Useful links & resources for investigators

Protocol templates developed by KCE Trials

IMP/MD Protocol template V5.0 5 May 2026 (use this template if your trial studies a drug or a medical device)
Non IMP/MD Protocol template V3.0 28 August 2026 (use this template if your trial studies an intervention that is not a drug nor a medical device)

Useful links on Pragmatic trials

Pragmatic trials are trials that are designed to compare treatment options in a real-world setting, as opposed to explanatory trials that test a physiological or clinical hypothesis, typically to develop new drugs or other treatments. Trials can be pragmatic with regards to several features, such as the way sites and patients are recruited, the choice of outcomes, the interventions and their delivery etc.

Pragmatic Trials

This NEJM paper gives more information on pragmatic trials: http://www.nejm.org/doi/full/10.1056/NEJMra1510059
The PRECIS (Pragmatic-Explanatory Continuum Indicator Summary) is a tool to help trialists designing clinical trials consider where they would like their trial to be on the pragmatic or explanatory continuum. It can be found here: https://www.precis-2.org/
Heterogeneity in pragmatic randomised trials: sources and management: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9615398/
The authors of the GetReal consortium (workpackage 3) have a series of interesting publications on pragmatic trials:
- Zuidgeest M, Goetz I, Groenwold et al. Pragmatic trials and real-world evidence-an introduction to the series. J Clin Epidemiol 2017 [in press] http://www.jclinepi.com/article/S0895-4356(17)30540-1/fulltext
- Worsley S, Oude Rengerink K, Irving E et al. Challenges in pragmatic trials: selection and inclusion of usual care sites. J Clin Epidemiol 2017 [in press] http://www.jclinepi.com/article/S0895-4356(17)30478-X/fulltext
- Oude Rengerink K, Kalkman S, Collier S et al. Participant eligibility, recruitment, and retention in pragmatic trials. J Clin Epidemiol 2017 [in press] http://www.jclinepi.com/article/S0895-4356(17)30480-8/fulltext
- Kalkman S, van Thiel G, Zuidgeest M et al. Challenges of informed consent for pragmatic trials. J Clin Epidemiol 2017 [in press] http://www.jclinepi.com/article/S0895-4356(17)30479-1/fulltext
- Welsing P, Oude Rengerink K, Collier S et al. Outcome selection and measurement in pragmatic trials. J Clin Epidemiol 2017 [in press] http://www.jclinepi.com/article/S0895-4356(17)30481-X/fulltext
- Irving E, van den Bor R, Welsing P et al. Collecting and reporting safety data and monitoring trial conduct in pragmatic trials. J Clin Epidemiol 2017 [in press] http://www.jclinepi.com/article/S0895-4356(17)30482-1/fulltext
- Meinecke A, Welsing P, Kafatos G et al. Data collection in pragmatic trials. J Clin Epidemiol 2017 [in press]http://www.jclinepi.com/article/S0895-4356(17)30776-X/fulltext
- Zuidgeest M, Welsing P, van Thiel, J et al. Pragmatic trials: defining questions, choosing comparators, allocating treatments. J Clin Epidemiol 2017 [in press]http://www.jclinepi.com/article/S0895-4356(17)30749-7/fulltext

Presentation on pragmatic trials by Professor Sandra Eldridge

In June 2017 KCE Trials was delighted to welcome Professor Sandra Eldridge (Professor of Biostatistics; Director, Pragmatic Clinical Trials Unit, Centre for Primary Care and Public Health, Blizard Institute, Queen Mary University of London, UK) to KCE to give a talk on pragmatic trials. This focused on issues and emerging designs. She also did a Q&A where she gave short answers on many key questions in pragmatic trials. Her talk and Q&A can be viewed via the link below.

Other resources

Patient Involvement

Website Ligue des usagers des services de santé: http://www.luss.be/
Website Vlaams Patiëntenplatform: http://www.vlaamspatientenplatform.be/
Website ‘Patiëntenfederatie Nederland’: https://www.patientenfederatie.nl/
Website ‘European Patient Ambassador Programme’: https://www.epaponline.org/
Website European Patients' Academy on Therapeutic Innovation: https://www.eupati.eu/
Amadea Turk, Anne-Marie Boylan, Louise Locock. ‘A Researcher’s Guide to Patient and Public Involvement’. https://oxfordbrc.nihr.ac.uk/wp-content/uploads/2017/03/A-Researchers-Guide-to-PPI.pdf

Further information and resources can be found on the website of INVOLVE, a programme funded by the National Institute for Health Research (UK) to support active public involvement in NHS, public health and social care research: www.invo.org.uk.

Sample size

You can also find a questionnaire, developed by Pr. Cook from Oxford University, to help applicants better justify their underlying justification of the sample size used in a randomised controlled trial grant proposal. The document can be found here.
DELTA2 Guidance – Difference Elicitation in trials https://www.csm.ox.ac.uk/research/methodology-research/delta2

Trial Design & reporting

NIH Collabatory – Guidance for Reporting of Pragmatic Trial Results: https://rethinkingclinicaltrials.org/news/february-22-2024-updated-template-provides-guidance-for-reporting-of-pragmatic-trial-results/
Guidance for biostatisticians on their essential contributions to clinical and translational research protocol review (includes a useful checklist), Journal of Clinical and Translational Science , Volume 5 , Issue 1 , 2021: https://www.cambridge.org/core/journals/journal-of-clinical-and-translational-science/article/guidance-for-biostatisticians-on-their-essential-contributions-to-clinical-and-translational-research-protocol-review/49B4D365DC2676532BDBDD922298D273#
The COMET (Core Outcome Measures in Effectiveness Trials) initiative: http://www.comet-initiative.org/
International Consortium for Health Outcomes Measurement (ICHOM) http://www.ichom.org
Equator Network Guidelines for Reporting Outcomes in Trial Reports https://www.equator-network.org/reporting-guidelines/consort/
The following documents may be useful:
- EMA guideline on adjustment for baseline covariates in clinical trials https://kce.fgov.be/sites/default/files/2023-11/EMA-guideline-adjustmen…
- EMA guideline on the choice of the non-inferiority margin https://kce.fgov.be/sites/default/files/2023-11/EMA-guideline-choice-non-inferiority-margin_en.pdf
- FDA Adaptive designs for clinical trials of drugs and biologics https://kce.fgov.be/sites/default/files/2023-11/FDA_adaptive%20designs%20for%20clinical%20trials%20of%20drugs%20and%20biologics.pdf
- FDA Multiple Endpoints in Clinical Trials https://kce.fgov.be/sites/default/files/2023-11/FDA_multiple%20endpoints%20in%20Clinical%20Trials.pdf
- Good Lay Summary Practice https://kce.fgov.be/sites/default/files/2023-11/Good%20Lay%20Summay%20Practice.pdf
- Merck commentary noninferiority trial https://kce.fgov.be/sites/default/files/2023-11/Merck_letter%20noninferiority%20trial.pdf
- Prospective reporting of statistical analysis plans for randomised controlled trials https://kce.fgov.be/sites/default/files/2023-11/Prospective%20reporting%20of%20statistical%20analysis.pdf
- SPIRIT 2025 explanation and elaboration; guidance for protocols of clinical trials https://www.bmj.com/content/389/bmj-2024-081660
- Statistics in Medicine; Sensitivity analysis for clinical trials with missing outcomes data https://kce.fgov.be/sites/default/files/2023-11/Statistics%20in%20Medic…

Risk-adapted approaches

MRC/DH/MHRA Joint Project - Risk-adapted Approaches to the Management of Clinical Trials of Investigational Medicinal Products
Risk based approaches: ICH E6 Asset Library - TransCelerate
ICH-E19 guideline on selective safety reporting which covers low interventional studies

Health Economics