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

British loumal ~ [ U r o l o g g (1995), 76, Suppl. 2, 23-28

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

Introduction

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 treatment 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’ volunteers 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.

Medical ethics - rights, duties and utility

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.

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 participation 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

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?

In contrast, the rights-based ethicist argues from the standpoint that it is the patient’s 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.

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.

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.

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.

Clearly, the two systems are closely related, with the

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24 H.D. ALDRIDGE and M.J. WALPORT

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].

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?

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: however, there is ethical pressure for every attempt to be made in this direction.

Is there a scientific question?

Scientific content

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 scientifically 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.

Therapeutic versus non-therapeutic research

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 particularly 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 cytotoxic 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.

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!

Equipoise

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

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THE ROLE OF THE RESEARCH ETHICS COMMITTEE 25

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.

Scientijc standards

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.

What is the question? As we have already discussed, research ethics committees have a duty to assure themselves that a particular protocol is addressing a worthwhile 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.

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 important 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.

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.

Health ofthe research subjects

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.

Regulations

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 investigators comply with these regulations.

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, without a DDX. Ethics committees will require to see copies of the relevant certificate before they will consider approving a study.

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 medical device, reagent, reagent product, kit, instrument, apparatus or system that is

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26 H.D. A L D R I U G E and M.J. WALPORT

intended to be used in vitro for the examination of substances derived from the human body. It seems likely that this directive will come into force sometime after 1996. These directives are enforced in the UK by the Medical Devices Directorate (MDD, Department of Health, 14 Russell Square, London WClB 5EP, UK) from which more information can be obtained.

Unlike the MCA, the MDD expects studies to have already received ethical approval before application is made to them. Ethics committees are unhappy with this arrangement and discussions are underway as to whether the system should be changed. However, it is important to ensure that any local regulations concerning safety have been adhered to before approaching your ethics committee.

Irradiation. Subjects may be exposed to irradiation in a research protocol through the administration of X-rays or radioisotopes. Additional X-ray exposure may arise from the taking of additional radiographs, or from X-ray screening involved in the positioning of catheters. Ethics committees will need to assure themselves that such administration is necessary and will therefore need to be informed of the doses involved. In addition it is not sufficient to tell them the research doses: they also need to be told the doses that will be administered for clinical reasons.

The administration of radioisotopes is controlled by the Administration of Radioactive Substances Advisory Committee, (ARSAC; Department of Health, Eileen House, 80-94 Newington Causeway, London SE1 6EF, UK) from whom a certificate can be obtained. An ethics committee cannot grant approval until it has seen such a certificate. It should be noted that the use of a standard radioisotope scan (e.g. a bone scan) as part of a research procedure is not covered by a clinical ARSAC certificate and that an additional research ARSAC certificate is required.

Recruitment of subjects and the taking of consent

The recruitment of volunteers and patients to research protocols needs very careful consideration. The subject should be capable of understanding all of the aspects of the protocol and giving fully informed consent for their participation. They should not be coerced into entering a study. Certain categories of volunteers may be more susceptible to coercion than others and these include junior members of staff, medical students, and relatives of patients. None of these categories of volunteers should be excluded from participation in research but an ethics committee may wish to see evidence that consent will be taken in a non-coercive way, and all consent forms and information sheets should emphasize that partici-

pation is entirely voluntary and that there will be no adverse consequences of non-participation.

Is it acceptable to pay participants in research studies? Participants in research should be re-imbursed for expenses involved in travelling and genuine loss of earnings. It would be clearly coercive and unacceptable to offer a volunteer €500 to undergo a liver biopsy, with a risk of serious morbidity. However, is it unacceptable to offer a volunteer € 2 5 an hour for participating in a phase 1 study of a novel drug, which involved no more than frequent measurement of blood pressure and blood sampling? A pragmatic answer has been provided by guidelines from the Royal College of Physicians and the Association of the British Pharmaceutical Industry [4]. Both organizations note that, (a) phase 1 research on drugs is an essential part of their development: and (b) that sufficient volunteers are unlikely to be recruited who are willing to participate for solely altruistic reasons. Consequently these organizations have taken the utilitarian view that payment of volunteers in compensation for the inconvenience of participation in this type of research is acceptable. However, ethics committees are likely to scrutinize closely the amounts of money offered in relation to the specific protocol and the source of the volunteers.

Research on patients unable to give fully informed consent requires special consideration and can be con- sidered in several categories: children, demented patients, some psychiatrically ill patients [ 5 ] , and unconscious or very ill patients. Can research be conducted on such patients? There are two circumstances in which this may be ethically acceptable and, indeed, desirable. Therapeutic research is acceptable because the patient stands to gain personal clinical benefit. In this case, patients could be put at significant disadvantage if their inabiIity to give consent prevented their participation in research. Non-therapeutic research may also be acceptable, on the condition that the particular research can only be conducted on patients of the particular category that is unable to give informed consent. For example. the pathophysiology of septic shock may only be fully understood by conducting experiments on patients suffering from that condition. It is absolutely essential that non-therapeutic research in such situations carries minimum risk.

Can someone else give informed consent on behalf of a subject incapable of giving informed consent: The strict legal answer is no. However, it is normal practice to obtain written consent from the next of kin or from a key carer.

At what age can a child give written consent (reviewed in [6] and discussed in [7])? There is no strict answer to this question, as children mature at different rates. There is a gradation in the capacity of a child to give informed

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THE ROLE OF THE RESEARCH ETHICS COMMITTEE 27

consent as they grow. Some 10 year olds may be perfectly capable of understanding the nature of a research protocol and deciding whether to participate, whereas certain 15 year olds may be quite incapable of such understanding. In general, a consent form suitable for children ought to be made available for protocols involving children older than 7-8 years. It is then up to the judgement of the individual clinician to decide whether to seek written consent from the child. If a child of whatever age refuses verbally to take part in a research study, their wishes should be respected. Written consent should also be obtained from the parent of any child younger than 16 years.

A great deal has been written concerning consent, with general recognition that every effort should be made to ensure that investigators take informed consent. Thus, there is a duty on investigators to ensure that potential subjects have all the information necessary to reach an informed decision. Clearly, this can be very difficult given the nature of much clinical research. However, ethics committees will scrutinize protocols to satisfy themselves that the information for patients is sufficient to enable them to exert their autonomy. This might mean giving the subject an opportunity to consult friends, relatives and other medical advisers. In general, written consent should be taken, as this reflects the importance of the decision being taken by the subject. However, ethics committees often allow investigators to take oral consent when the research does not require the subject to undergo any more hazardous procedures than venesection or answering a questionnaire. Written consent is, however, required for genetic studies [8].

Much attention needs to be given to setting out the consent form clearly in simple lay language. The consent must include a statement to the effect that: ‘you are free not to participate, or to withdraw from this research at any time, without having to give a reason and without affecting your future medical care.’ Several different consent forms may be needed if different types of subjects are involved in a research protocol. It would normally be necessary to provide one consent form for normal volunteers and another for patients, as each would require a slightly different explanation about the reason for their participation. The nature of the oral explanation accompanying the written consent form is also important. A study from Scandinavia found wide differences between subjects in their understanding of a research protocol in which they had participated [9].

What should a patient be told about the research protocol? The answer is, everything. Patients must be told if they are entering a placebo-controlled study, and the nature of a placebo explained. They must be told if treatment is going to be decided by randomization. They must be told about the side-effects of a therapeutic agent,

even if, as may be the case in a study of a new cytotoxic drug, these effects are unpleasant. Similarly, they must be warned to inform the investigator if they fall into an excluded category (e.g. pregnant or lactating women, patients taking particular drugs, etc.).

Some have argued that patients, particularly those with cancer, taking part in therapeutic studies should not be fully informed and this has been well-argued in recent articles by Tobias & Souhami [lo] and by Lantos [ll]. However, for every patient who may not wish to be told everything, there is a patient who seeks to make fully-informed autonomous decisions. How does one respond to a patient who says: ‘You didn’t tell me that I was part of study of a new treatment that cures cancer, but you gave me a dummy drug.’

Conclusion

Research ethics committees are a vital part of the process of conducting medical research. They protect the subjects of research, reassure the public and sometimes protect the investigators from their own excessive enthusiasm. The potential benefits of scrutiny of research proposals by research ethics committees apply both to the participants in research and to the investigators. The process of preparing an application to an ethics committee can often result in significant improvements in the protocol. Obsessional attention to detail is as essential to an application to an ethics committee as it is to an application to a grant-awarding body.

References 1 Beauchamp TL, Childress JF. Principles of Biomedical Ethics.

3rd edn. Oxford: Oxford University Press, 1989 2 Gillon R, Lloyd A. Principles ofHealth Care Ethics. Chichester:

John Wiley & Sons 1994 3 Levine RJ. Ethics of clinical trials. Do they help the patient?

Cancer 1993; 72: 2805-10 4 Foster CG. Manual for Research Ethics Committees, 2nd edn.

London: Centre for Medical Law and Ethics, King’s College, 1993

5 Brahams D. Consent to research in presence of incapacity (news). Lancet 1993: 341: 1143-4

6 Nicholson RH. Medical Research with Children: Ethics. Law and Practice. Oxford: Oxford University Press, 1986

7 Koren G, Carmeli DB, Carmeli YS, Haslam R. Maturity of children to consent to medical research: the babysitter test. J Med Ethics 1993: 19: 142-7

8 Harper PS. Research samples from families with genetic diseases: a proposed code of conduct. Br Med 1993:

9 Lynoe N, Sandlund M, Dahlqvist G, Jacobsson L. Informed consent: study of quality of information given to participants in a clinical trial. Br Med J 1991; 303: 610-3

306: 1391-4

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28 H.D. ALDRIDGE and M.J. WALPORT

10 Tobias JS, Souhami RL. Fully informed consent can be

11 Lantos J. Informed consent. The whole truth for patients? needlessly cruel. Br Med J 1993; 307: 1199-1201

Cancer 1993: 72: 2811-5

Additional reading

These are useful reference documents, particularly for committee administrators and chairpersons. Foster CG. Manual for Research Ethics Committees, 2nd edn. London: Centre for Medical Law and Ethics, King’s College, 1993. This is an invaluable compendium of information compiled for members of research ethics committees. It contains 13 sets of published guidelines, including those of the MRC, Department of Health, Royal Colleges and ABPI.

Department of Health. Standards for Local Rrsrrirch Ethics Committees - A Framework for Ethical Rcvirw. London: Department of Health, 1994 Department of Health. Standard Operating Procedures /or LRECs. London: Department of Health. 1994 Department of Health. Using Standards for LRECs. London: Department of Health, 1994

Authors H.D. Aldridge, BSc. PhD, Secretary, Research Ethics Committee. M.J. Walport, MA, PhD, FRCP, MRCPath. Professor of Medicine. Correspondence: Dr H.D. Aldridge. Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.

British Journal of Urology (1995), 76, Suppl. 2. 23-28

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

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