Ethics Of Placebo Research Articles

Deception and the ethics of placebo.

The placebo effect in many areas of neurological therapeutics is common and prominent. The importance of the response means that any new treatment must account for the placebo effect, but this in turn raises major challenges as to how to conduct scientifically meaningful research in an ethically acceptable fashion. Basic principles that may be in tension with one another are those of beneficence and respect for autonomy. It may be challenging to respect autonomy if the scientific design of a study depends upon the use of deception, but this is often mitigated by the information provided to trial participants as part of the informed consent process. Deception is a particular challenge if placebos are to be used in a clinical/therapeutic setting, outside the context of a clinical trial. While practice-based placebo use may on occasion be both beneficial and ethically acceptable, close attention must then be paid to ensuring that basic ethical principles are respected and that placebos are either prescribed in an open and honest fashion, or that any deception is authorized.

The ethics of using placebo in randomised controlled trials: a case study of a Plasmodium vivax antirelapse trial

BackgroundThe use of placebos in randomised controlled trials is a subject of considerable ethical debate. In this paper we present a set of considerations to evaluate the ethics of placebo controlled trials that includes: social value of the study; need for a randomised controlled trial and placebo; standards of care; risks of harm due to administration of placebo and the harm benefit balance; clinical equipoise; and double standards. We illustrate the application of these considerations using a case study of a large ongoing multicentre, placebo-controlled, double-blinded, randomised trial to determine primaquine anti-relapse efficacy in vivax malaria.Main BodyThere is an urgent need for primaquine anti-relapse studies in order to rationalise the management of a potentially fatal disease. An ethical justification for the use of the placebo arm is provided on the grounds that the actual current applied standard of care in most endemic places does not include primaquine. It has also been argued that there is clinical equipoise among the primaquine study arms and that the risk of harms of being in the placebo arm is the risk of having relapse, which is no more than not being included in the trial, and that there are no double standards.ConclusionBased on our set of considerations, we conclude that a placebo arm is not only justified but imperative in this study. We propose that similar considerations should be prospectively applied to other placebo controlled trials and observational control arms where no treatment is offered.

The Ethics of Placebo Effects in Clinical Practice and Research.

This chapter provides a synthetic overview of the contemporary debate over the ethics of placebos and placebo effects in both clinical and research contexts. Section 1 briefly reconstructs how ethical attitudes toward the use of placebos have changed during the last century following the emergence of autonomy in medical ethics. Next, Sections 2-4 chart the main ethical issues concerning the use of placebos in clinical settings, examining: the ethics of deceptive placebos; the ethics of placebos without deception; and the ethics of modulating placebo and nocebo effects without placebos. Finally, Section 5 outlines the role of placebos in research, discussing the ethics of placebos as controls in clinical experiments.

Placebos dans la pratique clinique : un aperçu éthique

The use of placebos in clinical settings raises a host of important ethical issues. On the one hand, ethical guidelines tend to categorically prohibit the clinical use of placebos because they require deception. On the other hand, a growing series of empirical studies has revealed that placebos can be clinically effective and are still widely used by health professionals. In this article we provide a synthetic overview of the ethical debate discussing: 1) the ethics of deceptive placebos; 2) the ethics of placebos without deception, and 3) the ethics of eliciting placebo responses without administering a traditional placebo.

Placebo - More hatred than love

A placebo is a sham medical intervention that can produce a placebo effect. Laboratory evidence supports the existence of several mechanisms of placebo effects in both healthy population and patients with a variety of medical conditions. The ethics of placebos have long been debated. However, accumulating ethical concern has arisen from the worldwide use of placebo in randomized control trials (RCTs), which may render their participants without early and optimal treatment. Although the pilgrimage of placebo is still on the way, refinement of controls in RCTs is worth paying new attention to.

The Ethics of Placebo in Studies with Fracture End Points in Osteoporosis

The authors suggest that placebo-controlled trials in osteoporosis are nearly always unethical, since several drugs that materially decrease the risk of fractures in such patients are currently available.

The Science and Ethics of Placebo in Pediatric Psychopharmacology

Pediatric psychopharmacology is a relatively new science. Although the use of psychotropic medications in children has risen in the past decade, there are few standard treatments for serious psychiatric or developmental disorders of childhood. The relative absence of standard treatments is further complicated by the fact that many of the agents used in pediatric psychopharmacology have been adapted from other fields. Therefore, investigators have a responsibility to make incremental progress from concept through pilot studies and large-scale, multisite efficacy and safety trials. Thus, although there is a pressing need to conduct medication trials that can guide clinical practice, there are scientific and ethical considerations to bear in mind when designing clinical trials in pediatric psychopharmacology. This article reviews essential ethical and scientific issues that are relevant to designing clinical trials in children with psychiatric and developmental disorders. Using examples from recently published literature, the article describes the challenges and pitfalls of various clinical trial study designs. The application of sound ethical and scientific principles is necessary to ensure that clinical trials are properly conducted and to guard against ambiguous results that can not guide practice.

Alternatives to Placebo-Controlled Trials

Until recently, the gold standard for assessing the efficacy and effectiveness of new medications has been the placebo-control randomized clinical trial (RCT). However, there are serious ethical concerns about placing patients on a placebo when effective treatments exist. Further, if a new agent is tested only against a placebo, there is no guarantee that it is more effective, or even as effective, as an existing agent. For these and other reasons, ethicists and regulatory bodies have said that, under these circumstances, new drugs should be tested against an active agent. There are three types of such trials: superiority, equivalence, and non-inferiority. In superiority trials, the goal is to establish that the new drug is better (i.e., more effective, or with a more benign side-effect profile) than the standard. Because such trials require much larger sample sizes than placebo-control studies, and are rarely required to bring a drug onto market, they are rarely done. In equivalence trials, the aim is to show that the new and standard agents have similar degrees of effectiveness or adverse events. Due to sample size requirements, most studies of new drugs are non-inferiority trials, in which it is sufficient to demonstrate that the new drug is not significantly worse than the existing ones. However, there are methodological concerns with equivalence and non-inferiority trials, including (a) an inability to determine if the drugs were equally good or equally bad; (b) poorly executed trials with low power can be mistaken for "proving" equivalence or non-inferiority; (c) the equivalence interval is arbitrary; (d) successive non-inferiority trials may lead to a gradual reduction in effectiveness; and (e) often larger trials are necessary. The paper also discusses "add on trials." It is recommended that, even when existing drugs exist, trials should consist of at least three arms, one of which is a placebo. This paper briefly considers the ethics of placebo, and conditions are stated under which such studies can be conducted.

Reply

To the Editor: I thank Mr Coffey and Dr Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar for their commentary on my article. They clearly enunciate a point of view which Emanuel and Miller2Emanuel E.J. Miller F.G. The ethics of placebo-controlled trials: a middle ground.N Engl J Med. 2001; 345: 915-919Crossref PubMed Scopus (285) Google Scholar have referred to as “active-control orthodoxy,” that is, the idea that placebo-controlled trials (PCTs) should never be performed for conditions for which there is “standard therapy.”2Emanuel E.J. Miller F.G. The ethics of placebo-controlled trials: a middle ground.N Engl J Med. 2001; 345: 915-919Crossref PubMed Scopus (285) Google Scholar My article is a brief refutation of this view. I agree with Coffey and Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar that scientific validity is not a sufficient condition for ethical clinical research, although it is a necessary condition. The first part of my article addressed why many investigators, the Food and Drug Administration, and I believe that there remain “compelling and scientifically sound methodological reason[s]” to use PCTs, despite the existence of “standard therapy.”3Onder R.F. The ethics of placebo-controlled trials: the case of asthma.J Allergy Clin Immunol. 2005; 115: 1228-1234Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar An important point raised by Coffey and Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar is their contention that asthma patients “were actually harmed” by enrollment in PCTs because subjects randomized to a placebo arm were more likely to withdraw for “worsening of asthma.”4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar This is, of course, expected if the active treatments in the PCTs are efficacious. What do Coffey and Ross1Coffey M.J. Ross L.F. Ethics of placebos in clinical asthma trials.J Allergy Clin Immunol. 2006; 117: 470Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar mean when they say patients were harmed? In another article, they state that “the harm of an asthma exacerbation may be short-lived and easily reversed (minor harm) or it may lead to hospitalization or even death (major harm).”4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar It would be a serious concern if patients in PCTs were suffering such “major harm” by being randomized to placebo. When one looks at the authors' data regarding reported hospitalizations, however, one finds that the rate of hospitalization for patients enrolled in placebo arms of PCTs (5 of 4398; 0.1%) was almost identical to that of patients enrolled in active-treatment arms (9 of 8867; 0.1%).4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar Of 1180 children who received placebos in asthma trials, there were no reported hospitalizations.4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar Finally, of all patients enrolled in PCTs, there was a 0.1% rate of hospitalization, whereas there was a 0.9% rate of hospitalization in patients enrolled in active-control and add-on trials.4Coffey M.J. Wilfond B. Ross L.F. Ethical assessment of clinical asthma trials including children subjects.Pediatrics. 2004; 133: 87-94Crossref Scopus (26) Google Scholar This may indicate that patients were monitored more closely, or sicker patients excluded, in PCTs. I believe that these data support my conclusion that properly designed, reviewed, approved, and monitored PCTs of asthma may safely and ethically be conducted.3Onder R.F. The ethics of placebo-controlled trials: the case of asthma.J Allergy Clin Immunol. 2005; 115: 1228-1234Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The issues of “exacerbations” and “equipoise” both concern the question whether research subjects may be allowed to sacrifice anything to promote the purpose of the research. If the answer to this question is no, then the entire biomedical research enterprise is on dubious moral grounds. If a subject may not ethically bear the risk of being randomized for a short time to placebo, how does one ask the same subject to consent to phlebotomies, lung biopsies, bronchoprovocation challenges, or exposure to unknown risks of new immune modifying agents? If the current Declaration of Helsinki stands for barring researchers and subjects from participating in well designed, carefully monitored PCTs, then the World Medical Association should revisit this document.

Ethics of placebos in clinical asthma trials

Ethics of placebos in clinical asthma trials

Developing the Ethics of Placebos in Physiotherapy

Summary The discussion of placebos in physiotherapy is affected by limited understanding of the size of the placebo effect in research and the lack of research specific to physiotherapy. The ethics of placebo use in physiotherapy research and clinical practice need to be debated fully. It is possible to use what is known of placebos to maximise treatment effect without ethical compromise, but the profession has yet to develop a model of placebos and ethics relevant to its own clinical practice. The discussion of placebos in physiotherapy is affected by limited understanding of the size of the placebo effect in research and the lack of research specific to physiotherapy. The ethics of placebo use in physiotherapy research and clinical practice need to be debated fully. It is possible to use what is known of placebos to maximise treatment effect without ethical compromise, but the profession has yet to develop a model of placebos and ethics relevant to its own clinical practice.

The ethics of placebo controlled clinical research and applied psychophysiology.

The ethics of placebo controlled clinical research and applied psychophysiology.

Ethics of placebo-controlled trials in developing countries.

Ethics of placebo-controlled trials in developing countries.

The ethics of placebos in AIDS drug trials.

The ethics of placebos in AIDS drug trials.