GUIDELINES FOR GOOD PRACTICE IN THE CONDUCT OF CLINICAL TRIALS IN HUMAN PARTICIPANTS IN SOUTH AFRICA

2. Protection of Study Participants - Contents

2.1 Guiding Documents
2.2 Ethical Review
2.3 Special Classes of Participants

2.3.1 Children and Adolescents
2.3.2 Women & Pregnancy
2.3.3 Pregnant Women as Participants
2.3.4 Foetuses in utero as Participants
2.3.5 Foetuses ex utero, including Nonviable Foetuses as Participants
2.3.6 Prisoners
2.3.7 People with Mental Disabilities
2.3.8 Vulnerable Communities
2.3.9 Other Special Groups

  1. PROTECTION OF STUDY PARTICIPANTS
2.1 GUIDING DOCUMENTS

The welfare and personal integrity of the participants is the responsibility of the principal investigator. The principal investigator must follow fully the guidelines set out in the Declaration of Helsinki, ICH Guidelines for Good Clinical Practice (Appendix A) and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (CIOMS 1993).

2.2 ETHICAL REVIEW

All medical research involving human participants must undergo an independent ethical review. An autonomous accredited ethics committee must ascertain that the protection of the participant is assured in the evaluation of clinical trial applications.

In the evaluation of clinical trials protocols or study applications, these bodies must ensure the protection of participants in accordance with international standards and guidelines.

An ethics committee should consider the following issues when reviewing a proposal for a clinical study:

  • the scientific relevance of the clinical study;
  • the suitability of the investigator(s) for the proposed study in terms of his/her availability, qualifications, experience, supporting staff, and available facilities;
  • the relevance of the study rationale and the appropriateness of the inclusion / exclusion criteria to the South African context;
  • the suitability of the study application in relation to the objectives of the study; i.e. the potential for reaching sound conclusions with the smallest possible exposure to risk of participants, and the justification of predictable risks and inconveniences weighed against the anticipated benefits for the participants and/or others;
  • the suitability of study population, whether they constitute a vulnerable group, if so whether justified and whether sufficient measures to protect their interest are in place;
  • that the number of participants to be recruited is adequate to demonstrate the predicted effect;
  • the risk-benefit analysis take full cognisance of benefits and harms beyond the life of the study itself, particularly in relation to chronic life-threatening conditions;
  • if placebos are to be used, whether their use can be justified;
  • that by their participation in a clinical study the participants or other persons in the establishment or clinical centre are not denied timely access to medical personnel, investigations, equipment or procedures;
  • the means by which initial recruitment is to be conducted and by which full information is to be given and informed consent is to be obtained. All written information for the participant and/or legal representative must be submitted in its final form;
  • the adequacy and completeness of the written information to be given to the participants, their relatives, guardians and, if necessary, legal representatives;
  • that the application allows the participants and/or their representatives adequate time to consider the patient information package before informed consent is sought;
  • the content of any advertisements or public notices which will be used to recruit participants to a study;
  • that the study protects participants’ rights to privacy;
  • the provision of compensation/treatment in the case of injury or death of a participant if attributable to a clinical study, and the insurance or indemnity to cover the liability of the investigator and sponsor;
  • the extent to which investigator(s) and participants are to be compensated for participation;
  • making specific recommendations regarding the continuation of treatments beyond the life of the study, or mechanisms to ensure that participants are fairly protected;
  • the demographic information available to assess whether the patient population is adequate to support the study;
  • whether there is any cost to the participant and no charges to medical aids or insurance for protocol specific procedures;
  • whether the product will be made available to participants after the study ends, and if so whether there is any cost to the participant to continue treatment;
  • whether any restrictions will be placed on the publication of results; (i.e. ensure there is a written commitment from investigators to publish the results of trials and there is no contractual clause which reserves the right of publication to the sponsor only;
  • the adequacy of the statistical methods proposed to evaluate the data generated; and
  • whether the study is advancing the body of knowledge on the subject.
2.3 SPECIAL CLASSES OF PARTICIPANTS

South African ethics committees must give special consideration to protecting the welfare of special classes of participants, such as children and adolescents, pregnant women, prisoners, people with mental disabilities, people for whom English is not a first language or people from vulnerable communities. The following are guidelines for the inclusion of such populations in a clinical trial.4

2.3.1 Children and Adolescents

Research in children should only be approved if:

  • The research does not place the child / minor at no greater than minimal risk.
  • The research involves more than minimal risk but provides direct benefit for the child / minor. The risk must however be justified by the potential benefit.
  • The research involves greater than minimal risk, with no prospect of direct benefit to the child / adolescent but there is a high probability that it will provide "generalisable knowledge about the subject’s disorder or condition that is of vital importance for the understanding or amelioration of the subject’s disorder or condition" (IRB, 1996:11). In addition the risks must represent only a minor increase over minimal risk and the intervention or procedure "presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social or education settings" (IRB, 1996:11).
  • In all cases, assent from both child and permission from their parents or legal guardians must be sought. No other caregiver can provide consent on behalf of a child to participate.
  • Child Assent:5 The Ethics committee must ensure that adequate steps are outlined in the protocol to obtain the child’s assent, when in the judgement of the Ethics Committee the child is capable of providing such assent. When the Ethics Committee decides that assent is required, it must also state if and how assent must be documented.
  • Parental Permission: Where the research does not involve greater than minimal risk to the child, or involves greater than minimal risk but presents a likely direct benefit to the child, the Ethics Committee may find that the permission of one parent is sufficient. Permission from both parents is necessary where the research involves greater than minimal risk, no direct benefit to the child but is likely to produce generalisable knowledge about the subject’s condition. "Exceptions would include: 1) one parent is deceased, unknown, incompetent, or not reasonably available, or 2) when one parent has legal responsibility of the care and custody of the child". (IRB Policy and Procedure Manual 1997:4).
2.3.2 Women and pregnancy

Ethics Committees must give extra attention to research that involves women who are or may become pregnant, because of the additional health concerns of mothers during pregnancy and the need to avoid unnecessary risk to the foetus. Reasons for excluding women from trials should be adequately justified both from the point of view of protecting the health of a foetus and from the perspective of whether such exclusion is scientifically supportable. The IRB: Policy and Procedure Manual (1997) states that "No research activities involving pregnant women and foetuses may be undertaken unless:

  • Appropriate studies on animals and non pregnant individuals have been completed;
  • The purpose of the activity is to meet the health needs of the mother of the particular foetus, the risk to the foetus is minimal and, in all cases, is the least possible risk for achieving the objectives of the activity;
  • Individuals engaged in the activity will have no part in 1) any decision as to the timing, method and procedures used to terminate the pregnancy, and 2) determining the viability of the foetus at the termination of the pregnancy; and
  • No procedural changes which may cause greater than minimal risk to the foetus or the pregnant woman will be introduced into the procedure for terminating the pregnancy solely in the interest of the activity.
2.3.3 Pregnant Women as Participants6

No pregnant woman may be involved as a subject in any research activity unless

  • the purpose of the activity is to meet the health needs of the mother and the foetus will be placed at risk only to the minimum extent necessary to meet such needs, or
  • the risk to the foetus is minimal.

Any activity permitted above may be conducted only if the mother is legally competent and have given informed consent after having been fully informed regarding possible impact on the foetus. The father's informed consent need not be secured if

  • the purpose of the activity is to meet the health needs of the mother;
  • his identity or whereabouts cannot reasonably be ascertained;
  • he is not reasonably available; or
  • the pregnancy resulted from rape.
2.3.4 Foetuses in utero as Participants

No foetus in utero may be involved as a subject in any research activity unless

  • the purpose of the activity is to meet the health needs of the particular foetus and the foetus will be placed at risk only to the minimum extent necessary to meet such needs, or
  • the risk to the foetus imposed by the research is minimal and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means.

Any activity permitted above may be conducted only if the mother and father are legally competent and have given their informed consent. The father's informed consent need not be secured if

  • his identity or whereabouts cannot reasonably be ascertained;
  • he is not reasonably available; or
  • the pregnancy resulted from rape.
2.3.5 Foetuses ex utero, Including Nonviable Foetuses, as Participants

Until it has been ascertained whether or not a foetus ex utero is viable, a foetus ex utero may not be involved as a subject in any research activity unless

  • there will be no added risk to the foetus resulting from the activity, and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means, or
  • the purpose of the activity is to enhance the possibility of survival of the particular foetus to the point of viability.

No nonviable foetus may be involved as a subject in any research activity unless

  • vital functions of the foetus will not be artificially maintained;
  • experimental activities which of themselves would terminate the heartbeat or respiration of the foetus will not be employed; and
  • the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means.

Any activity permitted above may be conducted only if the mother and father are legally competent and have given their informed consent, except that the father's informed consent need not be secured if

  • his identity or whereabouts cannot reasonably be ascertained;
  • he is not reasonably available; or
  • the pregnancy resulted from rape.
2.3.6 Prisoners

Ethical review must take cognisance of the impact of a prisoner’s incarceration on their ability to make a truly voluntary and uncoerced decision whether or not to participate as participants in research.

In addition, when reviewing research involving prisoners, ethics committees must meet the following specific requirements:

  • A majority of the ethics committee (exclusive of prison members) shall have no association with the prison(s) involved, apart from their membership on the ethics committee; and
  • At least one member of the ethics committee shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one ethics committee only one ethics committee need satisfy this requirement.

The following clinical trials involving prisoners is permitted:

Clinical trials conducted or supported in South Africa may involve prisoners as participants only if 1) the research has been registered with the National Health Research Ethics Council, and 2) and in the judgement of the MCC and the relevant approved ethics  committee, the clinical trial involves the following:

  • study of the possible causes, effects, and processes of incarceration, and of criminal behaviour, provided that the study presents no more than minimal risk and no more than inconvenience to the participants;
  • study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the participants;
  • research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) only after appropriate experts have been consulted; or
  • research on practices, both innovative and accepted, that have the intent and reasonable probability of improving the health or well-being of the subject. In cases in which those studies require the assignment of prisoners in a manner consistent with protocols approved by the Ethics Committee to control groups that may not benefit from the research, the research may proceed only after appropriate experts have been consulted.
2.3.7 People with Mental Disabilities or Substance Abuse Related Disorders

People with mental disabilities include: those people with psychiatric, cognitive or developmental disorders. The issue with these groupings of people when it comes to research is their capacity for reason regarding participation and comprehend information provided. This issue is also applicable to research on persons with substance abuse related disorders. Institutionalisation may also further compromise a person’s ability to make a truly voluntary decision to participate in a study.

Research in people with cognitive disabilities or with substance abuse related disorders must therefore:

  • Be relevant to mental disabilities or substance abuse related disorders so that it is necessary to involve people who are mentally disabled or with substance abuse related disorders.
  • Provide sufficient justification for involving people with mental disabilities or substance abuse related disorders who are institutionalised as the study population.
  • Ensure appropriate evaluation procedures for ascertaining participants’ ability to give informed consent. If participants are deemed unable to understand and to make a choice, then an appropriate individual, able to consent on their behalf must be sought.
  • Ensure that consent is free from coercion and risk to patients.
  • Ensure that no more than minimal risk is involved, or if minimal risk is involved, the risk is outweighed by the anticipated benefits of the study for the participants and the importance of the knowledge which will emanate from the research.
2.3.8 Vulnerable Communities

South Africa is home to a number of vulnerable communities.7 Particular caution must be practised before undertaking research involving participants in such communities and ethics committees must ensure the following:

  • persons in these communities will not ordinarily be involved in research that could be carried out in populations from developed communities.
  • the research is responsive to the health needs and the priorities of the community in which it is carried out.
  • research participants should know that they are taking part in research and this research should only be carried out with their consent. This implies that particular attention is paid to the content, languages and procedures used to obtain informed consent.
  • the research protocol should not adversely affect the routine treatment of patients, nor disrupt routine management protocols.
2.3.9 Other Special Groups

The discussion on special groups should not be limited to those already mentioned. Other special groups include: Traumatised and comatose patients, terminally ill patients, elderly or aged patients, minorities, students, and employees. Ethics committees must ensure special consideration is given to all these groups, particularly around informed consent. For a more detailed discussion on informed consent please refer to the section 3.5 of this document.

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Footnotes

[4] For further, more detailed discussion on special classes of participants refer to Chapter 5, Institutional Review Board (IRB) Guidebook, 1993, NIH, USA, http://www.nih.gov/grants/oprr/irb/

[5] Worth noting is the following discussion provided by the IRB Guidebook on gaining the assent of children to participate in a trial. “While children may be legally incapable of giving informed consent, they nevertheless may possess the ability to assent to or dissent from participation.  Out of respect for children as developing person, children should be asked whether or not they wish to participate in the research, particularly if the research: (1) does not involve interventions likely to be of benefit to the subjects; and (2) the children can comprehend and appreciate what it means to be a volunteer for the benefit of others.  The [Ethics Committee] must determine for each protocol – depending on such factors as the nature of the research and the age, status and condition of the proposed subjects – whether all or some of the children are capable of assenting to participation.  Where appropriate the [Ethics Committee] may choose to review on a case-by-case basis whether assent should be sought from given individual subjects.  Assent should be sought when, in the judgement of the [Ethics Committee], the children are capable of providing their assent.  [Ethics Committees] are to take into account the ages, maturity and psychological state of the children involved.” (IRB, 1996:12)

[6] Clinical trials involving pregnant women or nursing mothers should ideally involve products where the toxicology in adults is established and is acceptable.  In the case of pregnant women the potential risks associated with using a substance whose short term and long term effects on a foetus and developing infant are unknown, should be outweighed by the benefits.  An example of a positive risk benefit ratio would be the use of anti-retrovirals in mother to child HIV transmission studies.  For nursing mothers, the amount of drug passing into breast milk should be established and the potential impact on a breast fed infant anticipated, and the mother so advised.

[7] UNAIDS define vulnerable communities as having some or all of the following characteristics: Limited economic development; Inadequate protection of human rights and discrimination on the basis of the health status; Inadequate community/cultural experience with the understanding of scientific research; Limited availability of health care and treatment options; Limited ability of individuals in the community to provide informed consent.

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