Part 1: FDA Workshop Highlights Global Regulatory View on Biosimilar Development

Part 2 and Part 3 are now available.

In the FDA’s workshop on increasing the efficiency of biosimilar development, speakers representing regulatory agencies around the world highlighted the science behind approval requirements for different regions.

The workshop focused on reevaluation of the need for comparative clinical efficacy studies for biosimilars, which many experts have argued are unnecessary, expensive trials that do not provide any sufficient information beyond the data that are already presented in preclinical and pharmacodynamic (PD)/pharmacokinetic (PK) studies.

Day 1 of the event hosted 7 representatives from the United Kingdom, the World Health Organization (WHO), the European Union (EU), Canada, Japan, the Republic of Korea, and the FDA to discuss how comparative clinical efficacy studies are being used in global biosimilar development programs and what agencies have learned over time about the value of these trials.

Hye-Na Kang, VMA, a scientist in the Norms and Standards for Biological Products team of the WHO, mentioned a 2020 analysis that found the long-term safety, efficacy, and immunogenicity data for licensed biosimilars since 2006 do not raise concerns. Additionally, current data suggested that analytical and functional testing and robust PK and PD studies are sufficient to demonstrate biosimilarity between products and that animal toxicology studies aren’t needed. Kang said that the WHO will update its guidelines from 2009 to reflect the new science.

According to René Anour, chair of the European Medicine Agency’s (EMA) Biosimilar Working Party, the EU does not use clinical efficacy testing for all products, saying that the EMA plans to publish a concept paper outlining principles for implementing a tailored clinical approach to biosimilar evaluations based on quality data, with a primary focus on monoclonal antibodies. Molecules that do not require clinical efficacy trials include:

• Recombinant granulocyte-colony stimulating factor
• Low–molecular weight heparins
• Recombinant human insulin and insulin analogues
• Interferon beta
• Recombinant erythropoietins
• Recombinant follicle-stimulating hormone
• Somatropin

To date, Canada has 53 federally approved biosimilars, including 6 insulin products and 8 adalimumabs, as presented by Bradley Scott, senior clinical evaluator at Health Canada. Of the 68 submissions for biosimilars, 51 have included data from comparative clinical efficacy studies. Submissions without these data (human insulin, n = 1; enoxaparin sodium, n = 5; filgrastim, n = 2; pegfilgrastim, n = 1) had characterizable PD end points with clinical relevance.

Scott said that Health Canada updated its labeling expectations for biosimilars, advising that comparative studies aren’t needed to appear in Product Monographs. Additionally, the Biosimilar Working Group is revising guidance to explore where comparative trials are needed only in special circumstances, and the organization will take comments from the public before a finalized version is adopted.

Ryosuke Kuribayashi, PhD, deputy review director at the Office of Cellular and Tissue-based Products at Japan’s Pharmaceuticals and Medical Devices Agency, outlined Japan’s progress, saying that 32 products have been approved between 2009 and 2022, 23 of which were approved using comparative efficacy data and PK/PD data. Three filgrastim, 4 insulin, and 1 agalsidase beta biosimilars were approved without comparative efficacy data. Kuribayashi echoed the other speakers’ sentiments about PK and PD studies providing sufficient enough evidence to assure comparability of biosimilars and their innovator products.

Stacey M. Ricci, ScD, director of the scientific review staff, Office of Therapeutic Biologics and Biosimilars within the Office of New Drugs, Center for Drug Evaluation and Research, FDA, explained why the United States still relies on comparative efficacy data. Back when the biosimilar program was new and there was a lack of experience using biosimilars, there were theoretical concerns about safety and efficacy, and clinical efficacy end points were used to build confidence in the new drug development paradigm.

However, Ricci said that new science has shown a need to shift building confidence to comparative analytical data, with more efforts being directed at understanding functional analytical comparisons demonstrating that biosimilars are “highly similar” and can provide the same clinical performance as their reference products. She also stressed that more risk-based criteria are needed to justify when a limited clinical assessment is sufficient to complement analytical data to demonstrate biosimilarity.

Ricci concluded, “Once there’s an agreed upon approach for how to streamline clinical data expectations, then we as regulators can provide updates to our guidelines as appropriate.”