FDA researchers are investigating the utility of pharmacodynamic, or PD, biomarkers to demonstrate biosimilarity. This research can potentially help developers demonstrate that their proposed product is biosimilar to, or interchangeable with an FDA-approved biological product, and improve the efficiency of biosimilar development.*

Biological products have revolutionized the treatment options for many illnesses such as chronic skin and bowel diseases, arthritis, diabetes and cancer. Although these innovative products can enable longer lifespan and improved quality of life, the high cost of these products limits access.

Due to the complexity of biological products, the process of establishing biosimilarity can be quite challenging and costly, and may require more investigations than might be needed to support the approval of a generic drug.

FDA guidance documents outline how biosimilars may be approved based on pharmacokinetic (PK) data and PD biomarker data without a comparative clinical efficacy study. Reliance on PK and PD data allows for shorter and less costly clinical studies that can often be conducted in healthy participants. PD biomarkers are indicators of a drug’s pharmacological effect on its target or targets. 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.

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, these PD biomarkers had been closely associated with or had been demonstrated to be surrogates for clinical outcomes. However, an established relationship with clinical outcomes is not necessary for a PD biomarker to be used in biosimilar development.

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.

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.

FDA has also 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 a 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 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 interferon biologics.

Large-scale proteomic methods would allow developers to simultaneously study changes in the expression of thousands of proteins after administration of a drug or biologic. 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.

*A biosimilar is a biological product that is highly similar to, and has no clinically meaningful differences from, an FDA-approved reference product. Approval of biosimilar products relies on existing scientific knowledge and regulatory findings about the safety, purity, and potency of the reference product.

Resources

• Pharmacodynamic Biomarkers: Their Role in Biosimilar Product Development | FDA
• FDA Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
• January 2023 special issue in Clinical Pharmacology and Therapeutics
• Biosimilars Action Plan
• BsUFA III commitment letter