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A case to remove reduntant trials of biosimilars reaches FDA

  • The calls to reduce the scope of clinical trials of biosimilars are slowly reaching regulatory agencies. The FDA has just announced a new initiative to make trials more effective and useful, which, among others, will discuss the usefulness of confirmatory clinical studies of biosimilars.
  • Evidence collected to date suggests that large confirmatory studies are not needed to ensure the availability of safe and effective biosimilars. Hundreds of biosimilar trials were conducted and failed to detect any clinically-relevant differences.

The FDA has just announced a new workshop to increase the efficiency and usefulness of clinical research, called “Enhancing Adoption of Innovative Clinical Trial Approaches”. The event will take place in March 2024, during which the stakeholders will discuss barriers and challenges to incorporating innovative clinical trial approaches. An open portal has been launched to gather comments and suggestions from the public to reduce the redundant testing that increases costs and prolongs the time to approval of new medications.

One of the issues that will certainly be discussed is confirmatory clinical studies (CCSs) of biosimilars. For a couple of years now, experts were advancing strong arguments in favor of reducing the scope of clinical evaluation of these products. Their argumentation is based mainly on historical considerations, but regulatory and scientific aspects are also being cited:

  • Analytical similarity to the reference product is a foundation of biosimilarity assessment. Methods evaluating the physical and biochemical properties of biologics have improved over the years and are now able to pin down even the slightest differences that could influence the clinical activity of the developed biosimilar.
  • None of the reported 200 trials of biosimilars showed any difference in the primary efficacy outcomes. Similarly, from over a thousand of publications analyzing the results of CCSs, none reported any clinically-relevant differences. In such circumstances, the human testing of the next biosimilar products, for which analytical similarity has been already established, can be viewed as unnecessary and even violating the ethical standards.
  • Although the CCSs would be abandoned, the limited PK/PD studies of healthy individuals would still be conducted and available for regulatory review. Such studies are already being accepted by regulatory authorities as a valid evidence of similarity (see e.g. FDA’s approval of filgrastim and erythropoietin biosimilars). The PK and PD data combined with in vitro bioanalytical package should be sufficient to conclude a very low risk of relevant differences in clinical use.
  • Methodology of CCS design is arbitrary and in certain cases can make trials too challenging and financially unviable. Sample size is influenced by the actual difference between reference drug and placebo/control, and this can be minute for certain drugs and indications. To achieve the recommended study power and demonstrate lack of difference, the number of enrolled subjects could go in thousands, with development costs exceeding the financial capabilities of the sponsor.
  • Pharmacovigilance surveillance systems, including observational studies based on biosimilar registries, are more capable of identifying risk issues than CCSs, which typically enroll less than 1000 subjects.

Naturally, the removal of redundant trials is of particular interest to biopharmaceutical industry. The costs of clinical trials typically add up to around 70% of the entire biosimilar development budget and can stall the development program for many years. Regulatory agencies such as the MHRA and now the FDA are starting to acknowledge the arguments put forward by experts and industry representatives, and setting up initiatives to expedite the development of biosimilars. One of the most visible signs that the tides are changing, is a recent publication from former EMA employees, which reviewed 36 biologics filings and concluded that CCSs are not required to establish biosimilarity. However, it is clear that it will take at least few more years for the biosimilars’ regulations to be revised.


  1. Sarfaraz K. Niazi, „BioRationality: FDA Launches a New Opportunity to Remove Redundant Trials of Biosimilars”, AJMC The Center for Biosimilars (November 6, 2023).
  2. Food and Drug Administration (FDA). „Enhancing the Adoption of Innovative Clinical Trial Approaches” (October 11, 2023) Link: https://www.fda.gov/drugs/news-events-human-drugs/enhancing-adoption-innovative-clinical-trial-approaches-03192024#event-information
  3. Niazi, Sarfaraz K. “Biosimilars Adoption: Recognizing and Removing the RoadBlocks.” ClinicoEconomics and Outcomes Research (2023): 281-294.