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Ethics

Ethical issues in placebo-controlled trials in Alzheimer's disease

Robert D Goldney and Brian F Stoffell

MJA 2000; 173: 147-148

The use of placebos and the dubiousness of patients' ability to give informed consent give rise to various ethical concerns

  The use of placebos in clinical drug trials is the most conclusive method of elucidating the effectiveness of new medications. However, it has long been recognised that there are significant ethical issues with such trials, as some patients will be given no specific therapy.1,2

Few would argue against the use of placebos in drug trials when there are no effective treatments available. However, there comes a time in the treatment of most illnesses when one or other treatment is recognised as effective. It is then that ethical questions arise in the use of placebos in evaluating other new treatments for the same condition. For example, it is difficult to justify the use of placebos in trialling new medications for treating depression. Gold standards such as tricyclic antidepressants, or the now well-established selective serotonin reuptake inhibitors, are generally used as benchmarks in studies examining the efficacy of new antidepressants.

How well established do new treatments have to be before they themselves become the standard against which other new drugs should be investigated rather than subjecting patients to the risk of having no treatment at all? This situation is addressed in Section 12.4 of the recently published National Health and Medical Research Council (NHMRC) Statement on ethical conduct in research involving humans,3 which states:

"The use of a placebo alone or the incorporation of a non-treatment control group is ethically unacceptable in a controlled trial where: (a) other available treatment has already been clearly shown to be effective; and (b) there is risk of significant harm in the absence of treatment. If there is genuine uncertainty about the net clinical benefit of a treatment, a placebo controlled trial or a trial with a no-treatment arm may be considered."
This is clearly relevant in the emergence of approved treatments for Alzheimer's disease, for which new agents are now available.4 The two drugs available in Australia, tacrine and donepezil, have proven effective in double-blind randomised-controlled trials.5,6 This level of evidence (E2 or Level II)7 was considered sufficient for these drugs to have been approved for marketing by the Commonwealth Therapeutic Goods Administration. That being so, one would assume that at least criterion (a) above has been met.

Criterion (b) above could be assumed if one accepts that Alzheimer's disease is a progressive condition. This would be significant if one were proposing a prolonged trial to demonstrate the efficacy of a medication, even if an established drug may only halt the process of decline.

This has, for example, become relevant in the initial treatment of schizophrenia. One study showed more severe negative and positive symptoms in schizophrenia associated with a delay in the initiation of treatment, not attributable to poorer premorbid functioning actually delaying the commencement of treatment.8 Another study showed that cortical volume deficits were progressive, but that after treatment they appeared to be static or even partly reversible.9

The analogy between these findings for schizophrenia and the situation with Alzheimer's disease is compelling. The role of plaques containing amyloid beta-peptide (Abeta) in Alzheimer's disease has been elucidated, and there is now evidence of a correlation between elevated levels of Abeta plaques and cognitive decline.10 As the cholinesterase inhibitors tacrine and donepezil influence the formation of Abeta plaques,11 these drugs may be truly disease modifying. Naturally, such findings add to the debate about the wisdom of using placebo controls when a treatment is available.

These issues in relation to Alzheimer's disease have been discussed recently in the international literature.12-18 Knopman et al noted that "the design of clinical trials must evolve as new therapies become available", and stated that "there is now a compelling case for alternatives to trials that include a treatment arm with no active therapy".14 In similar vein, Kawas et al concluded that "As new and more effective treatments emerge, the ethical framework for placebo use in AD (Alzheimer's Disease) studies will require frequent re-examination".17

This is of particular relevance to Alzheimer's disease, as the question arises as to whether or not the patients themselves are able to give informed consent. This is also addressed in the NHMRC Statement on ethical conduct in research involving humans,3 under Sections 5.2 and 5.3, which state:

"Consent to participation in research by a person with an intellectual or mental impairment must be obtained from: (a) the person with the intellectual or mental impairment whenever the person is of sufficient competence and, where the impairment is temporary or recurrent, at a time when the impairment does not prevent the person giving or refusing consent; or failing that (b) the person's guardian, or an authority or other organisation or person having that responsibility at law. A Human Research Ethics Committee (HREC) must not approve, and consent cannot be given for, research which is contrary to the best interests of the person with the intellectual or mental impairment."

The task of ethics committees is particularly onerous in light of these recommendations. The very fact that drugs have been approved by the Therapeutic Goods Administration must again be seen as compelling in terms of there being a treatment available which should be provided for patients in their potential best interests. However, although tacrine and donepezil have been approved for marketing, they are expensive and as yet not subsidised by the Pharmaceutical Benefits Scheme. This raises the question of whether or not it is ethical for those who will not be able to afford to continue with the treatment to be placed in a trial merely in the hope that they may be given the active drug and gain some temporary benefit. It is doubtful whether this is an ethically acceptable argument for allowing participation in such trials, especially as proxies will usually be giving consent, and their legitimate concern for the patient may give this "opportunity for an expensive therapy" too much moral weight.

Institutional ethics committees will be increasingly confronted with these challenges in the coming years. It behoves all such committees to carefully consider these points, bearing in mind that there may also be changes in community attitudes about these issues.

Robert D Goldney
MD, Professor of Psychiatry, University of Adelaide
The Adelaide Clinic, Gilberton, SA
rgoldneyATmedicine.adelaide.edu.au

Brian F Stoffell
PhD, Director of Medical Ethics
Flinders Medical Centre
Flinders University of South Australia, Adelaide SA

Reprints: Professor R D Goldney, The Adelaide Clinic, 33 Park Terrace, Gilberton, SA 5081

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