Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation

Abstract

Biologic drugs such as infliximab and other anti-tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohn's disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti-tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD.

The Rituximab Biosimilar CT-P10 in Rheumatology and Cancer: A Budget Impact Analysis in 28 European Countries

“…Despite the stringent regulatory requirements for extrapolation, concern can still exist among physicians regarding this process, as was initially the case for some inflammatory bowel disease (IBD) specialists after approval of CT-P13 in IBD [68]. In the case of CT-P13 (clinical trials of which were performed in RA and ankylosing spondylitis), initial concerns about extrapolation centered around possible differences in the mechanisms of action of infliximab in IBD versus rheumatology indications, although these were subsequently proved unfounded [69]. Post-approval data on the real-world use of CT-P13 in IBD has since provided reassurance on its efficacy and safety in this setting, as evidenced in a recent statement from the European Crohn’s and Colitis Organisation which asserts that switching from an originator or reference product to a biosimilar in IBD patients is acceptable [70].…”

Ustekinumab in treatment of Crohn’s disease: design, development, and potential place in therapy

“…The UNITI-2 data show that it may also potentially have a role among TNF antagonist naïve patients considering its favorable safety profile, potentially as a first-line biologic. However, this may be limited by cost considerations, especially with the introduction of biosimilars that are either FDA approved (infliximab biosimilar, CT-P13) or pending approval (adalimumab biosimilar, ABP 501) 71,72…”

The current state of the art for biological therapies and new small molecules in inflammatory bowel disease

“…As such, the term biosimilar is used when referring to medications attempting to replicate off-patent originator biologics. 75 There is a requirement to prove that they are highly similar to the originator biologic with no clinically meaningful difference in purity, safety, and effectiveness, and to demonstrate comparable efficacy in a clinical trial for a single indication that can then subsequently be extrapolated to other conditions including UC and CD. 76 It is also important to distinguish biosimilars from next-generation biologic agents (e.g., adalimumab and golimumab), which though aimed toward the same molecular target as first-generation agents (e.g., infliximab), are chemically different, independently developed, and do not rely upon demonstration of biosimilarity with an originator product for abbreviated approval.…”