Patients Enrolled in Randomized Controlled Trials Do Not Represent the Inflammatory Bowel Disease Patient Population

doi:10.1016/j.cgh.2012.02.004

Clinical Gastroenterology and Hepatology

Volume 10, Issue 9, September 2012, Pages 1002-1007

https://doi.org/10.1016/j.cgh.2012.02.004 Get rights and content

Background & Aims

Multiple randomized controlled trials (RCTs) have been conducted to determine therapeutic efficacy of the biological agents for the inflammatory bowel diseases (IBD). However, the external validity of findings from RCTs might be compromised by their stringent selection criteria. We investigated the proportion of patients encountered during routine clinical practice who would qualify for enrollment into a pivotal RCT of biological agents for IBD.

Methods

We performed a retrospective cohort study of adult patients with moderate–severe IBD who presented to a tertiary referral center. Inclusion and exclusion criteria were extracted from published RCTs of biologics approved by the Food and Drug Administration and applied to the study population.

Results

Only 31.1% of 206 patients with IBD (34% with Crohn's disease [CD], 26% with ulcerative colitis) would have been eligible to participate in any of the selected RCTs. Patients would have been excluded because they had stricturing or penetrating CD, took high doses of steroids, had comorbidities or prior exposure to biologics, or received topical therapies. Of the trial-ineligible patients with ulcerative colitis, 23.3% had colectomies, and 31.7% received infliximab, with a 63.2% response rate. Approximately half (49.4%) of the 82 trial-ineligible patients with CD received biological therapies, with lower response rates (60%) than trial-eligible patients (89%; P = .03).

Conclusions

Most patients with moderate–severe IBD evaluated in an outpatient practice would not qualify for enrollment in a pivotal RCT of biological reagents; this finding raises important questions about their therapeutic efficacy beyond the clinical trial populations. Additional evaluation of the transparency of RCT design and selection criteria is needed to determine whether trial results can be generalized to the population.

Section snippets

Study Population and Data Collection

We performed a retrospective chart review of consecutive adult IBD patients with moderate–severe disease activity presenting to the Mount Sinai Medical Center for an escalation or adjustment of their medical therapy from January 2008 to June 2009. Moderate–severe disease activity was defined as a Harvey–Bradshaw Index (HBI) score between 8 and 16 for CD and a Mayo UC disease activity index score between 6 and 12 for UC.7, 15 Patients with indeterminate colitis, suspected but not established

Patient Characteristics

Two hundred six patients with moderate–severe IBD met enrollment criteria during the 18-month study period. Of the 125 CD patients, 34% of patients (n = 43) would have qualified for enrollment into at least 1 of the 7 included RCTs. Trial eligibility for the RCTs for infliximab, adalimumab, certolizumab pegol, and natalizumab ranged from 8% for the SONIC trial to 27% for the CHARM and PRECISE1 trials. Only 25% of the UC patients (n = 21) would have qualified for enrollment into the ACT trial.

Discussion

The biologics are among the most prescribed medications for symptomatic IBD patients. The evidence supporting their increasing utilization is largely based from RCT data. However, our study suggests that IBD patients enrolled in the major RCTs of the FDA-approved biological agents might not be completely representative of patients encountered during routine clinical practice where anti-TNF therapy is often considered as the next step of management. Compared with the patients enrolled in the

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Washout Periods in Inflammatory Bowel Disease Trials: A Systematic Literature Review and Proposed Solutions
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Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases
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Advances in science have led to the development of multiple biologics and small molecules for the treatment of inflammatory bowel diseases (IBDs). This growth in advanced medical therapies has been accompanied by an increase in methodological innovation to study and compare therapies. Guidelines provide an evidence-based approach to integrating therapies into routine practice, but they are often unable to provide timely recommendations as new therapies come to market, and they have limited incorporation of real-world evidence when making recommendations. This limits the scope and usability of guidelines, and a gap remains in defining how best to position and integrate advanced medical therapies for IBD. In this review, we provide a framework for clinicians and researchers to understand key differences in sources of evidence, how different methodologies are applied to study the comparative effectiveness of advanced medical therapies in IBD, and considerations for how these sources of evidence can be used to better integrate current guideline recommendations. Over time, we anticipate this framework will allow for a transition to living guidelines and/or practice recommendations.
Comparing clinical trial population representativeness to real-world users of 17 biologics approved for immune-mediated inflammatory diseases: An external validity analysis of 66,639 biologic users from the Italian VALORE project
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To date, no population-based studies have specifically explored the external validity of pivotal randomized clinical trials (RCTs) of biologics simultaneously for a broad spectrum of immuno-mediated inflammatory diseases (IMIDs). The aims of this study were, firstly, to compare the patients’ characteristics and median treatment duration of biologics approved for IMIDs between RCTs’ and real-world setting (RW); secondly, to assess the extent of biologic users treated for IMIDs in the real-world setting that would not have been eligible for inclusion into pivotal RCT for each indication of use. Using the Italian VALORE distributed database (66,639 incident biologic users), adult patients with IMIDs treated with biologics in the Italian real-world setting were substantially older (mean age ± SD: 50 ± 15 years) compared to those enrolled in pivotal RCTs (45 ± 15 years). In the real-world setting, certolizumab pegol was more commonly used by adult women with psoriasis/ankylosing spondylitis (F/M ratio: 1.8–1.9) compared to RCTs (F/M ratio: 0.5–0.6). The median treatment duration (weeks) of incident biologic users in RW was significantly higher than the duration of pivotal RCTs in almost all indications for use and most biologics (4–100 vs. 6–167). Furthermore, almost half (46.4%) of biologic users from RW settings would have been ineligible for inclusion in the respective indication-specific pivotal RCTs. The main reasons were: advanced age, recent history of cancer and presence of other concomitant IMIDs. These findings suggest that post-marketing surveillance of biologics should be prioritized for those patients.
Infliximab is an effective option in patients with ulcerative colitis previously exposed to full subcutaneous anti-TNF agent: Results from a real-world multicenter study
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Data on infliximab efficacy in bio-exposed patients with ulcerative colitis (UC) are limited.
To evaluate infliximab effectiveness and its predictors in UC patients with prior exposure to subcutaneous (SC) anti-TNF agent.
In this multicenter retrospective study (8 centers), we included all consecutive UC patients with prior exposure to subcutaneous anti-TNF, starting infliximab for symptomatic UC, excluding acute severe colitis. Corticosteroid-free clinical remission (CFREM) was assessed at week 14 (W14) and W52 while endoscopic improvement (CFREM + endoscopic Mayo score≤1) was evaluated at W14.
Overall, 104 patients were included (pancolitis=54.8%, primary failure to subcutaneous anti-TNF=57.4%, concomitant immunosuppressant=53.8%, median partial Mayo score at baseline=7[5–8]). The rate of CFREM was 33.6% (35/104) at W14 and 40.4% (42/104) at W52. At W14, endoscopic improvement was achieved in 29.8%(31/104). In multivariable analysis, concomitant immunosuppressant was associated with higher rate of CFREM at W14(OR=2.83[1.06–7.54], p = 0.037) and W52(OR=2.68[1.16–6.22];p = 0.021), while primary failure to a previous subcutaneous anti-TNF agent led to lower rate of CFREM at W14 (OR=0.37[0.14–0.98], p = 0.046). After a median follow-up of 20.9 months[11.7–33.7]), 50.0%(52/104) patients had discontinued infliximab.
Infliximab is an effective option in UC patients previously exposed to prior subcutaneous anti-TNF agent and should be used with concomitant immunosuppressant.
Second–Line Biologic Therapy Following Tumor Necrosis Factor Antagonist Failure: A Real–World Propensity Score–Weighted Analysis
2023, Clinical Gastroenterology and Hepatology
Tumor necrosis factor (TNF) antagonists often are used as first-line medications to treat moderate to severe inflammatory bowel disease (IBD), but many patients do not achieve or maintain response. Our aim was to compare the effectiveness of second-line treatments (ustekinumab, vedolizumab, or a second TNF antagonist) after TNF antagonist exposure in patients with Crohn’s disease (CD) and ulcerative colitis (UC) from 2 electronic health records–based cohorts.
We identified patients with prior TNF antagonist exposure who switched to a different biologic in the Mount Sinai Health System (MSHS) electronic health records (CD, n = 527; UC, n = 165) and the Study of a Prospective Adult Research Cohort (SPARC) from the Inflammatory Bowel Disease Plexus Program of the Crohn’s & Colitis Foundation (CD, n = 412; UC, n = 129). Treatment failure was defined as the composite of any IBD-related surgery, IBD-related hospitalization, new prescription of oral/intravenous corticosteroids, or need to switch to a third biologic agent. Time-to-event analysis was conducted with inverse probability of treatment-weighted data.
Overall, treatment failure occurred in 85% of MSHS and 72% of SPARC CD patients. In SPARC, the likelihood of treatment failure was significantly lower with ustekinumab compared with vedolizumab as second-line treatment (adjusted hazard ratio, 0.66; 95% CI, 0.54–0.82; P < .001), a trend confirmed in MSHS (adjusted hazard ratio, 0.89; 95% CI, 0.77–1.04; P = .15). In both cohorts, the superiority of ustekinumab compared with vedolizumab was shown when considering treatment failure as prescription of steroids or a third biologic agent. In UC, no differences between second-line treatment groups were identified.
In 2 independent real-world cohort settings, second-line therapy in CD with ustekinumab after TNF antagonist treatment failure was associated with a lower likelihood of treatment failure than second-line vedolizumab.

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: This article has an accompanying continuing medical education activity on page e78. Learning Objectives—At the end of this activity, the successful learner will be able to identify the potential limitations of clinical trial data when translated to a real-world clinical practice.

: Conflicts of interest These authors disclose the following: Asher Kornbluth has served on the Advisory board for Igen/Biodec, Abbott, Elan, and Centocor; provided research support for Abbott and Centocor; and has been on the Speaker's Bureau for Abbott and Centocor. Corey A. Siegel has been on the Consultant/Advisory board for Abbott, Elan, UCB; CME lecturer for Abbott and Janssen; and received research funding from Abbott. Thomas Ullman has been a Consultant for Abbott, UCB, and Centocor. The remaining author discloses no conflicts.

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Original articleAlimentary tractPatients Enrolled in Randomized Controlled Trials Do Not Represent the Inflammatory Bowel Disease Patient Population

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Population and Data Collection

Patient Characteristics

Discussion

Gastroenterology

Gastrointest Endosc

Lancet

Gastroenterology

Gastroenterology

Lancet

Lancet

Gastroenterology

Gastroenterology

Respir Med

Am Heart J

Lancet

An evidence-based systematic review on medical therapies for inflammatory bowel disease

Am J Gastroenterol

Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis

Am J Gastroenterol

Original article
Alimentary tract
Patients Enrolled in Randomized Controlled Trials Do Not Represent the Inflammatory Bowel Disease Patient Population