28 June 2006- 'Clinical trials: Who really benefits?'

Medical research in the field of HIV and AIDS has been of material relevance in prevention and treatment, from the time the disease was discovered in the 1980's to the present day. Research and clinical trials can bring about meaningful change by reinforcing the researcher's understanding and after successful trials, also by transforming the lives of, not only the research trial's participants, but of much broader communities as well. Studies such as the trials of nevirapine to prevent mother-to-child-transmission of HIV, have made a huge difference in reducing vertical transmission of HIV.

By Mbonisi Zikhali

No trial can be successful without the commitment of the people it recruits as subjects. Clinical trials are even more essential today in pursuit of medical solutions to the HIV and AIDS pandemic. However, given that many of the participants in these researches come from very vulnerable communities, there are concerns relating to the morality of conducting clinical trials in resource-poor countries. Despite best efforts to avoid them, participants are also sometimes victims of ethical abuses. To open up debate on these issues, SAfAIDS held a discussion forum on 28 June 2006, which drew interesting perspectives from both the panelists and the participants regarding the direction of clinical trials in Zimbabwe.

The forum, entitled "Clinical trials: Who benefits" was a chance to tease out the ethical guidelines adopted by researchers when conducting these trials. Professor Peter Mason, Director General of the Bio-Medical Research and Training Institute in Zimbabwe was the guest speaker, along with three other key panelists from organisations that deal with research and the ethical considerations that revolve around it. Mrs Rose Chekera (Co-ordinator) represented the Medical Research Council of Zimbabwe (MRCZ) and the Medical Control Authority of Zimbabwe (MCAZ) was represented by Mr Rutendo Kuwana, its assistant director. Sister Gloria Tinago represented the UZ Clinical Research Centre (CRC): DART (Development of Anti-Retroviral Therapy in Africa) Study.

According to the Bio-Medical Research and Training Institute's website, its mission is to ‘promote the health and quality of life of the peoples of Africa through research and training in the field of biomedicine.' It places emphasis on the need for the establishment and maintenance of ‘the highest levels of quality, professionalism, ethical standards and efficiency' in its activities. Professor Mason's presentation sought to outline the ethical issues in clinical trials and he began by clarifying the misconception that clinical trials referred only to drug trials. ‘It merely refers to the method of doing research', he stressed.

Clinical Trials and Ethical Issues: Guidelines

Professor Mason noted that there was a wide-ranging and dynamic approach to ethical issues. Ideas and approaches change over time and are therefore subject to review and discussion. He traced the development of international ethical codes, quoting the Nuremberg Declaration (1947) and the Helsinki Declaration (1964) as the most critical moments in shaping current ethical debates and frameworks. According to the World Medical Association, the two declarations were set in place to protect the rights of human participants in clinical trial studies. Since clinical trials occur on a global scale, the protections outlined in the two declarations are to be observed by all countries in which trials are conducted.

The Nuremberg Declaration is the first internationally recognized ethical code for the conduct of human research, based on a set of ten principles. It was drafted following the post-World War 2 Nuremberg trials of physicians and scientists who had performed horrifying experiments on prisoners during the Nazi era. Its first principle recognises voluntary consent by the human subject as an absolute requirement. The Helsinki Declaration has as its first principle the protection of the ‘life, health, privacy, and dignity' of medical research subjects. Professor Mason pointed out that the World Health Organisation (WHO) saw it fit that these codes be recognised globally and through the Council for International Organisations of Medical Sciences (CIOMS), which was established jointly with UNESCO in 1949, it has sought to maintain an international standard of bioethics. These are referred to as the CIOMS Guidelines.

Principles of Research Ethics

Professor Mason listed the key principles of research ethics. These involve respect for the persons involved in the research, beneficence (the relationship between harm and benefits) and distributive justice. The CIOMS Guidelines say that respect involves granting the participants the power of self-determination, so that the research is in line with their personal goals. The researcher should also respect the needs and aspirations of those participants with less autonomy, such as the disabled, mentally challenged, prisoners or detainees, ethnic groups, the poor and socially disadvantaged and participants affected by gender imbalance. Beneficence refers to the need to ensure that any positive benefits from the clinical trial should be maximised among trial participants. Justice refers to the need for all participants to be treated equally and the professor defined distributive justice as a situation whereby members of the community that carries the risks of research also benefit from its outcomes. This aspect is particularly important in developing countries, where health care resources are often limited.

The speaker stressed that informed consent is the principal consideration in any research and participants should understand the aims of the research, risks, benefits and the overall value of the research to their lives. He acknowledged that it is difficult to ensure informed consent in resource-poor countries where participants have limited education.

Another key aspect of an ethical clinical trial is that there should be no coercion. However, he added that subtle coercion was possible. There are recorded instances of family, group, family or peer pressure to either participate or not participate in a study. At times gifts are given to encourage enrolment, though it is important that these are not seen as inducements to participate. In some instances, especially in resource-poor countries, recompense might also be necessary if for instance a participant has to put his or her work on hold to participate in the research. This might affect that person's household income and hence compensation is essential. Funds to cover transport costs to make the necessary visits to the trial site might also be necessary.

Confidentiality is also very important as there is need to protect participants from any social stigma and in certain cases, they may be under threat from the authorities, as for instance where a trial involves sex workers, but sex work is illegal in the country concerned. Therefore only a few, relevant people must have access to information regarding trial participants.

Misconceptions

However, there are many misconceptions regarding clinical trials. Participants may see participation in a trial as the only way to access treatment, as has happened in Zimbabwe with the ongoing ARV trials. High medical fees may force some potential participants to conceive trials as insurance, while some agree to take part, because they have concluded that participating means they can obtain treatment they might not otherwise be able to afford. With so many different motivations, there is almost bound to be an element of discontent, which is avoidable if the researchers clarify the objectives of the study prior to its inception. During the study it is advisable to reiterate this, so as to eliminate all misunderstanding between the researcher and the participants.

Clinical Trials in Zimbabwe

The co-ordinator of the Medical Research Council of Zimbabwe (MRCZ) , Mrs Rose Chekera stated that the MRCZ is responsible for providing ethical guidance and also coordinates the Institutional Review Boards that assess whether human subjects are harmed during the research. She also said that the MRCZ does not have exact figures of how many trials are actually being carried out in Zimbabwe, but that it was the council's imperative to ensure that all researches carried out were relevant to the health needs of the country. Mrs Chekera stressed the point that proposed research studies were scrutinized to ascertain any potential harm to participants, as well as the type of questions the research was asking. They also verified the credentials of those carrying out the work to ensure that they were suitably qualified to do the research.

Mr Rutendo Kuwanda of the MCAZ said that the mandate of the MCAZ is to make science-based recommendations to the Secretary of Health based on their assessment of a research's compliance to the regulations. For example, the MCAZ tries to negotiate with the trial funders that they should provide any effective drugs to the participants in clinical trials, for a longer period of time. This was problematic as funders were often reluctant to commit to investing any more money in a trial. Sometimes it was a difficult decision when a trial meant that Zimbabweans could benefit from new treatments, even if only for a short while. If Zimbabwe made too many demands on trial funders, then the trials would go to other countries.

In trials of ARVs, the initial agreements were that trial participants would be entitled to register on the government ARV programme. However the public sector roll out is strained and this creates the possibility that researchers will prey on the desperation of potential participants to be recruited to clinical trials. Although it is mandatory that participants be compensated in the event of harm and trials take out insurance cover for this purpose, it is often difficult to determine what the minimum insurance cover should be and this is determined by the insurance companies.

Sister Tinago, representing the UZ CRC Dart Study, was particularly concerned with how antiretroviral drugs could be given in resource-limited settings. The Development of ART (DART) Study is a randomised controlled trial based on a method of structured treatment interruption to assess whether the toxicity of ARVs can be reduced without compromising the effectiveness of the drugs. She lamented the fact that for most people from poor communities, the choice to enrol or not was very limited, especially when they were already sick.

Discussion

In the discussion that followed, Lynde Francis, the executive director of the Centre asked if people living with HIV and AIDS were consulted prior to approving regulations that govern particular research trials, or were invited to sit in the Institutional Review Boards. Mrs Chekera responded by saying that in the MRCZ no protocol was advanced without PLWHA. She however stressed that the involvement of PLWHA was purely an institutional choice. The MRCZ was also questioned on the number of researches going on in the country and it emerged that although there is a clinical trials registry, with a database, which captures all health-related research, it was difficult to ensure the information was accurate. Where researchers had difficulties or delays in obtaining funding, although a trial was approved, the MRCZ had no way of knowing if the trial had actually begun. Other trials terminated early citing problems with funding and again the MRCZ was not informed.. This presented problems in reviewing the number of trials currently being

conducted.

Tendai Westerhoff inquired as to whether the DART trial was accepting people with CD4 counts above 200, a question which gave Sister Tinago the opportunity to clarify other issues concerning the DART trial. The DART trials wanted people who have never been on treatment, and gave preference to those with a CD4 count below 200. DART was no longer recruiting people, but there were other trials beginning which people could enquire about. All trials have strict rules of eligibility, but the DART team was prepared to show people where to go to access treatment.

Lois Chingandu, the executive director of SAfAIDS asked who represented the voice of participants on trials, to which she got the reply that when it came to informed consent, there was a thorough assessment of whether the participants had decided for themselves or if they had pressure exerted on them by family or community members. She also wanted to know if there were any unapproved trials going on in the country. Mr Kuwanda acknowledged that there have been a lot of medicines smuggled into the country by researchers and investigations into such misconduct were part of the duties of the MCAZ and the MRCZ.

A member of a support group called Gamuchirai Community, which consists of HIV positive participants in Glen Norah and Glen View involved in the

DART trial, said that the support group had met to discover routes of survival after the trials. They had formed the group in recognition of the fact that once the trial ended they would no longer have access to their life-saving medication. He said there was a need for strong policies that would empower people economically, so that they do not need to look to trials as a means of staying alive, but that individuals also needed to look out for themselves.. Nevertheless, researchers need to understand that without the participants, trials would be impossible. Therefore at the end of the day, the participants should be the chief beneficiaries, rather than the researchers.

Summary of Action Points
1. the MRCz should keep a register and disseminate information on ongoing research.
2. Researchers should not take advantage of the participants' lack of knowledge regarding the processes and outcomes of research and should know the duration during which their participation in a trial will be required.
3. Participants in clinical trials should also look beyond the trials themselves and find ways of empowering themselves economically.
4. The MCAZ should seek innovative ways of ensuring that participants are able to continue any beneficial treatment initiated whilst on the trial.

Sources
http://www.wma.net/e/press/2003_2.htm
http://www.cdc.gov/OD/ads/intlgui3.htm
Karen Gervais. Draft 3 - 02/09/04. The Ethical Foundations of the Federal Regulations Governing Human Subjects Research in the United States.
Find draft on the following link:
www.stolaf.edu/academics/irb/Policy/Ethical%20Foundations%20-%2002-09-04.pdf