GUIDELINES FOR GOOD PRACTICE IN THE CONDUCT OF CLINICAL TRIALS IN HUMAN PARTICIPANTS IN SOUTH AFRICA
9. Ethical Consideration For HIV/AIDS Clinical and Epidemiological Research - Contents
9.1 Background
9.2 Selected Issues Relating to HIV/AIDS Clinical & Epidemiological Research9.2.1 Research Should be Appropriate for South Africa
9.2.2 Research Standards9.3 HIV Related Drug Trials
9.3.1 Access to HIV Related Medication
9.3.2 Placebo Control Trials
9.3.3 Adverse Drug Effects
9.3.4 Patient Management after Withdrawal from a Study
9.3.5 Access to Study Medications Following the Completion of Clinical Trials9.4 HIV Testing
9.4.1 Confidential HIV Testing
9.4.2 Unlinked Anonymous HIV Testing
9.4.3 Linked Anonymous HIV Testing9.5 Population Based Studies to Prevent HIV Transmission
9.6 Informed Consent and Incentives
9.7 Researcher Issues9.7.1 Incentives
9.7.2 Releasing and Publishing Research Results
9.7.3 Implementing Research Findings
9.7.4 Research Ethics Committees & Field Support9.8 HIV Vaccine Research
9.9 Involvement of People Living with HIV/AIDS
9.10 Special Considerations to Specific Sub-Groups of Society
This section emanated out of a series of consultations held by the Task Group on Ethical Guidelines for HIV research. While this document aims to provide broad ethical guidelines that address the current challenges posed by HIV/AIDS research, it is understood that new problems will continue to present themselves. For this reason this section will be continuously reviewed and revised when necessary. The particular ethical challenges posed by HIV vaccine research will be addressed in a subsequent Department of Health (DOH) guideline.
9.1 BACKGROUND
In recent years there has been an increase in HIV related clinical and epidemiological research. This has included advances in anti retroviral therapy, which has influenced the clinical course of HIV infection, reduced mother to child HIV transmission and HIV transmission following occupational exposure to HIV. There has also been an increase HIV vaccine research that is now an international priority. HIV related clinical research includes strategies to prevent HIV infection (i.e. vaginal microbicides) and to investigate medications that may increase the risk of HIV infection (i.e. long acting progestins). This research often necessitates determining the HIV status of individuals involved in clinical trials.
Clinical and epidemiological research involves complex ethical challenges. These include issues such as access to clinical trials, informed consent, use of medications after the completion of drug trials, drug toxicities, informed consent, long term side effects, the appropriateness of proposed research for South Africa, and the release and publication of the research results.
South Africa is a middle income country with severe economic disparities. The majority of the population is of a low socio-economic status. South Africa, however, is in many ways an ideal country for clinical and epidemiological HIV related research. It has a rapidly expanding HIV/AIDS epidemic which is favourable for research studies. Its well-developed infrastructure offers clinical and scientific expertise, academic institutions of good standing, good laboratory and clinical facilities and an industrial infrastructure, with high standards in communications and other relevant technologies. Information gained from clinical and epidemiological research could have critical implications for South Africa and globally.
This document attempts to address several ethical issues relating to HIV/AIDS clinical and epidemiological research in South Africa. There are also national and international vaccine initiatives in South Africa. This will stimulate the development of appropriate ethical considerations relating to vaccine research.
With many ethical issues there are not always clear right or wrong answers. There are however several universally accepted ethical principles. These principles should be applied within the context of South Africa and this document is intended to facilitate a more uniform approach to common ethical issues relating to HIV/AIDS related research.
9.2 SELECTED ISSUES RELATING TO HIV/AIDS CLINICAL AND EPIDEMIOLOGICAL RESEARCH
9.2.1 Research should be appropriate for South Africa
International research ethical guidelines, including those of the Council for International Organisations of Medical Sciences, emphasise the need for proposed research to undergo ethical and scientific review in both the initiating and host countries. This is to avoid exploitation of patients in the host country and be responsive to the needs of vulnerable communities. Vulnerable communities are defined by UNAIDS as having some or all of the following characteristics:
- Limited economic development;
- Inadequate protection of human rights and discrimination on the basis of HIV antibody status;
- Inadequate community/cultural experience with or understanding of scientific research;
- Limited availability of health care and treatment options; and,
- Limited ability of individuals in the community to provide informed consent.
As a result of past exploitation and oppression, South Africans are vulnerable to ethical abuses. Care and sensitivity should be applied to prevent exploitation of South Africa’s disadvantaged community.
Research from developed countries, including Phase I and Phase II clinical trials, should not be conducted in South Africa merely because we can offer better research opportunities. Research conducted in South Africa should be relevant to the health needs of this country.
Research and clinical trials however should be conducted within various settings and applied to communities with different social and economic circumstances. Research projects being undertaken in South Africa should be carefully evaluated and examined as to its current and future relevancy. The science of HIV/AIDS is developing rapidly and proposed interventions, which may seem to be costly and inappropriate at present, may indeed become realistic options in the future.
9.2.2 Research Standards
Vulnerable communities are often characterised by sub optimal living conditions and poor access to health and social services. This should not lessen the need for high research and use of universally accepted ethical standards. It is imperative that good research and ethical standards be applied in vulnerable and non-vulnerable communities.
9.3 HIV RELATED DRUG TRIALS
HIV related clinical trials not only refer to anti-retroviral drugs but also to trials with medications such as immune modulators, and drugs for the treatment and prevention of HIV related opportunistic infections.
9.3.1 Access to HIV related medication
Drug trials are conducted to determine various outcomes such as efficacy, safety, impact on health status of the individual, possible short and long term side effects, survival benefits, quality of life, adherence to drugs regimens, compliance with therapy and comparisons with other therapeutic options.
While antiretroviral therapy is effective, it is expensive and not available in the South African public sector. Participation in drug trials is often the only way of gaining access to antiretroviral therapy. Drug trials should not be conducted solely because they facilitate access of drugs for some patients, although this may often provide very positive benefits to the individual.
The rationale for drug trials should be independently assessed and evaluated on its merits. Researchers must ensure that patients in drug trials provide informed consent and understand the implications of the trial. This includes the advantages and disadvantages of all drug regimens, and the potential limitations in taking medications only for the period of the drug trial.
Ethics committees should consider these advantages and disadvantages to the trial participants and the general community to determine whether such trials are appropriate and relevant in the South African context.
Patient autonomy needs to be respected. Endeavours to promote autonomy should be pursued through seeking opinions of representatives of vulnerable communities including persons living with HIV/AIDS.
9.3.2 Placebo controlled trials
Ethical guidelines that apply to controlled therapeutic trials are generally sufficient to protect the rights of HIV-infected persons. A special case involves the use of placebo after an intervention has been shown to be effective. The general principle is that the use of placebo in these circumstances is unethical. However with increasing disparities in health care between wealthy and poor countries, therapy that has been shown to be effective is often unaffordable in resource-poor settings. This is particularly true of therapeutic advances in HIV infection, which is a far bigger health care problem in poor countries in sub-Saharan Africa than it is in the industrialised countries. It may be justifiable to use placebo in communities that do not have access to interventions that are the standard care in resource-rich settings.
In order to reach the ethical principle outlined above, the balance between potential harms and benefits should be such that the potential benefits to the community would considerably outweigh the harm. This issue is controversial and there is no international consensus. Widespread consultation is advisable prior to embarking on such studies.
9.3.3 Adverse Drug Effects
Drug trials have the potential to cause short and long term ill effects. The patient information section of the informed consent document should specify what action is to be taken in the event that the study drug or drugs are withdrawn due to side effects. In such a situation appropriate therapy required to manage the adverse drug effects should be made available within the study framework at no cost to the patient, by referral to the local health service, or through the patient’s medical insurance unless exceptions have been agreed upon by all parties.
9.3.4 Patient Management after Withdrawal from a Study
If a patient withdraws from a study for any reason, or where a study is completed, they should be advised about the ongoing management of their condition. Except in cases where therapeutic efficacy is demonstrated (see 9.3.5), ongoing therapy should be according to the local standard of care. Costs of this care should be borne by the local health service, the patient’s medical insurance or the patient themselves.
9.3.5 Access to Study Medications Following the Completion of Clinical Trials
Many patients who participate in HIV/AIDS treatment trials have no alternative access to drug therapy. Where a patient has a therapeutic response to a study drug, that patient should be offered ongoing treatment. In designing studies, consideration should be given to the costs of long term provision of study drugs and of clinical monitoring, including the costs of medical staff. The duration of drug therapy in a study should be clearly stated in the patient information section of the informed consent document.
9.4 HIV TESTING
HIV testing is frequently required in clinical and epidemiological research. These areas include:
- Epidemiological studies, e.g. sentinel surveillance on pregnant women;
- Observational studies, e.g. the effect of long acting progestins on the risk of HIV transmission in women;
- Drug trials, e.g. establish the efficacy and safety, etc; and,
- Vaccine trials.
HIV testing is a complex issue with important implications and consequences to the individual. Informing persons that they are HIV positive impacts on their quality of life and should be considered to be a major intervention.
Knowing one’s HIV status may have important advantages and disadvantages:
Selected advantages may include:
- Availing oneself to health care and counselling for HIV which has many benefits;
- Preventing the transmission of the HIV to sexual partners;
- Informing one’s partner so that he/she can also prevent the spread of HIV;
- Avoiding blood donations; and
- Preventing mother to child HIV transmission
Selected disadvantages may include:
- Mental stress, depression and despair;
- Stigmatisation;
- Discrimination; and
- Rejection by family, friends, sexual partners and / or spouse.
The advantages and disadvantages of HIV testing should be carefully considered and included in informed consent forms.
9.4.1 Confidential HIV Testing
In confidential HIV testing, the following criteria need to be met:-
- Adequate pre-test counselling;
- Informed consent. In the case of children informed consent must be obtained from the parent or lawful guardian, as well as from the child if sufficiently mature. Consent for HIV testing should form part of the consent document for research that requires HIV testing of an individual;
- Adequate post-testing counselling; and
- Referral to an accessible centre for ongoing psychosocial support and basic medical care. The centre should provide care that conforms at least to the national standard of care for HIV prevention and treatment including the provision of condoms.
9.4.2 Unlinked Anonymous HIV testing
This form of HIV testing is done for surveillance purposes such as the national antenatal survey. It is considered ethically acceptable to do anonymous unlinked testing without consent if the following criteria are met:
- Blood is routinely collected for a reason other than HIV testing;
- After routine testing personal identifiers are removed;
- Leftover blood or blood products are then used for HIV testing; and,
- No other non-routine interventions (including questionnaires) may be done.
Ideally, confidential HIV testing should be available to individuals in the target population where unlinked HIV testing is conducted. Referring individuals to voluntary counselling and testing centres should be considered.
9.4.3 Linked Anonymous HIV testing
In linked anonymous testing the HIV result is linked to a patient’s other clinical data, but this is done without being able to identify the patient who remains anonymous. An independent person randomly assigns code numbers to patients’ serum prior to HIV testing. The patients’ identities are then removed from database and the order of patients is then changed. The HIV result is added to the database and "linked" to the other data obtained before being returned to the investigators. This form of testing is best suited to research where HIV infection is a major confounder and not when HIV infection is the endpoint. Patients should provide informed consent to linked anonymous testing and be offered confidential HIV testing (see 9.4.1).
In unlinked anonymous and linked anonymous HIV testing, researchers should not be able to directly or indirectly identify HIV test results of individuals.
9.5 POPULATION BASED STUDIES TO PREVENT HIV TRANSMISSION
These are studies designed to assess the impact of an existing or proposed intervention on the transmission of HIV in a particular population. Examples include studies to determine the impact of improved STD care in a community on the incidence of HIV; the effect of long term use of contraceptives on the risk of acquiring HIV infection, post sexual abuse antiretroviral prophylaxis, or placebo controlled mother to child transmission.
Observational research studies may not provide immediate personal benefits and usually requires large numbers of participants. Such studies require active community participation in both the design and the monitoring of this type of study if the intervention is to be applied to a population. Consent of community representatives is not a substitute for individual consent.
If an intervention has been shown to effectively reduce HIV transmission it should not be withheld from research participants. All subjects must be given information and the means to prevent HIV transmission by means of practising safer sex and effective treatment for sexually transmitted diseases. Any treatment offered should conform at least to the local standard of care.
9.6 INFORMED CONSENT AND INCENTIVES
Informed consent may be difficult to achieve, especially when engaging people from disadvantaged and vulnerable communities where literacy and education opportunities are inadequate and where there are language barriers. However, every effort must be carried out to achieve informed consent.
Incentives for patients to submit themselves for research purposes need careful consideration. Incentives should not be so excessive so as unfairly influence the patients to submit themselves to the trial. Incentives such as financial, transport, and food should be fair and reasonable without ‘making the patient an offer they cannot refuse’ and thereby influence the patient to overlook other important consideration.
9.7. RESEARCHER ISSUES
9.7.1 Incentives
Pharmaceutical companies doing research on their products frequently offer researchers incentives. Researchers should guard against these ‘incentives’ promoting excessive allegiance with a pharmaceutical company, which may adversely affect their objectivity and neutrality. Researchers and members of ethical committees should disclose their financial interests relating to proposed research projects.
9.7.2 Releasing and publishing research results
In recent years some investigators have released preliminary research data prematurely to the press with serious and negative consequences. This may result in the release of sensational, inaccurate, misleading and irresponsible information on HIV/AIDS. Unfounded claims may mislead the public and create unrealistic expectations. In order not to create unrealistic or misleading expectations the following must be carefully considered:
- Researchers should not communicate the results of clinical trials to the public without first subjecting the study to peer review and to the normal rigorous scientific scrutiny needed for therapeutic and vaccine trials.
- Phase I and II trials should be published in scientifically refereed journals or presented to scientific forums where the results can be openly viewed and scrutinised. These results should not be released to the mass media before peer review because they may be misinterpreted, misunderstood, sensationalised and result in serious public misunderstanding.
- Important findings, which need to be urgently released, should be done via the ‘fast track’ system employed by most reputable scientific journals. Most medical journals have now developed this system to fast track review and publish important research findings.
9.7.3 Implementing Research Findings
Research, which has direct public health implications, such as vaccine trials, require wide consultation. This should include discussions with the South African Department of Health and the Medical Research Council so that implementation of study results can be addressed at an early stage.
9.7.4 Research ethics committees and field support
Proposals for clinical and epidemiological research should be submitted to relevant local ethics committees or to the South African Medicines and Medical Devices Regulatory Authority for approval.
Principle researchers or investigators must provide adequate supervision to ensure that ethical considerations are met in a full and proper manner by their delegated staff.
9.8 HIV VACCINE RESEARCH
There are currently a variety of international and national vaccine initiatives in South Africa. This research is highly specialised and it raises many ethical issues. This document will not address the range of issues that are being addressed by the appropriate vaccine research groups. Some of the important ethical considerations include:
- The implications of wide spread HIV testing on high risk populations;
- The impact of local HIV prevention initiatives on research outcomes;
- The possible influence of the vaccine candidates to offer a disincentive for people to take necessary precautions to prevent HIV transmission;
- The implications of ‘false positive’ HIV tests in patients who agree to vaccine trials; and,
- The appropriateness of the vaccine clade to the local population.
Vaccine research should be done in consultation with the national and international initiatives.
9.9 INVOLVEMENT OF PEOPLE LIVING WITH HIV/AIDS (PWAS)
The many tensions, dilemmas and ethical consideration surrounding HIV/AIDS related research necessitates a wide consultative process. PWAs are critical to this process and should form part of the consultation from the very early stages of the research process.
9.10 SPECIAL CONSIDERATIONS TO SPECIFIC SUBGROUPS OF THE SOCIETY
In addition to vulnerable communities, there are vulnerable populations that require special consideration. These include women, prisoners, and children. Women should be appropriately represented as research participants unless there is a clear and compelling rationale that such inclusion is inappropriate.
In research involving prisoners, researchers should ensure that voluntary informed consent is provided. Ethics committees considering research proposals involving prisoners should consider the inclusion of prisoners or prison representatives on such reviews.
In investigations regarding pregnant women, researchers should not limit normal standards of care nor inappropriately affect decisions concerning pregnancy termination.