Placebo and the helsinki declaration — What to do?

The Helsinki Declaration is the ‘gold standard’ — a directive, not a law, on how to conduct controlled studies in humans in conformity with ethical principles. In spite of many discussions about their unsuitability some articles have remained unchanged in the most recent (sixth) revision of the Declaration. The demand to use “the best treatment” excludes use of placebo in the control group and presents an obstacle to the scientific evaluation of a number of drugs and treatments in general. The use of placebo is justified whenever its use does not cause irreversible damage or considerable suffering to the well informed patient. It must be, is, and will be used in the controlled clinical trials of treatments of a great number of diseases especially those which have a tendency to spontaneous improvement, even healing, or have a pronounced psychological component An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Placebo: Its action and place in health research today

The place for the placebo in human clinical research is addressed in this paper. The World Medical Association which is comprised of some 80 National Medical Associations uses much of its resources to address medical ethics and human rights issues. It adopted the Declaration of Helsinki in June 1964 which addressed the protection of individuals in clinical trials. The use of placebos assumes an important role in this document. Five Revisions of the Declaration of Helsinki have occurred and the most recent was adopted in October 2000. The provisions on placebo are now in Paragraph 29 which reads as follows: “The benefit, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic methods exists.” The reactions to the newly revised version of the Declaration of Helsinki were numerous and rapid, not the least of which was the paragraph I quoted above. At the direction of the WMA Council, a small group of experts together with the WMA workgroup studied the Paragraph 29 to ensure that no ethically sound research was being restricted by the revision. The outcome was approved by the Council and later the WMA General Assembly in October 2000. This gives a note of clarification as to the appropriate use of placebos. Numerous papers and statements over the last several years have described positions very much in line with the Note of Clarification cited above. This paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Clinical trials: active control vs placebo — What is ethical?

The quest for effective medicines is very old. In modern times two important tools have been developed to evaluate efficacy of drugs: superiority and non-inferiority types of clinical trials. The former tests the null hypothesis of μ (the difference between a tested drug and comparator) ≤ 0 against μ > 0; the latter tests the null hypothesis of μ ≤ - Δ against, μ > - Δ, where Δ is the clinical difference from the comparator. In a superiority trial, a new drug is tested against a placebo; in a non-inferiority trial, a new drug is tested against active treatment. In this paper, arguments are presented to show that a superiority trial against a placebo is scientifically sound but ethically unacceptable, whereas a non-inferiority trial against active treatment is ethically sound but scientifically not reliable. Switching from a superiority type of trial with placebo to a non-inferiority trial with an active-control — following the latest revision of Declaration of Helsinki — is in practice switching from the violation of the uncertainty principle to uncertainty of results. Given human and financial resources, it appears an academic question as to which is more unethical: to violate patients’ rights or to produce results without scientific value. All presented considerations lead to the conclusion that the use of a superiority trial of design with an active control instead of placebo will satisfy scientific needs, expectation of patients, and the ancient quest for effective medicines. In the era of Good (Clinical, Laboratory, Manufacture) Practice, the attention of those performing clinical trials is focused on the procedure, not always on its essence. However even the excellent performance of a trial which is not worth doing is fruitless. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Applying evidence to support ethical decisions: Is the placebo really powerless?

Using placebos in day-to-day practice is an ethical problem. This paper summarises the available epidemiological evidence to support this difficult decision. Based on these data we propose to differentiate between placebo and “knowledge framing”. While the use of placebo should be confined to experimental settings in clinical trials, knowledge framing — which is only conceptually different from placebo — is a desired, expected and necessary component of any doctor-patient encounter. Examples from daily practice demonstrate both, the need to investigate the effects of knowledge framing and its impact on ethical, medical, economical and legal decisions. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

The CIOMS view on the use of placebo in clinical trials

Based on worldwide consultations with experts in science and ethics the revised CIOMS 2002 International Ethical Guidelines for Biomedical Research Involving Human Subjects provide guidance on when the use of placebo as a comparator in clinical research is ethically acceptable. The article reviews the main points of the CIOMS Guidelines and commentaries including the use of placebo in situations where the best current method is available and the relation of placebo to established effective intervention. It discusses the use of placebo in externally sponsored research in low-resource countries and requirements for informed consent related to placebo studies. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Placebo in the investigation of psychotropic drugs,especially antidepressants

The paper presents major ethical, legal and methodological problems related to the use of placebo in mental disorders, especially in depression. It is pointed out that although authoritative groups of experts and numerous publications in the field of psychopharmacology indicate advisability of the double blind design with placebo in clinical trials of antidepressants, in recent years there have been more and more voices questioning legitimacy of this method. Objections of an ethical nature are raised, and reliability of this approach is put into doubt from the methodological viewpoint. These issues are discussed in more detail in the paper. Available alternative solutions should be implemented in psychotropic drug studies. The author shares these objections and doubts of an ethical nature, and believes that the placebo procedure is not a necessity in clinical trials of antidepressants. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Informed consent and the use of placebo in poland: Ethical and legal aspects

The concept of informed consent was one of the most fruitful ideas that deeply changed the relationships between physicians and their patients from paternalism to respect for the personal autonomy of subjects needing professional medical care. The great progress in medicine, also involving the pharmaceutical industry, has created an increasing need to perform different clinical and experimental trials. The evolution of clinical research in the last decades has influenced strongly the design of these studies. One of the most important changes in this field has been the use of placebo groups in double-blind controlled studies. The controversies have involved not only the use of placebo when standard or proven treatment was available, but also some specific problems concerning the procedure of obtaining informed consent in such trials. This paper briefly presents the evolution of informed consent in Poland as well as different ethical and legal problems concerning informed consent and the use of placebo controls in clinical trials. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

The use of the placebo effect in clinical medicine — ethical blunder or ethical imperative?

The current debate in medical ethics on placebos focuses mainly on their use in health research. Whereas this is certainly an important topic the discussion tends to overlook another longstanding but nevertheless highly relevant question, namely if and how the placebo effect should be employed in clinical practice. This paper describes the way the placebo effect is perceived in modern medicine and offers some historical reflections on how these perceptions have developed; discusses elements of a definition of the placebo effect; and suggests some conditions under which making use of the therapeutic potential of the placebo effect can be ethically acceptable, if not warranted. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003. Nikola Biller-Andorno, MD, PhD, is Assistant Professor in the Dept. of Medical Ethics and History of Medicine, University of Goettingen, Germany. Dr. Biller-Andorno also serves as an ethicist for the World Health Organization (WHO). This paper does not necessarily reflect the views of the World Health Organization.     

Placebos and the UK medical research council — and the consumer perspective

The UK Medical Research Council, in order to further its mission of maintaining and improving human health, supports a substantial number of clinical trials on a wide variety of medical questions; some of these trials involve the use of placebos as controls or to maintain blinding. Before providing support, proposed trials are carefully reviewed to assess scientific quality, and to determine whether a placebo is required and is ethical — in addition to ethics review by independent Research Ethics Committees. Some questions such as the choice of placebos in trials in developing countries, in surgical trials and those involving alternative medicine require consideration of additional, specific issues. Involvement of consumers in MRC work has been increasing and includes the establishment of a Consumer Liaison Group; members of this group comment on patient information leaflets for clinical trials, helping to improve patient understanding of trials and ensuring topics like placebo use are explained clearly. Views differ on the value of placebos in clinical care and on their mechanism of action; continuing research is helping to clarify the issues. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

What does the public think of placebo use? The Canadian experience

Part of the National Placebo Initiative in Canada included public consultations, based on the belief that the views of the public should inform Canadian policy development on what constitutes appropriate placebo use. Public consultations took place nationally in 2003. A deliberative dialogue approach was used, or a structured discussion format designed to facilitate the consideration of complex issues and build consensus. The placebo debate was characterized as having 3 distinct approaches and each were explored. The first approach “Maximize Patient Protection” identified the need for experts to determine appropriate placebo use and that placebos should only be allowed under very restricted conditions. The second approach “Maximize Medical Knowledge” identified that placebos give essential information about the safety and efficacy of new drugs, and are appropriate when the rights, safety and well-being of research participants are ensured. The third approach “Maximize Patient Autonomy” identified that the current system of regulating placebo use is paternalistic and that patients should be able to define what is in their best interests and have more leeway to determine for themselves if they wish to participate in a placebo-controlled trial. Advantages and disadvantages of each approach were considered and feedback on what constitutes appropriate placebo use was sought. The major findings were that: PCTs were considered a valuable and acceptable part of advancing medical knowledge; research using placebos must be valid and justifiable; a patient-centred approach needs to be fostered; patient autonomy (choice) should be a first consideration and take clear precedence in trials of low to medium risk; patient protection (or health) may need to “trump” patient autonomy at higher levels of risk and/or patient vulnerability; placebos are not a violation of the duty of care as duty of care is best met by identifying a choice for patients, whenever a choice is available. These consultations clearly were not designed to produce conclusive evidence, but rather to provide some useful insights into what the public may think about placebo use; additional studies are indicated. Funding for the public consultations was provided by Health Canada and the Canadian Institutes of Health Research. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

The definition of adequate care in externally sponsored clinical trials: The terminological controversy about the concept “standard of care”

The treatment of the control group in externally sponsored clinical trials is the issue of one of the most heated debates in international research ethics. The paradigmatic cases are the mother-to-child HIV-transmission trials that took place in 16 developing countries in 1997, where the control group received a placebo while proven treatment was available in industrialized countries. From this circumstance results the controversy as to whether the sponsor and researchers of externally sponsored trials have to supply a treatment that is usually not available in the host country. From the beginning of the debate the controversial level of treatment has been called “standard of care”. However, besides the disagreement about the quality of the care that has to be supplied, there is as yet no widely accepted clear meaning of this concept. This article examines the fundamental ambiguity of the term and its formal function as an ethical criterion including suggestions on its further use. This paper was presented at the 6th International Bioethics Conference on the subject of ‘The Responsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3–4 June 2005.     

Evaluation of drug toxicity in clinical trials

An increasing number of drugs removed from the market because of unacceptable toxicity raises concerns regarding preapproval testing of drug safety. In the present paper it is postulated that the non-inferiority type of trial should be abandoned in favor of the superiority trial with active controls and less stringent (p<0.1, both for efficacy and toxicity) statistics. This approach will increase sensitivity of detection of drug-induced adverse effects at the expense of increasing false positive results regarding the difference in efficacy between the tested and reference drug. Such a move will increase the protection of future patients. In addition, the proposed design is far more acceptable from the clinical (e.g. no need to specify the statistically expected “unimportant” number of deaths) and ethical points of view, as well as being favored by the strong incentive of involved parties. In the second part of this paper arguments are presented in favor of the hypothesis that placebo (still used in some superiority trials) does not induce adverse effects. The assertion that placebo may induce adverse effects is probably biased by the nature of the clinical experiment. Such a conclusion is supported by studies indicating that placebo-induced adverse effects are disease — and treatment — specific. The modification of clinical trials according to the proposed changes may increase the trials’ sensitivity at detecting adverse effects of drugs. A lecture on the subject of this paper was presented at the 6th International Bioethics Conference on the subject of ‘The Responsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3–4 June 2005.     

Using empirical data to inform the ethical evaluation of placebo controlled trials

There has been considerable debate about the ethical acceptability of using placebo-controls in clinical research. Although this debate has been rich in rhetoric, considering that much of this research is predicated upon the assumption that data from this research is vital to clinical decision-making, it is ironic that researchers have introduced little data into these discussions. Using some published research concerning the use of placebo-controls in clinical research in hypertension and psychiatric drug trials, I suggest some ways that such data might be incorporated into the ethical analysis concerning placebo use in clinical trials. This approach promises to be important for enhancing conceptual and scientific understanding as well as public policy decision-making. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Homeopathic remedies as placebo alternatives — verification on the example of treatment of menopause-related vegetative and emotional disturbances

With the example of treatment of menopause-related vegetative and emotional disturbances, the author verifies the effectiveness of the use of Ignatia amara containing complex homeopathic remedies (IACCHR) as an alternative to placebo. Substantial improvement in psychological and psychosomatic symptoms was observed. Climacteric complaints diminished or disappeared completely in the majority of women (95.7% by patient evaluation and 96.2% by physician evaluation). Compared to standard pharmaceuticals, IACCHR treatment was tolerated better and lower risk of side effects was observed. The results obtained in this work indicate the significant therapeutic potential of this group of treatments, which is in line with the therapeutic effect of the placebo. Nevertheless, the showing of specific effects in pharmacological tests disqualifies the investigated treatments from use in a clinical trial in place of a placebo. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.     

Placebo and criminal law

This article considers issues concerning cases where the use of placebo is lawful or is not lawful under aspects of German criminal law. It will differentiate between cases of individual therapy and cases of supervised experiments within the scope of medical tests. Thereby, it reveals that a medication of placebo with regard to an individual patient seems to be lawful if there is no alternative possibility of a better treatment using a chemically effective medicine and if the limits of presumed consent are complied with. On the other hand, in the context of the supervised experiment, the assignment of a patient to a group treated with placebo is only lawful if the patient has been fully informed about the possibilities of a treatment and if the patient has given consent to it. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003. The author’s interests include International Criminal Law, Comparative Criminal Law and Philosophy of Law.     

The protection of patients’ rights in clinical trials

The Helsinki Declaration is a very important document regarding the protection of patients’ rights in clinical trials and one of the fundamental sources of operational principles for every ethics committee. Although they have been updated, the international guidelines for ethics committees continually fail to address certain issues pertaining to the protection of patients’ rights in clinical trials. These issues include, most significantly, the method of electing ethics committees (a free, secret ballot should be preferred to direct appointment), the avoidance of conflict of interest during the election of ethics committee members, and the necessary insurance coverage for the participants of clinical trials. Polish law should, on the other hand, be developed in such way as to not limit the effectiveness of ethics committees in protecting patients’ rights in clinical trials. The ideal solution would be to draft a uniform law concerning not only clinical trials, but all medical experiments. The opinions of experts who have been reviewing medical research projects for several years may prove to be especially valuable in this setting. This paper was presented at the 6th International Bioethics Conference on the subject of ‘The Responsible Conduct of Basic and Clinical Research’, held in Warsaw, Poland, 3–4 June 2005. The author is Chairman, Bioethics Committee of the Warsaw Regional Chamber of Physicians and Dentists.     

He said,she said: Episodic retrieval induces conflict adaptation in an auditory Stroop task

People respond more slowly if an irrelevant feature of a target stimulus is incompatible with the relevant feature or the correct response. Such compatibility effects are often reduced in trials following an incompatible trial, which has been taken to reflect increased cognitive control. This pattern holds only if two trials share some similarities, however, suggesting that it may be modulated by the episodic context. To look into this possibility, we had participants respond to high- or low-pitched tones by saying “high” or “low,” respectively, and ignore the simultaneously presented auditory word “high” or “low.” As expected, performance was impaired if the heard word was incompatible with the required response, and this Stroop-like effect was reduced after incompatible trials. This sequential modulation was observed, however, only if the voice in the two successive trials was the same, whereas no modulation was obtained when the speaker changed. The results suggest that sequential modulations are due to the automatic retrieval of episodic event representations that integrate stimuli, actions, and situational and task-specific control information, so that later reactivation of some elements of a given representation tends to retrieve the other elements as well.     

Rights: Foundations, Contents, Hierarchy

It would seem that we in the West are suffering from an increasing glut of rights. To the sixty-odd human rights that the Universal Declaration and its Covenants have long given us, must now be added the particular rights claims of an increasing number of ‘oppressed’ minorities, claims to compensation rights for just about every conceivable harm done and claims to ever more trivial things. This tendency is harmful insofar as it trivialises rights and devalues the coverage of rights. Human rights are fundamental and ought to be protected from these tendencies. Using an analysis of the foundations of human rights, and their function in maintaining autonomy in particular, this article analyses the content of rights – what must be fulfilled in order for a right to be protected – as a means of demonstrating the possibility of reducing the volume of rights without reducing rights coverage and of creating a defensible hierarchy.     

The Universal Declaration’s Problematic Rights Justification

Abstract

In this paper I aim to critically analyse the underlying moral justification of the rights enshrined in the Universal Declaration of the Rights of Mother Earth. The aim of the critique is to highlight some of the problematic areas that underpin the Declaration’s rights and in doing so to point to ways that one can begin to rectify the problems with them and the Universal Declaration itself. The paper aims to critically examine the moral justification for the Universal Declaration’s rights, which is found in the works of Thomas Berry and his commentators who use the notion of ‘subjectivity’ to justify the existence of such rights. The paper critically examines such a notion and argues that it is not strong enough to do the work required of it, and that it is too problematic to serve as a justification for the Universal Declaration’s rights, as the ethical framework it provides is too cryptic and indeterminate, and does not provide us with an adequate action- and law-guiding framework upon which to establish the Universal Declaration and its rights.     

The placebo effect in popular culture

This paper gives an overview of the placebo effect in popular culture, especially as it pertains to the work of authors Patrick O’Brian and Sinclair Lewis. The beloved physician as placebo, and the clinician scientist as villain are themes that respectively inform the novels, The Hundred Days and Arrowsmith. Excerpts from the novels, and from film show how the placebo effect, and the randomized clinical trial, have emerged into popular culture, and evolved over time. An earlier version of this paper was presented at an international conference, “Placebo: Its Action and Place in Health Research Today,” held in Warsaw, Poland on 12–13 April, 2003.