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Upcoming WHO Guideline Changes May Reduce Data Requirements for Biosimilar Development


In advance of the World Health Organization (WHO) updating its guidelines for biosimilar development, a review article concluded that comparative clinical efficacy and safety studies may not be helpful for the evaluation of biosimilars.

In most cases, comparative clinical efficacy and safety studies are “redundant” for the evaluation of biosimilars, concluded a review article providing recommendations for the World Health Organization (WHO) Expert Committee on Biological Standardization (ECBS), in anticipation of their upcoming revision of WHO guidelines.

The authors explained that state-of-the-art analytical and in-vitro functional tests, combined with robust clinical pharmacokinetic (PK) and pharmacodynamic (PD) studies, are sufficient to demonstrate biosimilarity in most cases.

The WHO published guidelines on the development and evaluation of biosimilars in 2009. Because of recent advancements in analytical characterization of biosimilars, regulatory approval processes have been “increasingly criticized,” the authors said, for “demanding unnecessary clinical studies.” In 2019, supported by the ECBS, WHO initiated this review of scientific evidence to explore the possibilities for streamlining the clinical development of biosimilars.

According to the reviewers, the revised guidelines should reflect that the degree of residual uncertainty regarding biosimilarity after analytical, structural, functional, and human PK/PD studies “is now substantially reduced” compared to the time of the original publication in 2009.

Insights From Guidelines of Other Regulatory Bodies

As a first step in their review, the authors analyzed guidelines from the US Food and Drug Administration (FDA), Health Canada, and European Medicines Agency (EMA). From these guidelines, the authors suggested that the new WHO guidelines should have more emphasis on the importance of state-of-the-art physicochemical and structural comparability evaluation and in-vitro functional tests, noting that if clinical data requirements are reduced, analytical and in-vitro functional data will become relatively more important as part of the totality of evidence for a biosimilar.

They called the value of in-vivo toxicological tests in biosimilar development “questionable,” and recommended reducing requirements for these studies as well. They recommended that biosimilar development should proceed in a stepwise, risk-based manner, and the degree of residual uncertainty at critical steps in development should be used to plan appropriate studies to address those uncertainties.

For clinical studies, their analysis of the European Medicines Agency, FDA, and Health Canada found all 3 provide some flexibility regarding comparative clinical efficacy and safety studies, “if certain requirements are met, especially availability of PD markers that are relevant markers or even surrogates for efficacy.” However, these resource-intensive studies are still expected for most biosimilar products, according to the authors.

Long Term Safety of Biosimilars

The authors also conducted a literature search to evaluate the long term efficacy, safety, and immunogenicity of biosimilars and identify any potential long term problems. They reviewed the long term safety data on biosimilar somatropin, filgrastim and pegfilgrastim, epoetin alfa, insulin glargine, tumor necrosis factor alpha (TNF) inhibitors, and anti-cancer monoclonal antibodies from post-marketing clinical studies and real-world studies.

They noted that in the European Union, no biosimilar products have been withdrawn from the market for safety reasons, and no adverse effects specific to a biosimilar have been added to the product information. Their review found the current data on long term safety of biosimilars “validate the current concept of biosimilar development and create a foundation for analyzing redundancies, especially the need for large ‘confirmatory’ efficacy and safety studies.”

The Role of Comparative Clinical Studies in Benefit-risk Evaluation of Biosimilars

Next, another literature search for articles on the role of clinical efficacy and safety studies in the benefit-risk evaluation of biosimilars was carried out. The goal of biosimilar development, they said, is to establish a manufacturing process to produce a product highly similar to the originator, and the essential elements to achieve that goal are state-of-the-art analytical orthogonal methods, comparative in vitro functional testing, and PK/PD studies. Efficacy and safety studies, in contrast, are regarded as “confirmatory,” according to the authors. They noted that in the European Union, several biosimilars have already been approved based on PD studies, and further reductions in clinical data requirements are anticipated.

They cited three retrospective analyses on the role of confirmatory efficacy and safety studies in regulatory decision-making, the results of which, they said, “question the added value of phase III-type efficacy and safety studies on top of analytical, in vitro functional, and clinical PK studies.”

When Clinical Efficacy and Safety Studies May Be Needed

The reviewers acknowledged the results of these analyses “do not definitely prove that the confirmatory safety and efficacy studies are useless.” There were 2 cases where increased immunogenicity was revealed in the confirmatory efficacy and safety study. However, “in the first case, unacceptable high levels of host cell impurities were already observable at the analytical level.” The second case was epoetin alfa, “a product with a high immunogenic risk, for which immunogenicity data will likely be necessary also in the future.”

However, in most cases, they suggested “adequately powered PK and/or PD trials will provide sufficient clinical safety and immunogenicity data.” They added that the revised guidelines should include criteria for situations in which a confirmatory efficacy and safety study should be required.

Recommendations for the Revised WHO Guidelines

The authors concluded with recommendations on what should be included in the revised WHO guidelines:

Additional clarity regarding quality, including analytical characterization, risk assessment of quality attributes, use of sensitive orthogonal analytical methods, and establishment of comparability ranges for quality attributes.

A stepwise progression of non-clinical studies that reduces or eliminates the need for in vivo nonclinical tests.

Based on the review of guidelines from other regulatory bodies, clarification is needed on scenarios in which a foreign reference product may be used instead of a domestic product.

A reduction in the requirement for confirmatory efficacy and safety studies.


Kurki P, Kang HN, Ekman N, Knezevic I, Weise M, Wolff-Holz E. Regulatory evaluation of biosimilars: refinement of principles based on the scientific evidence and clinical experience. BioDrugs. 2022;36(3):359-371. doi:10.1007/s40259-022-00533-x

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