BioRationality: FDA Advice to Biosimilar Developers on Using PD Markers, Avoid Clinical Efficacy Testing

On 10 April 2023, the FDA added a new page to its website, titled “The Role of Pharmacodynamic Biomarkers in Biosimilar Drug Development,” presenting a summary of the extensive efforts that the FDA has made, including conducting multiple clinical trials reporting the findings in the January 2023 special issue in Clinical Pharmacology and Therapeutics.

It is worth noting that 18 years after the first biosimilar approval in the United States, the FDA has continuously applied scientific approaches to revise and add more approval guidelines. Significant changes include the removal of the term “animal toxicology” and replacing it with “nonclinical” testing;[1] allowing waiver of immunogenicity testing where immunogenicity does not impact pharmacokinetics, such as in the case of insulins; allowing waivers of clinical efficacy testing in patients where pharmacodynamic (PD) biomarkers are available; and continuously updating and adding advice on the conduct of clinical trials that directly add to 138 guidelines, addressing a myriad of issues like ethics, modeling, data collection, and analysis.

The FDA has concluded that to demonstrate that a PD marker is sufficient to establish clinical efficacy. These new findings expand the scope of the initial guideline, titled “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product,” issued in April 2015.

Without a comparative clinical efficacy study, the FDA has clarified that biosimilars may be approved based on pharmacokinetic (PK) data and PD biomarker data. 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.

An examination of the FDA-licensed biosimilars shows that 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 demonstrated to be surrogates for clinical outcomes.

However, an established relationship with clinical outcomes is unnecessary for a PD biomarker to be used in biosimilar development. This last statement is of great significance that will push the pendulum back to analytical assessment as a vital consideration.

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 2 products. This provides opportunities for biomarkers previously used as secondary and exploratory endpoints to play essential roles in biosimilar development programs. There is also an opportunity to identify new PD biomarkers with novel methodologies if the information on a suitable PD biomarker is unavailable.

The FDA also suggests focusing on biosimilar innovations, including proteomics research for identifying PD biomarkers for biologics. Large-scale proteomic methods would allow developers to simultaneously study changes in the expression of thousands of proteins after administering a drug or biologic. Biomarker research has been revolutionized by the availability of proteomic technologies to measure the thousands of proteins in the body and changes in their levels or molecular modifications caused by pharmacologic interventions. Transcriptomics and metabolomics are analogous technologies that allow one to do the same for RNA molecules 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 expand 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.

I strongly urge stakeholders to take an active role in pursuing the suggestions made by the FDA and continue to develop novel PD and PK comparisons that will significantly reduce the time and cost of biosimilar approval. The FDA amount took the steps to a significant paradigm shift. It is now up to the developers to reap the benefits from the scientific teachings of the FDA.

Reference

[1] Han JJ. FDA Modernization Act 2.0 allows for alternatives to animal testing. Artif Organs. 2023;47(3):449-450. doi: 10.1111/aor.14503.