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Abstract
The introduction of biologic drugs represents the most significant advance in the management of immune-mediated inflammatory diseases for a decade. However, complex proteins are expensive to produce and manufacture. Biosimilar versions of established biologics are becoming available as another version of the reference medicinal product and are expected to provide substantial cost savings. However, because of their complexity, the approval of biosimilars requires strict controls to ensure that all therapeutically relevant characteristics are comparable to the reference medicinal product. This review summarizes the scientific principles and data requirements underpinning regulatory approval of biosimilars and the assumptions that enable extrapolation of data between indications. These important concepts are exemplified by CT-P13 (Remsima®, Inflectra®), the first biosimilar monoclonal antibody approved in Europe.
Financial & competing interests disclosure
S Schreiber has served as a consultant or advisory member for Abbvie, Boehringer Ingelheim, Celltrion, Ferring, Genentech, Hospira, Janssen, MSD, Mundipharma, Pfizer, Roche, Takeda and UCB; and has served as a speaker for Abbvie, Celltrion, Falk Pharma, Ferring, Janssen, Hospira, MSD, Mundipharma, Shire Pharmaceuticals and UCB. J Panés has served as a consultant or advisory member for Abbvie, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celltrion, Ferring, Galapagos, Genentech, Hospira, Janssen, MSD, Nutrition Science Partners, Pfizer, Robarts, Roche, Takeda, Tigenix, Topivert and TxCell. J Panés has also served as a speaker for Abbvie, Ferring, Janssen, MSD, Shire Pharmaceuticals and Tillots; and has received research funding from Abbvie and MSD. L Peyrin-Biroulet has received consulting fees from Merck, Abbott, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Shire, Therakos, Pharmacosmos, Pilège, BMS, UCB-pharma, Hospira, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, Pfizer and HAC-Pharma. He has also received lecture fees from Merck, Abbott, Takeda, Janssen, Ferring, Norgine, Tillots, Vifor, Therakos and HAC-Pharma. B Kwon and S Hong are full-time employees of Celltrion, the manufacturer of CT-P13. The authors have no other 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 apart from those disclosed. Editorial support (writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Mark O’Connor (Aspire Scientific Limited, Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).
Potential sources of variation in the manufacture of biologics are numerous, leading to a degree of heterogeneity even between batches of a specific product.
With any biologic, the manufacturing processes will generally have been modified several times over the years, but sophisticated quality assurance systems are designed to avoid changes that might affect its efficacy and safety.
Recognizing this complexity in manufacturing biologics, there are well-established, specific regulatory procedures for approval of biosimilars, requiring that comparability with the reference medicinal product (RMP) is assessed using a combination of analytic testing, biologic assays, and appropriate non-clinical and clinical data.
These principles have led to the introduction of biosimilars for treatment of a range of chronic and life-threatening diseases, and post-marketing studies have established their efficacy and safety in clinical use.
During regulatory review of biosimilars, extrapolation of efficacy and safety data from one indication to another may be considered, if biosimilarity to the RMP has been shown by the comprehensive comparability program.
CT-P13, a biosimilar infliximab, was approved in September 2013 in Europe for the same indications as the RMP (Remicade®), including rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis and psoriasis, based on a large comparability program.
The comparability program demonstrated that CT-P13 and RMP are highly similar in terms of the therapeutically relevant biologic and physiochemical properties, as well as efficacy, pharmacokinetic, immunogenicity and safety in rheumatoid arthritis and ankylosing spondylitis. These data also led to the extrapolation of the approved indications for CT-P13 to inflammatory bowel disease by many regulatory authorities.
Although there are important questions relating to the extrapolation of indications for the infliximab biosimilar, the totality of the evidence suggests that this regulatory decision was justified.