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Establishing bioassay studies for biosimilar development is important for supporting regulatory filings.
With a growing number of biosimilars achieving regulatory approval and moving through clinical development, the need for bioanalytical studies to determine correct structure and function of these molecules is increasingly important. Additionally, data generated from these bioanalytical studies are necessary for supporting regulatory filings for a biosimilar candidate.
In discussing the need for and importance of bioanalytical assays in the development of biosimilars, BioPharm International spoke with Kelli Phillips, associate director, Immunochemistry; Gwen Eak, manager, Immunochemistry; and Edward Tabler, director, Immunochemistry, all at PPD Laboratories’ bioanalytical lab.
BioPharm: What are the most challenging issues in analytical assessments of biosimilar molecules?
Phillips (PPD): Biosimilar drugs are subjected to both structural and functional assessments. Structural assessments occur early in the drug development process and are significantly more robust than those assessments required during the original [innovator] drug development. Because biologics are the products of living organisms, the products produced are heterogeneous, often with variance in post-translational modifications. Key structural characteristics assessed for both the innovator and biosimilar drug product include amino acid sequence, aggregation levels, charge heterogeneity, and the glycosylation profile.
Biosimilar products also must be compared to the innovator product in non-clinical and clinical trials to assess the performance of the biosimilar drug, with a focus on efficacy and safety. For this [step], assays must be developed to detect both the biosimilar and innovator equally in a single-assay approach. The most critical need in this step is the acquisition of reagents. Often the original innovator assays are completed with specialized reagents provided by pharmaceutical development R&D teams. These components can help to build more robust assays, with maximized assay sensitivity and tolerance. Biosimilar sponsors do not always have access to these specialized innovator materials and may need to rely on commercially available reagents that have not been optimized to their needs. As well, the innovator drug product necessary for developing a single assay is usually only available as a commercial dosing solution, provided with a fixed concentration and formulation buffer. While these challenges can make it more difficult to meet the target sensitivity and tolerances achieved by the original innovator methods, the improvements in instrumentation and methodologies that have occurred in the last decade contribute to the success of the biosimilar assessment.
BioPharm: What key data or analytical studies are required for biosimilar product development?
Eak (PPD): Data for the reference and biosimilar products are generated and evaluated in a sequential process starting with structural and functional characterization, moving to animal studies and then to clinical studies. The data from each of these steps is compared between the products to establish if the biosimilar product is highly similar to and has no clinically meaningful differences from the reference product.
Biosimilar product applications must contain three components. The first is analytical studies that do not contain bioanalytical data but do demonstrate that the biosimilar product is highly similar to the reference product. The second is animal studies, which often include bioanalytical data to assess toxicity. The third is a clinical study or studies in one or more of the indications that the reference product has previously been licensed. Bioanalytical data supporting clinical studies may include quantitative pharmacokinetic (PK) and pharmacodynamic (PD) results and safety data including antibody and neutralizing antibody qualitative results.
In addition to these three requirements, an application for an interchangeable product must include two aspects: data demonstrating that the product is expected to produce the same clinical results in any patient and for products with multiple dose administrations, clinical study data supporting the switching between dosing with the reference and biosimilar products that does not increase safety risks or reduce effectiveness compared to patients dosed solely with the reference product. Bioanalytical data supporting both of these requirements again include PK and PD results and safety data (1).
BioPharm: What regulatory challenges exist, and how does the regulatory aspect drive the type of data or testing needed to support a regulatory filing for a biosimilar?
Tabler (PPD): Prior to the existence of regulatory pathways for biosimilars, comparator studies were uncommon for biologics when compared to their generic/small-molecule counterparts. Since bioanalytical data is extremely critical to these submissions, the shift to these types of studies for large molecules resulted in increased regulatory scrutiny on methods and processes used to detect biologics and their anti-drug antibodies (ADAs).
For early biosimilar submissions, a significant challenge was in predicting what standard the regulatory agencies would apply during their review. A single-assay approach hadn’t been widely adopted, and there was no standard approach for comparing the biosimilar against approved drugs in method validation. For ADA analysis, immunogenicity guidance existed, but it was still in draft, and many sections were still the subject of debate.
FDA and the European Medicines Agency have now approved a significant number of drugs through their respective biosimilar pathways. Comparisons during method validation have largely been standardized and immunogenicity guidance has been finalized. While interpretations of standards and guidance are still evolving, today’s regulatory challenges are primarily in addressing program-specific concerns. These are generally driven by comparisons against historical data for the originators, which may not have followed the same standards as the biosimilar. For ADA methods, concerns during these comparisons also may be affected by the increased sensitivity of today’s methods, as well as improved knowledge about related issues like drug tolerance, cut point establishment, and patient population adjustments.
BioPharm: Why would a drug developer invested in biosimilar product development seek/require the bioanalytical services of an outsourcing partner?
Phillips (PPD): There are many advantages when working with outsourcing partners for biosimilar product development. Because contract research organizations (CROs) routinely support biosimilar product submissions to regulatory agencies, the current best practices expected by regulatory agencies are well understood, and internal practices have been developed to address the most recent expectations. As well, CROs are usually subjected to regulatory audits for biosimilar programs, providing them with valuable insights that can be leveraged when managing new biosimilar bioanalytical programs. Finally, CROs have processes in place that allow for fast-paced method development/validation and sample analysis—including automation and priority track for data review—allowing biosimilar clients to meet the aggressive timelines that usually accompany these programs.
1. FDA, “Biosimilar Development, Review, and Approval,” www.FDA.gov, Oct. 20, 2017.
Feliza Mirasol is the science editor for BioPharm International.
Vol. 34, No. 10
When referring to this article, please cite it as F. Mirasol, “Bioanalytical Studies Support Biosimilars Approval Pathway,” BioPharm International 34 (10) 42–43 (2021).