Round Table on Ongoing Trials

Round Table Participants included:
Dr Voahangy RASOLOFO, Institut Pasteur de Madagascar, Madagascar
Dr Jie Siu WANG, Director, Tianjin Centre for Disease Control and Prevention, China
The Round Table was chaired by Pr Anne FAGOT-LARGEAULT.

Ethical Issues in Clinical Trials in China - Professor Jie Siu WANG

History of Clinical Trial Ethics World Wide

The main sources of guidance on the ethical conduct of clinical trials are contained in the Nuremburg Code (1947), the Helsinki Declaration (1964/2002), the Belmont Report (1979), the WHO Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products (1982/1993), the Council of Europe's Convention on Human Rights and Biomedicine (1997), and the Guidelines and Recommendations for European Ethics Committees of the European Forum for Good Clinical Practice (1997). Many of these were developed in response to specific events.

The Belmont Report contains seven requirements providing a systematic and coherent framework for clinical trials: social or scientific value, scientific validity, fair subject selection, favourable risk-benefit ratio, independent review, informed consent, and respect for potential and enrolled subjects.

The Development of Clinical Trial Ethics in China

China faced many problems in ethics before 1999. There were no ethics committee at the national or regional levels. Proposals were thus not approved by ethics committees, and individuals were uninformed or inadequately informed about the clinical trials. There was no requirement for individuals to sign consent forms, and certain individuals were involved in trials without their informed consent. With the development of the world wide standard on clinical trial ethics, China introduced a drugs inspection law in 1985. In 1995, Good Clinical Practice (GCP) was finalised for approval, and came into operation in 1999. In 2001 a new Drug Inspection Law was introduced, replacing the old law. This legislation provides that:

· Trials can only be conducted in places approved by the SDA.
· Investigators must be trained, qualified and have certain experience with GCP in China.
· The clinical trial proposal must be approved by the Ethics Committee.
· Trial subjects should have adequate access to information and be aware of the risks, benefits and rights that apply.
· Informed consent forms must be signed by the trial subjects.
· The subjects should have their privacy protected and the opportunity to unilaterally withdraw from the ongoing research.

The legislation thus significantly improved clinical trials in China. However, certain Chinese scientists urged that clinical trials be made more ethical. For example, in 1999, Dr Hu Minyan suggested the composition, duties and functions of the Ethics Committee. In 2001, Dr Ba Denian recommended the creation of a National Medical Ethics Committee as quickly as possible. In 2001, Dr Lu Yuan proposed that trial subjects' benefits and rights should be protected.

raining courses focused on ethics have now been held in China. One such course held in Beijing brought together 90 participants from related provinces and HIV prevention centres. Professor Nancy King from the US and various Chinese scientists presented their experience and studies in the development of clinical trial ethics.

China's recognition of the ethics of clinical trials have been strengthened by these academic activities.

The Ethics of Clinical Trial Study A in Tianjin

In 1999, the IUATLD began to consult with the TTI in CDC on Study A, in which sub-centres in Tianjin and Henan participated. Prior to the implementation of this study, local ethics committees approved the research protocol in terms of the IUATLD requirements. All of the enrolled subjects signed an informed consent form. This was the first time that Tianjin CDC and TTI worked to make clinical research more ethical.

Before Study A was carried out, a survey was held of Tianjin citizens' attitudes to the clinical trials. They were informed of the trial details and made a decision as to whether they would participate. Of the 100 patients identified, 50% agreed to participate, and 41% refused to participate. 66% agreed to participate in a clinical trial of new vaccines; and 44% refused.

During Study A, the IUATLD held a workshop on clinical trials ethics in Tianjin in March 2001. Over 100 scientists from over 10 provinces attended the workshop. Dr Naomi Bock presented the concept of clinical trial ethics and the details of the Helsinki Declaration. The post-workshop evaluation showed that 90% of participants heard about the Helsinki Declaration for the first time at the workshop, and that it allowed them to acquaint themselves with clinical trial ethics.

The slide shows details of the informed consent form used in Study A. Of the 146 individuals who fulfilled the criteria for Study A, 45 refused to participate in the trial. 101 agreed to participate but a further 33% refused to sign the form. We therefore finally enrolled 68 patients in the trial.

The reasons given for the refusal to sign included first, that individuals had doubts about signing the form itself. Second, they had doubts about the new medicine and the treatment regimen for the trial. Third, some patients were already being treated and had shown an obvious improvement. They were unwilling to take the risk of changing to a new treatment. Fourth, the parents of some patients aged 16 to 18 were unwilling to allow their children to undergo the risks of the trial. Fifth, in some cases, the patient's company paid their medical charges and some patients wanted to pay for the treatment themselves. Finally, a higher level of compensation was required by some patients.

Future Challenges in China

Even though the situation has improved greatly, there is still great room for progress. The recognition of clinical trial ethics among the medical authorities, Chinese doctors and patients is still not widespread. Some clinical trials are proposed without consideration of the trial subject's rights and benefits. Chinese people tend to regard the informed consent as a bonding contract, and they prefer to have an oral agreement.

The Chinese Ethics Committee is not properly constituted. Due to a large variety of advertisements on new drugs and treatment, people doubt the validity of physician's explanations of the trial. There is a shortage of research budgets and economic compensation for the problems and side effects encountered during trials.

I would make the following suggestions for the future. Extensive training of experts in the clinical ethics field should be funded by international organisations. An organisation is required to establish a Chinese clinical trial ethics team. The Tianjin Centre for Disease Control and Prevention would like to be the coordinating centre for clinical trial ethics research and training. The preferred trainees should include the principal investigators, the head of institutes potentially involved in conducting clinical trials, members of the Ethics Committee, and relevant medical staff and government officials. Signature of the informed consent form could be modified to provide for oral consent, verified by a third party signature.

Conclusion

We are confident about being able to establish and improve the clinical trials ethics system in China. However, China needs the support of the European Commission and of other international organisations in order to carry this issue forward.

Clinical Trials in Madagascar - Dr Voahangy RASOLOFO

I will be discussing the evolution of values and ethics in medicine in Madagascar.

History of Vaccination in Madagascar

Madagascar became a French colony in 1896, governed by General Gallieni. At the time of his arrival, Madagascar was affected by a serious small pox problem. At the end of the 19th century, the Tananarive Institute distributed a small pox and rabies vaccine throughout the country. In 1921, Madagascar was affected by a plague epidemic. The EV vaccine against the plague was developed in 1931. In terms of tuberculosis, the BCG strain was obtained from Calmette in 1924, and was produced by the Institut Pasteur of Madagascar in 1926. In 1993, production of the BCG vaccine was brought to an end due to G&P problems. In 1961, the mission of the Institut Pasteur of Madagascar was changed to that of public health, and it became the research centre for the Ministry of Health.

Madagascar Ethics Committee

As late as the 1990s, Madagascar did not have an ethics committee; only the Minister of Health could issue authorisation for medical studies. The Minister at that time considered that the Malagasy people were not guinea pigs, and she refused all clinical trials in the country. The National Ethics Committee for Biological Research was created in 1995. All members are appointed by the Minister of Health. Institutions submit projects to the Ministry of Health, which transfers them to the National Ethics Committee. In 2001, five such projects were under review by the National Ethics Committee.

Conclusion

Ethical issues in clinical trials in developing countries are problematical where political interests are more important than ethics.

Round Table Discussion

Dr Anne FAGOT-LARGEAULT
I believe you all have many questions on HIV testing.

Brigitte GICQUEL
We are beginning several trials on new drugs and vaccines. We will also be considering variations in populations with a view to determining whether certain genes are linked to sensibility. To this end, we have to determine whether tuberculosis in patients is associated with HIV or not. Therefore, when we begin a study, we need to include HIV testing as well as PPD testing. In many cases, this is problematical.

Dr Anne FAGOT-LARGEAULT
Why do you not test for genetic predisposition as well?

Brigitte GICQUEL
We currently have more information on innate immunity. We know that certain receptors on phagocytes are responsible for entry of the bacilli. A study dealing with this has already been published on leprosy, and several studies will be carried out on tuberculosis.

Dr Anne FAGOT-LARGEAULT
Why do you not then test for HIV, tuberculosis and genetic factors?

Brigitte GICQUEL
The variations in some genes are relevant to innate immunity for tuberculosis. However, this is not the aim of the study.

Dr Anne FAGOT-LARGEAULT
What are the arguments in favour of testing and the arguments against testing?

Solomon BENATAR, Department of UCT Bioethics, University of Cape Town
Let us imagine that a researcher is interested in obtain new knowledge. He or she has many scientific questions to be answered. If these questions are answered, not only will knowledge be improved, but the treatment provided to patients will also be improved.

Brigitte GICQUEL
If we discover an important variation related to the disease, this could be part of the diagnosis process in the future.

Solomon BENATAR
The role of the scientist is thus to pursue new knowledge with a view to better diagnosis and treatment in the future. In order to do that, research has to be carried out in humans. There is a risk that the researcher will use people who are ill as a means to the end of answering those questions. The whole history of medical research is based on the concept that the needs of society should not override the needs of individuals. The use of individuals as a means to an end is considered to be unethical, for example, under the Helsinki Declaration. Therefore, if you want to do research on people suffering from HIV or from tuberculosis, the research must have some benefit for them. Furthermore, the individuals involved must understand that they are the subjects of research and not of treatment. Dr

Marc DOHERTY
We should not underestimate the people participating in trials. I have often been surprised by the willingness of people in some of the poorest rural zones of Africa to participate in the trials with a view to helping their community.

Solomon BENATAR
Many people in developing countries are more trusting than the average sceptical Western subject. We cannot simply arrive in countries with a view to carrying out research without taking into account the existing, and often inadequate, health care systems in those countries. We have to do something that will improve the situation of the people in the country. Unfortunately, researchers do not often see this as their role. There is thus a tension between using people to obtain the information you want, and abusing people to obtain that information. About 40% of the world's population do not have access to any of the scientific progress that has been made in the past 100 years. There is no guarantee that the new knowledge obtained will result in a benefit for a very significant proportion of the world's population. However, these are the very people that we want to do research on.

Dr Hazell DOCKRELL
The project we have been running in northern Malawi for the past 25 years is completely free standing and not attached to any local institution. Over that time, the unit has made a great contribution to the community. Our staff on site are often concerned that we are not putting more back into the community. However, we are partly funded by the Wellcome Trust, which argues that it is not an aid body but a research body.

Solomon BENATAR
This is one of the most contentious issues in the debate on international research ethics. We need greater coordination between the different bodies working in each country, which often do not know what the others are doing. I believe that research workers have a responsibility to use their influence to drive more resources for aid in the country. Researchers are often reluctant to do this, arguing that they are not aid or care givers.

Richard ASHCROFT
The original question refers to a vaccine trial that requires HIV negative subjects. This requires the carrying out of HIV screening at enrolment. Part of the consent process would include counselling people that you are going to test for HIV. One could argue that the researcher's role ends there; they are not responsible for then providing HIV treatment. Alternatively, once could argue that by testing for HIV, the researcher becomes responsible for providing HIV treatment to those who test positive. In this context, I would suggest the analogy of someone who comes upon an individual drowning in the Seine. Most people would argue that the right thing to do would be to jump in and save the person. However, are you then responsible for that person, for example, if you know that he or she has suicidal tendencies? Are you more responsible if you happen to be a psychiatrist or if you are a researcher in the epidemiology of suicide? As a researcher, do you have a duty to people who enter into your purview? Simply by being in that place at that time, have you created a relationship with those people that gives you greater responsibility?

Brigitte GICQUEL
We are not going to undertake a trial just anywhere. It will be undertaken in conditions where people can be treated. We should provide a benefit, for example, by increasing the capacity for diagnosis. This would be of mutual benefit for both the country and for the researcher. By choosing the site for the trial in collaboration with people involved in controlled programmes, many of these problems can be avoided.

Dr Marc DOHERTY
If the person saved from the Seine advises you that he or she was driven to suicide by significant debts, are you then responsible for paying that person's debt? In many cases in Africa, it is not possible to make any significant impact on HIV with the resources that are available for clinical work.

Solomon BENATAR
A basic ethical principle provides that, if you cannot do any good, you should at least not do any harm. By testing someone for HIV and advising them that they are HIV positive, you could do some harm given that you cannot offer them any treatment. In the 1960s and 1970s it was possible to eradicate tuberculosis from the world. We had the resources to do this, but not the political will. We could find a cure or a vaccine for HIV, but it is likely that this will not reach the very people who need it. This raises the issue of whether we can really translate our scientific knowledge into useful action. If researchers themselves do not see this as part of that role, no one else will.

Dr Marc DOHERTY
We would not consider doing a trial if we did not consider that it would have a benefit for the individuals involved. The polio figures over the last few decades show that we can make a difference.

Dr Anne FAGOT-LARGEAULT
You seem to imply that a TB diagnosis is neutral, but that a HIV diagnosis will lead to strong social discrimination. However, in the past in France for example, a TB diagnosis was considered as a source of shame.

Solomon BENATAR
We can cure tuberculosis, but we cannot cure HIV. The stigma attached to HIV is still very high both for individuals and communities. Are we doing enough to reduce that stigma? For example, Doctors without Borders have been offering anti-retroviral treatment on a selective basis in a certain area of Africa. Many more people are now coming to the centre for HIV testing, because they know that they have the possibility of being treated. No one wants to be tested when there is no possibility of treatment.

Dr Marc DOHERTY
In many African countries, TB or leprosy is still highly stigmatised, even though they are treatable diseases. In Ethiopia for example, someone who is diagnosed with leprosy will be excluded from the family or village, even when they are cured.

Dr Voahangy RASOLOFO
The problem is not the stigma attached to HIV but how can we take care of HIV positive patients. For example, anti-retroviral therapy is not available in our country. This is why we have suggested carrying out an anonymous test, but is this ethical?

Boubacar BAH, CHU Ignace Deen, Guinea
The problem of HIV testing is a real problem in our countries. Some individuals will accept an HIV test, because they do not know exactly what it means in terms of consequences. Those who have more information, may either refuse the test or agree to it. In relation to tuberculosis, the greatest reluctance to testing arises in more educated people, who fear that they will lose their jobs if they test positive. Given that we are unable to offer any treatment, I believe that if a patient refuses to undergo an HIV test, the test should not be carried out.

Dr Anne FAGOT-LARGEAULT
I agree completely. It is not possible to carry out an HIV test without the knowledge of the person.

Dr Voahangy RASOLOFO
However, if a patient agrees to be HIV tested, and in fact tests positive, what do we then do? Certain countries such as Uganda have a national AIDS programme. However, when the national AIDS programmes are either non-existent or very poor, what do we do? If we do anonymous, non-correlated testing, we will know we have HIVs in our cohort. What is our resulting responsibility?

Eduardo TICONA, Hospital Nacional Dos de Mayo, Peru
The development of ethics committees in many countries involves various social and political issues. The right balance must be found in each country.

Brigitte GICQUEL
If a research institution obtains the authorisation the national ethics committee in the country where the trial will be carried out, does it also need the authorisation of the ethics committee in its own country?

Dr Anne FAGOT-LARGEAULT
Vaccine trials are usually very large and carried out over many different countries. Do all the ethics committees in each country have to be consulted?

Richard ASHCROFT
Usually, there is no one single ethics committee that can provide approval. I was struck by the Madagascar example where the national ethics committee was not consulted at all. This would seem to argue for the need for approval from the home country and from the country where the research will be carried out.

Solomon BENATAR
Any researcher from the North who wants to undertake research in a developing country should have approval from both the home country's ethics committee and the ethics committee of the developing country. This ensures that researchers do not undertake unethical actions outside of their own countries. Of course, it could be possible that both ethics committees agree to something that is unethical.

Dr Anne FAGOT-LARGEAULT
In most countries where the protocols are made, there is no national rule that requires people to have their protocol reviewed at home before applying it in another country. This issue has been discussed in France but has not yet been made a legal obligation.

Solomon BENATAR
We should go beyond legal requirements, which often lag behind practice or only set minimum standards. We should encourage people to meet a higher standard than they are currently meeting. Hopefully, this would become part of the law in due course.

Dr Anne FAGOT-LARGEAULT
For example, if a protocol of the Institut Pasteur was to be applied in Thailand, to which ethics committee should the request by submitted?

Solomon BENATAR
To the ethics committee of the Institut Pasteur.

Brigitte GICQUEL
Should we not also submit the protocol to a national ethics committee, if it exists?

Dr Hazell DOCKRELL
We would not let anyone carry out work without prior approval from our own ethics committee. If the study is being carried out in the UK, we would also require approval from the local NHS trust. However, if the work is to be performed in another country, there is no relevant body in the UK who could approve it.

Brigitte GICQUEL
Obtaining approval from our own ethics committees does not prevent us from going to the national authority.

Dr Marc DOHERTY
We have found that local authorities will not review studies that are not being carried out in their areas. We therefore submitted our proposal to the WHO. However, the WHO does not have the resources to carry out such reviews at the global level. There is thus no authority that can cover these issues.

Eduardo TICONA
The situation of each country must be considered in determining what can be done in each country.

Brigitte GICQUEL
Each country should have its own ethics committee, which will make a decision according to the situation in that country. For example, anti-retroviral therapy is available in some countries and not in others. In some countries, such therapy is associated with a stigma, and in others not.

Richard ASHCROFT
In some countries, the national ethics committee may be willing to provide its opinion on research to be carried out outside of the country. In others, they will not. Researchers can ask committees for an opinion and commit to following the opinion, even if it is not legally binding.

Dr Anne FAGOT-LARGEAULT
The local committees I am familiar with have declared themselves as being not competent to provide an opinion in such cases.

Solomon BENATAR
Local ethics committees will usually only be reluctant to provide advice in very complex cases. In South Africa, for example, none of the ethics committees of any of our universities felt that they were sufficiently competent to provide an opinion on the early HIV vaccines trials. We therefore produced a set of guidelines for HIV vaccine trials, which will become the national guidelines. It will now be possible for local ethics committees to provide an opinion on the basis of those guidelines. We are trying to grapple with these complex issues and provide guidance. UNAIDS is also working on developing some guidelines in this area.