The PRECIS-2 tool: designing trials that are fit for purpose

The PRECIS-2 tool has been introduced to support trialists in making design choices consistent with the intended purpose of the trial, be it explanatory or pragmatic (BMJ 2015;350:h2147). Using PRECIS-2, a multidisciplinary team can score a proposed trial design in a four step process on nine domains to determine if the trial design matches the intended use of the trial results. This is an important development of the original PRECIS tool, now providing a guidance paper with optimised domains. We propose that this revised tool could be taken even further, from the drawing table into the practice of trial conduct.

Experience with pragmatic trials shows that moving a trial design towards the pragmatic side of the continuum, often leads to significant operational challenges (1-5). For example, in a pragmatic trial one would try to recruit the real world prescribers of a drug, but these sites may not be trained and equipped to participate in a clinical trial. Also, comparison with “usual care” is a preferred strategy for pragmatic trials but the operationalization of such a “usual care” arm in practice without introducing biases and while ensuring generalizability of the results is challenging. And how to ensure monitoring at an adequate level without changing usual practice? All of these challenges can strongly impact on the feasibility of the trial design and the applicability of the trial findings, and thus limit the original goal of the design choice.

Therefore we propose that considering not only the design choice itself but also explicitly trying to anticipate the operational challenges that derive from that choice, will help trialists to more fully understand the consequences of their choices, including their possible impact on feasibility, validity and generalizability. They can then weigh the different aspects and reach a balanced decision on a design that is expected to be not only fit for purpose in theory but that also has the best chance of being successful in practice.

Work package 3 of the IMI GetReal project (www.imi-getreal.eu) is aiming to provide guidance and tools to help pragmatic trial designers be aware of consequences of their choices and maximise the pragmatic nature of the study design while ensuring operational feasibility. This will assist to tap the full potential of pragmatic trials conducted in clinical practice.

If a pragmatic trial is designed and executed well, it combines the strength of RCTs, in that it addresses confounding (by indication) through randomization, while generating real world evidence on relative effectiveness by representing real life clinical practice as closely as possible.

Mira G. Zuidgeest 1, Iris Goetz 2, Diederick E. Grobbee 1,
on behalf of WP3 of the GetReal consortium

1. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands
2. Eli Lilly and Company Ltd., United Kingdom

References:
1. van Staa TP, Dyson L, McCann G, Padmanabhan S, Belatri R, Goldacre B, et al. The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. Health technology assessment 2014;18(43):1-146
2. New JP, Bakerly ND, Leather D, Woodcock A. Obtaining real-world evidence: the Salford Lung Study. Thorax 2014;69(12):1152-4
3. Segal JB. The Prospect of Early Pharmaceutical Pragmatic Clinical Trials: A Background Paper: Center for Medical Technology Policy, 2013
4. Laken MA, Dawson R, Engelman O, Lovelace O, Way C, Egan BM. Comparative effectiveness research in the "real" world: lessons learned in a study of treatment-resistant hypertension. Journal of the American Society of Hypertension : JASH 2013;7(1):95-101
5. Kolitsopoulos FM, Strom BL, Faich G, Eng SM, Kane JM, Reynolds RF. Lessons learned in the conduct of a global, large simple trial of treatments indicated for schizophrenia. Contemporary clinical trials 2013;34(2):239-47

Funding source: The work leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° [115546], resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007 ‐ 2013) and EFPIA companies’ in kind contribution.