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

Published:February 17, 2012DOI:https://doi.org/10.1016/j.cgh.2012.02.004

      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.

      Keywords

      Abbreviations used in this paper:

      ACCENT 1 (A Crohn's Disease Clinical Study Evaluating Infliximab in a New Long-Term Treatment Regimen), ACT 1 and 2 (Active Ulcerative Colitis Trials), anti-TNF (anti–tumor necrosis factor alpha), CD (Crohn's disease), CHARM (Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance), CLASSIC 1 (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease), ENACT (Efficacy of Natalizumab as Active Crohn's Therapy), ENCORE (Efficacy of Natalizumab in Crohn's Disease Response and Remission), FDA (Food and Drug Administration), HBI (Harvey–Bradshaw Index), IBD (inflammatory bowel diseases), PRECISE1 (Pegylated Antibody Fragment Evaluation in Crohn's Disease), RALES (Randomized Aldactone Evaluation), RCT (randomized controlled trial), SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease), UC (ulcerative colitis)
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      References

        • Talley N.J.
        • Abreu M.T.
        • Achkar J.P.
        • et al.
        An evidence-based systematic review on medical therapies for inflammatory bowel disease.
        Am J Gastroenterol. 2011; 106: S2-S25
        • Ford A.C.
        • Sandborn W.J.
        • Khan K.J.
        • et al.
        Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis.
        Am J Gastroenterol. 2011; 106: 644-659
        • Schnitzler F.
        • Fidder H.
        • Ferrante M.
        • et al.
        Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort.
        Gut. 2009; 58: 492-500
        • Loftus E.V.
        • Feagan B.G.
        • Colombel J.F.
        • et al.
        Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn's disease: patient-reported outcomes of the CHARM trial.
        Am J Gastroenterol. 2008; 103: 3132-3141
        • Feagan B.G.
        • Panaccione R.
        • Sandborn W.J.
        • et al.
        Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn's disease: results from the CHARM study.
        Gastroenterology. 2008; 135: 1493-1499
        • Lichtiger S.
        • Binion D.G.
        • Wolf D.C.
        • et al.
        The CHOICE trial: adalimumab demonstrates safety, fistula healing, improved quality of life and increased work productivity in patients with Crohn's disease who failed prior infliximab therapy.
        Aliment Pharmacol Ther. 2010; 32: 1228-1239
        • Rutgeerts P.
        • Sandborn W.J.
        • Feagan B.G.
        • et al.
        Infliximab for induction and maintenance therapy for ulcerative colitis.
        N Engl J Med. 2005; 353: 2462-2476
        • Rutgeerts P.
        • Diamond R.H.
        • Bala M.
        • et al.
        Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease.
        Gastrointest Endosc. 2006; 63: 433-442
        • D'Haens G.
        • Baert F.
        • van Assche G.
        • et al.
        Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial.
        Lancet. 2008; 371: 660-667
        • D'Haens G.
        • Van Deventer S.
        • Van Hogezand R.
        • et al.
        Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial.
        Gastroenterology. 1999; 116: 1029-1034
        • Targan S.R.
        • Feagan B.G.
        • Fedorak R.N.
        • et al.
        Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial.
        Gastroenterology. 2007; 132: 1672-1683
        • Sandborn W.J.
        • Colombel J.F.
        • Enns R.
        • et al.
        Natalizumab induction and maintenance therapy for Crohn's disease.
        N Engl J Med. 2005; 353: 1912-1925
        • Lichtenstein G.R.
        • Hanauer S.B.
        • Sandborn W.J.
        • et al.
        Management of Crohn's disease in adults.
        Am J Gastroenterol. 2009; 104: 465-483
        • Kornbluth A.
        • Sachar D.B.
        • Practice Parameters Committee of the American College of Gastroenterology
        Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.
        Am J Gastroenterol. 2010; 105: 501-523
        • Harvey R.F.
        • Bradshaw J.M.
        A simple index of Crohn's disease activity.
        Lancet. 1980; 1: 514
        • Hanauer S.B.
        • Feagan B.G.
        • Lichtenstein G.R.
        • et al.
        Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.
        Lancet. 2002; 349: 1541-1549
        • Hanauer S.B.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.
        Gastroenterology. 2006; 130: 323-333
        • Colombel J.F.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.
        Gastroenterology. 2007; 132: 52-65
        • Sandborn W.J.
        • Feagan B.G.
        • Stoinov S.
        • et al.
        Certolizumab pegol for the treatment of Crohn's disease.
        N Engl J Med. 2007; 357: 228-238
        • Colombel J.F.
        • Sandborn W.J.
        • Reinisch W.
        • et al.
        Infliximab, azathioprine, or combination therapy for Crohn's disease.
        N Engl J Med. 2010; 362: 1383-1395
        • Sokka T.
        • Pincus T.
        Eligibility of patients in routine care for major clinical trials of anti-tumor necrosis factor alpha agents in rheumatoid arthritis.
        Arthritis Rheum. 2003; 48: 313-318
        • Herland K.
        • Akselsen J.P.
        • Skjønsberg O.H.
        • et al.
        How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease?.
        Respir Med. 2005; 99: 11-19
        • Masoudi F.A.
        • Havranek E.P.
        • Wolfe P.
        • et al.
        Most hospitalized older persons do not meet the enrollment criteria for clinical trials in heart failure.
        Am Heart J. 2003; 146: 250-257
        • Van Spall H.G.
        • Toren A.
        • Kiss A.
        • et al.
        Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review.
        JAMA. 2007; 297: 1233-1240
        • Juurlink D.N.
        • Mamdani M.M.
        • Lee D.S.
        • et al.
        Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
        N Engl J Med. 2004; 351: 543-551
        • Rothwell P.M.
        External validity of randomised controlled trials: “to whom do the results of this trial apply?”.
        Lancet. 2005; 365: 82-93
        • Treweek S.
        • Zwarenstein M.
        Making trials matter: pragmatic and explanatory trials and the problem of applicability.
        Trials. 2009; 10: 37
        • Kingsley G.H.
        • Khoshaba B.
        • Smith C.M.
        • et al.
        Are clinical trials in rheumatoid arthritis generalizable to routine practice?.
        Rheumatology (Oxford). 2005; 44: 629-632

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