Two pivotal international research ethics documents are currently undergoing substantial revisions. These documents are the World Medical Association’s (WMA) Declaration of Helsinki, and the Council for International Organizations of Medical Sciences’ (CIOMS) International Ethical Guidelines for Biomedical Research Involving Human Subjects. Both documents are of fundamental importance with regard to the conduct of international collaborative research. The United Nations AIDS organisation’s Ethical Review Committee demands “assurance that the Principal Investigator has confirmed in writing that the research will be conducted in conformity with the Declaration of Helsinki.”
There is nothing unusual, of course, about research ethics guidelines evolving over time to adjust to changing societal perceptions about what is and what is not ethical. However, opponents of many of the proposed changes argue that this time we are faced with changes that constitute a major threat to the few research ethics protections that are currently afforded to research subjects in developing countries. The battle lines, so to speak, have been drawn in the sand by US researchers and some bioethicists supporting the changes and, on the other side, strongly opposing the changes are academics and activists in developing countries, Europe, Australia and Japan.
Much of this article will deal with the Declaration of Helsinki. The reason for this is that the CIOMS deliberations take place in complete secrecy. The proponents of changes to the CIOMS research ethics guidelines, however, are the same as those pushing for changes to the Declaration of Helsinki. Dr Bankowski, the long-serving CIOMS Secretary General refuses to provide any information about the proposed changes, the group authoring the new CIOMS guidelines, the process governing the proceedings, timelines or anything else related to this issue. Considering the international importance of the CIOMS guidelines, this is nothing short of scandalous and wholly unacceptable. A new regime for the establishment of international research ethics guidelines is called for, that doesn’t rely on anonymous, unaccountable organisations and experts that are chosen on the basis of unknown criteria.
The most contentious of the proposed changes is the one proposing different standards of care, depending on where a given trial takes place. The current text of the Declaration requires that in any research clinical trial “every patient should be assured of the best proven diagnostic and therapeutic method.” The proposed change adds to this sentence “… that would otherwise be available to him or her.” The implications of this seemingly inoccuous change are wideranging. Should this proposed change succeed in becoming the new wording of the Declaration of Helsinki, we would find ourselves with two sets of research ethics standards - one for people in rich countries, and one for subjects living in poor countries. Suppose, you are German and you participate in a preventive HIV vaccine trial. If something unfortunately goes wrong during the trial, and you get infected with HIV, or you get sick after the trial you fortunately live in a society with functioning public health care, hence you will be taken care of by German medical doctors. Triple combination therapy will not only keep you alive, it will even allow you to go back to work one day, or else you’ll be furnished with a disability pension that allows you to live a decent life. Change of scenario. – Imagine now that you are a participant in a preventive AIDS vaccine trial that takes place in Uganda or Ivory Coast. The resources of the health care system are stretched far beyond its limits. Combination therapy is unaffordable, and it is certainly not the local standard of care. If you are one of the 30% or so of volunteers of any such trial who has a serious misconception of the nature of the trial, and as a consequence of that misconception you get HIV infected and sick, under the proposed watered down version of the Declaration of Helsinki you will only receive whatever the local standard of care is. In economic terms, clearly, that is an excellent deal for any pharmaceutical multinational on the look-out for cheap research subjects. In any developed country such an organisation would have to foot the substantial bill to provide their research subjects with the best local standards of care, while in many developing countries the outlay would be negligible to non-existent. Furthermore, the idea that there is such a thing as a local standard of care is problematic. The reality is that it is a standard of care dictated by prices Western pharmaceutical multinationals set regardless of the consequences for millions of people in developing countries. It allows the introduction of placebo controls in clinical trials that would be considered unethical in Western countries. A case in point is the now infamous mother-child HIV transmission prevention trials. This has been discussed widely in the medical and bioethical literature. What was offered as an ethical reason for the introduction of a placebo control in this trial was not a medical reason. It proposed that none of the women in the trial were worse off. The reason for this claim is that the local standard of care in Thailand, Uganda and any of the other developing countries participating in this trial was no intervention and those who got AZT, a proven intervention and the standard of care for developed nations were better off than they would otherwise have been. Those who got a placebo were not worse off, because if they had not participated they would not have received AZT either. Quite obviously, what we have in these trials is the proposed change to the Declaration of Helsinki in action; exploiting the vulnerability of poor research subjects in countries where AZT is made unaffordable by the price its manufacturer sets. Even the pseudo-justification, that these trials had to be done, in order to produce affordable drugs for people living in developing countries, proves to be a smokescreen. The lower-dosage regimen that was the result of these trials is so expensively priced by its manufacturer that even the health minister of South Africa which is a middle income country announced they she would not fund this intervention because it doesn’t constitute, in the local environment, a cost-effective means of HIV prevention. I proposed some time ago that for this reason alone these trials should have never taken place.
The bottom-line of this proposal is that it is acceptable to withhold a proven intervention for purely economic reasons. Without going too much into the details of the economical aspects of this problem, it should be mentioned here that the international trade regime allows for compulsory licensing of drugs in developing countries if lives are at risk. The US government threatened the South African government with trade sanctions if it made use of this provision. The South African government planned to compulsoryily license a whole range of AIDS drugs in order to manufacture them locally at affordable prices in order to save the lives of millions of infected citizens of that country. The US intervention made that impossible. Ethical justifications of the trials in question, and of the local-standards-of-care concept tend to ignore these vital facts. Despite ample evidence of seriously deficient informed consent procedures in developing countries the proposed changes permit waivers of informed consent when the research involves only a “slight risk”. Clearly, what constitutes a “slight risk” depends very much on the interpretation of individuals, in this case the principal investigators. In societies where most research subjects could not afford the costly litigation that is possible in Western countries, reducing the informed consent based requirements is deeply disconcerting.
Further problematic proposed changes suggest an increase in the use of placebo controls in clinical trials. The justification seems to be a utilitarian one, based on the idea that placebo controls often speed up trial results. Peter Lurie, MD of Public Citizen, has argued in a letter to the WMA president that this justification is unsound because equivalency studies could produce the same results just as fast. They would require more research subjects, but such a hurdle could clearly be overcome by means of aggressive recruiting and multicentre studies.
The proposed changes would also make it easier for medical journals to publish research that violated the requirements of the Declaration of Helsinki. Richard Nicholson, the editor of Bulletin of Medical Ethics, who has waged for a long time a one-person campaign against the proposed changes to the Declaration of Helsinki, argues that the physician’s responsibilities toward their research subjects are watered down unacceptably.
I have highlighted in the above paragraphs only the ethically most problematic of the proposed changes. Not all of the proposed changes are unethical, but undoubtedly many are. Their primary objective seems to be, as Nicholson suggested, to “satisfy the perceived needs of American researchers.” The WMA is accountable to its national medical association members, and partly due to sustained criticisms by delegates from the UK, Japan and a number of developing countries, the organisation has sent the proposal back to its members associations for further consultation, despite efforts by US American ethicists and researchers to pass them. The next WMA Assembly meeting in October in Israel will discuss the proposed changes again. I doubt that the proposed changes have much chance of success, largely because the protests against them are growing, and because the potential they have of causing more harm than good are all too obvious. The mother-child transmission trials caused a lot of indignation among researchers who were caught in the act of breaking the current Declaration of Helsinki and the CIOMS research ethics guidelines. Activists and academics slammed the obvious exploitation of HIV infected pregnant women in developing countries. The current proposals are an attempt to rectify this situation by not changing the research conduct, but by changing the guidelines.
UNAIDS Ethical Review Committee. Provisional Terms of Reference and Procedures. Journal International de Bioethique 1998; 9(4): 125-128, 126.
This paragraph relies heavily on information provided to me by Dr Peter Lurie of Public Citizen, Dr Bebe Loff, Monash University Faculty of Medicine, and Dr Richard Nicholson, Editor of the Bulletin of Medical Ethics.
Udo Schüklenk. Unethical Perinatal HIV Transmission trials Establish Bad Precedent. Bioethics 1998; 12:312-319.
See e.g. Robert A. Crouch and John D. Arras. AZT Trials and Tribulations. Hastings Center Report 1998; 28(6): 26-34.
Filho O Queiroz de Fonsecoa and Reidar K Lie. Informed consent to preventive AIDS vaccine trials in Brazil. AIDS and Public Policy Journal 1995; 10: 22-26.QA Karim, SSA Karim et al. Informed consent for HIV testing in a South African Hospital: is it truly informed and truly voluntary? American Journal of Public Health 1998; 88: 637-640.
Peter Lurie and Sidney M. Wolfe. Personal communication. 29 March 1999.