An Overview of Challenges and Approaches to Minimize Bias in Randomized Controlled Trials in Perioperative Medicine
- 85 Downloads
Purpose of Review
Randomized controlled trials (RCT) are recognized as the most robust design to study the relationship between exposure and outcomes. The conventional RCT design is commonly used in pharmacological trials. Some surgical interventions are not be well suited to a conventional RCT design and may be associated with methodological challenges. Approaches have been proposed in non-pharmacological trials to overcome some of these challenges and minimize the risk of bias.
Imbalance in prognostic factors between intervention groups, lack of allocation concealment, unblinding, non-intention-to-treat analysis, and losses to follow-ups can all threaten the validity of RCT results to various degrees. Procedure-based trials raise also specific challenges since physician expertise and training can affect the intervention, exposing to potential differential-expertise bias. Lack of statistical power can also affect the confidence in a trial’s result. Small sample sizes also usually mean small number of events for comparison between interventions, resulting in less statistically robust findings.
Minimizing risk of bias and achieving adequate statistical power are crucial to producing high quality and meaningful results. Non-pharmacological trials pose certain methodological challenges, and several approaches have been proposed to address the risk of bias. Large sample sizes are also usually required to achieve sufficient statistical power to provide answers to meaningful clinical questions. However, small perioperative trials remain frequent and result interpretation based solely on P values might not always appropriately inform on the confidence in a trial’s results. The Fragility Index can be used to further inform on the confidence of statistically significant result.
KeywordsPerioperative care Clinical trials Randomized controlled trial Research methods
Compliance with Ethics Guidelines
Conflict of Interest
Emmanuelle Duceppe and Emilie Belley-Coté declare that they have no conflict of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as • Of importance •• Of major importance
- 12.Montenij L, de Waal E, Frank M, van Beest P, de Wit A, Kruitwagen C, et al. Influence of early goal-directed therapy using arterial waveform analysis on major complications after high-risk abdominal surgery: study protocol for a multicenter randomized controlled superiority trial. Trials. 2014;15:360.CrossRefPubMedPubMedCentralGoogle Scholar
- 15.•• Evaniew N, Carrasco-Labra A, Devereaux PJ, Tikkinen KA, Fei Y, Bhandari M, et al. How to use a randomized clinical trial addressing a surgical procedure: users’ guide to the medical literature. JAMA Surg. 2016. - This publication of the Users Guide to the Medical Literature RCTs provides comprehensible review of use and misuse of RCTs in the surgical setting. Google Scholar
- 18.Devereaux PJ, Choi PT, El-Dika S, Bhandari M, Montori VM, Schunemann HJ, et al. An observational study found that authors of randomized controlled trials frequently use concealment of randomization and blinding, despite the failure to report these methods. J Clin Epidemiol. 2004;57(12):1232–6.CrossRefPubMedGoogle Scholar
- 36.• Cook JA, Elders A, Boachie C, Bassinga T, Fraser C, Altman DG, et al. A systematic review of the use of an expertise-based randomised controlled trial design. Trials. 2015;16:241. - A systematic review that informs on the current use of expertise-based design in RCTs. Expertise-based design has gained popularity in the last decade as a novel approach to conduct RCT, especially in non-pharmacological and surgical trials.Google Scholar
- 42.Abraha I, Cherubini A, Cozzolino F, De Florio R, Luchetta ML, Rimland JM, et al. Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study. BMJ. 2015;350:h2445Google Scholar
- 48.•• Walsh M, Srinathan SK, McAuley DF, Mrkobrada M, Levine O, Ribic C, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol. 2014;67(6):622–8. - This publication discusses the issue of fragility in trials and introduced the Fragility Index. The Fragility Index is an novel metric that is proposed to complement p-value in assessing statistically significant results reported in trials. Google Scholar