Education And Debate

When placebo controlled trials are essential and equivalence trials are inadequate

BMJ 1998; 317 doi: http://dx.doi.org/10.1136/bmj.317.7162.875 (Published 26 September 1998) Cite this as: BMJ 1998;317:875
  1. Martin R Tramèr, research fellow (martin.tramer@hcuge.ch)a,
  2. D John M Reynolds, consultant clinical pharmacologistb,
  3. R Andrew Moore, consultant biochemista,
  4. Henry J McQuay, clinical reader in pain reliefa
  1. aPain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ
  2. bDepartment of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE
  1. Correspondence to: Dr M R Tramèr, Division of Anaesthesiology, DAPSIC, Geneva University Hospital, 1211 Geneva 14, Switzerland
  • Accepted 9 June 1998

Arguments against the use of placebo groups in clinical trials have been based on opinion rather than evidence. Ethical issues have been raised,1 but these are contentious. 2 3 Scientific requirements should not override ethical ones, but if placebo controls are not used, then active controlled trials (trials using other active drugs as controls) have to be able to determine the efficacy of an intervention and its likelihood of causing harm.

Summary points

  • Many consider the use of placebos in clinical trials to be unethical, but can trials without placebo controls provide sensible and useful results?

  • One problem is finding a gold standard comparator—for example, no gold standard comparator exists for the prophylactic antiemetic ondansetron

  • Another problem is the underlying variation in likelihood of an event (wanted or unwanted); the incidence of postoperative nausea and vomiting, for example, can range from 1% to 80% within 6 hours and from 10% to 96% within 48 hours after surgery

  • Ondansetron (pooled 4 mg and 8 mg data) seems better than metoclopramide 10 mg at preventing postoperative nausea and vomiting within 6 hours of surgery but not after 6 hours; comparisons with all the other antiemetics and data on adverse effects are inconclusive

  • In clinical settings where no gold standard treatment exists and where event rates vary widely, trial designs without placebo controls are unlikely to yield sensible results

  • The ethics of recruiting patients into trials that cannot yield sensible results is dubious

  • Systematic reviews could provide ethics committees and trialists with the necessary information to question the ethics of a trial design

Evidence from placebo controlled trials

We used the antiemetic ondansetron to explore the value of active controlled trials for two reasons. Firstly, the ethics of using placebo controls in ondansetron trials has been questioned repeatedly, both in oncology 4 5 and after surgery,6 causing confusion …

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