Children included in randomised controlled trials of biologics in inflammatory bowel diseases do not represent the real‐world patient mix

Abstract

Summary Background Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. Aim To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. Methods We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12‐month steroid‐free remission (SFR) without switching biologics or undergoing surgery. Results We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate–to‐severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2–4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. Conclusion Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice.

90K/Mac-2 BP Is a New Predictive Biomarker of Response to Infliximab Therapy in IBD Patients

“…Patients who developed ATIs were considered non-responders, and showed high serum levels of CRP and 90K. Several studies in recent years have shown a correlation between high serum CRP levels and a loss of response to anti-TNF treatment [ 20 , 32 , 33 , 34 , 35 ]. Interestingly, we found that non-responder patients showed higher 90K serum levels at baseline than responders.…”

“…C-reactive protein (CRP) is the most common serum biomarker of inflammation in IBD, and its characteristics are useful for grading inflammation, monitoring the response to therapy, and to identify recurrent inflammation after medically or surgically induced remission [ 20 , 32 ]. Recent studies associated CRP levels with biomarkers and clinical disease activity indices in IBD patients [ 33 , 34 , 35 , 36 , 37 ]. In two distinct cohorts of pediatric IBD patients, an elevated CRP level was considered a risk factor for biologics treatment [ 34 , 35 ].…”

“…Recent studies associated CRP levels with biomarkers and clinical disease activity indices in IBD patients [ 33 , 34 , 35 , 36 , 37 ]. In two distinct cohorts of pediatric IBD patients, an elevated CRP level was considered a risk factor for biologics treatment [ 34 , 35 ]. In a multicenter study, the CRP levels were used to monitor the clinical response between the anti-TNF drug Adalimumab and biosimilars in IBD patients, both CD and UC; no significant difference was found in CRP levels between patients switching from the originator to biosimilar or between biosimilars [ 36 ].…”

Effectiveness of strategies to suppress antibodies to infliximab in pediatric inflammatory bowel disease

“…3,4 Although index studies in pediatric IBD have reported a lower primary nonresponse rate, recent data have shown this is likely due to more stringent inclusion criteria in clinical trials compared with the use of these drugs in realworld patients. 5 A common cause of pharmacokinetic loss of response is the formation of antibodies to IFX (ATIs), which is associated with lower trough levels and the occurrence of infusion reactions. 6 Immunogenicity-related factors include IFX therapy without a concomitant immunomodulator (IM), [7][8][9][10] suboptimal drug concentrations, 4 and carriage of the HLA-DQA1*05 allele.…”

“…However, primary nonresponse affects up to 40% of adults with IBD, while secondary nonresponse occurs in 20%–37% 3,4 . Although index studies in pediatric IBD have reported a lower primary nonresponse rate, recent data have shown this is likely due to more stringent inclusion criteria in clinical trials compared with the use of these drugs in real‐world patients 5 . A common cause of pharmacokinetic loss of response is the formation of antibodies to IFX (ATIs), which is associated with lower trough levels and the occurrence of infusion reactions 6 .…”