Equivalence of glatiramer acetate products: challenges in assessing pharmaceutical equivalence and critical clinical performance attributes

ABSTRACT

Introduction: This review discusses the challenges to characterize and evaluate the peptide based drug glatiramer acetate (GA) and its follow-on products used for treatment of multiple sclerosis patients.

Areas covered: GA is a highly complex mixture of peptides consisting of four amino acids. The various (physico)-chemical approaches and bioassays used for characterizing this complex drug product are described. It is not possible to link data from preclinical performance to outcomes observed in clinical trials as no critical attributes suitable for predicting the clinical performance in MS patients have been identified yet. The limited insight into the precise mechanism(s) of action of GA may explain why these critical clinical performance attributes still have not been identified.

Expert opinion: The complexity of GA and lack of understanding of critical clinical performance attributes leads to a number of issues to be resolved as they hamper industry and regulatory bodies in designing and evaluating follow-on/generic applications of GA. The following questions are waiting to be addressed: Preclinical characterization vs clinical outcome: what is the relation? What are possible biomarkers? How to choose the right patient group? What is the experience with existing follow-on versions? Is there a place for GA ‘betters’? How to evaluate existing and draft new guidance documents and pharmacopoeial monographs?

KEYWORDS:

• Glatiramoids
• multiple sclerosis
• Copaxone
• Glatopa
• Food and Drug Administration (FDA)
• European medicines agency (EMA)
• genetic profiling
• physico-chemical characterization
• glatiramer acetate
• follow-on versions/generics

Article highlights

• Glatiramer acetate (GA) belongs to the glatiramoids. This family of peptide-based compounds is member of the group of non-biological complex drugs (NBCD). They cannot be fully characterized by (physico)chemical analysis nor by biological assays. GA’s efficacy and safety highly depend on its complex, multistep manufacturing process.

• The still not fully understood mechanism of action of GA in treating multiple sclerosis adds to its complexity.

• Critical quality attributes of GA have not fully been identified and the correlation between such properties and clinical outcome could therefore not be established.

• Advanced bioassays for the characterization of GA will likely be considered for inclusion into monographs of the European and US pharmacopoeias. The current regulatory strategies to assess therapeutic equivalence and potentially exchangeability of glatiramer products need a critical review.

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Acknowledgments

They acknowledge the interactions with TEVA Pharmaceutical Industries, Ltd., and Momenta Pharmaceuticals, Inc. for providing material for this expert report.

The opinions expressed in this article are those of the authors and not of any regulatory, industry, or medical organization they may be affiliated with

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper is not funded