Ethical issues in clinical research: the role of the research ethics committee

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<ul><li><p>British loumal ~ [ U r o l o g g (1995), 76, Suppl. 2, 23-28 </p><p>Ethical issues in clinical research: the role of the research ethics committee H.D. ALDRIDGE* andM.J. W A L P O R T t Royal Postgraduate Medical School and tDepartment ofhledicine, Hammersmith Hospital, London, UK </p><p>Introduction </p><p>There is a moral duty on the medical profession to endeavour continually to improve the health of patients, through the development of improved methods of treat- ment and care. Equally, it is generally accepted that it is unethical to expose patients to new procedures or treatments, when the risks of doing so have not been evaluated nor the efficacy of the treatment assessed. The role of the research ethics committee is to consider medical research involving patients and healthy volun- teers in an ethical context, with the welfare of the research subject (normally patients) being of critical importance. Research ethics committees have to reach a decision after considering the risks associated with a particular project and its potential benefits to the patient, other patients or the wider community. In this paper we will discuss some of the ethical issues that a research ethics committee has to consider when discussing clinical research projects, and that are relevant to clinical researchers when planning and implementing a research programme. </p><p>Medical ethics - rights, duties and utility </p><p>The background to current ethical thinking, particularly as applied to the practice of medicine, is complex and interesting. Its roots are in the philosophies of the ancient world, particularly ancient Greece, and, of course, the Judaeo-Christian tradition. However, for the purposes of this discussion it is probably useful to describe briefly two widely accepted (but not mutually exclusive) sets of ethical definitions, the primary aims of which are to assist both those involved in clinical research (and medical practice more generally) and ethics committees to reach reasonable decisions. </p><p>The first system, the dutyhightshtility system, describes the ways in which different people approach ethical problems. Practitioners of duty-based medical ethics take the view that their individual duty of care to their patient should dominate decisions about the partici- pation of that patient in research. Using this approach, it may be argued that it might not be in the best interests of particular patients for them to be fully informed that </p><p>they are participating in a placebo-controlled study of a cancer chemotherapy, or to give them a full and detailed account of the side-effects of a novel cytotoxic drug. The duty-based ethicist may argue that patients should not be told that they are entering this trial. It could cause significant psychological harm to a patient to appreciate that they might be randomized to receive a placebo - an agent with no effect against their cancer. Equally, why should a group of patients be told the horrific potential side-effects of a treatment that has no effect? </p><p>In contrast, the rights-based ethicist argues from the standpoint that it is the patients right to understand everything about the treatment being offered and the duty of the doctor is to provide the information to help the patient make an informed decision. </p><p>The utilitarian view is that the participation of a few patients in a research study may benefit others and that the potential harm to those individuals participating in this type of study may be offset by the benefits to many other future patients. A utilitarian view of the allocation of medical resources may be acceptable, e.g. if given a limited budget then we cannot afford a particular expens- ive medical intervention. However, a utilitarian approach to the participation of patients in research is potentially very dangerous. The means cannot justify the ends if even a few patients suffer as a consequence. </p><p>In practice, the ethical attitude that has been adopted in the UK is a rights-based approach. The welfare of actual patients participating in research is paramount and fully informed consent must be sought. </p><p>The second system is the four principles approach, which comprises the following [1,2]. 1. Autonomy, i.e. the right of a patient to make his or her own decisions about their care and treatment. Consequently, to behave ethically, a clinician ought to respect patients autonomy and thus give them as much information as possible to reach a decision. 2. Beneficence, i.e. the duty of a clinician to do good to his or her patients. 3. Non-maleficence, i.e. the duty of a clinician not to harm his or her patients. 4. Justice, i.e. the moral obligation to act on the basis of fair adjudication between competing claims. </p><p>Clearly, the two systems are closely related, with the </p><p>0 1995 British Journal of Urology 23 </p></li><li><p>24 H.D. ALDRIDGE and M.J. WALPORT </p><p>rights-based ethicist putting the stress on autonomy, the duty-based ethicist on beneficence and non-maleficence and the utilitarian on justice (i.e. the fair distribution of risks and benefits). These are very simplistic definitions and those interested in pursuing this topic are referred elsewhere [1,2]. </p><p>The ethical context of clinical research When preparing an application for ethical approval, there are several key questions. 1. 2. Is the proposed research therapeutic or non- therapeutic? 3. Is there equipoise between the opposite arms of the study? 4. Does the protocol accord with accepted scientific standards? 5. How will the health of the research subjects be affected? 6. Have all the necessary regulations been followed (i.e. those relating to drugs, devices and radiation)? 7. Are there proper procedures for obtaining consent? </p><p>The welfare of the subjects is critical and it is important to consider the research from their point of view. In this context, it might be useful to consider potential research subjects as being partners in the project who need to be fully and willingly involved. Consequently, not only is it important to ensure that their welfare is not threatened, but also that they are fully aware of the investigators aims and are in agreement with them. In many cases, this may seem a rather demanding requirement: how- ever, there is ethical pressure for every attempt to be made in this direction. </p><p>Is there a scientific question? </p><p>Scientific content </p><p>It is generally accepted that it is unethical to perform research that is unlikely to add to knowledge. Although research ethics committees are not normally qualified to review the scientific details of projects brought before them, they are required to assure themselves that the research programme proposed is clinically or scientifi- cally worthwhile. Clearly, it would not be ethical to expose patients to risk when there are unlikely to be any scientific or clinical benefits at the end of the study. Similarly, it would not be ethical to waste resources on a scientifically worthless project, nor, even when there is no tangible risk associated with the research, to waste patients time. Consequently, in presenting a proposal to an ethics committee it is important that the submission includes a brief description of the scientific background to the study and a clear statement of why the research question needs to be answered. </p><p>Therapeutic versus non-therapeutic research </p><p>When considering a research project in ethical terms, it is important to be clear as to whether the patients themselves are likely to gain benefit from taking part in the research. Is the research therapeutic! This is particu- larly important in relation to the consideration of risk. It is generally accepted that it is ethically acceptable for patients to be exposed to some risk in the course of a clinical research project as long as there are potential benefits for them. An example of therapeutic research would be the experimental introduction of a new cyto- toxic agent into the treatment of a malignant disease. If this disease had a high mortality rate over a short time, it may well be justified to try a new drug that had the potential for severe side-effects, even including death. It would then need to be explained to the patient that on one side of the scales was a disease with a high mortality and on the other, a drug with a potential for prolonging life, but also a risk of shortening it. </p><p>By contrast, an example of non-therapeutic research would be a study of the distribution within the body of a radiolabelled drug, given in tracer quantities, where there is no potential for clinical improvement to the individual patient. Non-therapeutic research is only acceptable if the patients are not exposing themselves to any more than a minimal risk by participating in the study. Unfortunately, there is no hard and fast means of defining minimal risk, particularly as we are all exposed to some risk of death or injury from almost every aspect of our daily lives. Consequently, there has been a great deal of discussion in an attempt to devise examples of activities the risks of which can be understood by most patients. For example, it is widely accepted that the risk of death associated with a transatlantic flight can be used as a standard for defining minimal risk. Finally. it is important to recognize that the risks associated with participation in research are usually better understood by those doing the research than by those participating in it! </p><p>Equipoise </p><p>The majority of clinical research involves the compari- son of two or more treatments, normally an established treatment regimen (the Gold Standard) and a new, experimental treatment. From an ethical point of view it is important that the clinicians delivering the treatments to their patients are genuinely unaware which of the two treatments is better, either in terms of efficacy or by virtue of having fewer or less severe side- effects: this is the concept of equipoise (discussed by Levine [ 3 ] ) . Clearly, it would be unethical to enter a patient into a study where one of the treatment arms is </p><p>British Journal of Urology (1995), 76, Suppl. 2. 23-28 </p></li><li><p>THE ROLE OF THE RESEARCH ETHICS COMMITTEE 25 </p><p>known to be less effective than one of the other experimental treatments or the current conventional treatment. The judgement as to whether there is equipoise is often very difficult and sufficient information should be presented to the ethics committee to allow it to form a view. </p><p>Scientijc standards </p><p>Ethics committees have a duty to satisfy themselves that a protocol is likely to address adequately the hypothesis the investigators have set themselves, i.e. the committee must assess whether the protocol has been designed in a scientifically acceptable manner. There are two prob- able key questions in this regard. </p><p>What is the question? As we have already discussed, research ethics committees have a duty to assure them- selves that a particular protocol is addressing a worth- while clinical or scientific question. Consequently, it is important that the hypothesis that the study aims to address is very clearly stated: it is not for the ethics committee to attempt to imply from a protocol what the hypothesis is. In addition, as with most well-designed research, it is advisable for each protocol to address only one hypothesis. </p><p>Is the study well designed? Will the protocol provide an answer to the question or hypothesis posed? In this regard, it is important that investigators give a very clear description of the study, in terms that can be understood by a non-expert readership. It is also import- ant that this description includes an accurate description of the procedures involved in the research and the statistical methods to be used to analyse the data. </p><p>As mentioned earlier, it is unethical to recruit patients or healthy volunteers to a study when it is clear that the study will in all probability not generate any mean- ingful data. One reason why clinical studies sometimes fail is because no adequate hypothesis had been formu- lated: a second and equally common reason is because an inadequate number of subjects had been entered. In many instances it might be necessary for a pilot study to be carried out so that the size of the effect to be measured can be estimated. Once the quantitative effect of the intervention has been estimated and the statistical significance to be achieved if detected, then it is possible to calculate the number of subjects needed for the study; ethics committees are increasingly expecting to see such calculations. </p><p>Health ofthe research subjects </p><p>It is important that the protocol states clearly and honestly the potential effect of the research on the health of the research subjects. For example, are there possible hazards, and if so, adequate facilities to deal with them, and what degree of discomfort or distress is foreseen! Similarly, although not necessarily related to their health directly, it is important that patients understand precisely what recruitment into a study will involve for them: what procedures will they have to undergo, what measurements will be made, how long they will take and what special visits to the hospital will be needed. </p><p>Regulations </p><p>In addition to the more abstract issues already discussed, there is an increasing number of statutory regulations governing the use of drugs, devices and radioactivity, and ethics committees are expected to ensure that inves- tigators comply with these regulations. </p><p>Drugs. The manufacture, sale and importation of drugs is controlled by statute administered by the Medicine Controls Agency (MCA; Department of Health, Market Towers, 1 Nine Elms Lane, London SW8 5NQ, UK). There is often confusion as to when a Clinical Trial Certificate (CTC), Clinical Trial Exemption Scheme (CTX) or Doctors and Dentists Exemption Scheme (DDX) is appropriate when applying for ethical approval of a clinical trial involving the giving of medicines to patients (studies on healthy volunteers do not require certifi- cation). Put simply, the CTC and CTX are granted to the pharmaceutical company sponsoring the trial, while a DDX will be granted to a physician wanting to carry out research using a medicinal product that does not have a product licence for that use. Drugs that have a product licence for one indication cannot be used in a research project investigating its use for another indication, with- out a DDX. Ethics committees will require to see copies of the relevant certificate before they will consider approving a study. </p><p>Devices. Since 1 January 199 3 regulations governing the use of active implantable devices (e.g. cardiac pace- makers, neurostimulators and infusion pumps) have been in force [The Active Implantable Devices (AIMD) Directive.] On 1 January 1995 further regulations come into force implementing another, more wide-ranging directive [The General Medical Devices (GMDD) Directive] that covers all other implantable devices. A third directive [the In Vitro Diagnostic Medical Devices (IVD) Directive] will cover any med...</p></li></ul>

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