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Healthcare research is haunted by a history of unethical studies in which profound harm was caused to vulnerable individuals. Official systems for gaining ethical approval for research, designed to prevent a repetition of these shameful examples, can prove bureaucratic and inflexible in practice. The core ethical principles of respect for autonomy, prevention of harm, promotion of benefit, and justice (which form the basis of professional codes of research conduct) must be applied flexibly to take account of contextual, methodological, personal and practical considerations. Ensuring that the design and conduct of all research is ethically sound is the responsibility of all involved—including researchers, research institutions, ethics review committees and regulatory bodies.
Recognizing and responding to the ethical dimension of research is a fundamental part of the research governance process. Ethical codes of practice and regulatory frameworks reflect concern about actual or potential examples of unethical research. Translating these broad ethical principles into the specific context of individual research projects in different social and cultural settings poses challenges for researchers, ethics review committees, and regulatory bodies.1 Concepts such as informed consent are open to interpretation and influence within specific social and political contexts. In France, for example, legal and ethical guidelines are less restrictive in relation to research on patients who lack competence than in other European countries, reflecting a cultural tradition that places more emphasis on therapeutic benefit than self determination.2 In this paper, we explore the relationship between fundamental ethical principles, the ethics review process, and the conduct of medical research, with particular attention to the principle of informed consent.
The Nuremberg Code3 was developed in response to the medical experiments conducted under the Nazi regime. Its main focus was on protecting research participants from harm and ensuring that they had given valid consent. Other examples of potentially harmful research on participants who were not fully informed or who had no choice whether to participate4-6 have reinforced the need to protect research participants from harm and obtain informed consent. These are the two core principles of the Declaration of Helsinki7 which was developed by the World Medical Association and first adopted in 1964. Its most recent version was ratified in 2000. The Helsinki declaration, and other international codes of research, has tended to be interpreted as referring to clinical or biomedical research. In recent years there has been increasing recognition of the need for ethical regulation of other forms of research (for example in the social sciences) and of activities that have not traditionally been classified as research (such as medical audit). This reflects earlier discussion in the series regarding `what is research?', the delineation between different research-type activities and the sometimes varied application of ethical principles to these according to the label used (e.g. audit, quality improvement or research).8 From an ethical perspective, it is the nature of the study undertaken, and the involvement of participants in the study, that generates the requirement to comply with the principles of ethical conduct, and not the label given to it. Some national and international codes of research ethics are listed in Box 1.
A third principle articulated in many ethical codes is to promote benefit. Research should benefit either research participants directly, or the wider population, and the benefit of the research should significantly outweigh the potential harm to participants. Additional ethical principles may come to light when particular examples of research practice cause concern. The principle of justice, for example, was a key concern in the debate over studies of HIV treatments in developing countries.9,10 The principles of honesty and integrity (of researcher, research institution and research sponsor) were highlighted by the Olivieri case, in which a researcher was impeded in publishing her concerns over toxicity of a study drug in a trial funded by a pharmaceutical company.11
These core principles inform the duty of care that a researcher owes to research participants, and the duty that a research institution or sponsor owes to both participants and researchers. The purpose of the ethical review process is to ensure that the researcher and research sponsor are discharging their duty of care to research participants, informed by the core ethical principles set out in the national and international codes of conduct (Table 1). While the main focus of the review process is on the effect of research on the participants, there is also an ethical requirement to identify and minimize potential harm to researchers. Reports have previously documented researchers encountering physical and psychological harm during the research process.12,13 This includes risk of exposure to disease,14 distress, or physical and emotional abuse from participants, carers or colleagues.15 Whilst some types of fieldwork have rightly been identified as `dangerous',12,13 risk and harm to researchers may also arise in areas considered `safe'13 and through coding or analysing data that concerns sensitive issues.16 Researchers from ethnic or sexual minorities or who are untrained or inexperienced may be particularly vulnerable,11,14 and in many cases researchers are offered little in the way of protection.15
A key requirement of ethical codes is that the importance of the research objective is in proportion to the inherent risk to the participant. In a clinical trial, there is a potential direct benefit to some research participants (for example, the opportunity to take a new, highly effective medicine that is not yet licensed for general use). But a clinical trial would be unethical in the absence of clinical equipoise (i.e. if the researchers knew beyond doubt that the drug was more effective than other interventions, they would not be justified in withholding it from half the participants). What the participant is being asked to do is share in the uncertainty (they might gain some benefit—but they might be randomized to the control arm, or the new medication might prove less effective than existing treatments, or have harmful side effects). In other words, there is rarely a guarantee of direct benefit for the individual clinical trial participant. An important rule of thumb is that a `control' intervention should equate to best available treatment—or at the very least, to best usual care. For this reason, it is rarely acceptable to have a placebo or `no intervention' arm when testing drugs, educational interventions, or healthcare policies except in situations where no intervention has ever been shown effective.
The main benefit of much observational research is to future patients or to society in general—for example, phase two vaccine trials on healthy volunteers or epidemiological studies to identify risk factors for specific diseases. But being in a research study may bring indirect (secondary) benefits to the participant. Assessing these benefits, like assessing risk, is not straightforward. Secondary benefits may include closer monitoring of a patient's condition in the therapeutic research or increased feelings of self worth through knowledge that they are helping others.17 In reviewing a proposal a research ethics committee needs to form a view on the relative risks and benefits of the research, but researchers must also carefully consider this balance at the earlier stage of developing the research protocol, as part of their duty of care to participants.
In weighing up the risk-benefit balance in research, the following should be taken into account:
In the UK, it is no longer part of the remit of the research ethics committee to evaluate the science of a proposal, but they are required to obtain independent information on the risks and benefits of the proposed research. A study that involves significant risk of harm to research participants will need to show a significant potential benefit. For example, many studies of new malaria vaccines involve infecting participants with malaria via mosquito bites. The potential harm to the participants from contracting malaria if the vaccine is ineffective may be considered justifiable (provided they have given informed consent) because of the huge potential benefit to the world wide community in developing such a vaccine.
Respect for the integrity and autonomy of the individual underpins the requirement for informed consent of research participants. One of the key functions of ethical review is ensuring that consent for participation in research is properly obtained and documented. The process of obtaining consent must be sensitive to the cultural values of the potential participants if their autonomy is to be truly respected. This is particularly relevant when research is conducted in communities that may not share the cultural values of the researchers, for example research in developing countries, or with refugee populations. Valid consent for any medical procedure, be it research or clinical care, requires that: (a) the person is informed of the nature of the procedure, including its likely risks and benefits; (b) the person is competent to make the decision; and (c) the decision is made freely and without coercion. All three elements of the consent procedure need to be considered in the specific context of the proposed research, and all three are informed by the principle of respect for autonomy.
Research participants cannot make an autonomous choice about whether to participate in a study if they do not have information that is relevant to their making that choice. In research, as in clinical practice, there are two key factors in ensuring that consent is truly informed. One is the content of the information provided, its accuracy, comprehensiveness and clarity. The other is the process of information sharing, how it is presented, the context in which it occurs, time allowed for reflection and discussion, and the balance of power between researcher and participant. The process of information sharing will vary depending on the type of research. A questionnaire survey may require only a clear information sheet whereas a clinical trial of a new drug treatment will involve a more complex process more akin to a clinical consultation. In this situation the model of concordance may be useful.18 Provision of information requires particular care when the research involves vulnerable groups, for example children, or when there are language and cultural differences between researcher and participant. Researchers working with Navajo interpreters using a translation of the standard consent form in a diabetes clinical trial found that the consent process caused `embarrassment, confusion and misperceptions that promoted mistrust'.19
Valid consent must be freely given. Researchers and research ethics committees need to consider whether the process of obtaining informed consent includes implicit or explicit coercion of participants. For example, presentation of information can emphasize benefits of participation and obfuscate risks, or payment to participants may potentially be coercive, depending on the context and amount offered. The context in which patients are approached, or asked for their consent may be coercive, for example if not enough time is allowed for participants to consider the information. A more subtle area of potential coercion is the relationship between researcher and research participant. In many instances of healthcare research the researcher is also the participant's medical carer and patients may fear that refusal to participate in a study will jeopardize their care. Health research within universities has raised concerns about the overuse of student participants and the pressure they experience due to a fear of losing course credits or upsetting their tutors.20
A valid consent requires that the person giving consent is competent to do so. Competence is assessed in relation to the decision being made, for example a 14 year old may be competent to consent to take part in a survey on smoking behaviour in adolescents but not competent to consent to take part in a phase two study of an HIV vaccine. The legal definition of capacity (in English law) to consent to medical treatment (which would probably also apply to research) is that the person understands the relevant information, believes the information and is able to evaluate the information and make a choice.20 It is possible to conduct research with patients who are not competent to give consent, including children, but national and international guidelines, and in some countries specific legislation,21 place limits on the type of research that can be carried out (see Table 2). In most cases consent or assent of a family member or someone with legal responsibility for the participant will be required. In general, research cannot be carried out on individuals who lack capacity to give consent unless it is not possible to conduct the research in any other way—for example, research on neonates or in intensive care. In these cases the research should be therapeutic (i.e. have the potential to benefit the research participants), or if non therapeutic must involve minimal harm.
There are some situations where consent for research studies is difficult or impossible to obtain, even from people who are capable of giving it. The development of national and international regulatory frameworks for the conduct of research, the expansion of the focus of such frameworks to include different methodological paradigms—for example, social science research—and the increasing emphasis on individual informed consent within these regulatory frameworks, has raised challenges for both researchers and the research ethics community. An example of this is an increasing emphasis in UK law on consent to use stored data and tissue for research purposes which has generated heated debate within some research communities with claims that whole categories of research will become virtually no-go areas. UK guidelines for researchers have been developed in some of these areas.22-24 More recently, there has been some movement away from a blanket ban approach to research where there is no individual consent to one where researchers are encouraged to present an argument for conducting the research with reference to: the benefits of the research; the need for this type of study; the risk of harm to participants; and the reason why individual consent cannot be obtained. There has also been an increasing interest in exploring concepts of informed consent in contexts where individual consent is difficult or impossible to obtain, and in developing alternative models of consent that may be both practically achievable and ethically justifiable in these situations. Table 3 gives some examples of these models. Thus the focus on individual informed consent has led to an evolving and richer interpretation of the concept of consent. This may facilitate ethical research by permitting some research to be conducted without individual informed consent while not disregarding the key ethical principle of respect for autonomy.
In conducting healthcare research, both researchers and participants are to some extent a means to an end—the improvement of healthcare for patients and/or the general population. It is thus essential that healthcare research in all its forms is underpinned by core ethical principles that protect participants and researchers from harm and respect their integrity as individuals. Ethical review and governance processes play an important role in ensuring that these core principles are translated into the practice of research. There is some concern that the potential benefits of medical research are not given enough weight in the ethical review process, and that the inflexibility of informed consent requirements has led to potentially valuable research being lost.25,26 Reducing unnecessary bureaucracy may facilitate the passage of research protocols through the ethical review process. The UK Department of Health has recently published a report on the operation of NHS research ethics committees that makes recommendations in this area.5 As healthcare research becomes more diverse—both in the type of research and the populations studied—ethics committees, researchers and research sponsors face a continuing challenge in interpreting and balancing these principles in specific situations without severely limiting the progress of important research, which may in itself be harmful.
This is the third and final paper in a series on research governance [Series editors: Trisha Greenhalgh and Sara Shaw]