The Role of PD Biomarkers in Biosimilar Development – To Get the Right Answer One Must First Ask the Right Question

Abstract

The potential for pharmacodynamic (PD) biomarkers to improve the efficiency of biosimilar product development and regulatory approval formed the premise for the virtual workshop Pharmacodynamic Biomarkers for Biosimilar Development and Approval hosted by the US Food and Drug Administration (FDA) and Duke Margolis, September 2021. Although the possibility of PD biomarkers replacing the to‐date routine comparative phase III confirmatory study currently expected by the FDA was discussed, the motivation and feasibility for biosimilar sponsors developing such markers and the regulatory risks entailed largely were not. Even more fundamental is the already established greater comparative value of the pharmacokinetic (PK) study as the most sensitive clinical assay for detecting subtle differences between two products. Consequently, the comparative analytical assessment and the head‐to‐head PKs will have already answered the core questions as to the biosimilarity of the candidate product to its reference. No further actionable information is obtained with either a PD study or a comparative clinical phase III study even as they may provide some reassurance of what is already known. When a suitable PD biomarker is available for the originator reference product they have already been used for biosimilar development. We must carefully consider the core requirements and timelines inherent in biosimilar development and how they occur in parallel rather than in the series we see for originator products. In order to improve the efficiency of biosimilar development, we need to ask the right questions based on a full understanding of how biosimilars have been developed to date and can be in the future.

Future Evolution of Biosimilar Development by Application of Current Science and Available Evidence: The Developer’s Perspective

“…As a result, development of a new PD biomarker will not comport with the timelines necessary for biosimilar development. As such, even when a PD biomarker already has been established with the reference biologic, PD biomarker studies are not expected to contribute to greater efficiencies in biosimilar development [ 34 – 36 ].…”

Advancing Innovations in Biosimilars

“…These articles and others 6 also discuss how modeling and simulation (or model‐informed drug development (MIDD)) can be used to optimize study design and analyses. Other articles focus on characterizing the relationship between product quality characteristics (e.g., structural and functional characterization) and clinical performance to further streamline clinical development 7–9 . Global alignment of regulatory expectations for biosimilar approval makes biosimilar development more efficient and attractive to sponsors, and we are happy to see articles in this issue from regions around the world; in addition to the United States, this includes articles with viewpoints from Canada, 10 Europe, 7 India, 11 and Japan 12 .…”

“…Other articles focus on characterizing the relationship between product quality characteristics (e.g., structural and functional characterization) and clinical performance to further streamline clinical development. [7][8][9] Global alignment of regulatory expectations for biosimilar approval makes biosimilar development more efficient and attractive to sponsors, and we are happy to see articles in this issue from regions around the world; in addition to the United States, this includes articles with viewpoints from Canada, 10 Europe, 7 India, 11 and Japan. 12 Finally, other articles focus on the importance of educating clinicians and patients about biosimilars and assessing the cost to patients.…”