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Developers Advised to Challenge Regulatory Standards to Speed Development of Biosimilars


In a recent paper, Sarfaraz K. Niazi, PhD summarizes some of his central ideas on the relevance of FDA biosimilar testing standards.

Developers can bring biosimilars to market more quickly and at lower cost by challenging regulatory requirements and restricting testing of these agents to analytical similarity and clinical pharmacology, Sarfaraz K. Niazi, PhD, writes in a December 2021 paper in the journal Expert Opinion on Biological Therapy.

Niazi is an adjunct professor of biopharmaceutical sciences at the University of Illinois and the University of Houston, founder of the biosimilars companies Karyo Biologics and Adello Biologics, and a Center for Biosimilars® Advisory Board member.

After analyzing regulatory documents for over 100 biosimilars, Niazi concluded that excluding the other main processes contributing to approvals—animal testing and clinical efficacy testing—would not have changed any approval decisions.

Niazi, who has previously challenged FDA and World Health Organization biosimilar approval guidelines, says the agencies will not reject rational scientific plans that dispense with tests that do not provide helpful information. They have modified and relaxed many requirements in recent years, he says.

“While the agencies may be slower in changing their guidelines, the onus lies on the developers to challenge the guidelines to restrict the testing to analytical similarity and clinical pharmacology. Even these testings can be reduced significantly without compromising their value to establish biosimilarity,” he writes.

Future challenges will lead to “a new era of faster, lower-cost approval of biosimilars without risking their safety and efficacy,” he says.

Animal testing is not helpful for biosimilar approvals because differing animal and human pharmacodynamics mean toxicology studies do not provide useful data, Niazi says. No biosimilars have failed in animal toxicology testing, “because they cannot.”

In the past, the FDA has often declined to evaluate animal studies of biosimilars, and its Center for Drug Evaluation and Research is now encouraging use of new approach methodologies, he writes. Alternative approaches include human and animal cells, organoids, organ-on-chips, and in silico modeling.

Organoids are multicellular constructs that mimic the activity or tissue environment of human organs. Organ-on-chips are devices that mimic the human physiological and mechanical environment for the purposes of medical study, and in silico models are digitized representations of pharmacologic and physiologic processes.

Niazi provides several arguments why developers should avoid clinical efficacy studies. Comparing supposedly identical products is “a statistical challenge” based on “arbitrary assumptions,” he writes. The FDA allows use of pharmacokinetic and pharmacodynamic (PD) biomarker data in healthy patients instead, which generally requires shorter, less costly studies and produces more sensitive results. The agency has already licensed several products on PD evaluation only.

Efficacy testing is mostly “a checkmark item” that “constitutes unnecessary human exposure,” he writes.

He says clinical studies of comparative equivalence are not useful, as they are unlikely to fail and have never resulted in the rejection of biosimilarity. They are also difficult to conduct for some drugs for which recruitment of homogeneous populations or comparable patients is a challenge, such as anticancer agents.

In the future, regulators will approve biosimilars based solely on analytical assessment and clinical pharmacology profiling, Niazi argues. These areas can also be made less complex. He advises developers to avoid orthogonal testing during analytical assessment and follow agency recommendations that they explore creative methods, such as using ultraviolet and fluorescence spectroscopy to compare secondary and tertiary structures.

Novel testing modalities should also be considered for clinical pharmacology comparisons. Niazi suggests keeping to narrow criteria for study subjects in order to reduce study sizes. He also recommends consolidating all expected outcomes in a single study, while at the same time avoiding unnecessary meetings with FDA officials to prevent development plan delays.


Niazi SK. Biosimilars: a futuristic fast-to-market advice to developers. Expert Opin Biol Ther. Published online December 27, 2021. doi:10.1080/14712598.2022.2020241

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