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AAPS Newsmagazine, biosimilars, biotechnology, Carol Kirchhoff, Shefali Kakar, Totality of Evidence
By Carol Kirchhoff and Shefali Kakar
Biosimilar is the term used to describe a biological therapeutic that has been developed to be highly similar to a marketed biological therapeutic (reference) product that has exhausted its patent protection and is approved via a stringent regulatory pathway. By 2020, biologics that have exhausted their patents are estimated to represent over $80 billion in sales. Development of biosimilars potentially represents not only billions of dollars in health care savings but also a significant increase in patient access. This concept has been well recognized for small molecule reference products and their corresponding generics and is beginning to translate to large molecules with recently developed approval pathways globally.
Biosimilars have been approved and on the market in much of Europe since 2006. While these products have been proven to be safe and effective, their global acceptance varies. Many health care providers still have less confidence in a biosimilar than in a small molecule generic. This may, in part, be due to lack of understanding of how biosimilars are developed, as well as the currently marketed “intended copies” (also known as noncomparable biologics). Unlike biosimilars, developers of intended copies may conduct only limited similarity assessments against the reference product. The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) recently published a policy statement on noncomparable biotherapeutic products, in which the typical differences between an intended copy and a biosimilar in the depth and breadth of similarity assessments back to the originator are outlined.
Since pharmacokinetic (PK) equivalence can be a good surrogate for the efficacy and safety of a small molecule, a PK equivalence study is sufficient to confirm the extent and duration of the effect. The effect (safety and efficacy) of a biological therapeutic, however, is affected by not only the molecule but also possibly the formulation, impurities, and posttranslational modifications (e.g., glycosylation); therefore, the efficacy and safety of a protein therapeutic requires a more comprehensive assessment to confirm a similar clinical safety and efficacy profile. These include extensive analytical characterization and similarity assessments between the proposed biosimilar and the biological reference product, nonclinical in vivo and/or ex vivo studies, as well as safety and efficacy studies in patients or healthy subjects. The overall license application submission is not based on sequential hierarchy of assessments, but rather, the totality of evidence supporting biosimilarity.
The cover article in the May issue of the AAPS Newsmagazine examines multiple aspects of biosimilarity and how they are achieved. Read Achieving Biosimilarity through “the Totality of Evidence,” from the BIOTEC section, and then participate in the discussion point below.
What do you envision to be the greatest challenge in achieving biosimilarity?
I believe the main obstacles for biosimilars will be immunogenicity, long tern efficacy, and cost. In particular, I have many questions regarding the biosimilars that intend to mimic Remsima (Infliximab). Infliximab is a chimeric monoclonal antibody used to treat a variety of inflammatory diseases. However, a small group of patients can develop an immune response to the mouse portion of the antibody (Infliximab is 25% mouse and 75% human). As a result, the efficacy can be greatly diminished in this small group of individuals. My concern with making a biosimilar for Infliximab: would there also be this immune response in some populations and would this undermine its overall efficacy? Also, would the cost of a biosimilar for Infliximab be significantly lower than the proprietary version? (Currently it is very expensive to produce and purify monoclonal antibodies.)
Hello Thomas,
You do bring up a good theoretical scientific issue with biosimilars. However, similar to any other biosimilar package, any pre-approval data package for an infliximab biosimilar would include immunogenicity data from healthy adults (PK/PD studies) as well from patients for whom the drug is indicated (clinical confirmation studies) and should demonstrate similarity in immunogenicity in the totality of evidence for the biosimilar claim. In particular the immunogenicity data from approved biosimilars (those that have undergone a stringent health authority review and approval) have reported immunogenicity at or below that of the reference drug. This includes the recently approved Infliximab biosimilar from Celltrion. In addition, all biosimilars should be subjected to the same pharmacovigilance standards that are applied to all biologics, including collection of reports of inadequate efficacy and to ensure the safety of these products.
Regarding cost of biosimilars, in order for biosimilars to be viable commercial products, the overall costs to consumers and the healthcare system would likely be lower than the reference product. The technological advances in manufacturing these products should eventually lower the cost to manufacture these biosimilars. However, the cost structure itself is outside the scope of this scientific discussion.
Hope this answers your question. If you have any further questions, do feel free to reach out.
– Shefali