When placebo controlled trials are essential and equivalence trials are inadequate

doi:10.1136/bmj.317.7162.875

From trainee to consultant, BMJ Group offers doctors around the world tailored information, special events, learning resources and recruitment services at every step along their career path.

... by doctors, for doctors, for patients
We are open for entries!

Online learning

BMJ Learning

High-quality CME / CPD for doctors and other healthcare professionals. BMJ Learning features hundreds of accredited, peer-reviewed learning modules in text, video, and audio formats. Find out more

Courses and Qualifications

BMJ Masterclasses

BMJ Masterclasses, led by experts, help clinicians to use the latest evidence and recent guidelines in practice and meet their CPD/CME requirements. Find out more

Exam Preparation

The leading provider of online exam preparation, helping over 167,000 healthcare professionals to pass their exams. Find out more

onExamination

Search all BMJ education articles:

From

Limit by

Access to the full text of this article requires a subscription or payment. Please log in or subscribe below.

Martin R Tramèr, research fellow (martin.tramer@hcuge.ch)a,
D John M Reynolds, consultant clinical pharmacologistb,
R Andrew Moore, consultant biochemista,
Henry J McQuay, clinical reader in pain reliefa

^aPain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford OX3 7LJ
^bDepartment of Clinical Pharmacology, Radcliffe Infirmary, Oxford OX2 6HE

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 …