Dr. Roach: Welcome to the CDER Small Business and Industry Assistance (SBIA) Chronicles Podcast Series.

Today’s topic: The Role of PharmacoDynamic Biomarkers in Biosimilar Drug Development

My name is Dr. Sara Roach, and today we are joined by Dr. Jeffry Florian, Associate Director of the Division of Applied Regulatory Science in the Office of Clinical Pharmacology, Office of Translational Sciences, in FDA’s Center for Drug Evaluation and Research. Dr. Florian will share how FDA is conducting research that would help developers demonstrate that their proposed product is biosimilar to, or interchangeable with, an FDA-approved biological product.

Hi Dr. Florian, thanks for joining us today!

Dr. Florian: My pleasure!

Dr. Roach: Dr. Florian, I wondered if you could start by defining what we mean by a biological product and the concept of biosimilarity between a proposed biosimilar and its reference product.

Dr. Florian: Biological products have revolutionized the treatment options for many illnesses such as chronic skin and bowel diseases, arthritis, diabetes and cancer. And although these innovative products can enable longer lifespan and improved quality of life, the high cost of these products limits access. And unlike small molecule drugs, exact copies of biological products generally cannot be made.

So to address this, legal frameworks and scientific guidelines were established to enable approval of biosimilars. A biosimilar is a biological product that is highly similar to, and has no clinically meaningful differences from, an FDA-approved reference product. The approval of biosimilars relies upon existing scientific knowledge and regulatory findings about the safety, purity, and potency of the reference product.

Dr. Roach: So because of the complexity of biological products, the process of establishing biosimilarity can be quite challenging and costly, and it requires more investigations than might be needed to support the approval of a generic drug.

Dr. Florian: Yes, that’s right, but we are investigating a promising approach that could help us address this issue.

FDA researchers are investigating the utility of pharmacodynamic, or PD, biomarkers to demonstrate biosimilarity and improve the efficiency of biosimilar development. We have FDA guidance documents that outline how biosimilars may be approved based on pharmacokinetic (or PK) data and PD biomarker data without a comparative clinical efficacy study, and reliance on these two kinds of data – PK and PD biomarker data - allows for shorter and less costly clinical studies that can often be conducted in healthy participants.

Dr. Roach: And for clarification, PD biomarkers are indicators of a drug’s pharmacological effect on its target or targets.

Dr. Florian: Yes. For example, the target might be a receptor molecule that initiates a complex signaling cascade. Changes in the levels of proteins along the signaling cascade or modifications to them could be considered pharmacodynamic responses. Therefore, these proteins could be considered PD biomarkers and used to help establish biosimilarity.

However, only a limited number of biosimilar approvals have been based on PK and PD similarity data from clinical pharmacology studies without a large comparative clinical study using efficacy endpoints. These biosimilar products used previously well-established and sensitive PD biomarkers associated with known pharmacology for the reference product. In addition, the PD biomarkers had been closely associated with or had been demonstrated to be surrogates for clinical outcomes. However, it’s important to keep in mind that such an established relationship with clinical outcomes is not necessary for a PD biomarker to be used in biosimilar development.

Dr. Roach: Would you please describe some important considerations with using PD biomarkers to show biosimilarity?

Dr. Florian: PD biomarker use in biosimilar development is meant to demonstrate similarity rather than to independently establish the safety and effectiveness of a biosimilar product, so considerations for PD biomarkers intended to support a demonstration of biosimilarity are different from considerations to support new drug approvals. As such, a correlation between the PD biomarker and clinical outcomes, while beneficial, is not necessary. PD biomarkers that reflect the mechanism of action of the biological product have the potential to be more sensitive endpoints for detecting clinically meaningful differences between two products. This provides opportunities for biomarkers that were previously used as secondary and exploratory endpoints to play important roles in biosimilar development programs. There is also an opportunity to identify new PD biomarkers with novel methodologies if information on a suitable PD biomarker is not available.

Dr. Roach: In terms of making this a reality, what are some specific steps FDA has taken to advance PD biomarker development?

Dr. Florian: To support the development of biosimilars and to increase scientific and regulatory clarity for the biosimilar development community, FDA released its Biosimilars Action Plan in July 2018. A key component of this plan was for FDA to create “information resources and development tools that can assist biosimilar sponsors in developing high quality biosimilar and interchangeable products using state-of-the-art techniques.” In addition, the Biosimilar User Fee Amendments, or BsUFA, III commitment letter specifically mentions increasing PD biomarker usage as part of the regulatory science pilot program.

Dr. Roach: Turning to the actual research, can you tell us more about how CDER’s investigators are working to advance PD biomarker development?

Dr. Florian: Well, under the Biosimilars Action Plan, the FDA has been conducting applied research to advance the science around PD biomarkers for biosimilars. This research will inform evidentiary strategies and criteria to bring greater clarity to the agency’s expectations for the use of PD biomarkers to support a demonstration of biosimilarity. As part of these activities, the FDA conducted three PK/PD biomarker clinical pharmacology studies covering six different products. Various biomarkers reflecting each of the six drugs’ mechanism of action were studied, but not all biomarkers had been previously used as a surrogate endpoint. Additionally, some of the biomarkers studied were part of a broader complex signaling system and had not been used in development of the reference product.

These studies collected intensive PK and PD biomarker data at several dose levels for each of the six drugs studied. This strategy enabled the evaluation of different PD biomarkers and model-based approaches for analyzing the data. These studies also included experiments in which large-scale proteomic methods and other technologies were used to explore novel methods for PD biomarker identification. Findings from these studies were published in the January 2023 special issue in Clinical Pharmacology and Therapeutics focusing on innovations in biosimilars, including proteomics research for identifying PD biomarkers for interferon biologics.

Dr. Roach: Dr. Florian, you mentioned large-scale proteomic methods. If I understand correctly, these would allow developers to simultaneously study changes in the expression of thousands of proteins after administration of a drug or biologic.

Dr. Florian: That’s right. Biomarker research has been revolutionized by the availability of proteomic technologies to measure the thousands of proteins present in the body and changes in their levels or molecular modifications that are caused by pharmacologic interventions. Transcriptomics and metabolomics are analogous technologies that allow one to do the same for RNAs and metabolites, respectively. These progressively maturing technologies could potentially provide the scientific evidence needed to identify candidate PD biomarkers or a signature of PD biomarkers that could support a demonstration of biosimilarity.

Under circumstances where an established and sensitive PD biomarker is not known, other omic technologies like transcriptomics and metabolomics may provide an opportunity to identify new, sensitive, and robust candidate biomarkers for further investigation as PD biomarkers for future use in clinical pharmacology studies.

This work could lead to an expansion of biosimilar products for which comparative clinical studies with efficacy endpoint(s) would not be needed to demonstrate biosimilarity; ultimately broadening patient access to advanced treatment.

Dr. Roach: Thank you, Dr. Florian! We look forward to hearing more about this research as it moves forward. It has been a pleasure speaking with you!

You can find a link to the full SBIA Chronicles article at www.fda.gov/cdersbiachronicles. Also visit www.fda.gov/cdersbia to stay connected with upcoming webinars and conferences, sign up for SBIA email updates, and follow SBIA on LinkedIn. Thanks for tuning in!