IGBA Seeks Waiver of Comparative Clinical Efficacy Studies

A global biosimilar trade association has issued a fresh call for regulatory authorities to streamline the application process for biosimilars by paring down the need for comparative clinical trials. “The decision to request a comparative clinical efficacy study should be based on a scientific evaluation assessing whether such a study would add scientific value to a given application,” the group contends.

The International Generic and Biosimilar Medicines Association (IGBA) said that technological advances have made the comparative trials requirement largely redundant and that regulatory authorities are clinging to an outdated process that prevents these lower-cost medicines from reaching market.

“Fostering a sustainable, multi-source medicines environment requires regulators to further streamline regulatory requirements for biosimilar approval,” the group said. “Regulators should respond to advances in analytical science that provide more detailed and clinically-relevant information than was possible in the past by encouraging tailored clinical development programs to support approval of biosimilar medicines.”

Biosimilar Confirmation Process

The general approach to confirm biosimilarity to the reference product involves comprehensive structural and functional characterization of the biosimilar, a phase 1 study in healthy volunteers to assess pharmacokinetic (PK) comparability, and then a clinical efficacy trial to assess safety and effectiveness. These latter trials may be required in the United States and Europe to round out the evidence in support of a biosimilar approval appllication.

The group contends that based on a review of biosimilars developed prior to 2010, in 95% of approvals in the European Union and the United States “the comparative efficacy study added no scientific value to the review process.” In the remaining 5%, differences between the biosimilar and reference product were noted in immunogenicity rates, requiring manufacturing process improvements, the IGBA said.

“Importantly, these outcomes were observed in biosimilars that were developed prior to 2010, after which time no differences in clinical efficacy and safety, including immunogenicity, have been observed,” the group wrote.

The same review article suggests a streamlined pathway to developing biosimilars that excludes comparative efficacy studies.

Based on such findings, the IGBA recommended that regulatory authorities “move away from routinely requiring comparative efficacy trials to support biosimilar approval.” This would be achievable because advances in science have enabled better analytical and functional characterization of biologics and insight into their performance, the group said.

“If critical physicochemical and functional quality attributes of the biosimilar candidate are closely aligned to those of the reference product and comparative human pharmacokinetic and, if necessary, additional immunogenicity studies confirm that the biosimilar is equivalent to its reference biologic product, a scientific assessment should be undertaken to evaluate whether requesting a confirmatory comparative efficacy study will add scientific value,” the group said.

Waiver Policy

Current regulatory policies in the United States and Europe allow the waiver of the need for comparative efficacy studies if there are appropriate biomarkers to guide analysis of the respective clinical attributes of biosimilars and reference products; however, few biomarkers that achieve this purpose have been identified, making it difficult to get the comparative efficacy trial requirements waived, the IGBA said, quoting from the review mentioned earlier.

In part, the group based its demand for regulatory review streamlining on a recent study in which investigators concluded that “comparative efficacy trials are neither an effective discriminating tool for the comparison of the biosimilar with the [reference product], nor an efficient use of limited resources.”

Authors of that study also recommended that extensive comparative analytical studies combined with a modest application package containing pharmacokinetic and pharmacodynamic data would be “sufficient to assess biosimilarity in most cases.”

In December 2019, the FDA issued guidance waiving clinical immunogenicity and comparative efficacy testing for biosimilar insulins that match the analytical and pharmacokinetic/pharmacodynamic characteristics of the reference drug, as suggested by Sarfaraz Niazi, PhD, a biopharmaceutical entrepreneur and professor who also serves on the advisory board for The Center for Biosimilars®.

Reference

Bielsky MC, Cook A, Wallington A, et al. Streamlined approval of biosimilars: moving on from the confirmatory efficacy trial. Drug Discov. Published September 9, 2020. doi:10.1016/j.drudis.2020.09.006​