Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation

Shomron Ben-Horin; Niels Vande Casteele; Stefan Schreiber; Peter Laszlo Lakatos


Clin Gastroenterol Hepatol. 2016;14(12):1685-1696. 

In This Article

Abstract and Introduction


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.


Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are chronic, relapsing immune-mediated inflammatory diseases of the gastrointestinal tract. The advent of biologic drugs, starting with the anti–tumor necrosis factor (TNF) monoclonal antibodies, has significantly improved outcomes for patients with IBD.

The relatively high cost of anti-TNF agents and their looming or actual patent expiration have triggered the development of highly similar versions of these drugs that are known as biosimilars. Compared with originator biologics, biosimilars follow an expedited process for regulatory approval. Most notably and provided that certain requirements are met, virtually all regulatory agencies allow, in principle, for extrapolation of indications. Extrapolation means that once biosimilarity has been established in 1 or more indications, a biosimilar may be approved for additional or all other indications for which the originator, or reference product (RP), has been approved without the need for clinical trials in the latter indications.[1,2] Nonetheless, there has been much debate on the validity of extrapolation of clinical data for biosimilars.[3–6] In this review, we consider the fears and facts regarding extrapolation of biosimilar data to IBD, starting with a brief introduction to some important biosimilar concepts.