More ethical and more efficient clinical research: multiplex trial design

BMC Research Notes

Maarten W Nijsten¹  Iwan CC van der Horst¹  Frederik Keus¹ 

[1] Department of Critical Care, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands

关键词: Bias;    Interaction;    Simultaneous randomization;    Factorial design;    Clinical equipoise;    Trial design;   

Others  :  1130493
DOI  :  10.1186/1756-0500-7-530

 received in 2014-02-10, accepted in 2014-07-30,  发布年份 2014

【 摘 要 】

Background

Today’s clinical research faces challenges such as a lack of clinical equipoise between treatment arms, reluctance in randomizing for multiple treatments simultaneously, inability to address interactions and increasingly restricted resources. Furthermore, many trials are biased by extensive exclusion criteria, relatively small sample size and less appropriate outcome measures.

Findings

We propose a ‘Multiplex’ trial design that preserves clinical equipoise with a continuous and factorial trial design that will also result in more efficient use of resources. This multiplex design accommodates subtrials with appropriate choice of treatment arms within each subtrial. Clinical equipoise should increase consent rates while the factorial design is the best way to identify interactions.

Conclusion

The multiplex design may evolve naturally from today’s research limitations and challenges, while principal objections seem absent. However this new design poses important infrastructural, organisational and psychological challenges that need in depth consideration.

【 授权许可】

   
2014 Keus et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 1987, 317:141-145.
• [2]Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck Ytter Y, Schünemann HJ, GRADE Working Group: What is "quality of evidence" and why is it important to clinicians? BMJ 2008, 336:995-998.
• [3]Halpern SD, Karlawish JHT, Berlin JA: The continuing unethical conduct of underpowered clinical trials. JAMA 2002, 288:358-362.
• [4]Savović J, Jones H, Altman D, Harris R, Jüni P, Pildal J, Als-Nielsen B, Balk EM, Gluud C, Gluud LL, Ioannidis JP, Schulz KF, Beynon R, Welton NJ, Wood L, Moher D, Deeks JJ, Sterne JA: Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med 2012, 157:429-438.
• [5]Wikipedia – Multiplexing [http://en.wikipedia.org/wiki/Multiplexing webcite]
• [6]Montgomery AA, Peters TJ, Little P: Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Methodol 2003, 3:26.
• [7]Green S, Liu PY, O’Sullivan J: Factorial design considerations. J Clin Oncol 2002, 20:3424-3430.
• [8]Fries JF, Krishnan E: Equipoise, design bias, and randomized controlled trials: the elusive ethics of new drug development. Arthritis Res Ther 2004, 6:R250-R255.
• [9]Felson DT, Glantz L: A surplus of positive trials: weighing biases and reconsidering equipoise. Arthritis Res Ther 2004, 6:117-119.
• [10]Veatch RM: The irrelevance of equipoise. J Med Philos 2007, 32:167-183.
• [11]Causevic-Ramosevac A, Semiz S: Drug interactions with statins. Acta Pharm 2013, 63:277-293.
• [12]Stone GW, Maehara A, Witzenbichler B, Godlewski J, Parise H, Dambrink JH, Ochala A, Carlton TW, Cristea E, Wolff SD, Brener SJ, Chowdhary S, El-Omar M, Neunteufl T, Metzger DC, Karwoski T, Dizon JM, Mehran R, Gibson CM, INFUSE-AMI Investigators: Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction: the INFUSE-AMI randomized trial. JAMA 2012, 307:1817-1826.
• [13]Fröbert O, Lagerqvist B, Olivecrona GK, Omerovic E, Gudnason T, Maeng M, Aasa M, Angerås O, Calais F, Danielewicz M, Erlinge D, Hellsten L, Jensen U, Johansson AC, Kåregren A, Nilsson J, Robertson L, Sandhall L, Sjögren I, Ostlund O, Harnek J, James SK, TASTE Trial: Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med 2013, 369:1587-1597.
• [14]Yusuf S, Held P, Teo KK, Toretsky ER: Selection of patients for randomized controlled trials: implications of wide or narrow eligibility criteria. Stat Med 1990, 9:73-83.
• [15]Thorlund K, Imberger G, Walsh M, Chu R, Gluud C, Wetterslev J, Guyatt G, Devereaux PJ, Thabane L: The number of patients and events required to limit the risk of overestimation of intervention effects in meta-analysis–a simulation study. PLoS One 2011, 6:e25491.
• [16]Yusuf S, Collins R, Peto R: Why do we need some large, simple randomized trials? Stat Med 1984, 3:409-422.
• [17]Keus F, Wetterslev J, Gluud C, van Laarhoven CJ: Evidence at a glance: error matrix approach for overviewing available evidence. BMC Med Res Methodol 2010, 10:90.
• [18]McAlister FA, Straus SE, Sackett DL, Altman DG: Analysis and reporting of factorial trials: a systematic review. JAMA 2003, 289:2545-2553.
• [19]Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L: Industry sponsorship and research outcome. Cochrane Database Syst Rev 2012, 12:MR000033.