Simplifying Biosimilar Development to Ensure Long-Term Competition

I’m not sure if you saw it, but leading biosimilar industry scientists/advocates published in BioDrugs an exemplary summary of the steps regulators may take now to expand the biosimilar pipeline tomorrow. Importantly, these steps are not recommended to improve profits but because the regulatory science and biosimilar experience fully supports it.

Food and Drug Administration

The article, written by Hillel Cohen, Matthew Turner, Dorothy McCabe, and Gillian Woollett, and colleagues from Sandoz, Fresenius Kabi, Boehringer Ingelheim, and Samsung Bioepis, respectively, offered a strong argument for significantly lowering the bar on clinical studies and costs to biosimilar development, by following specific steps (some of which are already under consideration by the FDA). I’ve summarized a few of their important points below.

Mandate Comparative Efficacy Studies on a Case-by-Case Basis Only

Momentum has been gaining to deemphasize large-scale clinical studies in favor of analytical and structural evaluation of biosimilars. The FDA has acknowledged that the totality of evidence approach for biosimilar approval does not rely heavily on late-stage clinical trials. The authors write, “A review from 2019 revealed that no biosimilar found to be highly similar to their reference product in analytical and [pharmacokinetic] studies subsequently failed to obtain approval due to failed equivalence observed in a clinical efficacy study.”

Furthermore, these “noninferiority studies” generally lack sufficient statistical power to provide meaningful results. The authors suggest that FDA specify the need for these studies in cases where there is residual uncertainty as to the outcome. Currently, biosimilar manufacturers undertake these expensive phase 3 investigations to cover all their bases, which drives up the cost of development. They will continue to do so until regulators clarify early in the course of a development program when this is actually required.

Move Beyond Immunogenicity

The preponderance of real-world evidence, based on approximately 5 billion patient-days of therapy with biosimilars in the US and EU, has not yielded any important differences in immunogenicity resulting in adverse events or lack of efficacy relative to the reference products. “Based on these observations, the EMA and Heads of Medicines Agencies (Europe) issued joint statement in 2022 supporting the safety, efficacy, and immunogenicity of both single and multiple switches among reference products and biosimilars, and in 2023, the FDA provided similar support in a presentation to [healthcare practitioners],” according to the authors.

And far more evidence will accumulate in the US as patients taking Humira® are eventually switched to adalimumab biosimilars and then among the biosimilars. Although immunogenicity was an early concern of regulators, this has not proven to be an important barrier to biosimilar approval and utilization. Cohen and colleagues suggest that “immunogenicity analysis for biosimilars be moved to a risk-based consideration as opposed to a global and routine requirement.”

Reconsider the Interchangeability Designation

My opinion is “dump it ASAP.” The designation has quickly outlived its apparent utility, and it is a legal designation but not a scientifically based one. The sole purpose of the interchangeability assignment was to provide a mechanism by which biosimilar products could be automatically substituted at retail or specialty pharmacies. However, the conduct of multiple switching studies (which has not been consistently applied by the FDA), which were to instill confidence in the therapeutic equivalence of these products, has not revealed any immunogenicity differences and has instead sowed confusion as to (1) the relative quality of the products and (2) whether interchangeability applies across all product formulations.

The authors write, “As a scientific matter, we support immediate reconsideration of the requirements for US interchangeability and future elimination of this category. All biosimilars are, by definition, of the same quality as interchangeable biologics, and in practical terms, all biosimilars are interchangeable for the purposes of physician prescribing practices.” In essence, the public has to believe this simple statement about all biosimilars, as they would about any AB-rated generic medication: A biosimilar therapy can be substituted for another biologic in the same category to gain the same clinical outcomes.

Assume no Important Differences Between US and EU Reference Biologics

Although local biosimilar regulations require that pharmacokinetic comparison studies be performed against the locally available reference biologic, there is little justification for this mandate. The authors make the case that the same reference biologic produced in the EU and US are subject to bridging studies that assure that any manufacturing process changes do not result in important structural changes or differences in clinical outcomes. “To repeat bridging studies between foreign and locally sourced reference products for each subsequent jurisdiction offers no new scientific or clinical information,” state the authors. “Such studies significantly inflate the cost and delay biosimilar development and make some markets unviable, limiting patient access in those regions, and so should be eliminated.”

This recommendation also implies the possibility for the use of a single global standard for analytical, structural, and other testing. This could greatly reduce the cost of developers’ obtaining reference biologic samples, especially if there are large price differences country to country.

I’ve highlighted some of their recommendations here, but the gist of the argument is that the cost of biosimilar development can be reduced substantially. This will help ensure that both major biopharmaceutical firms and generic manufacturers will continue to introduce new biosimilar candidates in the future. This will be essential to managing the costs of specialty pharmaceuticals in the near term and to support our ability to afford innovative (i.e., expensive) therapies in the future.

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