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The Declaration of Helsinki² was the World Medical Association's (WMA's) response to the Nuremberg Code and its goal was to safeguard research subjects. However, in declaring the need to weigh the importance of the research objective against the risk to the subject (Article I.4), the Declaration was seen as a subtle retreat from the Code.³ Some fear that changes to the Declaration currently under consideration by the WMA would substantially "water down" the basic principles of ethical human research.

The Declaration does not specifically deal with international collaborations. In 1993, the Council for International Organizations of Medical Sciences (CIOMS) developed the International ethical guidelines for biomedical research involving human subjects,⁴ which address issues pertinent to the conduct of research in developing countries.

Despite the existence of the Declaration and other documents, it is apparent that the application of safeguards to protect research subjects is far from uniform, especially among impoverished or marginalised people.^5,6

Two proposals have generated a great deal of discussion and controversy. One concerns the abolition of the distinction between "therapeutic" and "non-therapeutic" research. The other (the main focus of this article) relates to provision of the best proven treatment and to use of placebo-controlled trials.

"a fundamental distinction . . . be recognised between medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research".

"The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient."

"The subjects should be volunteers -- either healthy persons, or patients for whom the experimental design is not related to the patient's illness."

Robert Levine, Professor of Internal Medicine at Yale University School of Medicine, argues that these Articles together rule out "all rational research on the causes of diseases or on their pathogenesis or pathophysiology".⁷ He notes that clinical trials may include both therapeutic and non-therapeutic agents.⁷ Others believe the division between therapeutic and non-therapeutic research to be firmly entrenched in research guidelines developed since and influenced by the Declaration and to be well understood in practice.⁹

To assume that all would like to be treated as people in affluent countries would, and to rely on this judgement as a basis for formulating an encompassing ethical ideal, is, to some extent, misguided. Classic egalitarian premises, upon which comparable rights documents, such as the Universal Declaration of Human Rights,¹⁰ are based fail to take account of subcultures and their priorities. Indeed, issues like gender and race are still inadequately addressed in these documents, in which the tacitly assumed "universal person" is the European white heterosexual male.¹¹ This difficulty is accentuated when privileged cultures interact with others. Is it true to say that standards appropriate for industrialised countries are equally relevant to others? If not, what are we left with?

Ruth Macklin, Professor of Bioethics at the Albert Einstein College of Medicine in New York, has analysed ethical concerns in international research according to the concept of justice.¹² She states that a prominent feature of justice is that no one group should "receive disproportionate benefits or bear disproportionate burdens",¹² a corollary being that like cases should be treated alike. One side argues that if the study is unethical in one place it is unethical in both. The other argues that risk-benefit ratios are different in resource-poor countries and therefore require a different response and, further, that if the benefit is actually to accrue and only to accrue to the developing country, this is ethically significant.¹² Her conclusion in this debate is that both sides can claim that their arguments observe the ethical requirement of justice.

Advocates of placebo-controlled trials in resource-poor countries cite local support and participation in defence of their views. Thus, in the case of trials of less expensive regimens to prevent vertical transmission of HIV, Edward Mbidde, a Ugandan physician, said in a now oft-cited statement, "(t)hese are Ugandan studies, conducted by Ugandan investigators, on Ugandans ... for the good of their people".¹³ It would be too simple a response to discount this comment entirely as being no answer to a breach of ethical standards.¹⁴

Yet, even when a host country agrees to allow drug trials, substantial ethical difficulties remain. One of us (J B), after working for 10 years as a clinician in Mozambique (where the local provincial health service budget was about $US3 per capita per year), believes that the basic rights of potential trial participants in some parts of Africa may be so compromised that refusal to participate is not an option:

"This is the sort of health service where every clinician finds him or herself from time to time looking at the pharmacy cupboard and wondering how to divide the remaining three vials of penicillin between the five patients in the ward who need it. (Whether to give starting doses to everyone in the hope that the promised new supplies will arrive, or just give it to one seriously ill child, for whom at least it represents a curative course.) From that perspective, enrolling patients in a clinical trial will always look attractive, no matter how unethical that research may turn out to be."

Perhaps international collaborations, particularly those involving complex drug trials, should not be conducted where there is this degree of poverty. Speaking at the same symposium,¹⁵ Pascale Allotey, Lecturer in International Programs at the Key Centre for Women's Health, Melbourne University, made the point that the possibility of enhanced services or cashflow to a community will mean that community leaders will very likely agree to trials taking place, as, ostensibly, will community members. However, they may resent doing so. Fears of a diminished standard of care as a result of withdrawal from a trial are quite real in these circumstances.

The following suggestions were offered to the participants in the aforementioned symposium¹⁵ for consideration, and most agreed that more discussion was required to flesh out what these ideas might mean in practice (the suggestions are not entirely new and are broadly consistent with the CIOMS guidelines and draft UNAIDS guidelines¹⁶):

(a) Where a population does not possess basic economic or social rights it should be regarded, prima facie, as one whose members' capacity to freely consent is gravely impaired. Research studies in such populations, especially those involving randomised trials, require special justification. An exception might be where the research goal is to work out how to apply a proven technology: for example, an assessment of whether open or covered buckets are more suitable water containers in a refugee camp (Associate Professor Michael Toole, Macfarlane Burnet Centre for Medical Research, personal communication).

UNAIDS guidelines¹⁶ state that, in international collaborative programs, strategies should aim to balance inequalities by involving members of affected communities from very early on in the design and development stage, and by imposing a number of safeguards around the process of informed consent.

(b) A research protocol should describe the conditions that might make a research population vulnerable to exploitation and the steps that will be taken to overcome them.¹⁶ The UNAIDS guidelines impose this requirement on research protocols. We further propose that these steps should be described in publications derived from the research, in order to give the issues greater prominence and to further this discussion.

(c) In planning research in populations severely deprived of civil and political rights, agreements with governments and ethics committees are insufficient. This is especially the case when governments have demonstrated grossly repressive or corrupt behaviour, or where ethical review systems can not be regarded as independent. Research should not take place in these circumstances. This recommendation should be distinguished from ethical guidelines applying to research in emergency or refugee settings.

(d) Thorough community-based consultation is required to determine local views, needs and priorities. Researchers need to establish what local research priorities exist (although, in many deprived populations, any problem area could be seen as a priority). This includes, in particular, consultation with people who have little power or are ostracised for whatever reason. Ethnographic studies could be conducted in advance of a proposed project to determine actual rather than supposed local attitudes, and debriefing could be required after completion of a trial (Deborah Zion, Centre for Human Bioethics, Monash University, personal communication). Including nationals on committees, or agreement by host governments and ethics committees, are not substitutes for community consultation.

(e) An analysis should be made, in advance of a project, of the long-term consequences of the intervention. Long-term considerations should certainly include, but not be limited to, sustained access to a trial drug. One of the possible adverse consequences to consider would be the diversion of local researchers and healthcare providers into projects that are not local initiatives. Consistent with current ethical standards, if there is no prospect of benefit to the community in its terms the research should not be undertaken. At the very least, a memorandum of understanding should be prepared before the commencement of any international collaboration, indicating what each party -- community, government, research institution and sponsor -- expects prior to, during and as a consequence of the trial.

"The meeting heard of widespread support for retaining the existing structure of the Declaration of Helsinki. It was agreed that the working group set up to consider amendments to the Declaration should report back with a proposed revision at next year's annual General Assembly meeting in Edinburgh, Scotland (3 October 2000)."

It is to be hoped that the Australian medical research community and other interested groups will debate the issues and arrive at a consensus.

1. The Nuremberg Code. From: Trials of war criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Nuremberg, Oct 1946-Apr 1949. Washington, DC: US Government Printing Office, 1949.
2. World Medical Association. Recommendations guiding physicians in biomedical research involving human subjects. As adopted by the 18th World Medical Assembly, Helsinki, June 1964 (the "Declaration of Helsinki").
3. Katz J. The consent principle in the Nuremberg Code: its significance then and now. In: Annas G, Grodin M. The Nazi doctors and the Nuremberg Code: human rights in human experimentation. New York: Oxford University Press, 1992: 227-239.
4. Council of International Organizations of Medical Sciences, in collaboration with the World Health Organization. International ethical guidelines for biomedical research involving human subjects. Geneva: CIOMS, WHO, 1993.
5. French H. AIDS research in Africa: juggling risks and hopes. New York Times October 9, 1997: A1, A14.
6. Allotey P. Clinical trials in developing countries: bringing people into the debate. Monash Bioethics Review 1999; 18: 18-23.
7. Levine R. The need to revise the Declaration of Helsinki. N Engl J Med 1999; 341: 531-534.
8. Brennan T. Proposed revisions to the Declaration of Helsinki -- will they weaken the ethical principles underlying human research? N Engl J Med 1999; 341: 527-531.
9. British Medical Association. BMA response to the proposed revision of the WMA Declaration of Helsinki. London: BMA, August 1999.
10. Universal Declaration of Human Rights. Adopted and proclaimed by the United Nations General Assembly on December 10, 1948. Geneva: Office of the United Nations High Commissioner for Human Rights.
11. Otto D. Rethinking the "universality" of human rights law. Columbia Human Rights Law Rev 1997; 29: 1-46.
12. Macklin R. Justice in international research. In: Kahn J, Mastroianni A, Sugarman J, editors. Beyond consent: seeking justice in international research. New York: Oxford University Press, 1998: 131-146.
13. Varmus H, Satcher D. Ethical complexities of conducting research in developing countries. N Engl J Med 1997; 337: 1003-1005.
14. Bayer R. The debate over maternal-fetal HIV transmission prevention trials in Africa, Asia, and the Caribbean: racist exploitation or exploitation of racism? Am J Public Health 1998; 88: 567-570.
15. Proceedings of a symposium. The Declaration of Helsinki: a symposium to review current proposals for change. Victorian Institute of Forensic Medicine; 1999 Aug 30; Monash University, Melbourne, VIC.
16. Joint United Nations Programme on HIV/AIDS. Ethical considerations in HIV preventive vaccine research: UNAIDS guidance document. Geneva: UNAIDS, February 2000.
17. Harris A. Foreword: the jurisprudence of reconstruction. California Law Rev 1994; 82: 741-785.

Reprints will not be available from the authors.
Correspondence: Ms B Loff, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC.
Bebe.LoffATmed.monash.edu.au

©MJA 2000
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