Researchers Take Issue With Methods Used to Arrive at Recommendation Against IBD Nonmedical Switching

A joint position statement on biosimilars for the treatment of inflammatory bowel disease (IBD) sparked backlash and criticism over the recommendation against nonmedical switching from reference infliximab to a biosimilar.
Deana Ferreri, PhD
June 22, 2020
The discourse on a joint position statement on biosimilars for the treatment of inflammatory bowel disease (IBD) issued by the Canadian Association of Gastroenterology and Crohn’s Colitis Canada1 drew backlash revealing the lack of consensus on this topic and highlighting ongoing controversies in the field.

The statement considered only the anti–tumor necrosis factor biologic infliximab (Remicade) and its biosimilar CT-P13 (Inflectra; Remsima). Following a full literature review, the statement suggested a biosimilar may be prescribed for biologic-naïve patients with Crohn disease (CD), but the authors called this a “weak recommendation based on low-quality evidence,” according to GRADE criteria. The authors, led by Paul Moayyedi, MB, ChB, PhD, of McMaster University, recommended using the originator if the price difference is “modest” and making decisions on a case-by-case basis between clinician and patient.

The statement cited insufficient evidence for recommending biosimilars to biologic-naïve patients with ulcerative colitis (UC). These conclusions are in contrast to the position statements of many other groups, such as the British Society of Gastroenterology, the Crohn's and Colitis Foundation, and the European Crohn’s and Colitis Organization regarding biologic-naïve patients. Of 15 statements issued since 2013 and detailed in the current publication, 12 recommend the use of biosimilars for biologic-naïve patients with IBD.

The statement recommended against nonmedical switching from infliximab to a biosimilar in patients with IBD who are doing well on the originator drug. Again, they described the recommendation as weak and based on low-quality evidence, adding “but data suggest that switching in this setting leads to an increased risk of worsening of disease, dose escalation and/or switching to an alternative therapy.”

Published comments on the statement from Ken Bassett, MD, PhD, and Vijaya Musini, MD, MDs, DPH, both researchers at the University of British Columbia in Vancouver, cited “several serious flaws” in the methodology Moayyedi and his coauthors used to reach their conclusion regarding nonmedical switching.2

First, Bassett and Musini criticized the inclusion of a conference abstract in the meta-analysis of switching data, saying the data “can’t be independently evaluated and verified.” A reliance on conference abstracts, rather than published trials, is a previously cited limitation of the existing evidence on biosimilars for IBD. However, Moayyedi et al argued “it is important to include conference abstracts so that all available evidence can be evaluated,” and they pointed out that excluding the conference abstract would not have altered their conclusions.3

Second, according to Bassett and Musini, the meta-analysis of nonmedical switching data “inappropriately” combined different end points from 2 trials, contending the data should not have been pooled. Moayyedi et al acknowledged this is a valid point for debate, saying it is “always a judgement call as to whether to synthesize such data.” However, they also claimed that analyzing the trials separately would have led them to the same conclusions.

Inherent in this debate are differing views among researchers on the primary published randomized control trial (RCT) on nonmedical switching in IBD (NOR-SWITCH), 1 of the 2 that Moayyedi et al considered in their analysis. NOR-SWITCH demonstrated similar efficacy and safety of nonmedical switching in patients across several inflammatory conditions including CD and UC; however, as Bassett and Musini acknowledged in their comments, the NOR-SWITCH trial lacked the statistical power to demonstrate noninferiority within individual disease groups. This limitation plus a nonsignificant trend toward disease worsening in the CD subgroup (pointed out by Moayyedi et al in their position statement) have caused disagreement regarding the safety of nonmedical switching from infliximab to CT-P13 in IBD.

The third criticism was the omission of a switch study on patients with CD, which “showed no differences in rates of clinical remission, loss of response or disease worsening.” Moayyedi et al included this trial in their analysis of biologic-naïve patients, but they say they excluded the nonmedical switching period of the study because the short follow-up duration and large proportion of patients not in clinical remission failed to meet their predefined inclusion criteria.

Finally, Bassett and Musini criticized the position statement for excluding uncontrolled studies, to which Moayyedi et al respond by calling their decision to include only RCTs and cohort studies with a control group “the main methodological strength of our approach.”

The position statement’s concern over the proportion of studies on nonmedical switching in IBD without a control group echoes those of a recent review article. Moayyedi et al argued uncontrolled studies provide only low-quality evidence, and the lack of a control group taking the originator drug makes it difficult to assess the safety of biosimilars, adding “Our goal was to evaluate the best-available evidence objectively, according to current best practice as a basis for our recommendation rather than to seek evidence that would support a predefined position.”

The debate around the official statement from the Canadian Association of Gastroenterology and Crohn's Colitis Canada makes it clear that as of yet there is no broad consensus on nonmedical switching from infliximab to CT-P13 in IBD, and the statement itself and raises doubts about the use of CT-P13 in biologic-naive patients with UC.

For now, some official statements and reviews of the literature are in favor of  biosimilars, saying they are safe and effective and should be more widely used in IBD, while others advise more caution regarding the existing data on nonmedical switching, arguing more research is needed before policy decisions—and individual physician–patient decisions—can be made with confidence.

References
1. Moayyedi P, Benchimol EI, Armstrong D, Yuan C, Fernandes A, Leontiadis GI. Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease. J Can Assoc Gastroenterol. 2020;3(1):e1‐e9. doi:10.1093/jcag/gwz035

2. Bassett K, Musini V. Response to the Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease. J Can Assoc Gastroenterol. 2020;3(2):96‐97. doi:10.1093/jcag/gwz046

3. Moayyedi P, Benchimol EI, Armstrong D, Yuan C, Fernandes A, Leontiadis GI. Response to Comments on the CAG/CCC Position Statement on Biosimilars for Inflammatory Bowel Disease. J Can Assoc Gastroenterol. 2020;3(2):98‐99. doi:10.1093/jcag/gwaa004

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