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The Declaration of Helsinki and research in vulnerable populations
Bebe Loff and Jim Black
Mooted changes to the Declaration on the agenda of the World Medical Association have sparked a vigorous debate on international research issues. The medical, research and ethics communities in Australia need to participate more broadly in this debate.
MJA 2000; 172: 292-295
For editorial comment, see Stockhausen
Introduction -
Proposed revisions -
The problem in resource-poor countries -
Where to from here? -
Conclusion -
Acknowledgements -
References -
Authors' details
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More articles on Ethics
| Introduction |
The Nuremberg Code, which was formulated to prevent a recurrence of
the horrific medical experiments carried out on humans during World
War II, is unwavering in its commitment to the primacy of the human
subject. It states that any person who is a research participant
"should be so situated as to be able to exercise free power of choice"
and that "(t)he experiment should be such as to yield fruitful results
for the good of society, unprocurable by other methods or means of
study, and not random and unnecessary in nature."1
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 | ||
Proposed revisions to the Declaration of Helsinki | |||
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A number of revisions are currently proposed to the Declaration to
make it more relevant to researchers (some of whom, it has been
suggested, commonly breach its provisions).7 Those who oppose the
amendments fear that research participants will be made more
vulnerable to harm in order to make research more efficient and
perhaps expedient (see Box).8
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. | |||
"Therapeutic" v "non-therapeutic" research | |||
The introduction to the Declaration requires that
"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".Article II.6 states that in "therapeutic" 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."Article III.2 states that in "non-therapeutic" research "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 | |||
"Best proven treatment" v "highest attainable treatment" | |||
| The changes proposed to Article II.3 (see Box) have generated extensive debate. Opinions are polarised between those in favour of the "best proven treatment or method" and those for the "highest attainable and sustainable treatment or method". The problem with the "best proven treatment" approach is that it may prevent valuable research being done, as treatments and services will not be readily available in resource-poor settings and may not be provided by researchers and their sponsors. The problem with the "highest attainable treatment" goal is that it may lead to a marked decline in care -- there are no clear criteria for establishing what level of treatment is acceptable or firm safeguards for applying it. | |||
The problem in resource-poor countries | |||
|
Perhaps the real issues to be debated are how best to enable people to
make meaningful choices and how to ensure that they are not treated
poorly and without respect because of their circumstances. What
should be examined are the problems created in some societies by a lack
of fundamental civil and economic rights, and whether this
advantages proposed research projects.
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."15 Almost any reward, even bars of soap or transistor radio batteries, is likely to ensure trial participation. 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. | |||
Where to from here? | |||
|
Are genuinely consensual relations possible between the research
community and participants who otherwise have little or no access to
healthcare or other basic rights and liberties? Can structures and
criteria be implemented that promote dialogue and recognise
diversity of approach, but discourage abuse of trial participants?
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. | |||
Conclusion | |||
Angela Harris, Professor of Law at the University of California,
Berkeley, has stated that modern human rights standards are at once
indispensable and inadequate.17 The same may be said for
ethical guidelines on medical research. The solutions are not
clearcut. The WMA meeting in Tel Aviv, Israel, in October 1999, at
which the Declaration of Helsinki was reconsidered, issued the
following brief statement:
"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. | |||
Acknowledgements | |||
| The authors warmly thank the following for their valuable contributions to "The Declaration of Helsinki: a symposium to review current proposals for change", held at the Victorian Institute of Forensic Medicine, Melbourne, on August 30 1999, and for their contributions to the discussion: Stephen Cordner and Helen McKelvie (Victorian Institute of Forensic Medicine), Norman Swan (Radio National), Sandra Hacker (Australian Medical Association), Louis Waller (Faculty of Law, Monash University), Pascale Allotey (Key Centre for Women's Health, Melbourne University), Deborah Zion and Justin Oakely (Centre for Human Bioethics, Monash University), Lyn Gillam (Centre for the Study of Health and Society, Melbourne University) and Ian Kerridge (Faculty of Medicine, Newcastle University). The views expressed in this article are those of the authors. | |||
References | |||
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Authors' details | |||
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Department of Epidemiology and Preventive Medicine, Monash
University Medical School, Alfred Hospital, Melbourne, VIC.
Bebe Loff, MA, LLB, NHMRC Public Health Scholar. Jim Black, MB BS, MCommH, DTM&H, NHMRC Medical Scholar.
Reprints will not be available from the authors. ©MJA 2000
Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company. Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/> ª 2000 Medical Journal of Australia. We appreciate your comments. | |||
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