Placebo-controlled clinical trials are the gold standard in drug development, in part to ensure that the efficacy of a new therapy exceeds the placebo response in the indication being studied. The placebo response is a measured improvement in clinical signs and/or symptoms that occurs in patients receiving a sham or “dummy” treatment. The placebo response is a complex psychological, biological and sociological phenomenon that confounds clinical data analysis, particularly for subjective and patient-reported outcomes. The placebo response is widely known to compromise evaluation of pain endpoints and has been suggested to contribute to as much as ~2/3 of the measured treatment effect in pain from various etiologies1, contributing to the high rate of Phase II and III clinical trial failure in this indication2. The placebo response is, however, not limited to pain trials; in fact, the understanding of the impact of this phenomenon in a wide variety of therapeutic areas is growing steadily. This article is part of a series that will examine the impact of the placebo response in drug development in pain and beyond.
Crohn’s disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD), are characterized by chronic inflammation of the gastrointestinal tract3. This is a chronic disease where periods of active illness are followed by periods of remission. The symptoms vary, depending on the severity and location of inflammation. The most frequent symptoms are diarrhea, fatigue, abdominal pain and cramping, blood in the stool, reduced appetite and unintended weight loss. The prevalence of inflammatory bowel disease exceeded 0·3% in North America, Oceania, and many countries in Europe4. In 2015, in North America, an estimated 3.1 million (1.3%) of U.S. adults had received a diagnosis of inflammatory bowel disease5.
As in many other diseases (e.g. pain, osteoarthritis, rheumatoid arthritis, Parkinson’s Disease, etc ), patients participating in clinical trials for IBD treatments may experience a pronounced placebo effect or placebo response. As IBD is a chronic disease, efficacy is comprised of improvement rates as well as remission rates; unfortunately, both are influenced by placebo response, albeit at different rates. The placebo response rates vary between 5 and 50% in CD and between 10 and 35% in UC, with respect to both clinical improvement and remission6,7. Also, as observed in other diseases, more invasive treatments lead to higher placebo response rates.
In a recent meta-analysis (over 6863 publications identified, 70 articles describing 73 randomised controlled trials)8, the authors observed that “the pooled placebo response rate was 27·3% (95% CI 24·3–30·9) using the global improvement endpoint, 34·4% (31·2–37·8) using the abdominal pain endpoint, and 17·9% (15·2–21·0) using the composite FDA endpoint responder definition, all with substantial heterogeneity between the trials”.
Several factors have been identified to be related of Placebo response in IBD, including study design and others. Low placebo response seems to be associated with lower disease intensity/activity at the beginning of the study9, and disease duration10. Prior exposure to specific treatments could be, depending on the treatment type, associated with lower (like TNF antagonists11 or higher placebo response12. Subjective patient related outcomes measurements when used to evaluate clinical efficacy are associated to higher placebo response (similar to other diseases). In a recent meta-analysis13, the placebo response rates of the health-related quality of life (HR-QoL) were as high as 41% for clinical improvement and 31% for remission. Lastly, studies with new and expensive class of drugs such as biologics produce higher placebo response rates14. While placebo response rates for objective endpoints may be lower than subjective endpoints, trials for IBS still rely primarily on patient reported outcomes to determine efficacy.
Some clinical trial designs may be considered to reduce placebo response rate, like run in phase for example, but meta-analysis have suggested that this approach as a marginal influence15.The observed placebo response rates jeopardizes the demonstration of efficacy of efficacy of new therapies for IBD and complicated data interpretation. IBD is a severe disease that is associated with poor quality of life, extensive morbidity and often results in complications requiring hospitalizations and surgical procedures16,17,18, thus new treatments are clearly needed. Historically, the placebo response in IBD may have been addressed by optimizing clinical trial design or using central raters for endoscopic endpoints19; however, with competition for IBD patients to participate in clinical trials20, innovative approaches that improve data efficiency stand to have a positive impact on IBD drug development.
At Tools4Patient, we have developed a platform solution (Placebell©™) to reduce the impact of the placebo response in clinical trials. This approach involved a sophisticated characterization of patient psychology in the prediction of each patient’s placebo responsiveness. Applying Placebell©™ in a clinical trial results in increased study power, improved p-values and a reduced risk of trial failure. Placebell©™ has been successfully applied in areas like pain, osteoarthritis and Parkinson’s disease, and is applicable to virtually any disease. To learn more about how Placebell©™ could be applied in gastrointestinal disease, contact us.
- Häuser W, Bartram-Wunn E, Bartram C et al. Systematic review: Placebo response in drug trials of fibromyalgia syndrome and painful peripheral diabetic neuropathy – Magnitude and patient-related predictors. Pain. 2011;152(8):1709-1717. doi:10.1016/j.pain.2011.01.050
- Dumitrescu TP, McCune J, Schmith V. Is Placebo Response Responsible for Many Phase III Failures? Clin Pharmacol Ther. 2019;106(6):1151-1154. doi:10.1002/cpt.1632
- Hanauer SB. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm Bowel Dis. 2006;12(Suppl 1):S3–9. doi: 10.1097/01.MIB.0000195385.19268.68.
- NG S, Shi H, Hamidi N et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. The Lancet. 2017;390(10114):2769-2778. doi: 10.1016/S0140-6736(17)32448-0.
- Xu F, Dahlhamer J, Zammitti E et al. Health-Risk Behaviors and Chronic Conditions Among Adults with Inflammatory Bowel Disease — United States, 2015 and 2016. MMWR. Morbidity and Mortality Weekly Report. 2018;67(6):190-195. doi: 10.15585/mmwr.mm6706a4
- Enck P, Klosterhalfen S. The Placebo and Nocebo Responses in Clinical Trials in Inflammatory Bowel Diseases. Front. Pharmacol. 2021;12:641436. doi:10.3389/fphar.2021.641436
- Gallahan WC, Case D, Bloomfeld RS. An analysis of the placebo effect in Crohn’s disease over time. Aliment. Pharmacol. Ther. 2010(1):102–107. doi:10.1111/j.1365-2036.2009.04125.x
- Bosman M, Elsenbruch S, Corsetti M et al. The placebo response rate in pharmacological trials in patients with irritable bowel syndrome: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2021(6):459-473. doi: 10.1016/S2468-1253(21)00023-6
- Su C, Lichtenstein GR, Krok K et al. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease. Gastroenterology. 2004;126(5):1257–1269. doi:10.1053/j.gastro.2004.01.024
- Macaluso FS, Maida M, Ventimiglia M et al. Factors Affecting Clinical and Endoscopic Outcomes of Placebo Arm in Trials of Biologics and Small Molecule Drugs in Ulcerative Colitis: A Meta-Analysis. Inflamm. Bowel Dis. 2019;25(6):987–997. doi:10.1093/ibd/izy365
- Duijvestein M, Jeyarajah J, Guizzetti L et al. Response to placebo, measured by endoscopic evaluation of crohn’s disease activity, in a pooled analysis of data from 5 randomized controlled induction trials. Clin. Gastroenterol. Hepatol. 2020;18(5): 1121–1132. doi: 10.1016/j.cgh.2019.08.025
- Ma C, Panaccione NR, Nguyen T et al. Adverse Events and Nocebo Effects in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J. Crohns Colitis. 2019;13(9):1201–1216. doi:10.1093/ecco-jcc/jjz087
- Estevinho M, Afonso J, Rosa I et al. Placebo Effect on the Health-related Quality of Life of Inflammatory Bowel Disease Patients: A Systematic Review With Meta-analysis. J. Crohns Colitis. 2018;12(10):1232–1244. doi:10.1093/ecco-jcc/jjy100
- Jairath V, Zou G, Parker C et al. Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn’s disease. Aliment. Pharmacol. Ther. 2017;45(8):1021–1042. doi:10.1111/apt.13973
- Lee S, Walker J, Jakul L et al. Does elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A meta-analytic evaluation. Depress. Anxiety. 2004;19(1):10-9. doi: 10.1002/da.10134
- Cohen RD. The quality of life in patients with Crohn’s disease. Aliment. Pharmacol. Ther. 2002;(9):1603–9. doi: 10.1046/j.1365-2036.2002.01323.x
- Bewtra M, Su C, Lewis JD. Trends in Hospitalization Rates for Inflammatory Bowel Disease in the United States. Clin. Gastroenterol Hepatol. 2007;(5):597–601. doi: 10.1016/j.cgh.2007.01.015
- Longobardi T, Jacobs P, Bernstein CN. Work Losses Related To Inflammatory Bowel Disease in The United States: Results From The National Health Interview Survey. Am. J. Gastroenterol. 2003;98(5):1064–72. doi: 10.1111/j.1572-0241.2003.07285.x
- Sealock R, Othman M, Das K. Endoscopic Diagnosis and Management of Gastrointestinal Trauma. Clin. Gastroenterol Hepatol. 2021;19(1):14-23. doi: 10.1016/j.cgh.2019.09.048
- Harris M, Howden C. Innovative Trial Designs in GI Drug Development: Why Trials Succeed and Fail—A Brief Report From 2018 Digestive Disease Week. Gastroenterology. 2019;156(5):1239-1242. doi: 10.1053/j.gastro.2019.01.001