Causal Inference Guidelines for Pragmatic Clinical Trials [Methods Study], United States, 2015-2020 (ICPSR 39642)

Version Date: Jan 6, 2026

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Principal Investigator(s):
Miguel Hernán, Harvard University

https://doi.org/10.3886/ICPSR39642.v1

Version V1

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Summary

In randomized controlled trials, or RCTs, researchers assign patients by chance to different treatments to compare the benefits and harms. In RCTs, researchers have a high level of control over how patients receive treatment. RCTs often take place in research clinics with staff who monitor how patients follow treatment plans.

Pragmatic RCTs, or pRCTs, take place where patients typically receive treatment, such as a regular clinic. pRCTs can help capture the real-world effects of treatment but determining whether a treatment works can be hard in pRCTs. Also, no clear guidance exists about how to collect and analyze data from pRCTs. Some kinds of analysis are better for helping researchers focus on what's important to patients.

In this study, the research team created guidance for collecting and analyzing data in pRCTs so that results reflect what matters to patients and researchers.

To access the methods and software, please visit the following Github repositories:

Citation

Hernán, Miguel. Causal Inference Guidelines for Pragmatic Clinical Trials [Methods Study], United States, 2015-2020. Inter-university Consortium for Political and Social Research [distributor], 2026-01-06. https://doi.org/10.3886/ICPSR39642.v1

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Funding

Patient-Centered Outcomes Research Institute (PCORI) (ME-1503-28119)

Subject Terms

Geographic Coverage

Distributor(s)

Inter-university Consortium for Political and Social Research
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Time Period(s)

2015 -- 2020
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Study Purpose

To develop guidance for designing pRCTs so that results reflect what matters to patients and investigators

Study Design

To understand what pRCT results matter to patients and researchers, the research team conducted focus groups with patients, semistructured interviews with pRCT statisticians, and a survey of pRCT principal investigators. The team then conducted a systematic literature review to determine how reporting of pRCTs compared with patient and investigator preferences. From this analysis, the research team developed four recommendations for causal inference in pRCTs:

  • Focus on superiority in effectiveness or safety, rather than noninferiority.
  • Involve patients in specifying subgroups during the study design phase.
  • Report absolute measures of risk.
  • Complement ITT effect estimates with per-protocol effect estimates. Per-protocol effects are effects that would have been observed if the analysis included only participants who had adhered to the original trial protocol.

Using six example studies, the research team demonstrated the use of three statistical methods to estimate per-protocol effects. The team also conducted simulation studies to further demonstrate the methods' statistical properties and inform guidance for the estimation of per-protocol effects.

Finally, the research team developed 14 recommendations describing how to choose a causal effect, clarify the appropriate methods to adjust for loss to follow-up and nonadherence, and define the effect of interest in the presence of competing events. The research team solicited feedback on the proposed guidance from stakeholders including patients, clinicians, and researchers.

Universe

Patients in Boston and investigators located primarily in the US.

Data Source

Data Sets, Qualitative analysis:

  • 3 focus groups with patients
  • 5 semistructured interviews with investigators of pRCTs
  • Surveys sent to all principal investigators who received funding from PCORI for pRCTs
  • Systematic literature review of pRCTs published in 4 top weekly medical journals over the last 10 years

Empirical analysis in 6 case studies using data from previous RCTs:

  • Coronary Drug Project
  • Strategic Timing of AntiRetroviral Treatment Trial
  • Prevención con Dieta Mediterránea Trial
  • Norwegian Colorectal Cancer Prevention Trial
  • Candesartan in Heart Failure Morbidity and Mortality Trial
  • Lipid Research Clinics Coronary Primary Prevention Trial

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Original Release Date

2026-01-06

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Notes

  • The public-use data files in this collection are available for access by the general public. Access does not require affiliation with an ICPSR member institution.

  • ICPSR usually offers files in multiple formats for researchers to be able to access data and documentation in formats that work well within their needs. If you have questions about the accessibility of materials distributed by ICPSR or require further assistance, please visit ICPSR’s Accessibility Center.