Time to Replace the Totality of the Evidence Approach to Biosimilars?

The development and regulation of biosimilars currently relies on a “totality of the evidence” approach, in which there is no one pivotal study that demonstrates biosimilarity, but a stepwise approach is taken to generate data to resolve residual uncertainty and to support a demonstration of biosimilarity. In highly regulated markets, approval of biosimilars typically relies on data generated in analytical studies, pharmacokinetic (PK) and pharmacodynamic (PD) studies, immunogenicity studies, switching studies, and clinical efficacy studies in the most sensitive indications.

According to a newly published paper, this approach to biosimilar development is unnecessarily burdensome and costly and should be replaced by a new paradigm.¹

The paper, published in BioDrugs, highlights the key principle of the predictability of the structure—function relationship for biologics; 2 biologics that are highly alike in their structure can be expected to function in the same way. No biosimilar that has been found to be highly similar to its reference in analytical and human PK studies, write the authors, has ever failed to be approved because it was found not to be clinically equivalent to its reference in a powered study.

In fact, these studies have been critiqued by the authors in detail elsewhere because their outcome is not in doubt; because these studies’ outcomes with respect to biosimilarity are not in question, they lack scientific—and therefore ethical—validity.²

Bridging studies, too, add to the burden of biosimilar development, and there have been no cases in which local versions of reference products could not be bridged to versions licensed in other highly regulated territories.

Instead of undertaking superfluous studies, write the authors, data from analytical studies, including PK studies, can serve to ensure that any differences between a biosimilar and its reference have no adverse impacts. “An analogy can be drawn to the copying of a key,” they write. “By comparing the physical size and shape of the copy to the original, we know whether it will function as intended without trying it in the lock; its function is reliably predictable from the examination of structure.”

Instead of the totality of the evidence approach to biosimilars, they propose, a “confirmation of sufficient likeness” paradigm should be implemented. They write that “‘confirmation’ recognizes that there is always important preliminary evidence of the likeness of the biosimilar and its reference...‘sufficient’ describes the endpoint of the confirmation…[and] ‘likeness’ implies a closer correspondence than ‘similarity’, which often implies that things are merely somewhat alike.”

Such a paradigm would not routinely require bridging studies, nonclinical in vivo studies, human PD studies (with potential exceptions for insulins), or powered human efficacy studies. Instead, it would rely on comprehensive analytical studies, nonclinical in vitro functional tests, human PK studies, and human immunogenicity studies including transitions.

This paradigm change, say the authors, would maximize the societal benefits of biosimilars by optimizing the regulatory burden on developers and encouraging multiple parties to develop biosimilars and engage in robust competition.

Reference

1. Webster CJ, Wong AC, Woollett GR. An efficient development paradigm for biosimilars [published online August 6, 2019]. BioDrugs. doi: 10.1007/s40259-019-00371-4.

2. Webster CJ, Woollett GR. Comment on “The end of phase 3 clinical trial in biosimilars development?” [published online August 16, 2018]. BioDrugs. doi: 10.1007/s40259-018-0297-y.