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Departures from the protocol during conduct of a clinical trial: a pattern from the data record consistent with a learning curve
  1. J M Taekman1,2,3,
  2. M Stafford-Smith1,2,3,4,
  3. E J Velazquez4,
  4. M C Wright1,2,3,
  5. B G Phillips-Bute1,3,
  6. M A Pfeffer5,
  7. M A Sellers4,
  8. K S Pieper4,
  9. M F Newman1,2,3,4,
  10. F Van de Werf6,
  11. R Diaz7,
  12. J Leimberger4,
  13. R M Califf4
  1. 1Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA
  2. 2Duke University Human Simulation and Patient Safety Center, Duke University Medical Center, Durham, North Carolina, USA
  3. 3Research Organization on Clinical Trials Section of the Global Perioperative Research Organization (GPRO), Durham, North Carolina, USA
  4. 4Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA
  5. 5Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
  6. 6Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium
  7. 7Instituto Cardiovascular de Rosario, Rosario, Argentina
  1. Correspondence to Jeffrey M Taekman, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710, USA; jeffrey.taekman{at}


Objective Recognition of learning curves in medical skill acquisition has enhanced patient safety through improved training techniques. Clinical trials research has not been similarly scrutinised. The VALsartan In Acute myocardial iNfarcTion, a large multinational, pragmatic, randomised, double-blind, multicentre trial, was retrospectively evaluated for evidence of research conduct consistent with a performance “learning curve”.

Design Records provided protocol departure (deviations/violations) and documentation query data. For each site, analysis included patient order (eg, first, second), recruitment rate and first enrolment relative to study start date.

Setting Computerised data from a trial coordinated by an academic research organisation collaborating with 10 academic and 2 commercial research organisations and an industry sponsor.

Interventions 931 sites enrolled 14 703 patients. Departures were restricted to the first year. Exclusions included patient's death or loss to follow-up within 12 months and subjects enrolled 80th or higher at a site. Departures were assessed for variance with higher patient rank, more frequent recruitment and later start date.

Methods and results 12 367 patients at 931 sites were analysed. Departures were more common for patients enrolled earlier at a site (p<0.0001). For example, compared with the 30th patient, the first had 47% more departures. Departures were also more common with slower enrolment and site start closer to the trial start date (p<0.0001). Similar patterns existed for queries.

Conclusions Research performance improved during the VALsartan In Acute myocardial iNfarcTion consistent with a “learning curve”. Although effects were not related to a change in outcome (mortality), learning curves in clinical research may have important safety, ethical, research quality and economic implications for trial conduct.

  • Cardiology
  • ethics
  • health services
  • medical informatics
  • therapeutics
  • human error
  • safety culture
  • team training
  • significant event analysis
  • randomised controlled trial

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  • T and SS are co-first authors and contributed equally to this paper.

  • Funding This study was funded in part by the National Institute of Neurological Disorders and Stroke grant #1R01NS49548-01 (JMT) and a grant from the Anesthesia Patient Safety Foundation (MCW). Work also funded in part by the Department of Anesthesiology GPRO/DCRI/Novartis Pharmaceuticals.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Duke University Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.