New WHO Biosimilar Guidelines Aim to Streamline, Clarify Regulations

The World Health Organization (WHO) has clarified the guidance it gives to member countries regarding the evaluation of biosimilars. The new guidelines are designed to reflect changes in the science of biosimilars and the modern economic realities faced by payers and regulators.

In a new report in Annals of the New York Academy of Sciences, study authors outlined the newest updates to the guidelines.

The WHO adopted guidelines for the evaluation of biologically similar biotherapeutic products (biosimilars) back in 2009. Five years later, the organization passed a resolution promoting access to biotherapeutic products. As part of that resolution, leaders called for a revisiting of the 2009 guidelines to ensure they aligned with the latest technological advances and the needs and capacities of national regulatory agencies. Thus began a lengthy process of reviews, surveys, and stakeholder conversations. Those efforts revealed a couple of key findings, the authors said.

First, they showed that the guidelines had helped establish biosimilars as a safe and efficacious part of the modern health care landscape; however, they also showed several significant hurdles to biosimilar evaluation, adoption, and access. Most of those challenges, the authors said, had to do with reference products.

“For example, obtaining sufficient quantities of reference products to conduct the comparability exercise and how to use the reference products sourced from outside of the country were the issues,” they wrote.

Another problem, they noted, is that in some countries, products are termed biosimilars even though they were not approved through the regulatory framework for biosimilars, thereby raising the risk of reducing public confidence in the efficacy of actual biosimilars.

In response to such concerns, in 2020, the WHO’s Expert Committee on Biological Standardization recommended another review and update of the organization’s biosimilars guidelines. Those revisions were adopted last year.

Some changes have to do with definitional clarity. For instance, initially, the guidelines referred to biosimilars as “similar biotherapeutic products,” but the new guidelines refer to “biological products that are highly similar” to well-characterized reference products. The revised language is meant to acknowledge that biosimilars can extend beyond biotherapeutics.

The organization also revised how biosimilars should be evaluated, replacing the term stepwise approach with tailored. The authors said this change was “based on current practices that show that biosimilar development proceeds in a ‘concurrent’ fashion rather than in a stepwise mode.”

Also included in the guidelines is new language about how regulators should evaluate nonlocal reference products.

“The increased flexibility and the clarity on the considerations provided now for use of nonlocal reference products opens the door wider for global biosimilar development, as some biosimilar manufacturers may want to use a reference product sourced from less-expensive markets and avoid duplicating studies already undertaken with the reference product licensed in another country,” they wrote.

They said the most significant change of all, however, comes in the guidelines related to clinical evaluation. The previous language said clinical comparison of biosimilars “should begin” with pharmacokinetic and pharmacodynamic studies and continue to clinical trials. The new language says such studies are “generally required,” but also allows for decisions to be made based on the totality of evidence.

The authors said this change reflects that “the regulatory perspective about comparative safety and efficacy studies is gradually shifting from a strict inflexible requirement to a case-by-case manner depending on the molecule and the data submitted for demonstration of biosimilarity based on the knowledge and the evidence accumulated to date.”

They concluded by explaining their belief that streamlined guidelines that maintain the goals of promoting safety and efficacy ought to help drive down the cost of biosimilar development and biosimilar therapies. However, they said they will continue to consider and revise these guidelines as conditions warrant.

Reference

Kang HN, Wadhwa M, Knezevic I, Ondari C, Simao M. WHO guidelines on biosimilars: Toward improved access to safe and effective products. Ann N Y Acad Sci. Published online January 24, 2023. doi:10.1111/nyas.14965