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Alternative Clinical Trial Designs Open access Review Trauma Surg Acute Care Open: first published as 10.1136/tsaco-2019-000420 on 4 February 2020. Downloaded from Alternative clinical trial designs John A Harvin ,1 Ben L Zarzaur,2 Raminder Nirula,3 Benjamin T King,4 Ajai K Malhotra,5 the Coalition for National Trauma Research Scientific Advisory Committee 1Surgery, University of Texas SUMMARY follow- up, and other factors that will not be covered McGovern Medical School, High- quality clinical trials are needed to advance the care in this review. In this review, we will focus on clin- Houston, Texas, USA 2Surgery, University of Wisconsin of injured patients. Traditional randomized clinical trials ical trial designs other than the traditional parallel Madison School of Medicine in trauma have challenges in generating new knowledge group randomized controlled trial (RCT). Alter- and Public Health, Madison, due to many issues, including logistical difficulties native trial designs can be used to generate new, Wisconsin, USA performing individual randomization, unclear pretrial generalizable knowledge in an efficient manner and 3 Surgery, University of Utah estimates of treatment effect leading to often unpowered improve the care of injured patients. These include School of Medicine, Salt Lake City, Utah, USA studies, and difficulty assessing the generalizability pragmatic, cluster randomized, cluster randomized 4Neurology, University of Texas of an intervention given the heterogeneity of both stepped wedge, factorial, and adaptive designs. at Austin Dell Medical School, patients and trauma centers. In this review, we discuss Additionally, we will contrast traditional frequen- Austin, Texas, USA alternative clinical trial designs that can address some tist statistical analysis with Bayesian methods of 5Surgery, University of Vermont Medical Center, Burlington, of these difficulties. These include pragmatic trials, inference. Vermont, USA cluster randomization, cluster randomized stepped wedge designs, factorial trials, and adaptive designs. Correspondence to Additionally, we discuss how Bayesian methods of PRAGMATIC RCTS Dr Ajai K Malhotra, Surgery, inference may provide more knowledge to trauma An explanatory or efficacy trial is one performed University of Vermont Medical and acute care surgeons compared with traditional, with experienced investigators at advanced sites Center, Burlington, VT 05401, USA; ajai. malhotra@ uvmhealth. frequentist methods. following strict enrollment criteria that ultimately org creates a narrow patient population receiving the intervention under ideal circumstances. Explana- Received 27 November 2019 tory trials are often appropriately used to test the copyright. INTRODUCTION Accepted 3 December 2019 efficacy of a new intervention or to determine Injury is the leading cause of death and disability the mechanistic causes for the observed treatment for those aged 1–45 and remains a significant effect. They focus more on the internal validity source of morbidity and mortality for older age of the study rather than the generalizability of groups. Although there have been many advances the intervention. Because of the focus on internal in the care of the injured patient during the last few validity at the expense of the generalizability of decades, these advances have largely been due to the study, the treatment effect that results from an either technological advances in fields outside of explanatory trial will likely overestimate the benefits surgery or the rapid need for knowledge generation of the intervention when applied to a ‘real world’ in the treatment of casualties during war. These include angioembolization of solid organ injuries, population with more heterogeneous patients. The result is the most common question physicians ask the maturation of CT scanning, and balanced blood http://tsaco.bmj.com/ product resuscitation.1–6 after reading a clinical trial: Does this apply to my 10 While these advances have contributed to a patients? reduction in mortality for some types of injured Contrary to explanatory trials, pragmatic patients, others have seen no change in decades.7 randomized clinical trials measure the effective- This failure to improve mortality in some types of ness of an intervention: How does this intervention injured patients is partially due to the lack of well- work in real clinical practice? There are typically designed clinical trials to guide care.8 9 Many of the few to no exclusion criteria in the population of best available guidelines used to inform treatment interest and the intervention is provided along with on October 1, 2021 by guest. Protected decisions are based on retrospective studies and routine care by a heterogeneous group of clinicians. low- quality data. To change practice and to improve External validity is explicitly valued during the morbidity and mortality for injured patients there is design phase of the study to maximize the general- an urgent need for clinical trials in this space. izability of the study. There are multiple barriers to performing high- While there is no clear line between an explana- © Author(s) (or their quality clinical trials in injured patient popula- tory and pragmatic RCT, there exists a continuum employer(s)) 2020. Re- use on which domains of an individual trial may have permitted under CC BY-NC . No tions. These include a lack of funding to allow for commercial re-use . See rights adequately powered studies, difficulty assessing the varying levels of each. One scoring system used and permissions. Published effect of an intervention in a heterogeneous patient to measure a study’s pragmatism is called the by BMJ. population, and difficulty assessing the general- PRagmatic- Explanatory Continuum Indicator 11 To cite: Harvin JA, izability of interventions given significant differ- Summary (PRECIS-2). PRECIS-2 rates an RCT on Zarzaur BL, Nirula R, et al. ences between trauma centers. Additional barriers a Likert scale of 1–5 (1=very explanatory; 5=very Trauma Surg Acute Care Open include issues with consent, difficulty in choosing pragmatic) in nine domains: eligibility, recruitment, 2020;5:e000420. appropriate outcome measures, a lack of long- term setting, organization, flexibility: delivery, flexibility: Harvin JA, et al. Trauma Surg Acute Care Open 2020;5:e000420. doi:10.1136/tsaco-2019-000420 1 Open access Trauma Surg Acute Care Open: first published as 10.1136/tsaco-2019-000420 on 4 February 2020. Downloaded from Table 1 Domains of the PRECIS-2 tool11 Table 2 Outcome of explanatory and pragmatic trials12 Domain Considerations Intervention equal to or Intervention better than control worse than control Eligibility How similar are the trial’s participants to a patient encountered in routine clinical practice? Does the trial include a narrowly selected Explanatory Equivocal—Will the intervention Clear—Do not implement patient population (explanatory) or a heterogeneous patient trial work in my patients? this intervention. population that represents most populations (pragmatic)? Pragmatic trial Clear—Implement this intervention. Equivocal—Why did the Recruitment How much additional effort is made to recruit patients compared intervention not work? with how you normally interact with patients during routine care? Does the study focus on the recruitment of specialized patients with targeted approaches (explanatory) or aimed at all potentially reader (table 2).12 Depending on the question being asked and eligible patients encountered during routine care (pragmatic)? the conclusion desired, the time to determine pragmatism is Setting How different is the setting of the trial compared with the setting during the design phase as a clinical trial with no consideration of routine care at the participating center? Are patients cared for external validity might result in a conclusion that has no rele- for in specialized research units or centers (explanatory) or in a vance outside the patients recruited. Pragmatic trials avoid this hospital setting more likely for the intervention to be implemented outcome by testing the intervention in an environment that most (pragmatic)? closely resembles how it will be used in the real world (table 3). Organization How different are the available resources, provider experience, and delivery of care compared with what is available in routine care? Can only the most experienced clinicians provide care to enrolled CLUSTER RANDOMIZATION patients (explanatory) or do all clinicians in a group provide the In a traditional parallel group clinical trial, patients are individ- intervention embedded in the routine care of the population ually randomized to a treatment arm and the treatment arm to (pragmatic)? which that patient is enrolled is independent of other patients’ Flexibility: How different is the flexibility in delivering the intervention in treatment allocation. When testing a new method or process delivery the trial compared with the flexibility in how the intervention of care (eg, a new care bundle), however, randomization at the would be delivered in normal practice? Is the intervention highly individual level can be infeasible. The bundle may be incom- protocolized and close monitoring performed to ensure standard delivery (explanatory) compared allowing the clinician flexibility pletely implemented in the experimental arm and contamination to implement the intervention as dictated by the patient’s routine of the control group with all or some of the intervention can clinical care (pragmatic)? occur. Both reduce treatment differentiation
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