Dear Editor,
We are responding to the Joint Canadian Association of Gastroenterology and Crohn’s Colitis Canada Position Statement on Biosimilars for the Treatment of Inflammatory Bowel Disease published on November 8, 2019 in the Journal of the Canadian Association of Gastroenterology, and authored by Dr. Paul Moayyedi and colleagues (https://academic.oup.com/jcag/advance-article/doi/10.1093/jcag/gwz035/5614781).
We believe that the position paper contains several serious flaws that negate the paper’s assertion that nonmedical switching from originator infliximab to biosimilar in patients with stable inflammatory bowel disease (IBD) who are doing well on the original product “leads to an increased risk of worsening of disease, dose escalation and/or switching to an alternative therapy.”
The position paper makes several errors that lead to erroneous conclusions by:
Using data from a conference abstract (Roder 2018) in a meta-analysis that can’t be independently evaluated and verified.
Inappropriately combining different endpoints from two trials (Jorgensen 2017 and Roder 2018). In particular, Jorgensen measures the rate of disease worsening while Roder combines the rate of disease worsening with withdrawal rates.
Omitting a 2019 randomized controlled trial (RCT) of patients with Crohn’s disease (CD), which showed no differences in rates of clinical remission, loss of response or disease worsening.
Failing to account for observational studies and systematic reviews of the safety and efficacy of switching infliximab to a bio-similar in IBD patients.
The two studies that should be considered in this review are Jorgensen 2017 and the Ye 2019. Both studies are noninferiority trials with noninferiority margins set at 15% and 20%, respectively. Neither study found CT-P13 inferior to infliximab.
A meta-analysis of these studies is problematic as they involve different populations and use different clinical outcomes.
Jorgensen 2017
This study includes adult patients with a diagnosis of CD, ulcerative colitis (UC), spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, or chronic plaque psoriasis on stable treatment with infliximab originator treated in a hospital setting for at least 6 months. CD (N = 155; 32%) and UC (N = 93; 19%) of the study population.
This study was not powered to demonstrate noninferiority within each diagnostic group. These analyses are prespecified as exploratory subgroup analyses.
Ye 2019
This study includes patients with active CD who had not responded to, or were intolerant to nonbiologic treatments. No UC patients are included. These patients were naive to infliximab therapy as they excluded patients who had been administered any TNF-alpha inhibitor. Unlike Jorgensen, Ye 2019 did not report disease worsening. Instead they defined response in terms of the CDAI-70 (CDAI is the Crohn's Disease Activity Index, a research tool to quantify the symptoms of Crohn's patients. Major research studies on medications in Crohn's disease typically define response as a fall of the CDAI of greater than 70 points.) at week 54 and defined clinical remission as sustained steroid-free remission of CDAI < 150 points at week 30 and 54 without use of corticosteroids in the 3 months before week 54.
Observational Studies
The CAG position paper did not include noncontrolled studies. In contrast, when the Therapeutics Initiative did a systematic review (https://ti.ubc.ca/wordpress/wp-content/uploads/2019/11/letter123-appendix.pdf) our search revealed 12 key systematic reviews including two relevant to IBD (Ebada, 32 studies in 3464 patients and Gisbert, 24 studies in 1326 IBD patients). As noted in the TI Letter (https://www.ti.ubc.ca/2019/11/11/123-biosimilars-or-biologics-whats-the-difference/), these systematic reviews support the conclusion that infliximab and its biosimilar molecules are equally effective and safe.
The available scientific evidence from RCTs observational studies, registries, cohorts and real-world experiences all conclude that the “effectiveness and safety were similar between CT P13 and infliximab.”