Developing PD Biomarkers Could Streamline Biosimilar Development

Last year, speaking at a meeting in the United Kingdom, Leah Christl, PhD, who was at the time the director of the therapeutic biologics and biosimilars staff in the office of new drugs in the FDA’s Center for Drug Evaluation and Research, explained that the FDA has been working to develop and validate pharmacodynamic (PD) biomarkers in-house for use in determining biosimilarity.

Christl explained that current PD end points for products like filgrastim and pegfilgrastim relate well to clinical outcomes, but for rheumatology products, PD end points—such as B-cell depletion with rituximab—are less refined. While the FDA has “had conversations about this” with developers, “we want to put resources behind this internally” to try to establish PD end points that will eliminate the need for developers to conduct large studies as one way to improve the efficiency of development.

Last month, writing in a perspective piece in Clinical Pharmacology and Therapeutics, a group of authors further explored the rationale for developing and using PD biomarkers in biosimilar development.

The authors point out that, as outlined in FDA guidance, biosimilars can be approved on the basis of pharmacokinetic (PK) and PD data without comparative clinical studies with efficacy end points. Relying on these biomarker data could allow for shorter, less expensive development and may allow studies to be conducted in healthy volunteers rather than in patients.

One advantage of using PK and PD data is that they may be more sensitive than clinical efficacy end points in detecting any differences between biosimilars and their references if any such differences exist.

Despite the utility of PD data, the authors note that, as of July 2019, just 5 of the approved US biosimilars—Nivestym, Zarxio, Udenyca, Fulphila, and Retacrit—have used PD similarity data as part of a demonstration of biosimilarity. These products used dose-dependent PD biomarkers: absolute neutrophil count for filgrastim and pegfilgrastim, CD34+ cells for filgrastim, and reticulocyte count and hemoglobin level for epoetin alfa.

Where sensitive biomarkers have not been established, there is an opportunity to identify such biomarkers to help expand the range of products for which confirmatory studies with efficacy end points may not be necessary to show biosimilarity. To extend PD biomarkers beyond surrogate end points, it will be important to invest in evaluating and synthesizing available information from the literature, conduct pilot studies, complete model-based assessments, and investigate novel or emerging technologies, say the authors.

“While PD biomarkers have not been prominently used across biosimilar approvals to date, there is ample opportunity to utilize such information alongside or in place of comparative clinical studies with efficacy end point(s) moving forward,” the authors write. “The impact on public health is such that the use of PD similarity data in biosimilar programs is a clear means for bringing more affordable, safe, and effective treatments to patients faster.”

Reference

Li J, Florian J, Campbell E, et al. Advancing biosimilar development using pharmacodynamic biomarkers in clinical pharmacology studies [published online October 31, 2019]. Clin Pharmacol Ther. doi: 10.1002/cpt.1653.