Education And Debate

Role of external evidence in monitoring clinical trials: experience from a perinatal trial

BMJ 2000; 320 doi: http://dx.doi.org/10.1136/bmj.320.7240.995 (Published 08 April 2000) Cite this as: BMJ 2000;320:995
  1. Peter Brocklehurst, consultant clinical epidemiologist (peter.brocklehurst@perinat.ox.ac.uk)a,
  2. Diana Elbourne, reader in health care evaluationb,
  3. Zarko Alfirevic, senior lecturerc
  1. a Perinatal Trials Service, National Perinatal Epidemiology Unit, Institute of Health Sciences, Oxford OX3 7LF
  2. b Medical Statistics Unit, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT
  3. c Department of Obstetrics and Gynaecology, Liverpool Women's Hospital, Liverpool L8 7SS
  1. Correspondence to: P Brocklehurst
  • Accepted 7 December 1999

The randomised controlled trial is the most scientifically rigorous way of evaluating interventions whose effects on important clinical outcomes are uncertain.1 Before conducting such a trial, investigators should undertake a systematic review of thevidence from existing trials, including, if appropriate, a meta-analysis. This prevents trials being carried out unnecessarily when the answer to the clinical question is already known.A priori power calculations should be made to determine how many participants will be required to answer the research question,2 and this process is increasingly being required by research ethics committees and funding bodies, among others.3 Nevertheless, under some circumstances recruitment to a trial may be halted before the planned sample size has been reached because

  • Funding has run out or further recruitment has become impossible because of a lack of interest in the participating centres—“trial fatigue”

  • The internal evidence emerging from accumulating trial data suggests that continuing would be unethical4

  • External evidence indicates that the trial should be halted.5

The process for stopping a trial early because of indications from internal data is well accepted and recognised and the statistical methodology has been discussed at length, but this is not the case for external evidence. The process by which trial investigators should consider external evidence and make decisions concerning further recruitment is unclear.

Summary points

Principal investigators of clinical trials should be responsible for obtaining relevant information emerging from other studies

Investigators should seek unpublished confidential information, but this requires sensitive handling

Meta-analysis is useful for incorporating ongoing trial data with existing and emerging evidence

The trial data monitoring committee is responsible for reviewing both internal and external information, but the trial steering committee should decide whether to modify or stop a trial

Methods

We describe our recent experience of stopping a large international trial because of external evidence …

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