A first step towards best practice recommendations for the design and statistical analyses of pragmatic clinical trials: A modified Delphi approach

British Journal of Clinical Pharmacology, vol. 88, pp. 5183–5201

Abstract

AIM: Pragmatic clinical trials (PCTs) are randomized trials implemented through routine clinical practice, where design parameters of traditional randomized controlled trials are modified to increase generalizability. However, this may introduce statistical challenges. We aimed to identify these challenges and discuss possible solutions leading to best practice recommendations for the design and analysis of PCTs. METHODS: A modified Delphi method was used to reach consensus among a panel of 11 experts in clinical trials and statistics. Statistical issues were identified in a focused literature review and aggregated with insights and possible solutions from experts collected through a series of survey iterations. Issues were ranked according to their importance. RESULTS: Twenty-seven articles were included and combined with experts' insight to generate a list of issues categorized into participants, recruiting sites, randomization, blinding and intervention, outcome (selection and measurement) and data analysis. Consensus was reached about the most important issues: risk of participants' attrition, heterogeneity of "usual care" across sites, absence of blinding, use of a subjective endpoint and data analysis aligned with the trial estimand. Potential issues should be anticipated and preferably be addressed in the trial protocol. The experts provided solutions regarding data collection and data analysis, which were considered of equal importance. DISCUSSION: A set of important statistical issues in PCTs was identified and approaches were suggested to anticipate and/or minimize these through data analysis. Any impact of choosing a pragmatic design feature should be gauged in the light of the trial estimand.

Authors 13

1. Victoria Palin

   University of Manchester

   Affiliation as printed

   Division of Informatics, Imaging & Data Sciences, Manchester Environmental Research Institute University of Manchester Manchester UK

   Division of Informatics, Imaging & Data Sciences, Manchester Environmental Research Institute University of Manchester Manchester UK

2. Tjeerd Pieter van Staa

   University of Manchester

   Affiliation as printed

   Division of Informatics, Imaging & Data Sciences, Manchester Environmental Research Institute University of Manchester Manchester UK

   Division of Informatics, Imaging & Data Sciences, Manchester Environmental Research Institute University of Manchester Manchester UK

3. Stephanie Steels

   Manchester Metropolitan University

   Affiliation as printed

   Department of Social Care and Social Work Manchester Metropolitan University Manchester UK

   Department of Social Care and Social Work, Manchester Metropolitan University, Manchester, UK

4. Andrea B. Troxel

   New York University

   Affiliation as printed

   Division of Biostatistics, Department of Population Health NYU Grossman School of Medicine New York USA

   Division of Biostatistics, Department of Population Health, NYU Grossman School of Medicine, New York, USA

5. Rolf H. H. Groenwold Aachen Department of Clinical Epidemiology Leiden University Medical Centre Leiden The Netherlands Department of Clinical Epidemiology

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Clinical Epidemiology Leiden University Medical Centre Leiden The Netherlands

   Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands

6. Thomas MacLennan MacDonald

   University of Dundee · Ninewells Hospital

   Affiliation as printed

   MEMO Research University of Dundee, Ninewells Hospital & Medical School Dundee UK

   MEMO Research University of Dundee, Ninewells Hospital & Medical School Dundee UK

7. David John Torgerson

   University of York

   Affiliation as printed

   Department of Health Sciences University of York York UK

   Department of Health Sciences, University of York, York, UK

8. Douglas E. Faries

   Eli Lilly (United States)

   Affiliation as printed

   Global Statistical Sciences, Eli Lilly & Co. Indianapolis IN USA

   Global Statistical Sciences, Eli Lilly & Co. Indianapolis IN USA

9. Pierre Mancini

   Sanofi (France)

   Affiliation as printed

   Sanofi R&D Chilly Mazarin France

   Sanofi R&D Chilly Mazarin France

10. Mario Ouwens

    AstraZeneca (Sweden)

    Affiliation as printed

    AstraZeneca, KC6 Gothenburg Sweden

    AstraZeneca, KC6, Gothenburg, Sweden

11. Kate Tsirtsonis

    Amgen (United Kingdom)

    Affiliation as printed

    Amgen Ltd Uxbridge UK

    Amgen Ltd, Uxbridge, UK

12. Graham MacLennan

    University of Aberdeen

    Affiliation as printed

    The Centre for Healthcare Randomised Trials University of Aberdeen Aberdeen UK

    The Centre for Healthcare Randomised Trials, University of Aberdeen, Aberdeen, UK

13. Clémentine Nordon corresponding

    AstraZeneca (United Kingdom) · AstraZeneca (France)

    Affiliation as printed

    formally LASER Research, Paris, France; currently AstraZeneca Cambridge UK

    currently AstraZeneca, Cambridge, UK

    formally LASER Research, Paris, France; currently AstraZeneca Cambridge UK