9. Assessment of the ethics of research6

9.1 Independent ethical review
All research involving healthy volunteers and patients must be subject to independent ethical review and this should be conducted by a Research Ethics Committee.

9.2 Knowledge of involvement
People who are participants in research, whether they are healthy or sick, must be made fully aware of their position and the nature of the research. This is entrenched in the South African Constitution (see also 5.1).

9.3 Clinician-patient relationship
The clinician-patient relationship is based on the belief that the clinician is concerned to put the interests of the individual patient first. Patients generally believe this, and it is essential that a relationship of trust should be fostered. Lack of truth or frankness about research on the grounds, for example, that the research is harmless and that consent need not be obtained because the process of obtaining it will cause needless anxiety, is a breach of the clinician-patient relationship and the constitutional rights of the patient.

9.4 Role and competence of the investigator14,15
The responsible investigator is appropriately qualified and experienced, and commands facilities to ensure that all aspects of the work will be undertaken with due discretion and precaution to protect the safety of the participants.

Adequate preliminary literature should have been studied, and experimental studies should have been undertaken to define, a far as practicable, the risks inherent in participation, and the investigators should be fully conversant with these.

Ethical issues regarding the role of the investigator include possession of the necessary attributes, competence and the release or publication of results.

The investigator needs two attributes: the sensitivity to identify an ethical issue and the responsibility to act appropriately in regard to such issues.

The character of investigators is critical for the quality of the scientific knowledge and for the soundness of ethical decisions in any research project. The integrity of investigators - their honesty and fairness, knowledge, qualification and experience - are the decisive factors. Investigators have a scientific responsibility to their profession and to participants to ensure that a research project yields knowledge worth knowing and that it is as controlled and well verified as possible. Independence of the research should be demonstrated from the funders of a research project as well as from participants.

The results of the research may be disseminated in written form in both popular and scientific journals. Radio and television broadcasts may also be used. Investigators should compile their research report as accurately and objectively as possible. Shortcomings and errors must be admitted.

9.5 Research Ethics Committees

9.5.1 The role of Research Ethics Committees, the history of their origin and details of their composition and organisation, have been provided by the Royal College of Physicians of London.6
9.5.2 Research Ethics Committees are of crucial importance in the proper regulation of research involving humans and animals, since investigators should not be the sole judges of whether their research conforms to generally acknowledged ethical codes.7,17
9.5.3 All research involving humans, whether patients or healthy volunteers, must be referred to a Research Ethics Committee. Sometimes class approval may be given in advance to applications for minor research, or a series of studies of a particular type carried out as a regular feature of a research or training programme. Even in these circumstances, the Committee will wish to be informed of each individual study by title at least.

9.6 Objectives6

9.6.1

The objectives of Research Ethics Committees are the following:

  1. to maintain ethical standards of practice in research;
  2. to protect research participants and investigators from harm or exploitation;
  3. to preserve the research participant's rights, which take preference over society's rights;
  4. to provide reassurance to society that this is being done.

In promoting these objectives, Research Ethics Committees should remember that research benefits society and that they should take care not to hinder it without good cause. Investigators should be helped to achieve a high standard of research ethics, if necessary by being provided with basic training in research ethics. Research Ethics Committees also protect investigators from unjustified criticism. International guidelines on human research7 indicate that a Research Ethics Committee should consider that:

  1. the objectives of research are directed to a justifiable advancement in knowledge compatible with prevailing community interests and priorities;
  2. interventions are justifiable in terms of these objectives.
9.6.2

The Research Ethics Committee should see to it that the responsible investigator is appropriately qualified and experienced. The Research Ethics Committee should also ensure that:

  1. Adequate preliminary literature has been consulted and experimental studies have been undertaken.
  2. Every reasonable effort has been made to inform prospective participants of the objectives and consequences of their involvement and particularly of identifiable risks and inconvenience. Informed consent should be obtained, as outlined in 5.1.
  3. Any arrangement to delegate consent has adequate justification, and that appropriate safeguards have been instituted to ensure that the rights of participants will not be abused.
  4. Appropriate measures have been adopted to ensure the confidentiality of data generated in the course of research, through the use of coding or anonymity of participants, for example.
  5. Every effort has been made to ensure that participants have an opportunity to comment on and, if they wish, to decline to participate, or to withdraw from a research project easily - without having to give a reason, and without any adverse consequence.
9.6.5 It is important to be continuously aware of the need to avoid impeding good research. Indeed, the Research Ethics Committee should seek to facilitate valid research in all possible ways, including the provision of training in research ethics and informed consent.

9.7 Scientific misconduct

9.7.1 A Research Ethics Committee should investigate allegations of scientific misconduct and report the findings to an appropriate body for action, such as an employer or research sponsor.
9.7.2 Following world-publicised cases of misconduct in science in recent times, concerns about integrity in the conduct of research, and about misconduct in science, have been extensively debated. The United States National Academy of Sciences, National Academy of Engineering and Institute of Medicine have jointly published the first of two volumes on Responsible Science: Ensuring the Integrity of the Research Process.18 In this report, specific actions are described which scientists, their institutions and their sponsors can take to preserve and strengthen the integrity of the research process and to deal with allegations of misconduct. The basic sentiments expressed in the report are encapsulated by the President of the National Academy of Sciences: 'Ensuring the integrity of the research process is one of the fundamental obligations that accompanies the right to search for truth'. It should be noted that two of the 22 distinguished panellists who produced this report have expressed general concerns that preclude their support of the report. These dissenting views, seen in the context of the bibliography provided - a condensed version of more than 1400 referenced items in the panel's project files - illustrate the complexity of the issues involved and the need for awareness and ongoing open debate on issues crucial to preserving the integrity of research. Background to research misconduct is given in a publication by the Royal College of Physicians of Edinburgh.19 A conclusion reached is that only demonstrable compliance with good practice, with appropriate training, and with quality assurance of all research activities will address this issue and ensure the quality of all research data.
9.7.3 Investigators have a duty to report perceived research misconduct (falsification, fabrication, plagiarism and departure from ethics standards); institutions have a duty to speedily and fairly investigate this with due transparency and regard for the reputations of whistle-blower and respondent according to the policy of the institution. Whistle-blowers who make allegations in good faith must be protected against retaliation. Examples of model procedures may be found at the Office of Research Integrity website (http://www.ori.dhhs.gov).

9.8 Function of Research Ethics Committees

9.8.1 Applications for approval
Committees deal with applications from named individuals. Applications should come before the Committee in written form. The Committee's attention is focused primarily on:

  1. the nature of the proposed research activity. The question of the extent to which scientific quality, design and conduct of a research project should be considered by a Research Ethics Committee continues to cause difficulty. Badly planned, poorly designed research that appears unlikely to produce useful or valid results, is unethical. Full scientific evaluation is beyond the capacity of most Research Ethics Committees, and therefore such committees should not hesitate to make use of external advisers for difficult problems, particularly in the areas of design and statistical evaluation of protocols. Ideally, applications for ethics clearance should be submitted only after evaluation of the scientific quality of a project by a body competent to evaluate it;
  2. the possibility of harm coming to the participant. The application should describe possible risks or side effects;
  3. the possible benefits of the proposed research;
  4. consent: how the participant is to be informed about the proposed research and the precise way in which consent is to be sought (see also 5.1);
  5. risk (or cost) benefit evaluation of the proposed research.
  6. In international collaborative research, the research proposals should conform to both South African and international guidelines, and indigenous communities should not be exploited.

9.8.2 Interview of applicants
The Committee may need to interview investigators. Personal contact with the Research Ethics Committee may clarify queries and confusions more rapidly than written communication. Investigators should have ready access to members of a Research Ethics Committee to obtain help prior to submitting a proposal for approval, or to the Committee itself in order to speed up and facilitate the process.

9.8.3 Terms of reference and scope6
A Research Ethics Committee should:

  1. advise its appointing authority on all matters pertaining to the ethics of research involving humans or animals;
  2. review proposals for human or animal research to be carried out in the institution or area of that authority;
  3. review proposals for human or animal research to be carried out by staff of the authority in places where there is no Research Ethics Committee;
  4. not undertake functions that might conflict with the above. For instance, it should not act as a research-funding or grant-giving committee;
  5. make an annual or more frequent report to the appointing authority, and make the report available to the public;
  6. monitor progress and problems that may be experienced in the conduct of research;
  7. react to any allegations of misconduct in research involving humans carried out by individuals within the Committee's area of authority.

(For details on Research Ethics Committees for Research on Animals, see Book 3.)

9.8.4 Cost of research
Although the allocation of resources has ethical implications, and consideration of this aspect of research should be given due attention, it is not the prime task of Research Ethics Committees. The fact of ethics approval does not imply that resources ought to be provided, and Committee approval should not be used to assert this.

The results of health, social or environmental research might later give rise to demands for costly implementation. However, this is not properly a concern in the decision made by a Research Ethics Committee on whether the research may ethically be undertaken. Such matters are, of course, a legitimate ethical concern for those responsible for allocation of scarce resources.

What is of concern to a Research Ethics Committee in an environment in which research resources are scarce, is proposed research that is expensive and out of balance with likely benefits. This imbalance implies low beneficence and limited justice in the allocation of resources, and such research should not be granted ethics clearance. Coupled to this is the use of hospital resources to do clinical research of a particular condition, when the treatment of such patients would not normally use those resources. In such circumstances, funding for the extra investigations or treatment must be obtained from sources other than those supplying the hospital.

9.8.5 Ethics of clinical practice9
From time to time a Research Ethics Committee may be approached by a clinician with an ethical problem in clinical practice, not of research. Research Ethics Committees are not constituted for this purpose, and it is unwise for a Committee to respond formally to requests that are outside its terms of reference.

9.9 Membership of the Committee

9.9.1 Principles

9.9.1.1

Two principles should determine membership of Research Ethics Committees.7

  1. Committees should command the technical competence and judgement to reconcile the physical and psychological consequences of participation with both the welfare of the research participants and the objectives of an investigation.
  2. Committees should also, with advantage, accommodate respected lay opinion in a manner that provides effective representation of the non-clinical community as well as clinical interests. Lay opinion in the non-clinical community means opinion from a lawyer, social worker, religious leader, teacher or similar person of standing able to contend with pressures from individuals within the broad health profession.
9.9.1.2 Members of Research Ethics Committees should be people of goodwill, with a high regard for the human personality, for truthfulness and for the continued advance of science in the interests of society.
9.9.1.3 It is important that members of Research Ethics Committees should look at applications critically from the participants' point of view.

It is also important that the community should have confidence in Research Ethics Committees. The composition of such a Committee and how to contact members should be public knowledge.

Experience has shown that non-clinical members are invaluable, particularly on issues of consent and information to participants. A non-clinical member with legal training can be of great value, but his or her role should be a general one, not solely to answer questions of law.

9.9.2 Composition of Research Ethics Committees
Ideally, membership of a Research Ethics Committee should include:

  1. Clinical members, including experienced clinical researchers, and at least one general practitioner. A majority of the clinical members should be involved in providing clinical care;
  2. At least one nurse, preferably in active practice with patients;
  3. At least one person not practising or trained in any health discipline;
  4. Both sexes, and individuals of different race groups;
  5. One or more representatives with knowledge of law, pharmacology, qualitative research and statistics;
  6. One member from outside the institution if clinical trials are being scrutinised according to international norms of Good Clinical Practice (GCP);
  7. Representatives of disadvantaged communities where research is to be carried out in such communities.

The Committee should elect its own Chairperson from among its members, and a Deputy Chairperson should be elected when the need arises. The Committee should be of manageable size with a quorum of not less than five members. It is not practical that the Committee should include specialists in all the fields of health and science of the various proposals that may come before it. All research projects that involve animals should also be referred to a separate Ethics Committee for Research on Animals (see Book 3).

9.9.3 Co-option
The Research Ethics Committee should have the power to co-opt additional lay or professional advisers for an individual application or meeting.

9.9.4 Appointments
After taking appropriate advice, the responsible authority shall formally appoint the Research Ethics Committee members. It is essential that members serve on the Committee as individuals and not as delegates taking instruction from other bodies or reporting to them.

9.9.5 Duration of membership
The period of membership may be prescribed, such as from three to five years, which may be renewed. It should be remembered that although the Committee should not stagnate, members need time to absorb the ethos and to develop skills of ethical review, and it is important not to lose a valuable and willing member simply because time has passed.

9.9.6 New members
Pending general arrangements for training, new members should be provided with appropriate core literature.

9.9.7 Administrative support
A Committee will require substantial administrative help, including secretarial help. Providing this help must be the responsibility of the appointing authorities.

9.10 Method of working6

9.10.1 Meetings
Reasonably frequent, regular meetings are essential to allow a Committee ethos to develop. To work entirely or almost entirely by mail, e-mail or by Chairperson's decisions, even if later put before a meeting, is unacceptable. A disadvantage of working by post is that Committee meetings may become so rare that the valuable mutual exchanges between members are lost, and lay members in particular will feel isolated. For these reasons it is inappropriate to seek to conduct all business without meetings.

For all the members of the Committee to be given the opportunity to express their views, it is important that meetings be held according to correct procedure.

9.10.2 Chairperson's approval
The Chairperson may deal with minor matters with or without consulting other members. Outcomes should be reported to, and the papers made available to all members at the next meeting of the Committee. Wherever possible, consensus should be sought between meetings, for example by e-mail.

9.10.3 Class approvals
Multiple projects that vary in detail but conform to the same general pattern, may be given a 'class' approval to avoid repetitive submissions. Examples might include some projects in epidemiology, or in training students, or using archived pathology specimens. This is particularly appropriate for projects that pose no risk of distress or injury to participants. However, a letter should be sent to the Research Ethics Committee for their records, stating that a particular investigation will be undertaken according to the class approval.

9.10.4 Decisions and quorum
It is necessary for a Research Ethics Committee to define the size and membership of a quorum, and to establish conventions for determining decisions. A quorum of five members, including at least one non-clinical member, is suggested to conform to international practice.8,9

9.10.5 Update
Research ethics is a dynamic area, so it is necessary to circulate to the Research Ethics Committee relevant publications on general policy, to ensure that the Committee is kept abreast of developments. Ideally, members of the Research Ethics Committee should be sponsored by the appointing authorities to attend courses or conferences to update ethics knowledge.

9.10.6 Adverse decisions and appeal
Although it is rare for a project to be found totally unacceptable, it is common for projects to be modified after discussion with a Research Ethics Committee. If an adverse decision is made, the reasons should be given to the applicant. Investigators should be made aware that they are entitled to have an adverse decision reviewed and to make written and oral representations to the Committee.

An appeal procedure should be available. For example, in the first instance this should be to the Research Ethics Committee that made the decision. If a decision is still adverse, an institution might get external opinion or set up an ad hoc committee of experts to review the project and decision.

9.10.7 Monitoring
It is generally impractical (even if desirable) for a Research Ethics Committee to monitor in detail the conduct of ongoing investigations, but Committees should not lose contact with those that they have approved. Some form of follow-up is desirable, if only an annual questionnaire to applicants. This should establish whether the project has been completed, abandoned (in which case the reason should be given) or is still in progress. The investigator should certify that the research is still being carried out according to the approved protocol. Any modification of substance to the original protocol must be notified to the Committee and permission obtained. Information on adverse events should be sought.

It is recommended that:

  1. Research Ethics Committees should require investigators in charge of approved research projects to submit a brief report of progress at least annually;
  2. Investigators should be requested to send an annual list of published reports to the Research Ethics Committee;
  3. A standard operating procedure for participants and investigators to approach the Research Ethics Committee when there is concern about the conduct of research, should be in place for each Research Ethics Committee. These may be based on the recommendations of the Office of Research Integrity or the Association of the British Pharmaceutical Industry (see http://www.ori.dhhs.gov and Appendix IV).

Applicants should be told in any guidelines or forms issued that adverse events should be reported within 72 hours of the event.

9.10.8 Sanctions
Research Ethics Committees have no direct sanctions, but if they learn of research being conducted without their approval or in breach of what they have approved, speedy arrangements should be made to interview the investigator. An investigator who bypasses or ignores the recommendations of a properly authorised Research Ethics Committee, creates a potentially serious situation that could make him or her vulnerable to professional disciplinary or even legal proceedings. Where a Committee is dissatisfied with the conduct of an investigation it may withdraw approval, provided full reasons are given. The Committee should then inform the investigator that approval has been withdrawn. The investigation should cease forthwith and the investigator may not then claim that the research had ethics approval. Removal of approval must be made known to the appointing authority who should inform any research sponsors, and to any national ethics body.

9.10.9 Reports
Research Ethics Committees should make a regular report, at least annually, to the appointing authority. In addition to a list of members, number of meetings and any other obviously relevant matters, it should include a list of the titles of projects approved. The reports should be available for inspection by the public. The only exception to public inspection may be to protect commercial interests. However, company names and product trade names may be included with the consent of the company. A full record of such commercial research must, however, be kept by the committee secretariat.

9.10.10 Clinical responsibility
Clinical responsibility for all patients ultimately reverts to the clinicians treating the individual patient, and the clinicians' agreement should be obtained for research conducted on their patients.

9.10.11 Confidentiality
Confidentiality of Research Ethics Committee proceedings (as distinct from decisions) should be preserved because the issues considered are often complicated and delicate. Uninformed or unbalanced publicity could arouse emotions damaging to all concerned, and especially to patients. Moreover, some investigators who have had an original idea fear that this may be passed to others in competition with them.

9.10.12 Declaration of conflict of interest
Just as applicants should declare any conflict of interests, so members of a Research Ethics Committee should declare theirs, such as where an application relates to testing a product of a company to which the member is an adviser. The Chairperson shall decide whether the interest disqualifies the member from the discussion. Where the Chairperson has an interest, a Deputy Chairperson should take his or her place. Anyone with a conflict of interests may not take part in the discussion or decision- making and this should be recorded in the minutes of the meeting. Members with a conflict of interests should recuse themselves when that protocol is discussed.

9.10.13 Research injuries
In the event of a serious research injury to research participants or research workers, the Research Ethics Committee should satisfy itself that a proper inquiry is conducted, and it should consider implications for continuation of the research study. It should also satisfy itself that provision has been made for compensation for injury.

9.10.14 Access to the Research Ethics Committee
Access to the Research Ethics Committee should be available to research participants who may be dissatisfied. It should be the responsibility of investigators to inform research participants of this.

9.10.15 Fees
In the case of direct applications from the private sector, a reasonable handling charge may be made. Members of Research Ethics Committees should not be paid, other than reimbursement of expenditures. If they receive an honorarium, it should be modest and should not be paid by a body having a financial interest in the outcome of applications.

9.10.16 Educational activities
Educational activities in institutions, which include research, may also include administration of drugs and other, sometimes invasive, procedures. These should be put before a Research Ethics Committee.

9.10.17 Publication
When investigators submit their research for publication, they should indicate that the research has been approved by a Research Ethics Committee, and should list the ethics clearance number. Most reputable journals require this. It is unacceptable in principle that an investigator should agree to conditions that may prohibit or impair the chance of publication, although delay may sometimes be inevitable.

9.11 Suggested format for applications to Research Ethics Committees
It is advisable for institutions to have a standard application form or checklist to help applicants provide information required by the Research Ethics Committee in making a decision. (The MRC application form is provided as Appendices I and II for quantitative research and qualitative research, respectively.)

Prior consultation with a member of the committee should be encouraged, to help applicants anticipate and correct ethics problems before an application is considered. The secretariat should have a list of committee members available for scrutiny by applicants.

9.11.1 All project proposals should state:

  1. the title of the proposed project;
  2. details of the investigators:
    • list names, qualifications, positions, departmental addresses, and functions in the proposed research of all investigators;
    • name of principal investigator;
    • experience of principal investigator in the field of research concerned;
  3. place where research is to be undertaken;
  4. statement of the problem to be studied, the aims and objectives of the research; the hypothesis which is to be generated or tested and the value of getting an answer; and the possible outcome of the research;
  5. the scientific background. If similar work has been done previously, state why it needs to be repeated. If it has not been done before, has the problem been worked out as fully as possible using animals or other alternative research methods?; An overview of applicable literature should be given;
  6. the design of the study. Give an outline of the proposed project, including methods to be used, and how the results will be analysed. State the likely duration of the project;
  7. the type of participants. Give details of the method of recruitment for each category (patients, controls, healthy volunteers). Specify whether participants are in a dependent relationship with the investigators, such as students, or whether they are especially vulnerable, such as children or the mentally handicapped;
  8. .substances to be given, such as drugs, special diets, isotopes, vaccines. State route, dose, frequency, precautions;
  9. samples to be obtained, such as blood, urine, cerebrospinal fluid, biopsy specimens. Give method and frequency of sampling, amount of each sample;
  10. other procedures. Give details, of radiographs, endoscopy, anaesthesia, for example;
  11. the potential risks and inconvenience to the participants, their estimated probability and precautions to be taken to minimise risks and inconvenience;
  12. benefits of research to research participant and/or community;
  13. the manner in which the participant's consent will be obtained. An information sheet, written in plain language and understandable by a lay person must be provided, whether the consent form be verbal or written. If the consent is to be written, the form must also be provided. Where relevant, translations in languages of the proposed participants will be necessary. These must be the work of a qualified translator.
  14. whether the participant's personal clinician is to be informed of recruitment of the participant before the study begins, and whether the participant's consent to such information being passed on to the clinician is a condition of participation;
  15. the regulatory status under the relevant legislation of any drug or appliance to be used or tested;
  16. investigators' 'interests' relating to the study, such as profit, personal or departmental, financial or otherwise;
  17. details of any payments to be made during the study;
  18. any conflicts of interest.

9.11.2 Other relevant matter
Attach any other relevant matter, such as letters of permission from an institution to do a study, details of payments to participants, copies of advertisements or any other recruiting matter for healthy volunteers or patients.

9.11.3 Testing medicines and appliances
If the study is sponsored by an industrial company there should be an indication of arrangements for compensation and insurance in the event of injury to participants or investigators according to Good Clinical Practice guidelines.9,10

9.11.4 Paediatric projects (see also 5.3.1.2)

9.12 Assessing the value and risks of research

9.12.1 Objectives of research
The Research Ethics Committee and the investigator should be satisfied that the proposed research is relevant or of scientific value. In coming to a decision, the Committee will bear in mind the magnitude of any intrusion and whether or not there is risk to the healthy volunteer, to the patient, or to the community, as well as the likely importance of the information sought.

9.12.2 Routine research in return for financial support

9.12.2.1 Some research involving patients or volunteers is of a routine nature and is undertaken by clinicians because it brings in financial support, rather than because the information being sought is important. These studies must conform to GCP guidelines.9,10
9.12.2.2 In routine research, importance is often restricted to the commercial interests of a manufacturer, in developing a generic formulation, for instance. When an investigator invites a patient or volunteer to participate in research, it is necessary to give reasons why the research is considered worthwhile. The participant should be informed that the clinician will gain financially from the participant's participation.
9.12.2.3 Research Ethics Committees should be alert to the potential for commercial exploitation of participants or communities, and should withhold approval from projects in which this aspect appears to outweigh the scientific value of the research.

9.12.3 The design of the study
Research Ethics Committees should examine the overall design of proposed research that comes before them. While the appropriateness of the scientific design of a study is not the prime concern of the Research Ethics Committee, it is clearly unethical to allow participants to be exposed to inconvenience or risk in the belief that they are contributing to an increase in knowledge when, in truth, there is no likelihood of such increase. Accordingly, the Research Ethics Committees will occasionally need to give detailed attention to such matters as the ability of investigators using quantitative strategies to make valid and reliable measurements. It should also consider whether the study is likely to produce adequate data for statistical analysis, with a reasonable chance of answering the question under examination. To help the Committee to do this, the research proposal should comment on the adequacy of the proposed statistical methods to evaluate the data generated. Attention also needs to be given to the ability of investigators using qualitative strategies to work in a trustworthy manner in data gathering and data analysis. To help the Research Ethics Committee do this, the research proposal should comment on evaluation of data collection and whether the study is likely to advance the body of knowledge on the subject.

9.12.4 Risk/benefit analysis
A key decision in the assessment of proposed research is whether the risk or inconvenience caused to the participant is justifiable in relation to the value of the information sought. This process is sometimes referred to as risk/benefit analysis. Consideration of the four ethics principles of beneficence, non-maleficence, justice and autonomy will be part of this.

9.12.4.1 Risk
The term 'risk' refers both to the probability of a harm resulting from an activity and to its magnitude. Risk often stands for the combined probabilities and magnitude of several potential harms, whether they be psychological, sociological or physiological in nature. It should be noted that even inactivity may be associated with some risk and that every intervention, however simple it may be, involves some degree of risk.

Risk includes the consequence of a breach of confidentiality and also risks to others, through the use of scarce resources for research that might otherwise be used for patient care.

9.12.4.2 Considerations in risk assessment
In the process of risk assessment the following should be considered:20

9.12.4.2.1 Risk identification is a qualitative description of the overall physical risks, the emotional or psychological hazards to the participant or his or her family, and the risks to which a participant or his or her family would not have been exposed had it not been for participation in the research project. Special care should be exercised in risk identification in vulnerable population groups, because some individuals are already exposed to such a degree of risk that it would be unacceptable to add to it the physical and emotional risks of being a research participant.20 Although excluding such populations from the potential benefits of research may seem inappropriate, added protection must be afforded these groups to ensure a just distribution of risks as well. It must be shown why it is necessary to study a particular vulnerable group.21 Institutionalised individuals should be research participants only if the research is related to problems associated with institutionalised individuals.21
9.12.4.2.2 Risk estimation is a description of the probability or relative magnitude of harm.20
9.12.4.2.3 Risk evaluation is the process of combining the results of risk identification and estimation with the perceptions of those involved. The perception of a risk formed by the participant or the participant's proxy is of overriding importance compared with the investigator's perception of the risk.20

9.12.4.3 Categories of risk
The definitions of the various categories of risk vary in different countries.20 The MRC agrees with many of the recommendations cited,1-9 but for the sake of clarity these recommendations are summarised and modified as follows:

9.12.4.3.1 Negligible risk (The smallest possible risk)
In some procedures, studies or experiments, the risk is so small that it may be ignored. This is sometimes equated with the sort of risk accepted in everyday life.5 In reality, however, this equation is meaningless because of the wide range in the risks of daily life for different members of the population. The only alternative is to accept the idea that negligible risk is relative to the risk to which a person is already exposed. The higher the risk to which a person is already exposed, the higher the level of risk in a research procedure on that person which can be neglected. Such an idea is intolerable.20

The MRC therefore defines 'negligible risk' as equal to the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives of people in a stable society or in the routine performance of physical or psychological examination or test.

Examples of negligible risks include simple physiological experiments involving exercise on healthy volunteers, procedures such as collecting urine by normal voiding, taking measurements of weight and height, collection of nail clippings or small samples of hair, developmental assessment, routine physical examination, observation of behaviour or changes of diet, or obtaining a single peripheral venous blood sample from an adult or bigger child.

9.12.4.3.2 Minimal risk
In more complex or invasive physiological and pharmacological studies it is helpful to consider not only the seriousness of an adverse effect that might result from a procedure, but also the probability of it happening. Therefore the term 'minimal risk' is used to cover two types of situations. The first is where there is a small chance of a recognised reaction which is in itself trivial, such as a mild headache or a feeling of lethargy. The second is where there is a very remote chance of serious injury or death, comparable, for example, to the risk of flying as a passenger on a scheduled aircraft.

An example of minimal risk includes obtaining a single peripheral venous blood sample, say up to 10 ml at a limb site, from a younger child by a competent venesector, provided that the amount of blood collected is not excessive for the size of the child, and that the risks to which a child is exposed before entry into a research project are considered.

9.12.4.3.3 More than minimal risk
Examples of more than minimal risk might include procedures such as spinal taps, biopsies, certain drug tests and interventions that may entail hospitalisation, and behavioural interventions likely to cause psychological stress.21 Also included is the situation in which a procedure is of minimal risk but the outcome of that procedure is not. For example, venesection for an HIV test is of minimal risk, but a positive result represents more than minimal risk for an individual.

9.12.4.4 Risks in therapeutic and non-therapeutic research

9.12.4.4.1 In therapeutic research, the benefits likely to accrue to a participant should outweigh the risk of harm.7 As a general rule, research involving patients should not incur risk greater than minimal. An exception to this rule is where there is great potential benefit to the individual.
9.12.4.4.2 In non-therapeutic research the healthy volunteer may be subjected to no more than minimal risk as a result of participation.6,7 The possibility or probability that a particular investigation will be of benefit to humanity or to posterity, affords no defence in the event of legal proceedings.7 Incompetent participants in research should not be subjected to more than negligible risk.

9.12.4.5 Benefit
A benefit is the opposite of a harm, and refers to any favourable outcome of the research to society or to the individual. The outcome of research is never certain at the outset, and it is thus proper to consider the probability of benefit as well as its magnitude. In practice, 'benefit' often stands for the combined probabilities and magnitudes of several possible favourable outcomes.

9.12.4.5.1 The difference is recognised between therapeutic and non-therapeutic research in the context of risk/benefit analysis, and an individual's choice whether or not to participate in the research. In practice, however, the difference is seldom clear-cut. The same principles of risk limitation apply in therapeutic research as in non-therapeutic research. The requirement to inform the individual about what is proposed and to seek his or her consent, is the same in therapeutic research as in any other form of research involving persons.

9.12.4.6 Assessment of risk and benefit

9.12.4.6.1 The assessment of risk is an inexact science even when applied to conventional investigations and well-established treatments.20 Research protocols provided to Research Ethics Committees must include estimates of the frequency and nature of complications associated with intended procedures and treatments, and this information should be contained in the participant information sheet.
9.12.4.6.2 Despite the lack of precision inherent in risk/benefit analysis when applied to research in humans, it is quite often a straightforward matter for a Research Ethics Committee to reach a conclusion that the risk is, or is not, reasonable in a particular case.
9.12.4.6.3 The risks of discomfort or other physical effects, as well as less obvious effects such as the possibility of psychological disturbance, breach of confidentiality and even simple inconvenience, must all be considered.
9.12.4.6.4 Committees should not rely solely on the view of the investigator when assessing the probability or the magnitude of harm. Independent expert opinion should be obtained whenever deemed necessary.

9.12.4.7 Reducing risk
Research Ethics Committees and investigators have a duty, before embarking on a risk/benefit analysis, to ensure that the risks inherent in the proposed research have been reduced to the minimum necessary to achieve the research objective. This duty includes consideration of whether alternative methods of obtaining the research information are available, consideration of whether lower risks might prevail in a different group of participants and whether participation by humans is required at all.

It is sensible for an investigator to discuss possible risks or benefits in a study with a member of a Research Ethics Committee before submitting an application.

9.12.4.8 Risk/benefit analysis and the individual

9.12.4.8.1 As well as taking steps to reduce the risk in research activities to the minimum, investigators should ensure that the study protocol effectively excludes special groups of people in whom the risk of participation would be particularly great, such as women of child-bearing potential in early trials of novel drugs.
9.12.4.8.2 Persons who consent to participate in a research project should have been given enough information to make their own choice. The concept of risk/benefit analysis should be conveyed as part of the procedure of seeking consent. The person's own assessment of risk and harm is sometimes more relevant to himself or herself than that of the expert. (See also 5.3.2.)

9.12.4.9 Outcome of risk/benefit analysis

9.12.4.9.1 The Research Ethics Committee needs to do more than a mere risk/benefit analysis in deciding whether research is justifiable. A proper assessment of whether the risk to a person is outweighed by the probable benefits, can be arrived at only if the Research Ethics Committee itself has a proper regard for the comfort and safety of the individual participant in terms of the principles of beneficence, non- maleficence, autonomy and justice. There is no easy method of defining the value to be put on comfort and safety, and a useful guide is probably whether or not members of the Committee would consent to participate in the research if they or members of their families were eligible to do so.
9.12.4.9.2 Whatever the perceived benefits, inhumane or careless treatment of participants is never justified.

9.13 Financial transactions and inducements

9.13.1 Inducements to healthy volunteers
There is a long tradition that both investigators and healthy volunteers in research are motivated by the desire to advance knowledge and help society. This spirit of altruism is to be admired and encouraged. However, many studies, particularly in pharmacology, are lengthy and tedious. It is reasonable that volunteers in this type of research should be paid, over and above reimbursement of expenses incurred. These payments are for inconvenience or discomfort.

Payments should never be for undergoing risk. Payments should not be to persuade people to volunteer against their better judgement or to induce them to volunteer more frequently than is advisable for their own good.

All payments to volunteers should be declared to and approved by the Research Ethics Committee.4 There is no absolute amount that can be defined, but what is reasonable is to provide transport and a meal at each session.

9.13.2 Inducements directed towards patients
Patients volunteer to take part in research for several reasons. A desire to help themselves is probably the commonest reason. Sometimes there is no likelihood of benefit to the individual patient. In this case the major motive may be a desire to help others who may have the disease, or mankind. Research Ethics Committees have a responsibility to ensure that patients are not 'used' in research and then abandoned.

9.13.2.1 Offer of otherwise unobtainable treatment
In the case of a new treatment which is known to offer important benefits to a patient when compared with other available treatments, but which is still in short supply, a requirement may be proposed that, in order to receive the treatment, the patient must consent to participation in research. Research Ethics Committees shall disapprove and discourage research projects that appear to take advantage of the strong desire of patients to receive the new treatment. This is a potential problem area in developing countries in which resources are scarce.

9.13.2.2 Offer of superior care and attention
Although participation in research may sometimes bring benefits, such as those which may result from unusually detailed and careful supervision, improved care should not be offered as an inducement to participate.

9.13.2.3 Loyalty to the clinician
Undoubtedly, patients who like their clinicians and have confidence in them, are inclined to agree to proposals to take part in research. The reasons are probably many and complex. The patient must be assured, first, that he or she is completely free to decline to take part; second, that the refusal will be accepted without question and, third, that his or her care will then continue as if the matter had not arisen.

9.13.2.4 Patient's expenses
Where patients incur personal expense as a consequence of participation in research, it is proper that they should be reimbursed for that expenditure by the sponsor of the research.

9.13.2.5 Additional payments to patients
Payments are usually undesirable but are occasionally acceptable in studies which are lengthy and tedious. Payments should not be for undergoing risk. Payments should not be to persuade patients to volunteer against their better judgement. Small gifts given to child participants after completion of a research project should be allowed.20 Any payments to be made should be declared to and scrutinised by the Research Ethics Committee. In deciding on what is a reasonable payment, a useful rule of thumb is to consider whether the payment will enrich a volunteer. There is no absolute amount that can be defined, but what is reasonable is to provide transport and a meal at each session.

9.13.3 Inducements directed towards investigators

9.13.3.1 Expenses
Where researchers incur personal expense as a direct consequence of undertaking research, it is quite proper for them to be reimbursed for that expenditure by the sponsor of the research.

9.13.3.2 Fees
Sponsors of research involving patients may properly engage clinicians to assist in that research, and it is proper for these clinicians to be paid a fee for their services. It is inappropriate that a clinician should be paid a fee for carrying out research work in sessions for which he or she is already being paid from another source. Sponsorship must be declared in the participant information sheet.

Ethical aspects of financial conflicts of interest in research have recently been addressed in some detail.22,23

9.13.3.3 Contracts, payments and the responsibility of investigators

9.13.3.3.1 Investigators, pharmaceutical companies and ultimately patients have much to benefit from the close co-operation of clinicians with the officers of pharmaceutical companies in research projects and clinical trials of drugs. In providing opinions and services to companies, the principles of GCP9,10 must prevail.

9.13.3.4 Payment for recruitment of patients into clinical trials
All financial arrangements and payments to investigators should be divulged to Research Ethics Committees and, in the case of employees, to the employing authority. The total company budget for a clinical trial does not have to be declared.

 

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09-Feb-2006

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