Defining Glatiramer Acetate: The USA Definition of Sameness and the EU Definition of Similarity (P3.415)

Objective: Analysis examines the divergent regulatory approaches taken in the USA and EU regarding approval of follow-on glatiramer acetate (FOGA) products for treatment of relapsing forms of MS. Background: Copaxone (active ingredient glatiramer acetate – GA) is a non-biologic complex drug (NBCD) composed of a mixture of immunogenic polypeptides of varying sequences and sizes impossible to measure even with state-of-the-art sequencing methods. Thus, unavoidably, GA is defined by reaction conditions utilized across synthesis, preparatory and final purification stages. As a result, the composition of GA, consequential therapeutic activity of Copaxone and its intended clinical effects, all strongly rely on the robustness of the manufacturing process, ensuring antigen homology, quality control, and the resultant consistent safety and efficacy profile of GA in Copaxone. Design/Methods: Regulatory route, product-specific criteria, need for clinical trials and interchangeability (ie substitution without the intervention of the health care provider who prescribed the product aspects) are compared. Results: In the USA, the FDA issued draft guidance on the Active Pharmaceutical Ingredient (API) sameness requirements for generic versions of GA Injection. FDA definition for sameness is based on four criteria including traditional physicochemical methodologies, and structural signatures for polymerization and depolymerization. FDA waived requirement for in vivo bioequivalence studies, and FOGAs are considered fully substitutable at pharmacy. In the EU, regulatory assessment of marketing application for FoGAs relies on establishing “similarity” rather than “sameness” of active substances. Biosimilar type approach was utilized in which quality, nonclinical and clinical studies were necessary to establish similarity. The decision of how FoGA is treated in terms of automatic substitution is taken nationally and to date, a few authorities have deemed EU FoGA non-substitutable requiring physician supervision for the switch. Conclusions: The varied approaches applied to the regulatory assessment of FOGAs underscore the challenges in determining therapeutic equivalence for a non-biological complex drug such as glatiramer acetate. Study Supported by: Teva Pharmaceutical Industries Disclosure: Dr. Melamed-Gal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Teva. Dr. Loupe has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Grossman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Zeskind has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Weinstein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Timan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Kolitz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Immuneering. Dr. Komlosh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Hasson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries. Dr. Sahly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Teva Pharmaceutical Industries.