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Getting Rid of Clinical Efficacy Testing for Biosimilars Is Needed, Ethical


In a recent paper, Sarfaraz K. Niazi, PhD, argues that getting rid of clinical efficacy testing for biosimilars could realign testing ethics with current guidelines, save companies money on development, and improve data sensitivity.

In a recent paper, Sarfaraz K. Niazi, PhD, argues that getting rid of clinical efficacy testing for biosimilars could realign testing ethics with current guidelines and save companies money on development.

The paper, published in Drug Design, Development and Therapy, could serve as a guide for policy makers to remove or replace requirements for clinical efficacy testing for biosimilars, describing the issues with this form of testing, suggestions for policy and guideline changes, and comparisons between the US regulatory system and the rest of the world.

The paper also comes as the World Health Organization prepares to update its guidance on clinical efficacy testing and a review reveals that clinical efficacy testing may not be necessary to establish the safety and efficacy of bioismilars.

Niazi noted the slow acceptance that generic drugs faced when they first entered the market, during which companies were required to establish bioequivalence in healthy subjects. Later, the FDA accepted waivers of bioequivalence testing for generics once it realized that drug with high solubility and permeability don’t need to be tested. Niazi claimed that “when the biosimilars arrived, the history was repeated.”

“Since this is the first time we have faced this type of equivalence testing, it is taking longer to act,” he wrote. "These walls of resistance are falling slowly, but they need to come down quickly to enable biosimilars to find their place in assuring the affordability of lifesaving drugs."

The FDA has taken a number of steps to expedite the biosimilar approval process, including extending Q&A presentations, revising draft guidance, and updating the Frequently Asked Question section of the Purple Book. However, the FDA is subject to the provisions passed in the Biologics Price Competition and Innovation Act (BPCIA), including the requirement for clinical efficacy testing.

Some language in the BPCIA states that biosimilar approvals can be based on pharmacokinetic (PK) and pharmacodynamic (PD) data without a comparative clinical safety and efficacy analysis. Niazi mentioned how clinical efficacy analyses are often “redundant and unacceptable” for demonstrating biosmilarity and suggested for developers to challenge requirements. However, changes in the FDA guidelines can’t happen without rule changes, which can’t happen without a lot of political work.

According to Niazi, clinical efficacy studies do not provide relevant information on biosimilarity or provide information that has already been established in other analyses. Clinical studies are also very expensive to developers, accounting for about 70% of the cost companies spend to develop biosimilars, costing about $150 million to $300 million.

Additionally, Niazi argued that clinical analyses violate the US provision that advises against unnecessary human testing, and since clinical efficacy studies are often least sensitive testing, their use creates ethical concerns.

Niazi wrote about some of the testing guidelines that other global entities have established. Although the European Union requires efficacy testing even with PD and PK data available, the region operates on a case-by-case basis, which it is able to do because the European Medicines Agency doesn’t require legislative action to make such changes.

The World Health Organizations revised its guidelines but refused to waive its recommendation for efficacy and safety study. When the United Kingdom finalized its guidelines in May 2022 after Brexit, it said that biosimilars would be evaluated on a case-by-case basis to evaluate whether clinical efficacy studies are needed. However, many countries treat biosimilars like generics and approve biosimilars without clinical testing.

Niazi gave some alternatives that would be better for confirming biosimilarity of biosimilars compared with their reference products, including:

  • Established PD parameters
  • Established PK data and IgG antibodies
  • Anti-drug antibodies formation
  • In-vitro models

He also called for sweeping regulatory changes around the world and predicted that developers will adopt newer testing methodologists that are more sensitive than clinical efficacy studies to establish similarity between 2 products.

Niazi concluded, “If a biosimilar product is well-characterized and demonstrates a highly similar clinical pharmacology profile, it should be safe and effective. Adding an efficacy study that is much less sensitive to identify is superfluous….But it will make biosimilars safer and more affordable. There is a dire need for the harmonization of biosimilars approval guidelines to remove many misconceptions, both at the regulatory agency and developer levels.”


Niazi SK. Scientific rationale for waiving clinical efficacy testing of biosimilars. Drug Des Dev Ther. 2022;16:2803-2815. doi:10.2147/DDDT.S378813

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