytical assays cannot fully evaluate functional effects. The draft guidance notes that a CES may also be necessary for “locally acting products such as intravitreally administered products” for which comparative PK data are “not feasible or clinically relevant” and “where a comparative clinical study with a clinically relevant endpoint other than an efficacy endpoint” provides unique safety or performance information.

But in general, the draft guidance makes clear that these are now exceptions to the general rule—again, at least for TPPs. The draft guidance, like the 2015 guidance, focuses specifically on TPPs, where FDA evidently considers analytical comparability mature enough to eliminate CESs in some cases.

While the agency continues to take a “totality of the evidence” approach to demonstrating biosimilarity, its approach to CESs effectively reverses the one taken in the 2015 guidance, under which FDA expected a CES unless the sponsor could justify scientifically why one was unnecessary. Now, FDA recommends that sponsors take the streamlined approach unless the circumstances justify otherwise and expects that sponsors engage the agency “prior to initiating clinical studies.”

As a reminder, the statute requires a biosimilar applicant to conduct a clinical study or studies to demonstrate safety, purity, and potency in at least one condition of use for which the reference product is licensed. 42 USC 262(k)(2)(A)(i). However, it also provides that FDA may, at its discretion, find that this required element is unnecessary. Id. at (k)(2)(A)(ii). Thus, it has always been within FDA's authority to waive a CES. However, relieving biosimilars of the CES requirement has been limited to only a few relatively simple TPPs. The draft guidance presages a radical departure from past practice and suggests going forward that the statutory CES requirement will be honored more in the breach.

Sponsors of biosimilar products under development can now be expected to evaluate whether ongoing or planned CESs will be necessary under FDA’s new approach and reallocate resources toward analytical comparability. These sponsors are encouraged to initiate early and frequent dialogue with FDA—preferably “early in product development,” as the draft guidance notes—to confirm alignment on whether a CES is needed and what evidentiary combination will satisfy the agency’s expectations. While FDA encourages the use of CAAs for TPPs, it still expects sponsors to demonstrate—as the Public Health Service Act requires—that a biosimilar is “highly similar to its reference product, notwithstanding minor differences in clinically inactive components.” Analytical methods must therefore be capable of demonstrating biosimilarity with statistical confidence. And even when FDA agrees that a CES is unnecessary, sponsors must still demonstrate that a proposed biosimilar and reference product do not differ in immune response potential. A biosimilar application lacking robust immune-response data may require additional clinical investigation—even under the new streamlined approach.

While it is not clear whether or how FDA will expand the draft guidance’s streamlined approach to other product classes (such as vaccines or cell and gene therapy products), it is clear that the draft guidance forms part of an evolving suite of FDA guidance documents that collectively redefine how sponsors demonstrate biosimilarity and interchangeability.

The draft guidance marks a meaningful shift in how sponsors can demonstrate biosimilarity—underscoring FDA’s trust in analytical technology as a driver of biologics access. This closely mirrors steps taken by other regulators. In its draft reflection paper, which may soon be adopted, the EMA also proposes relying more on advanced analytical and pharmacokinetic data, and reducing the data required to demonstrate biosimilarity, due to scientific advances and regulatory experience gained. This would allow for a tailored clinical approach under well-established conditions and would harmonize requirements across the globe, as we also highlighted in our publication last month.

If you have questions about how these developments impact biosimilars or innovator biologic programs, please contact the authors or your usual Hogan Lovells regulatory counsel.

Authored by Komal Nigam, Jason Conaty, Katie Kramer, and Julia Mischie.