Elsevier

The Lancet

Volume 359, Issue 9314, 13 April 2002, Pages 1337-1340
The Lancet

Department of Ethics
Placebo-controlled trials and the Declaration of Helsinki

https://doi.org/10.1016/S0140-6736(02)08277-6Get rights and content

Summary

A revised version of the Declaration of Helsinki, issued in October, 2000, remains a vital expression of medical ethics, and deserves unanimous support. A strict interpretation of the declaration seems to rule out clinical trials that use a placebo control group whenever licensed therapeutic methods already exist, preferring active controls. Although the efficacy of some new medicines can be satisfactorily established without the use of a placebo, for others the judicious use of placebo remains essential to establish their effectiveness.

Section snippets

Revised Declaration of Helsinki

The Declaration of Helsinki, first drawn up in 1964, has become standard guidance for all medical research that involves human beings. In particular, it has been widely used to guide the conduct of clinical trials done to develop new medicinal products. The revision of the declaration,1 issued by the World Medical Association in October, 2000, has been appropriately strengthened in several areas and its relevance and value remains as great as ever. However, the new version contains one section,

Clinical trials of new medicinal products

A wide variety of clinical trials are done during the development of a new product, in healthy individuals and in patients. The trials that could be affected by section 29 are done in phase III, and sometimes the later part of phase II. They are the trials done in patients with the target disease to provide pivotal evidence of efficacy. In such trials, the product should generally be tested in the planned manner of use in the intended population. Hence medical research is combined with medical

Advantages of placebo-controlled trials

There are well known reasons why placebo-controlled trials are generally more reliable than active-controlled trials in provision of conclusive proof of efficacy. The reasons are fully discussed in the E10 guideline Choice of Control Group,8 which was produced under the auspices of the International Conference on Harmonisation (ICH) and has been adopted in Europe, USA, and Japan. Other guidelines and publications also refer to this issue.9, 10, 11

Briefly, placebo-controlled trials provide their

Improvement over an active control

Some active-controlled trials have similar methodological strengths, namely those aiming to show the improved efficacy of the test product. Showing that a test product has improved efficacy compared with an already licensed product is clearly a satisfactory result, and has the same reassurance with respect to the internal validity of the trial. However, it is noteworthy that in comparative clinical trials many potentially valuable new medicinal products do not have greater efficacy than

Similar efficacy to an active control

The methodological difficulty that results in the continuing need for placebo-controlled trials relates to active-controlled trials intended to show that two treatments have similar effects. Similarity is a far more likely objective in practical situations, in which active controls might be considered. Such trials are often set up as non-inferiority trials rather than equivalence trials. In these studies, similarity or superiority to the active control are both regarded as satisfactory

Designs that reduce exposure to placebo

Even in a straightforward placebo-controlled trial, receiving placebo does not imply receiving no medical treatment. In most trials there will be other medications that are permitted in both treatment groups and that are expected to be used to a roughly similar extent. Rescue medication will be predefined, when appropriate, for use in circumstances described in the protocol. Additionally, a standard condition in all clinical trials is that at any stage patients can withdraw, either from

Ethically acceptable use of placebo control

Although alternative designs are always available, they often do not provide satisfactory answers. Straightforward randomised placebo-controlled comparisons are generally scientifically desirable for reliable evidence of efficacy, even when active treatments are already in widespread use. In what circumstances can such trials be ethically done?

In this connection it is important to draw a distinction between signs and symptoms that the patient could have without any irreversible harm, those that

Conclusion

Although our view of the ethicality of placebo might seem inconsistent with the meaning of section 29 of the declaration, it echos widely held opinions.16, 17 There are several areas of medicine in which licensed products are available, but in which placebo-controlled trials still remain the only means of conclusively assessing the efficacy of new medicinal products whose potential advantages lie in areas other than efficacy. Provided that the safety and interests of individual patients are

References (17)

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