The First Thing You Should Know About Biosimilar Inds to the US FDA

The First Thing You Should Know about Biosimilar INDs to the US FDA

July 26, 2020

This position paper is authored by staff members at Aleon Pharma International, Inc. based on their experience and understanding of FDA guidelines and regulations. This position paper is the sole property of Aleon Pharma International, Inc. and may not be redistributed without the express written consent of Aleon Pharma International, Inc.

Overview of Biosimilars

Biosimilar products are generally recognized as the biologic version of the small molecular generic drugs. However, there are significant differences between the small molecular generic drugs and biosimilar products due to the inherent nature of the small molecules and biologics. The small molecular drugs are usually low molecular weight, stable, with well-defined structure and are completely characterized chemicals produced by process-independent chemical synthesis. On the other hand, biologics are mostly high molecular weight, relatively unstable, complex and heterogeneous structures, impossible to fully characterize, and typically produced from living cell cultures by process-dependent manufacturing. A biosimilar is a protein-based therapeutic that is highly similar to a reference biologic and shows no clinically meaningful differences in safety, efficacy, quality characteristics, or biological activity. Unlike small molecule generic drugs, biosimilars are not identical to the reference biologic or to other approved biosimilars of the same reference biologic, because they are developed using different cell lines and undergo different manufacturing and purification processes.1 Additionally, the generic drug market is well-developed and mature in the United States while the biosimilars market still has great potential to grow in the US. For instance, 89% of prescriptions were filled with generics in the US in 2017.2 In contrast, the US shared only 2% of the global biosimilar medicine sales; nonetheless, 59% of the global biological medicine sales were from the US. How to define a biological product is a biosimilar to a reference product in the US regulatory? As aforementioned, due to its complex nature, defining a biosimilar product is not as straightforward as defining a generic drug. The FDA defines a biosimilar as a biological product that is highly similar to the reference product, notwithstanding minor differences in clinically inactive components. There are no clinically meaningful differences between the biosimilar product and the reference product in terms of safety, purity, and potency.1 Unlike small molecule drugs, whose structures can usually be completely defined and entirely reproduced, proteins are typically more complex and are unlikely to be shown to be structurally identical to a reference product. Many potential differences in protein structure can arise. Because even minor structural differences (including certain changes in glycosylation patterns and protein folding) can significantly affect a protein’s safety and/or effectiveness, it is important to evaluate these differences. The FDA defines “the biological product is biosimilar to a reference product” based upon data derived from:1,4 o Analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. o Animal studies (including the assessment of toxicity); o A clinical study or studies (including the assessment of immunogenicity and PK or PD) that are sufficient to demonstrate safety, purity, and potency in one or more appropriate

conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product. How to demonstrate the biosimilarity and get a biosimilar product approved The US FDA suggests a stepwise approach to evaluate attributes of biosimilar products. At each step, the US FDA recommends that the sponsor evaluate the extent to which there is residual uncertainty about the biosimilarity of the proposed product and identify next steps to address that uncertainty. This stepwise approach encompasses the following:1 • Step 1: CMC Study. Extensive structural and functional characterization of both the biosimilar product and the reference product, per the principles aforementioned, is the foundation for the biosimilar development program. • Step 2: Non-Clinical Study. Consider the role of animal data in assessing the protein when residual uncertainties remain about the safety of a biosimilar after extensive structural and functional characterization. Nonclinical studies may not be required if a biosimilar has been demonstrated to be highly similar to a reference product through analytical characterization.4 • Step 3: Clinical Study. Comparative human PK and pharmacodynamic (PD) studies are required along with comparison of the clinical immunogenicity of the two products in an appropriate study population. • Step 4: Additional comparative safety and effectiveness data will be needed to adequately address any residual uncertainty about biosimilarity after conducting structural analyses, functional assays, animal testing, human PK and PD studies, and the clinical immunogenicity assessment after the three steps above. How to demonstrate the biosimilarity-CMC The CMC attributes in step 1 aforementioned suggested by US FDA are considered to be the foundation of the demonstration that a proposed product is biosimilar to the reference product. CMC studies including rigorous structural and functional comparisons that show minimal or no differences between the proposed product and the reference product will strengthen the scientific justification for a selective and targeted approach to Non-Clinical and/or Clinical studies to support a demonstration of biosimilarity.1 The development process of biosimilar CMC development to IND typically includes: o Comparative analytical assessment for the at least 10 lots of reference product to establish quality attributes and acceptance criteria in the Drug Substance specification. o Comparative analytical assessment from at least 6 to 10 lots of the proposed product to adequately demonstrate the similarity between the proposed product and the reference product. o Comparative assessment includes quantitative quality data for physicochemical properties, functional studies (i.e. biological assays, binding assays, and enzyme kinetics), target binding, impurities (product related and process related) and stability, etc. o Comparative analytical assessment of the Drug Products is highly dependent on the formulation of the Drug Products. With typical formulations, product characterization

studies of a proposed product should be performed on the most downstream intermediate best suited for the analytical procedures used. For biosimilar IND applications, the extent and maturity of the analytical assessment should be complete. If CMC deficiencies are cited by FDA, the biosimilar IND will not be permitted to proceed. How to demonstrate the biosimilarity nonclinical and clinical The figure below visually summarizes and compares the development of an original biologic and a biosimilar. The reverse triangle on the left depicts the pathway of development and approval for an original biologic. The complete clinical studies demonstrating the safety and efficacy of the biologic usually required much more resources and time than the analytic characterization of the biologic. In contrast, the triangle on the right indicates that biosimilar development starts from the analytical data demonstrating biosimilarity to the reference product, which is the foundation of the biosimilar development. The FDA uses the Totality-of-the-Evidence Approach to access the demonstration of biosimilarity including detailed analytics (structural and functional characterization), non-clinical evaluation (animal studies), clinical pharmacology (PK/PD data), clinical immunogenicity data, and other comparative clinical studies.1 The goal of a biosimilar program is to demonstrate biosimilarity of the proposed product to the marketed reference product, rather than independently establishing the safety and efficacy of the proposed product.

o Non-clinical studies for biosimilar IND A Biosimilar IND application should generally include non-clinical study information demonstrating biosimilarity based on data derived from the following animal studies:1 • Animal Toxicity Studies • Inclusion of Animal PK and PD Measures • Interpreting Animal Immunogenicity Results

o Clinical studies in a biosimilar IND A sponsor must demonstrate that the proposed product is biosimilar to a single reference product that previously has been licensed by FDA.1 During the IND process, the clinical studies will generally include: • Human Pharmacology Data • Clinical Immunogenicity Assessment • Comparative Clinical Studies Summary and Conclusion To summarize, to have a successful biosimilar IND application, the CMC needs to be thorough and complete. Typically, no further comparative analytical assessment results will be provided to FDA. Additionally, nonclinical data from animal studies and proposed human clinical studies based on the comparative assessment results of the propose product and reference product are also included in the IND package. How we can help you With extensive expertise, the Aleon team can conduct thorough assessment and gap analysis for a proposed biosimilar IND application. Our team can also assist the sponsor in having meetings with the US FDA to communicate and obtain direct evaluation and feedback from the Agency for the biosimilar development. Providing high quality and trustable service to the client is always our goal. References 1 FDA Guidance: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (April 2015) 2 2017 Generic Drug Access and Savings in the U.S. Report 3 International Generic and Biosimilar medicines Association (IGBA). 2018. “Building on the Experience and Success of Biosimilar Medicines.” February 1. 4 Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations (May 2019)