Presented at the Annual meeting of the American Association for the Advancement of Science, San Francisco, February 20, 1994
The ethical issues associated with preventative AIDS vaccine trials in developing countries have been discussed for a number of years in the literature and at conferences. Two issues have been central in this discussion:
The issue of availability of vaccines to developing countries
Informed consent issues
Both of these issues are related to the emergence of research ethics in the 1970s. Partly in response to documented cases of abuse, it has by now become generally accepted that one should not carry out research in developing countries that is not acceptable in one's own country, and potential research subjects should be provided with all relevant information about the research before they give their consent to participate. In addition, ethics review committees are supposed to review research to ensure that acceptable standards of research ethics are adhered to.
It is in this context that one should consider the debate on the ethical issues of preventive AIDS vaccine trials in developing countries. Many have raised the worry that, because of the pressure to develop a vaccine, research will be carried out in these countries that can not be carried out in other countries, and more importantly, research may be carried out in these countries, but the vaccine will not be available to them because of its high cost. Therefore, a number of people have argued that a precondition for the participation of developing countries should be a guarantee that a vaccine will be made available to the countries once its efficacy has been proven. Let me give some representative quotations:
The FDA should not accept the results of clinical trials in developing countries unless the sponsor agrees to distribute he vaccine there. WHO may be able to assist such companies in planning adequate research and in selling a vaccine at a piece that covers appropriate costs and can be afforded by developing countries.
Justice requires equitable sharing, among the population, of the risks involved, and of the benefits that will derive from he research. The population in which the vaccine is tested is entitled to first priority in receiving the vaccine after its safety and efficacy have been established (p. 3; GPA:
Statement from the consultation on criteria for international testing of candidate vaccines, WHO)
The Consultation considers that WHO has a special role to play in securing the cooperation of industry, not only in developing safe and effective vaccines but also in ensuring their availability at affordable prices to developing countries, and in assisting the transfer of technology of vaccine manufacture to selected developing countries where it is likely to be used (ibid, p. 9)
I would like to make several comments with regard to this issue of availability. First, as a matter of fact, vaccine trials are now being initiated in developing countries before there are any guarantees that they will be available in these countries once they are shown to be effective. This says something about the great pressure that exists to develop a vaccine, and a willingness to initiate trials even though the stated ethical requirements have not been fulfilled. Second, I do not think that it will be possible to come up with any such guarantees before vaccine trials are initiated, given the current reality of drug development and patent protection laws, and given the uncertainty about vaccine development. Third, one should examine the role medical ethics has played and is playing in this public debate. Given that many feel that the availability question should be solved before trials are initiated, and given that an organization such as the WHO publicly states that it will play a special role in securing access to the vaccines, one may get the impression that this issue has been solved and one can therefore justifiably start vaccine trials in developing countries. For reasons just mentioned, I do not think that this issue can be resolved before trials are initiated. We are therefore faced with a choice: We can either conclude that vaccine trials should not be carried out in developing countries, or we can get on with the business of setting conditions for such trials, given that we will not necessarily be able to secure access to vaccines to these countries. However, by giving the impression that vaccines will be made available to developing countries, we may be in the process of passing by a chance to set realistic conditions for the participation of developing countries in such vaccine trials.
Let me now turn to informed consent requirements. There are at least three separate issues involved here. One is the more formal requirement that potential research subjects give their informed consent to take part in a trial or refuse to take part. There has been an extensive discussion in the bioethics literature concerning whether the notion of individualized consent is applicable to developing countries. In the recently issued CIOMS guidelines an allowance is made for the possibility of consent by community leaders on behalf of research subjects. Many have rightly been very skeptical of such ideas. I shall not discuss this issue further here.
The second set of issues concerns the need to initiate procedures which will ensure that potential research subjects understand what is involved in taking part in vaccine trials. WHO has taken the initiative of doing a number of things which could ensure adherence to ethical requirements:
1. Initiation of research on behavioral, social and ethical aspects of vaccine research
* e.g.studies of belief systems about illness
* studies of willingness to participate
* studies of beliefs about vaccines
* studies of understanding of key concepts, such as placebo, double blind methodology etc.
* studies of procedures of obtaining informed consent
* studies of counseling procedures
2. Involvement of community groups at all levels
3. Discussions in various fora
4. Direct WHO involvement in planning of vaccine studies
I am nevertheless skeptical about whether these efforts will ensure compliance with the requirements of ethics, for the following reasons:
1. Although WHO has repeatedly asserted that behavioral research of the kind mentioned is important, there have been problems in funding such research
2. Although community involvement in the process of preparing or clinical trials is important, this is no substitute for making sure that ethical requirements are adhered to. Community groups have their own reasons for wanting to push forward with research of questionable nature, such as:
Research of this kind gives hope for a cure
Fear that attention to ethics will deter advancement of science
3. Much of the behavioral research envisaged focus on issues of recruitment and compliance. That is, the question is taken for granted that vaccine trials are a good thing, and we now need behavioral research which will make sure that potential participants are recruited quickly and comply with the research protocols. That is, one seems interested in those things which may deter people from entering clinical trials, instead of focussing on those things which may lead people to want to take part in trials prematurely.
The third issue related to informed consent requirements is that the potential benefits of taking part in a trial should be in proportion to the possible harms. In particular, it is by now generally accepted that before human research is initiated one should know enough from animal or other basic research to be reasonably certain that no significant harm will result from taking part in the research. Since there is always a possibility of harm, there should be corresponding benefits, either to the research subjects themselves, or to future patients.
With regard to HIV vaccines, many have pointed out that there is no satisfactory animal model that will be able to demonstrate a protective effect of human vaccine candidates.
There is also no satisfactory candidate vaccine available as of now. This has led some to conclude that it is difficult to justify initiation of phase I and phase II studies now. The reasons for this are:
No benefit to research subjects
Possibility of harm
May not lead to phase III trials
In a situation such as this one it is difficult to fulfill the conditions of the Helsinki declaration which requires assurance that research subjects are not harmed in phase I trials, and that there is a possibility of benefit to future patients. Since less is known than usual from basic research
about the protective effect of AIDS vaccine candidates, it will be difficult both to assure participants that they will not be harmed, and assure participants that the vaccine will be of use in the future. All of this does not necessarily mean that it is impossible to justify the initiation of clinical trials, but a key issue will be to distinguish between genuine altruism, and a false expectation of protection by taking part in a trial.
What I have said so far concerns all vaccine trials in all countries. There are some additional issues related to testing in developing countries. The variability of strains means that a vaccine showing effect in the US will not necessarily have an effect in developing countries. It is therefore necessary to do trials in developing countries. Again there has been some concern over how these trials should be carried out in these countries.
WHO has recommended the following:
Phase I and phase II should initially be carried out in developed countries, followed by repeat phase I and phase II of some of these vaccines in developing countries where nutritional status and background infections may alter safety and immunogenicity. Then phase III studies should be carried out simultaneously in industrialized and in developing countries.
Again, it is interesting to note that we now nevertheless see phase I trials being planned in a country such as Brazil, in apparent disregard of WHO's own guidelines, and also apparently with the blessing of WHO. It is also interesting to note the comment by Dr. Esparza, head of AIDS vaccine development at WHO, after the disappointing results presented at NIAID's 6th Annual Conference on Advances in AIDS Vaccine Development where results were presented which showed thatcurrent vaccine candidates may not produce an immune response which protects against real-world strains of HIV. He said that it would still be important to go ahead with efficacy trials in developing countries even though there are these basic uncertainties about whether vaccines will be able to protect against infection.
When reflecting on these current developments, I think the issues Wendy Mariner raised in AJPH, January 1989 are still valid. She argued:
"Until there is a publicly accepted rationale for dispensing with animal studies and a clear definition of risks and benefits and useful endpoints of the research, clinical trials of AIDS vaccines are premature." Several possibilities are then open to us:
1. defer clinical trials until animal model is found
2. go beyond current practice of requiring animal studies
3. change codes of ethics
4. define minimal standards necessary, but needs to be done publicly before trials start
Although she wrote this in 1989 (in an article with the title Why clinical trials of AIDS vaccines are premature), I think her points are just as valid today, in particular with regard to research in developing countries. The issue is not necessarily that vaccine trials should not be initiated, but the issue is that we need a public discussion about the conditions of their initiation, given the non-ideal situation with regard to AIDS vaccine development.
Let me now say a few words about why we see this apparent disregard for international guidelines? I think it important to point out that there are various interest groups involved in the planning process, and they all have their own agendas.
These groups include:
1. Government officials
3. Community groups
There is a sense that some of these group see ethics as interfering with the advancement of science, and the discovery of an effective vaccine. In a way this is the traditional conflict between the emphasis on the protection of research subjects vs. emphasis on the possible benefit of a vaccine.
Traditionally, risky research on human subjects was justified because of the promise of great benefits in terms of the introduction of new treatments. However, the experience has shown us that such promised benefits often do not materialize, and there really is no alternative than to adhere strictly to the accepted guidelines for the protection of human research subjects.
1. More focus on whether trials should start at all
2. More focus on conditions of how trials should be conducted given non-ideal conditions
3. Create of expertise in research ethics in developing countries
4. Encourage the creation of an independent group of critical researchers instead of exclusive focus on behavioral research
5. Stop talking about availability as a precondition for starting trials. Instead: Given that vaccines will not be immediately available, under what condition should trials start in developing countries.
6. Develop alternatives to double-blind randomized controlled trials.