Placebo-controlled trials ethics

While serious ethical objections have been raised regarding the use of placebos in trials of drugs used in the treatment of psychiatric disorders (largely based on the possibility that the patients may commit suicide if they are inadequately treated, although such patients are usually excluded from placebo controlled trials), all regulatory authorities insist on properly conducted, placebo controlled trials as a basis for registering a new drug. 

Although some of these arguments against the use of a placebo involve questions of ethics, the use of a placebo treatment is often preferable to the continued use of treatments of unproven or dubious efficacy or safety. Some old remedies that are still in current use have never been subjected to a placebo-controlled trial, and the opportunity to include them in a placebo comparison may only be during the development of a new medicine. 

Temple, R., and Ellenberg, S.S. (2000) Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1 ethical and scientific issues. Ann Intern Med 133 455 63. 

While the issue of the ethical conduct of clinical trials in pediatric psychopharmacology is addressed comprehensively elsewhere in this book, it is important to present an FDA perspective on this important matter. It is also important to have the issue of ethics discussed in the context of the scientific needs for trials presented to the FDA in support of new drug applications. These trials must be adequate and well-controlled (U.S. Department of Health and Human Services, 2001). What this requirement essentially means is that, in order to support an efficacy claim, the trials must be interpretable and must be able to document efficacy. For treatments that are intended to improve symptoms, as is almost always the case for psychotropic drugs, placebo-controlled trials are the usual standard. This is especially true when there is a substantial failure rate in placebo-controlled trials for the drugs known to work in a particular therapeutic area, as again is the case for most psychotropic drugs. Where that is true,... 

Ethically motivated opponents consider trials with placebo control unacceptable if and when standard therapies or interventions are available for a particular patient population. Accordingly, placebo-controlled trials would be permitted only in the following circumstances ... 

In some situations double-blind placebo-controlled trials are not acceptable from an ethical standpoint examples are studies on patients in life-threatening conditions such as severe withdrawal symptoms (e.g. delirium tremens) or diseases with a high risk of suicide. To keep double-blind conditions in longterm treatment may also be difficult or even impossible, e.g. if one of the drugs used needs special safety monitoring or if the side-effect profile requires special treatment considerations. 

The WMA is concerned that Paragraph 29 of the revised Declaration of Helsinki (October 2000) has led to diverse interpretations and possible confusion. It hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should be used only in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances ... 

Laughren. T.P. The scientific and ethical basis for placebo-controlled trials in depression and schizophrenia an FDA perspective. Em. Psychiatry 16, 418-423, 2001. 

Emanuel E J, Miller F G 2001 The ethics of placebo-controlled trials — a middle ground. New England Journal of Medicine 345 915-919 Greenhalgh T 1997 Papers that report drug trials. British Medical Journal 315 480-483 (See also other articles in the series entitled How to read a paper. )... 

In an ideal world, no drug would become available before it had been thoroughly tested for safety and effectiveness in a randomized, double-blind, placebo-controlled trial in pregnant women (317). However, because of ethical concerns about the welfare of the mother and fetus, pregnant women are traditionally excluded from drug trials. Therefore, usage is most often based on indirect measures of safety, such as in vitro studies and animal models. However, the thahdomide affair reminds us of the potential inadequacy of animal models. 

Abrams et al. (2003) reported the effects of smoked cannabis in painful peripheral neuropathy secondary to human immunodeficiency virus (HIV) and/or antiretroviral treatment. In a preliminary uncontrolled pilot study (in preparation for a planned placebo-controlled trial) excellent correlation was reported between cannabis dosing and pain improvement, with 10 of 16 participants experiencing a greater than 30% reduction in pain. These results provide the ethical justification to proceed with the controlled trial. 

In recent years a number of vigorous criticisms have been made of placebo-controlled trials stressing the ethical problems in giving placebo where effective remedies exist (Rothman, 1996 Rothman and Michels, 2000). Anderson has gone so far as to criticize the usual assumption that placebo-controlled trials are more convincing than active controlled equivalence studies, arguing (correctly in my view) that even... 

From this point of view, the ethical solution is to use so-called add-on trials-that is, to randomize patients to receive either the new treatment or placebo in addition to standard therapy. In fact, if one studies the field of therapy for HIV infection, which is characterized by the seriousness of the disease and the rapidity of therapeutic progress, then this is exactly what has been done. The trials that have been run have been add-on trials and these are commonly described as placebo-controlled trials. Researchers and clinicians have come to the conclusion that active controlled trials would have been unethical. 

Anderson JA (2006) The ethics and science of placebo-controlled trials assay sensitivity and the Duhem-Quine thesis. Journal of Medicine and Philosophy 31 65-81. 

A] placebo controlled trial may be ethically acceptable, even if proven therapy is available,... 

Efficacy non-inferiority trials are often conducted in situations where a placebo-controlled trial would not be ethical, for example, when there exists effective therapy for a serious or life-threatening condition. Despite this, the ethical basis for non-inferiority trial has been called into question. For example, Garattini and Bertele (2007) argue that"... it is unethical to leave to chance whether patients receive a treatment that is anticipated to provide no extra benefit, but could be less safe and less effective than existing treatment options." While their comments were in the context of efficacy non-inferiority trials, the issue could be even greater in the context of a safety non-inferiority trial. The primary objective of a safety non-inferiority trial is to determine whether or not an experimental treatment causes an important harm on this basis alone, there would be little incentive for a prospective patient to participate. Patients must be fully informed of the purpose of such a trial, including the potential benefits and harms, before they can consent to participate. 

In a placebo-controlled randomized supplementation trial (approved by the ethic commission of Ethiopia) in the rural area (AZOZO) district of Gondar Ethiopia from 220 households, 161 children (2-5 years of age) were selected at random for the study at a first visit to the local clinic, nutritional assessment, and stool examination (parasites or ova) were performed (Biesalski et ah, 1999). 141 children with parasites were treated with mebendazole. Heparin blood was obtained for assessment of vitamin A, RBP, and TTR (transthyretine) concentrations. 

Given the ethical concerns about placebo-controlled study designs, several alternative procedures to reduce bias in clinical trials have been proposed ... 

This option assumes a comparable or even standard placebo response rate for historical data and the current trial. The historical improvement rate (on placebo or without any treatment) is then used for purposes of comparison with results of subsequent non-placebo-controlled studies involving the same investigator and protocol design but different drugs. For historical placebo response data it is recommended that a small placebo treatment arm is used for safety data purposes and to avoid observer bias although this proposal may resolve or diminish some ethical concerns, it raises a number of scientific problems ... 

When it is suspected that there may only be small differences between active treatments, and when placebo controls are unavailable for clinical or ethical reasons, then it is often necessary to resort to large-scale studies ( mega-trials ). A good, famous example was the clinical trial known by the acronym GUSTO, where streptokinase and recombinant tissue plasminogen activator (t-PA) were compared for acute coronary thrombosis (for a commentary, see Hampton, 1996). 

Superiority trials of one active compound over another provide the second most convincing proof of efficacy after placebo-controlled studies. The reason for selecting this design rather than placebo has been alluded to already, i.e. it is ethically unjustifiable to use a placebo or (less convincingly) marketing requirements. 

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