A limited number of medicines pragmatic trials had potential for waived informed consent following the 2016 CIOMS ethical guidelines

Rafael Dal Ré, Cristina Avendaño Solà, Anthonius de Boer, Stephan K James, Frits R Rosendaal, Richard Stephens, John Pa Ioannidis

Research output: Contribution to journalArticleAcademicpeer-review


OBJECTIVE: European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe.

STUDY DESIGN AND SETTING: Survey of all phase 4 'ongoing' RCTs on the EU clinical trial register between 1/July/2016 and 30/June/2018, to identify those with potentially high levels of pragmatism. Trials that were excluded: those conducted on rare diseases; masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic, assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients and REC members assessed the fulfilment of the CIOMS provisions as 'Yes', 'Not sure' or 'No'.

RESULTS: Of the 636 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials.

CONCLUSIONS: We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials.

Original languageEnglish
Pages (from-to)60-71
JournalJournal of Clinical Epidemiology
Publication statusPublished - 2019


  • medicines
  • phase 4 trials
  • pragmatic clinical trial
  • EU-CTR
  • informed consent
  • waiver


Dive into the research topics of 'A limited number of medicines pragmatic trials had potential for waived informed consent following the 2016 CIOMS ethical guidelines'. Together they form a unique fingerprint.

Cite this