Authors Propose Elimination of "Double Standard" for Biosimilars

Is there a double standard when it comes to regulatory requirements for data on originator biologics vs biosimilars?

Authors of an opinion article in BioDrugs argue that biosimilar developers are often required to perform comparability testing that is not expected of originator biologics developers. They suggest that via a “reliance” approach, regulators worldwide could share data and standards on biosimilar acceptance, leading to faster approvals, rather than expending resources conducting separate reviews and requiring study data that may be redundant.

The authors hinge their argument partly on advances in comparability assessments, which help determine whether a reference biologic produced by a new manufacturing process or a biosimilar has clinically meaningful differences from the previously approved originator product.

They note that originator companies often implement manufacturing process changes or extend biologics manufacturing to different locations and may not be required to do more than analytical testing to confirm consistency of product. Biosimilar development relies on conformity with the reference product; therefore, the regulatory requirements for acceptance should not be different, the authors argue

The authors contend that a consistent application of the science of comparability to all biologics would improve the efficiency of biosimilar development and review, stimulate market competition, and expand patient access.

Advances in Analytical Characterization

Modern analytical tools allow for more sensitive and reliable data on comparability that is “often sufficient to confirm comparability without the use of other methods,” they wrote. They outlined technological advances in 4 key areas that have driven the evolution of comparability assessments:

• Clear and convergent guidelines from regulators
• Use of risk-based methods for weighting analytical data
• Progressive improvements and innovation in analytical techniques
• Improved understanding of glycosylation and other post-translational modifications

Clinical Equivalence Studies

The authors noted that following a change to the manufacturing process of an originator biologic, analytical data “are almost invariably considered to be sufficient by all major regulators” to demonstrate that the change has not altered the approved version of the originator biologic. Incongruously, clinical studies may be required for a biosimilar to demonstrate similarity, they said.

However, following establishment of analytical and pharmacokinetic similarity, clinical equivalence studies “generally do not provide new information as regards biosimilarity,” the authors wrote, citing research on the approvals of approximately 100 biosimilars. This echoed concerns the same group expressed in a previous article published in 2019, where they called the “totality of evidence” biosimilars development paradigm “unnecessarily burdensome and inefficient.”

They noted that the United Kingdom’s Medicines & Healthcare Regulatory Agency (MHRA) has already moved toward a more efficient approach by downscaling requirements for clinical equivalence data for biosimilar approvals. Other regulators are considering similar revisions. These considerations, the authors said, are driven “partly by the typical redundancy of clinical equivalence trials to the conclusion of biosimilarity and the lack of ethical justification for unnecessary trials.”

In May 2021, MHRA released guidance on the licensing of biosimilar products stating that comparative efficacy trials may not be necessary to demonstrate biosimilarity in most cases. The United Kingdom’s post-Brexit guidance on biosimilars also does not require in vivo animal studies to support biosimilarity.

“Double Standard”

"Almost invariably,” regulators allow sponsors of reference biologics to “support their products’ indications in multiple jurisdictions by submission of the same clinical data,” the authors wrote.

The authors said regulatory requirements for additional layers of evidence (ie, bridging studies) demonstrating equivalence for biosimilars as “unnecessary and tedious impositions upon biosimilar sponsors to generate data whose conclusions are already known.” The same group of authors previously discussed costs associated with bridging studies in a review article published in 2017.

“Application of the same calculus to biosimilars as has been applied to reference biologics for decades,” they wrote, “would greatly facilitate the development of new biosimilars with no loss of scientific rigor or safety and no change in the product that is finally approved.”

Regulatory Reliance

This approach is “a particularly rational approach for biosimilars,” the authors said, in part because regulators would be familiar with the reference product marketed in their jurisdiction and because of the recent advances in analytical techniques: “The orthogonal and replicate nature of biosimilarity data ensures that conclusions are unequivocal and not liable to differ between competent reviewers.”

"Reliance upon a technical assessment conducted in another jurisdiction would not subsequently commit regulators to the same, or indeed any, regulatory action, and they would retain their statutory independence and responsibilities for regulation at all times," they wrote.