5. The legal and moral justification for research

5.1 Consent is essential
Section 12(2)(c) of the Constitution of South Africa Act, No 108 of 1996, states: ' Everyone has the right to bodily and psychological integrity, which includes the right... not to be subjected to medical or scientific experiments without their informed consent'. A literal interpretation might mean that only competent persons who are capable of giving consent to clinical research, whether therapeutic or non-therapeutic, interventionist or observational, may be research participants. However, this Section may be interpreted more flexibly (taking account of other existing South African legislation) to allow therapeutic research on an incompetent person to be carried out with the consent of someone acting lawfully on that person's behalf (proxy consent), since such research is of potential personal benefit to the person involved.^a

The wording used in the South African Constitution is identical to that used in the United Nations Covenant on Civil and Political Rights (1966), which is binding on the states that are party to it. It may therefore be argued that section 12(2)(c) may be interpreted in a fashion similar to the interpretation given to the Covenant by those states. This approach would entail that non-therapeutic research (see also 5.3.1.1.1) on an incompetent person might be permissible in limited instances, but only with the consent of someone who is legally authorised to act on that person's behalf, and provided that the incompetent person gives his or her assent. Assent implies a willingness that does not necessarily carry the greater understanding and legal implications that are generally understood by 'consent'.

While non-therapeutic intervention research is not permissible, observation research of a non-therapeutic and non-invasive nature might be permissible because there is no risk and no interference with the mental or physical integrity of the participant, provided that the research entails no more than negligible distress or discomfort to the participant.^b

Observation research of a non-therapeutic and invasive nature might also be permissible, provided that no more than negligible risk is foreseeable or known from routine clinical practice and that distress or discomfort is negligible.

To avoid the difficulty of obtaining consent, clinical research of no benefit or little benefit to the incompetent person is sometimes labelled as 'therapeutic'. However, all types of clinical research on incompetent people should be presumed to be non- therapeutic. This ensures that such research is subjected to strict scrutiny and conditions, and that incompetent persons are not abused or unduly influenced for research purposes.

5.2 Form of consent
In the absence of compelling reasons to the contrary, written information and consent forms should be the norm for health research interventions.

5.3 Requisites of consent
5.3.1 Capacity to consent
Consent must be given by someone who is legally and factually capable of consenting. Where a person, on account of age or physical or mental condition, is incapable of consenting to the proposed research procedure, proxy consent (consent by someone who is legally authorised to act on behalf of the incompetent person) must be procured. With regard to competence to consent and proxy consent, two broad categories of research participants must be distinguished.

5.3.1.1 Adults
Provided they are sane and sober, adults have the capacity to give valid consent to clinical interventions. Categories of adults whose competence to consent could be compromised under certain circumstances, are the following:

5.3.1.1.1 The mentally ill or mentally handicapped
Section 60A of the Mental Health Act, No 18 of 1973, provides for consent to clinical interventions (which would include research of a therapeutic nature) on institutionalised mentally ill patients. It provides that where a mentally ill patient is incapable of consenting to medical treatment or to an operation, the following persons, in order of precedence, may give written consent to the treatment or operation: a curator, the patient's spouse, a parent, a major child or a brother or sister. In the absence of such persons, or where they cannot be found after reasonable inquiry, the superintendent of the hospital where the patient finds himself or herself may give written consent. The superintendent must be convinced, on reasonable grounds, that the patient's life is in danger or that the patient's health is being seriously threatened by his or her condition, and that the treatment or operation in question is necessary.

Section 60A confirms the viewpoint that the individual mentally ill patient's competence to consent to medical treatment or to an operation depends upon whether, in fact and in the circumstances, the patient has the ability to appreciate the issues involved.

Section 60A, however, does not cater for consent to the medical treatment of, or an operation on, a mentally ill patient who is not institutionalised, but is in private care and has neither a curator nor relatives to consent on his or her behalf. Under these circumstances, an application should be made to the High Court for the appointment of a curator.

Should a mentally ill or mentally defective (incapacitated) patient be incapable of consenting to therapeutic research, proxy consent is permissible only where the proposed research pertains, directly or indirectly, to the mental illness or mental defect from which the patient suffers. In addition, the assent of the patient should be obtained, provided that the patient is mentally able to comprehend the issues involved.

Non-therapeutic research on incapacitated persons would not be permissible, with the following exception: proxy consent may be obtained for:

1. observation research of a non-therapeutic and non-invasive nature, as there is no risk and no interference with the integrity of the incapacitated person, provided that the research entails no more than negligible distress or discomfort to the incapacitated person involved;
2. observation research of a non-therapeutic and invasive nature, provided that normally no more than negligible risk is foreseeable or known from routine medical practice, and that distress and discomfort are negligible.

In addition to the above, the following requirements must be met in non-therapeutic research:

1. the research pertains, directly or indirectly, to the mental illness or mental defect from which the person suffers;
2. the assent of the person is sought and heed is given to his or her wishes expressed in any advance directives. An objection by the incapacitated person is decisive;
3. research involving incapacitated persons significantly benefits persons of the same category as the research participant;
4. the same scientific results cannot be obtained by other methods, or by research on persons who do not belong to this category.

5.3.1.1.2 The elderly
Old age alone does not render a person incapable of consenting to health research. In the absence of any indication to the contrary, elderly patients are generally assumed to be competent to consent to research. However, consideration should be given to the possibility of mental deterioration, the ability to comprehend, and the dependence and vulnerability of the elderly.

5.3.1.1.3 Pregnant women
Pregnant women are usually competent to consent to health research, but the circumstances may sometimes compromise their decision. Where possible, the father of the unborn child should be included in making the decision.

5.3.1.1.4 Unconscious patients
Unconscious persons are obviously incapable of consenting to anything, but provided

1. there are no indications to the contrary and
2. the informed consent of a competent relative is obtained, therapeutic research on an unconscious patient is legally permissible. With regard to non-therapeutic observation research, their position is similar to that of mentally ill or mentally handicapped persons (see also 5.3.1.1.1).

5.3.1.1.5 The dying
The capacity of the dying to consent to health research depends upon the circumstances of each case. Special consideration should be given to their vulnerability and dependence in any attempt to procure their consent to health research.

5.3.1.1.6 Members of vulnerable communities (see also 11)

5.3.1.2 Minorsc

5.3.1.2.1 Competent minors
In terms of Section 39(4) of the Child Care Act, No 74 of 1983, and in the absence of specific legislation to the contrary, minors who have attained the age of 14 years are legally capable of consenting to medical treatment of themselves and their children. Minors who have attained the age of 18 years are legally capable, in addition, of consenting to medical operations upon themselves. Such consent is valid only where the minor is sane and sober. The consent of a parent or legal guardian is required for treatment if the minor is under the age of 14 years, and for an operation if the minor is under the age of 18 years. In the event of conflicting views between the child's father and mother, the child's best interest settles the matter. 'Medical treatment' is not defined in the Act, but would probably exclude non-therapeutic medical research. Therapeutic research, therefore, may be undertaken with the consent of a minor over the age of 14 years if it takes the form of treatment, and with the consent of a minor over the age of 18 years if it involves an operation. Such minors' competence to consent accordingly extends to health research which is tantamount to treatment or an operation and, hence, to therapeutic research only. (In addition, consent from a parent or legal guardian is desirable.)

Non-therapeutic research on minors is not permissible, except where parental consent (and the assent of the minor concerned) is obtained for:

1. observation research of a non-therapeutic and non-invasive nature, because there is no risk and no interference with the integrity of the minor, provided that the research entails no more than negligible distress or discomfort;
2. observation research of a non-therapeutic and invasive nature, provided that normally no more than negligible risk is foreseeable or known from routine clinical practice, and that the distress or discomfort is negligible. (See also 9.12.4.1)

5.3.1.2.2 Incompetent minors
Proxy consent to therapeutic research on incompetent minors under 14 years (to treatment) or under 18 years (to an operation) must be obtained. Furthermore, the assent of the minors must also be obtained, provided they are mentally able to comprehend the issues involved. The research should pertain, directly or indirectly, to the illness or disease from which the child suffers.

Where non-therapeutic research is involved, proxy consent may be obtained for the following:

1. observation research of a non-therapeutic and non-invasive nature, because there is no risk and no interference with the integrity of the minor, provided that the research entails no more than negligible distress or discomfort to the minor;
2. observation research of a non-therapeutic and invasive nature, provided that normally no more than negligible risk is foreseeable or known from routine clinical practice and that the distress or discomfort is negligible. (See also 9.12.4.1)

In addition to the above, the following requirements must be met in non-therapeutic research:

1. the proposed research pertains, directly or indirectly, to a condition from which the minor suffers;
2. the assent of the minor is sought and his or her objection is regarded as decisive;
3. research involving minors significantly benefits minors of the same category as the research participant;
4. the same scientific results cannot be obtained by research on persons who do not belong to this category, or by other methods.

All types of clinical research on minors are presumed to be non-therapeutic. This avoids labelling clinical research of little or no benefit to the minor as 'therapeutic'. This ensures that such research is subjected to strict scrutiny and conditions, and that minors are not abused or unduly influenced for research purposes.

5.3.2 Informed consent

5.3.2.1 The nature and scope of adequate information
Research participants, or persons giving proxy consent, cannot give informed consent unless they know and appreciate what it is they consent to. To attain this, adequate information must be provided.

5.3.2.2 Participant autonomy
The requirement that consent in the health context must be informed consent is customarily associated with the so-called 'doctrine of informed consent'. This means that autonomy is a participant's fundamental right and rejects investigator paternalism. According to the doctrine, the ultimate decision to participate (informed consent), to refuse to participate (informed refusal), or to withdraw from an intervention, lies with the participant and not with the investigator. The doctrine of informed decision requires that the participant should understand the risks and benefits of the study before making that decision, whether positive or negative. The right to refuse may be acted on at any stage, even before the explanation of risks and benefits.

Within the context of health research the paternalistic 'participant's best interest' and the 'researcher knows best' attitudes are inappropriate.

1. The undeniably inherent potential for abuse of research participants requires a stricter adherence to the requirement of informed consent in health research than in standard practice.
2. The absence of personal benefit to the participant who consents to non-therapeutic research requires a stricter adherence to the requirement of informed consent in non-therapeutic research than in therapeutic research.

5.3.2.3 Nature, scope and limitations of the investigator's duty of disclosure
Investigators have the duty to empower research participants, or persons giving proxy consent, to decide on participation. This includes disclosure of potential risks and benefits (or the absence of any direct benefit) and alternative treatments in the case of therapeutic research.

Full disclosure means that the investigator informs the research participant, or person giving proxy consent, that the proposed investigation involves research. The investigator gives the research participant, or the person giving proxy consent, comprehensive and detailed information in understandable language about the following:

1. the precise nature, scope, purpose and duration of the proposed research project. That is, whether it is therapeutic, non-therapeutic, invasive, observational, a pilot study, controlled, randomised, single blind, double blind, triple blind or quadruple blind, and whether or not placebos are involved;
2. the nature, scope and consequences of the proposed research intervention;
3. the anticipated benefits and disadvantages compared to those expected from available standard therapy;
4. the foreseeable prognosis and all foreseeable and additional risks, dangers and complications, as well as the possibility of unforeseen risks, dangers and complications, irrespective of whether the proposed research is therapeutic or non-therapeutic;
5. personal benefits, including financial benefits, that may accrue from the research to participants, investigators and anyone giving proxy consent. Moreover, the research participant, or the participant's proxy, should be informed that participation is voluntary and that he or she is:
   1. under no obligation to consent to the research procedure and that a refusal will not adversely affect future treatment;
   2. free to withdraw consent at any time without adverse consequences and without having to state a reason.

Evidence suggests that the combination of written information supplemented with face- to-face interaction is the most desirable method of ensuring an informed decision.

In addition, the research participant, or the participant's proxy, should be given sufficient time to contemplate and decide on participation in the research project.

This leaves little room for therapeutic privilege or waiver of information as justifications for non-disclosure in cases of therapeutic research. Information should be given, even if the investigator takes the view that disclosure of the risks and dangers in such circumstances is unnecessary or undesirable.

In cases of non-therapeutic research, there is thus no room at all for therapeutic privilege or for waiver of information.

5.3.2.4 Free and voluntary, clear and unequivocal, comprehensive, revocable
Consent to health research must be free and voluntary, clear, unequivocal and comprehensive. It may be withdrawn at any time, without any reason being given.

5.3.2.4.1 Free and voluntary consent
Consent may not be induced by fear, force, threats, duress, coercion, compulsion, deceit, fraud, undue influence, perverse incentives or financial gain. There are categories of persons in whom the voluntary nature of consent may be compromised. These include prisoners and soldiers, students and employees, and other individuals in dependent relationships (see also 5.3).

Regarding prisoners and soldiers, the mere fact that someone is incarcerated or is a subordinate, does not render them legally incapable of consenting to research. However, the potential for abuse of the incarcerated and subordinated, who are either involuntarily detained or subjected to a hierarchical and authoritarian dispensation, may raise serious doubt about the required voluntary nature of their consent. This extends to information routinely collected from all prisoners without informed consent.

Regarding students and employees, due care should also be taken that their voluntary participation in health research is in no way compromised by their position. Other subordinate groups to be considered are listed in 5.3.

5.3.2.4.2 Clear and unequivocal consent
The expression is self-explanatory and needs no amplification.

5.3.2.4.3 Comprehensive consent
Consent must extend to the entire research proposal, inclusive of its potential consequences.

5.3.2.4.4 Revocable consent
Consent may be withdrawn without prejudice, in any form, and at any time prior to and during the proposed intervention.

5.4 Participant's friend
Investigators are responsible for procuring the informed consent of the research participant or person acting on his or her behalf, but it may sometimes be appropriate to appoint a special, informed person to act as an independent source of information and advice. This so-called 'research participant's friend' is not actively involved in the particular research project, but is an experienced clinician who acts in the interest of a research participant. This is a clinician who is not involved in treating the patient, is not a participant in the research, and acts as a neutral advisor to the patient or the patient's curator or relative. The concept of participant's friend helps to ensure understanding of what is required for participation in the research.