Abstract
Clinical trials are considered to be the gold standard of research designs at the top of the evidence chain. This reputation is due to the ability to randomly allocate subjects to treatments and to mask the treatment assignment at various levels, including subject, observers taking measurements or administering questionnaires, and investigators who are overseeing the performance of the study. This chapter section deals with the five major causes of bias in clinical trials: (1) selection bias, or the biased assignment of subjects to treatment groups; (2) performance bias, or the collection of data in a way that favors one treatment group over another; (3) detection bias, or the biased detection of study outcomes (including both safety and efficacy) to favor one treatment group over another; (4) attrition bias, or differential dropout from the study in one treatment group compared to the other; and (5) reporting and publication bias, or the tendency of investigators to include only the positive results in the main results paper (regardless of what is specified in the study protocol) and the tendency of journals to publish only papers with positive results. While other biases can (and do) occur and are also described here, they tend to have lower impact on the integrity of the study. The definitions of these biases will be presented, along with how to proactively prevent them through study design and procedures.
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Akl AE, Briel M, You JJ, Sun X, Johnston BC, Busse JW, Mulla S, Lamontagne F, Bassler D, Vera C, Alshurafa M, Katsios CM, Zhou Q, Cukierman-Yaffe T, Gangji A, Mills EJ, Walter SD, Cook DJ, Schünemann HJ, Altman DG, Guyatt GH (2012) Potential impact on estimated treatment effects of information lost to follow-up in randomized controlled trials (LOST-IT): systematic review. BMJ 344:e2809
Berger VW, Christophi CA (2003) Randomization technique, allocation concealment, masking, and susceptibility of trials to selection bias. J Mod Appl Stat Methods 2(1):80–86
Catalog of Bias Collaboration (2019). Catalog of Bias, November 19. Retrieved from catalogofbias.org
Chan A-W, Altman DG (2005) Identifying outcome reporting bias in randomised trials on PubMed: review of publications and survey of authors. BMJ 330(7494):753
Doll R (1998) Controlled trials: the 1948 watershed. BMJ 317:1217
Dunn K (2019) Shewhart charts, July 17. Retrieved from https://learnche.org/pid/process-monitoring/shewhart-charts
Dusingize JC, Olsen CM, Pandeya NP, Subramaniam P, Thompson BS, Neale RE, Green AC, Whiteman DC, Study QS (2017) Cigarette smoking and the risks of basal cell carcinoma and squamous cell carcinoma. J Invest Dermatol 137(8):1700–1708
Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E, Decullier E, Easterbrook PJ, Von Elm E, Gamble C, Ghersi D, Ioannidis JP, Simes J, Williamson PR (2008) Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One 3(8):e3081
Dwan K, Gamble C, Williamson PR, Kirkham JJ, Reporting Bias Group (2013) Systematic review of the empirical evidence of study publication bias and outcome reporting bias – an updated review. PLoS One 8(7):e66844
Dwan K, Altman DG, Clarke M, Gamble C, Higgins JP, Sterne JA, Williamson PR, Kirkham JJ (2014) Evidence for the selective reporting of analyses and discrepancies in clinical trials: a systematic review of cohort studies of clinical trials. PLoS Med 11(6):e1001666
Editorial (2014) #Trial: clinical research in the age of social media. Lancet Oncol 15(6):539
Hewitt CE, Kumaravel B, Dumville JC, Torgerson DJ, Trial Attrition Study Group (2010) Assessing the impact of attrition in randomized controlled trials. J Clin Epidemiol 63(11): 1264–1270
Higgins JPT, Altman DG, Behalf of the Cochrane Statistical Methods Group and the Cochrane Bias Methods Group (2008) In: JPT H, Green S (eds) Cochrane handbook for systematic reviews of interventions. Wiley, Chichester
Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, Ravaud P, Brorson S (2012) Observer bias in randomized clinical trials with binary outcomes: systematic review of trials with both blinded and unblinded assessors. BMJ 344:e1119
Kahan BC, Feagan B, Jairath V (2017) A comparison of approaches for adjudicating outcomes in clinical trials. Trials 18:266
Lachin J (1988) Properties of simple randomization in clinical trials. Control Clin Trials 9:312–326
Laursen DRT, Paludan-Muller AS, Hrobjartsson A (2019) Randomized clinical trials with run-in periods: frequency, characteristics and reporting. Clin Epidemiol 11:169–184
Lewis SC, Warlow CP (2004) How to spot bias and other potential problems in randomised controlled trials. J Neurol Neurosurg Psychiatry 75:181–187. https://doi.org/10.1136/jnnp.2003.025833
Marcus AD (2014) Researchers FRET as social media lift veil on drug trials: online chatter could unravel carefully built construct of ‘blind’ clinical trials. Wall Street Journal, July 29
Matts J, Lachin J (1988) Properties of permuted-block randomization in clinical trials. Control Clin Trials 9:327–344
Moher D, Hopewell S, Schulz KF, Montori V, Gøtzsche PC, Devereaux PJ, Elbourne D, Egger M, Altman DG (2010) Explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 340:c869
Noseworthy JH, Ebers GC, Vandervoort MK, Farquhar RE, Yetisir E, Roberts R (1994) The impact of blinding on the results of a randomized, placebo-controlled multiple sclerosis clinical trial. Neurology 44(1):16–20
Perlmutter AS, Tran VT, Dechartres A, Ravaud P (2017) Statistical controversies in clinical research: comparison of primary outcomes in protocols, public clinical-trial registries and publications: the example of oncology trials. Ann Oncol 28(4):688–695
Pullicino P, Thompson JLP, Barton B, Levin B, Graham S, Freudenberger RS (2006) Warfarin versus aspirin in patients with reduced cardiac ejection fraction (WARCEF): rationale, objectives, and design. J Card Fail 12(1):39–46
Ruffin JM, Grizzle JE, Hightower NC, McHardy G, Shull H, Kirsner JB (1969) A Cooperative Double-Blind Evaluation of Gastric Freezing in the Treatment of Duodenal Ulcer. New England Journal of Medicine 281(1):16–19
Rundle A, Wang Y, Sadasivan S, Chitale DA, Gupta NS, Tang D, Rybicki BA (2017) Larger men have larger prostates: detection bias in epidemiologic studies of obesity and prostate cancer risk. Prostate 77(9):949–954. https://doi.org/10.1002/pros.23350
Saltaji H, Armijo-Olivo S, Cummings GG, Amin M, da Costa BR, Flores-Mir C (2018) Impact of selection bias on treatment effect size estimates in randomized trials of oral health interventions: a meta-epidemiological Study. J Dent Res 97(1):5–13
Schulz KF, Altman DG, Moher D, for the CONSORT Group (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ c332:340
Sterne JAC, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, Wood AM, Carpenter JR (2009) Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 338:b2393
Temple R, Pledger G (1980) The FDA’s critique of the Anturane Reinfarction trial. NEJM 303(25):1488–1492
The Anturane Reinfarction Trial Research Group (1978) Sulfinpyrazone in the prevention of cardiac death after myocardial infarction. NEJM 298(6):289–295
Thomas ET, Heneghan C (2017) Catalogue of bias collaboration, outcome reporting bias. In: Catalogue of biases. http://www.catalogueofbiases.org//outcomereportingbias
Wangensteen OH (1962) Achieving “Physiological Gastrectomy” by Gastric Freezing. JAMA 180(6):439
Wirtz HS, Calip GS, Buist DSM, Gralow JR, Barlow WE, Gray S, Boudreau DM (2017) Evidence for detection bias by medication use in a cohort study of breast cancer survivors. Am J Epidemiol 185(8):661–672
Zhang S, Liang F, Li W (2017) Comparison between publicly accessible publications, registries, and protocols of phase III trials indicated persistence of selective outcome reporting. J Clin Epidemiol 91:87–94
Zhao W, Ciolino J, Palesch Y (2010) Step-forward randomization in multicenter emergency treatment clinical trials. Acad Emerg Med 17(6):659–665
Zhao W, Hill MD, Palesch Y (2011) Minimal sufficient balance—a new strategy to balance baseline covariates and preserve randomness of treatment allocation. Statistical Methods in Medical Research 24(6):989–1002
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Barton, B.A. (2020). Controlling Bias in Randomized Clinical Trials. In: Piantadosi, S., Meinert, C. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52677-5_214-1
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DOI: https://doi.org/10.1007/978-3-319-52677-5_214-1
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