Is it ethical to use a placebo?

C. Campbell and A. K. Jainer

St Michael's Hospital, South Warwickshire Combined Care NHS Trust, St Michael's Road, Warwickshire CV34 5QW, UK

Michelson et al (2001) evaluated the efficacy of fluoxetine in panic disorder and reported that fluoxetine was associated with a significantly greater proportion of panic-free patients compared with placebo. We read this double-blind randomised study with interest and wish to raise some concerns about the use of a placebo arm.

The use of placebo arms in randomised controlled trials remains a controversial issue and has been criticised on ethical grounds. In this context, the Declaration of Helsinki demands that individual patients in a study ‘be assured of the best proven diagnostic and therapeutic method’ even in the control group (Rothman & Michels, 1994). This statement clearly discards the use of a placebo as control when a ‘proven’ treatment exists. The declaration also directs that a study that violates its precepts should not be accepted for publication.

In addition to this, a trial that aims to establish whether a treatment is better than placebo may be trying to answer the wrong question. After all, even if a new treatment is worse than an existing one, it may still be ‘effective’ in that it is better than no treatment (placebo). In this regard, Hill (1963) pointed out that the essential medical question at issue is how the new treatment compares with the old one, not whether the new treatment is better than nothing.

As there are many drugs with proven efficacy in panic disorder (i.e. benzodiazepines, tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase A and buspirone), we are keen to know why the authors did not try to compare the efficacy of fluoxetine with existing drugs. It appears that they are keen to reflect a drug-specific effect rather than demonstrating the relative efficacy. In this context Cochrane (1989) stated that no new treatments should be introduced into medicine unless they have been shown, in randomised controlled trials, to be superior to existing treatments or equivalent to existing treatments but cheaper or safer.

EDITED BY MATTHEW HOTOPF

REFERENCES

Cochrane, A. (1989) Effectiveness and efficacy: random reflections on health services. BMJ, 10, 428-433.

Hill, A. B. (1963) Medical ethics and controlled trials. BMJ, i, 1043-1049.

Michelson, D., Allgulander, C., Dantendorfer, K., et al (2001) Efficacy of usual antidepressant dosing regimens of fluoxetine in panic disorder. Randomised, placebo-controlled trial. British Journal of Psychiatry, 179, 514-518.[Abstract/Free Full Text]

Rothman, K. J. & Michels, K. B. (1994) The continuing unethical use of placebo controls. New England Journal of Medicine, 331, 394-398.[Free Full Text]


 

Author's reply

D. Michelson

Lilly Research Laboratories, Indianapolis, IN 46285, USA

EDITED BY MATTHEW HOTOPF

Declaration of interest

D.M. is an employee of Eli Lilly and Co.

Drs Campbell and Jainer touch on an area of controversy in the design and conduct of psychiatric drug efficacy studies, arguing that the Declaration of Helsinki ‘clearly discards the use of placebo... when a "proven" treatment exists’. We disagree with their interpretation of the Declaration on several grounds, and note the broad support for careful use of placebo in psychiatric trials (Temple & Ellenberg, 2000) (including the support of the multiple independent ethical review boards that approved the protocol for our study). There are abundant data that non-specific interventions can have marked beneficial effects, albeit on average less than active drugs. Non-drug therapies are often offered to patients as an alternative to drug therapies, and the absence of risk related to adverse drug effects can offset the potential for lesser efficacy. In our trial, both treatment groups had marked improvement from baseline. In this regard, placebo is not ‘no treatment’.

Drs Campbell and Jainer suggest drawing conclusions about drug efficacy based solely on comparisons of active agents. Unfortunately, in many trials a drug previously shown to be active is not superior to placebo despite adequate powering and the use of standard trial designs. Such trials are often referred to as ‘failed’ and in anxiety and depression are extremely common. A comparison of a new agent against a drug previously shown to be active without a placebo comparator is uninterpretable unless one agent is superior to the other. Concluding that a drug is efficacious without a placebo comparison can lead to an incorrect assumption of drug-specific effects if neither the investigational drug nor the active drug was, in that trial, any better than placebo would have been if included. Introducing a drug into therapeutic use on the basis of such a trial would expose patients to a compound with no greater benefit than placebo but all the risks of a pharmacological intervention (Temple & Ellenberg, 2000). Placebo is also critical in the assessment of safety, as it provides a base rate for determining which adverse events are truly related to the investigational drug. For these reasons, placebo-controlled trials are almost universally demanded by regulatory bodies to demonstrate efficacy for new pharmacological interventions.

Drs Campbell and Jainer also assert ‘no new treatments should be introduced into medicine unless they have been shown... to be superior to existing treatments... [or] cheaper and safer’. This absolute statement reflects several misconceptions and confounds the investigation of a drug with its introduction into general use. There is no general agreement about how to define or demonstrate equivalent or relative efficacy — precisely the reasons why most regulatory bodies will not consider relative efficacy claims in labelling. Furthermore, clinical trials provide information about group responses. Individual patients may not respond to or tolerate a particular drug, yet benefit from a different drug that is not, on average, more efficacious or safer than the first agent — it is in patients' interest to have several choices. For example, using Campbell and Jainer's procedure, the selective serotonin reuptake inhibitors, now proven to be safer and better tolerated than tricyclic antidepressants, might well not have been introduced into practice.

Finally, price is not an issue of trial design or science, but determined by the value that patients and purchasers put on a drug, based on evidence about the drug and experience with it (effectiveness as well as efficacy). Whether new drugs for panic or other psychiatric disorders should be ‘introduced into medicine’ and how they should be priced are decisions made on the basis of assessments of data about safety, efficacy and potential place in the therapeutic armementarium — decisions that cannot be made before the data are collected. Campbell and Jainer may feel that the results of this trial do not warrant further investigation of the use of fluoxetine for panic disorder, although we would disagree. It is, however, wrong to suggest that the trial as designed should not have been performed or published.

REFERENCES

Temple, R. & Ellenberg, S. (2000) Placebo-controlled trials and active control trials in the evaluation of new treatments: part I: ethical and scientific issues. Annals of Internal Medicine, 133, 455-463.[Abstract/Free Full Text]





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