The scientific and regulatory rationale for indication extrapolation: a case study based on the infliximab biosimilar CT-P13

Abstract

Extrapolation of clinical data from other indications is an important concept in the development of biosimilars. This process depends on strict comparability exercises to establish similarity to the reference medicinal product. However, the extrapolation paradigm has prompted a fierce scientific debate. CT-P13 (Remsima^®, Inflectra^®), an infliximab biosimilar, is a TNF antagonist used to treat immune-mediated inflammatory diseases. On the basis of totality of similarity data, the EMA approved CT-P13 for all indications held by its reference medicinal product (Remicade^®) including inflammatory bowel disease. This article reviews the mechanisms of action of TNF antagonists in immune-mediated inflammatory diseases and illustrates the comparable profiles of CT-P13 and reference medicinal product on which the extrapolation of indications including inflammatory bowel disease is based.

Keywords:

• biosimilar
• CT-P13
• infliximab
• extrapolation
• inflammatory bowel disease
• mechanism of action
• pharmacokinetics

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Corrigendum

Financial & competing interests disclosure

W Reinisch has served as a speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corp, MSD, Otsuka, PDL, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult; as a consultant for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Bioclinica, Biogen IDEC, Bristol­Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grunenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corp, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Vifor, Zyngenia, and 4SC; as an advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grunenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corp, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Schering­ Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zyngenia, and 4SC, and has received research funding from Abbott Laboratories, Abbvie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik and MSD. E. Louis has received educational grants from MSD and Abbvie, and speaker fees from Abbvie, Ferring, MSD, Chiesi, Mitsubishi Pharma, Hospira, and Janssen. He has also served as an advisory board member for Abbvie, Ferring, MSD, Takeda, Mitsubishi Pharma, and Celltrion. S. Danese has served as a speaker, a consultant and an advisory board member for Schering-Plough, Abbott Laboratories, Abbvie, Merck & Co, UCB Pharma, Ferring, Cellerix, Celltrion, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Alfa wassermann, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Pharmacosmos, Tigenix, Vifor, and Johnson and Johnson. 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 Rick Flemming (Aspire Scientific Limited, Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).

Key issues

• The EMA approved CT-P13 for all indications held by the infliximab RMP based on evidence from a comprehensive comparability program that demonstrated equivalence in efficacy, safety and pharmacokinetics.

• The extrapolation of clinical data is fundamental to the development of biosimilars, but its use in the approval process is still subject to some debate.

• The overexpression of TNF is a common feature of many immune-mediated inflammatory diseases, and the efficacy of TNF antagonists is well established.

• The role of TNF in the pathogenesis of inflammatory bowel disease (IBD) is varied, but infliximab has been shown to affect key mechanisms of action including reverse signaling and regulatory macrophage induction. The similarity in this regard between CT-P13 and infliximab reference medicinal product suggests that CT-P13 has comparable effects with infliximab RMP in patients with IBD.

• Emerging real-life efficacy and safety data from patients with IBD treated with CT-P13 support the extrapolation of data to include IBD indications for CT-P13.

• The extrapolation of clinical data as part of the biosimilar approval process is valid, but requires stringent analysis on a case-by-case basis. Strict postapproval pharmacovigilance is necessary.

Notes