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Oct-Dec2001-9(4)
DISCUSSION
The revised Helsinki
Declaration: is it enough?
Asad Jamil
Raja
Inequities in global health care, an increasing
disease burden with decreasing availability of affordable remedies in the
developing world, uneven public allocations for health, and the commercial
demands of the pharmaceutical industry - all these have fed into an intense
debate on the ethics of health research.
These fundamental questions have become narrowly
focused. Some of them relate to the funding of trials for diseases rampant in
the developing world, the expected standards of care during the trial, the study
population's post trial benefits and the availability in the community of
affordable treatments. These questions were asked of research responding to the
HIV epidemic in the third world. Trials conducted over the last decade in
sub-Saharan Africa and South Asia provoked criticism, as they were considered
exploitative and unethical (1,2,3).
It was amidst these intense international debates
that the Declaration of Helsinki was revised for the fifth time in October 2000.
The focus of the debate amongst the medical community has now shifted to the
revised Declaration. The new revision attempts to define strict ethical
standards of research with strong, carefully selected, words.
Studies in the industrial world satisfied the
previous version of the Helsinki Declaration. Many argued that the Asian and
African studies would have never been approved in the West; it was unethical to
have conducted them with impunity in the developing world. One might ask why
such studies were ever conducted in the developing world when guidelines were
present prohibiting them. Surely it was not a lacuna in the Declaration itself
or in other guidelines. Will revised declarations - and perhaps legislation -
prevent unethical research in the future? Will the world become more ethical by
revising declarations? Or is the problem something more than a simple lack of
guidelines? Opposing groups are at loggerheads fighting battles of attrition.
They seem to measure their success according to their ability to add or delete
words from declarations. When celebrating these trivial gains, they are
oblivious of the greater and grim picture of global health care.
Let us first examine the changes in the Declaration
of Helsinki which claim to ensure marginalised research subjects protection and
freedom from exploitation.
Clause 19 states that "Medical research is only
justified if there is reasonable likelihood that the populations in which the
research is carried out stand to benefit from the results of the research." A
number of things are not clear in this clause and need interpretation. What is a
reasonable likelihood? How reasonable is reasonable? It states that research
populations should 'benefit from the results of the research'. A Phase II or
even a Phase III trial conducted anywhere in the world does not project the
price of the drug. How is one to assess whether the research population would
benefit from this research? The eventual price of the drug may be beyond the
reach of the researched population. Researchers argue that initially the prices
are high due to the expense on research and development, but that the prices
eventually do come down.
Another interpretation of this clause is that the
study should be responsive to the health needs of the country where the research
is carried out. To be useful and ethical in this situation, a clinical trial in
a developing country must use a control that is relevant to the country (4).
This means, in most situations, a placebo. Does this mean that the Declaration
of Helsinki accepts different standards of care? It is evident that such
ambiguities will open doors to all kinds of interpretations to suit everyone's
interests. Clause 29 states, "The benefits, risks, burdens and effectiveness of
a new method should be tested against those of the best current prophylactic,
diagnostic and therapeutic methods. This does not exclude the use of placebo or
no treatment in studies where no proven prophylactic diagnostic or therapeutic
method exists." This is the most contentious clause of all. It raises major
scientific issues regarding the randomised, placebo controlled trial (RCT). RCTs
are generally considered the gold standard as they provide the best scientific
evidence in a relatively short duration and are considered economical. Active
control designs while useful and appropriate in many diseases often cannot
provide reliable information on new treatments (4). Such designs are considered
to weaken the evidence and thus science. Scientists believe that as medicine
advances, evidence to show the difference between therapies is marginal. Such
differences can be picked up within in a short time only by randomised, placebo
controlled trials. Active control trials, where best options would be employed,
require large numbers, continue for long periods, and in some cases could be an
exercise in futility (5).
One may ask why it is necessary to have the
strongest possible evidence. Should one really lower ethical standards in the
interest of science? Why should we not accept equivalency trials instead of
randomised placebo controlled trials? (6) The clause not only disallows the use
of a placebo where treatment options are available, it also expects that people
in the control arm receive the best current treatment. Should this be the best
current treatment in the West or the best that is locally available? Providing
the locally available standard of care can be considered a violation of the
principle of justice. On the other hand, if one permits the use of placebo
controlled trials when options are available, impoverished populations in
developing countries - who are unable to afford the gold standard treatment -
will become a human laboratory. Placebo controlled trials can be conducted there
because the locally affordable care is often nothing more than placebo (7). This
clause is also criticised by some as an impediment to identifying alternative
treatments that are both affordable and effective, even if somewhat less
effective than the expensive treatment available in the West. This is an
important public health goal for developing countries, and a research priority
for many international funding agencies (4). For example, suppression of
breast-feeding to prevent transmission of HIV has major implications in
developing countries. Generalising this practice would mean losing all that WHO
has achieved after years of hard work. Women with HIV will be easily identified
and stigmatised. Certainly, the standard of care in the United States - which is
dominated by the practice of defensive medicine against litigation (8) - should
not be emulated throughout the world. It is not sustainable. Then what should
the research design be? What standard of care should be offered to research
participants?
In biomedical research, compromises have tended to
reduce ethical requirements and sacrifice human value to ensure the 'best'
science (7). Does clause 29 really protect research participants from
exploitation? Or is it an impediment to finding remedies affordable and relevant
to the needs of the developing world?
Finally, clause 30 states, "At the conclusion of
the study, every patient entered into the study should be assured of access to
the best proven prophylactic, diagnostic and therapeutic methods identified by
the study." This needs many clarifications. What does one understand by 'assured
access'? Is it free access? For how long? If an anti-hypertensive drug is
tested, should participants receive free access to the drugs life long? What
precisely does one owe the community once research is over?
Is one trial enough to prove that it is the best
therapy? How many more trials are necessary before it should become practice?
The results of one study might not be sufficient to justify a change in
practice, but it may in some case lay the foundation for such changes. After the
conclusion of a successful phase II trial of a drug it could take another four
to six years before regulatory bodies approve this drug as a proven treatment.
Before that, it is all research. How does one interpret this clause in the
context of a community which is undergoing a Phase II trial? Also, consider the
logistics and financial constraints to adopting a new treatment or intervention
on a population-wide basis. At times they may be almost insurmountable (10).
This again raises questions which have no obvious answers.
Unfortunately this document does not provide much
respite to the developing world. During the discussions, there has been a sense
of reluctance to look beyond the obvious. Maybe what is distant is difficult to
change but then why bother with half-baked remedies which are unlikely to work
at their best?
The statistics on health care inequities are
telling. The majority of the developing world spends less US$10 per head on
health. Of the US $56 billion spent annually on medical research worldwide, at
least 90 per cent is spent on the health needs of the richest countries, which
represent a mere 10 per cent of the world's population (11). The result is
severely stunted health care in developing countries, further worsened by the
burdens of illiteracy and poverty.
Ethical Review Committees (ERCs) in some developing
countries are likely to be most vulnerable to unethical or exploitative clinical
research. Unfortunately these ERCs may have the least developed review systems
(10). More important, researchers in developing nations derive substantial
individual and institutional benefits from sponsored research, irrespective of
their status as initiators of, or collaborators in, such research (6). Because
of this conflict of interest, the importance of ERCs' integrity, independence
and capacity for ethical review cannot be overemphasised. The fact that existing
mechanisms provide minimal monitoring of research aggravates the potential for
exploitation even in well-off countries. These issues call into question the
ability of developing countries to conduct independent, competent and quality
ethical review and monitor researchers' compliance of approved protocols.
The pharmaceutical
industry
The discussions are inadequate without a mention of
the role played by the pharmaceutical industry, which operates like any other
industry. Its investment decisions are based on the need to maximise returns. As
such, it responds to economic demands rather than to statements on social or
human needs (9). It is necessary to reflect on the role of the pharmaceutical
industry in world health, particularly its business in the 'third world', where
up to 50 per cent of people do not have access to even the most basic drugs
(10). This is summed up in the regrettable statement that two-thirds of the
world's population is "superfluous from the perspective of the market. By and
large we do not need what they have; they can't buy what we sell" (11). Research
problems are compounded by the fact that the interaction between the medical
profession and the pharmaceutical industry has long been a contentious issue. In
the US, pharmaceutical companies spend more than $11 billion annually promoting
and marketing drugs - between $8,000 and $13,000 per physician. This process has
been shown to affect prescribing and professional behaviour (12).
All these questions stem from global inequities in
health care, an issue which is consistently ignored. On the other hand, some
believe that the economic, social, technological, and political disparities that
weigh so heavily on this discussion should not be used as reasons to undermine
it (13). Ijsselmuiden (7) "stresses the need to recognise the human rather than
economic or scientific primacy, the consideration of alternatives to arrive at
what is optimal, just and sustainable, and therefore, relevant to human progress
especially in underdeveloped countries." On the other hand Singer and Benatar
(8) suggest that "new proactive research ethics must be concerned with the
greatest ethical challenge - the huge inequities in global health. Research
ethics must more forthrightly address the social, political, and economic forces
that widen global inequities in health and it must ultimately be concerned with
reducing inequities in global health and achieving justice in health research
and health care." Certainly research ethics should never be weakened by
imperatives like economics, relevance and affordability. But this argument seems
too abstract. How can one separate the ethics of health care from that of health
research? Who will act to regulate the pharmaceutical industry? Who will look at
the ethics of international monetary agencies responsible for the fiscal mess in
developing countries? Their policies of structural adjustment have led to an
increase in poverty and social inequity. Comparatively few resources have been
allocated to health care and health research (14).
The remedies being suggested are trying to treat
the symptoms of the disease, which is deeper rooted and needs more than
guidelines and declarations. It is like child labour. Nobody in his right mind
would ever support it, but an overnight boycott of products from industries
which employ children will surely condemn those children to poverty. Is it more
ethical to boycott the products or to do something about the cause of the
problem?
We do not think it is unethical in this part of the
world to deny liver transplantation to a patient dying with end stage liver
disease, which is the standard of care in the West. At the same cost, we could
save thousands of children dying of diarrhoea and dysentery. This is a question
of setting priorities when there are limited resources. What is principally,
ethically and morally wrong has to be judged in the local context, unless we
believe we are living in an ideal world. The concept of universality of care is
merely a slogan, whether in research ethics or in health care ethics.
If we are actually going to make any difference to
this world, which is divided mainly on economic lines, we shall have to make a
genuine attempt to reduce these disparities. The economic giants of this world
(G7) need to do more about the poor. They must stop the economic strangulation
of the world's poor majority to meet their geopolitical goals. They must avoid
instigating proxy wars in the developing world to establish their economic and
geographical hegemony. The West also must put an end to detrimental fiscal
policies and economic exploitation by international monetary agencies which have
so far only kept borrowing countries on the verge of bankruptcy. Their policies
have only been successful in increasing indebtedness. Has any country in the
world been able to break the vicious cycle of 'borrowing for debt servicing'?
oThe developed world has a duty to examine the
ethics of the pharmaceutical and biotechnology industry. This 'industry' must be
harnessed in order to reduce its hegemony. The giant mergers currently taking
place are a bad omen for the poor majority of the world. One wonders if the
products of this industry will ever be accessible at an affordable price in the
developing world. If there is any honesty of purpose, at least essential and
life saving drugs should be available at cheap prices in the developing world.
Or they should be exempted from patent laws. The relation between medicine and
the industry should be expressed in clear international guidelines serving the
interests of global health care.
oThe WHO must play a more proactive role in global
policy decisions on resource allocation for health care and health research,
geared to the needs of the developing world. Major donor and funding agencies
need to prioritise their investments according to the problems faced by the
majority of the world.
oThere is a dire need to develop and strengthen the
capacity to review research in developing countries if there is an honest desire
to protect poor subjects of research in developing countries.
I have no hesitation in admitting that all this is
a tall order. If there is an earnest desire to genuinely improve the ethics of
health care and health research one will have to explore and debate issues
honestly, appreciate and comprehend the gravity and cause of the problem and act
by not only empathising but with some action. Anything short of this would
simply amount to rhetoric, hypocrisy and ethical imperialism.
References:
1. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the Human Immune Deficiency Virus in developing countries. N Engl J Med 1997; 337: 853-55
2. Angell M. The ethics of clinical research in the third world. N Engl J Med 1997; 337: 847-49
3. Varmus H., Satcher D. Ethical complexities of conducting research in developing countries. N Engl J Med 1997; 337: 1003-5
4. Koski G. Issues concerning the October 2000 version of the Declaration of Helsinki. Statement at Revised Declaration of Helsinki: Implementing and Interpreting Ethical Principles in Biomedical Research March 27-28, March 2001.
5. Levine R. The testing of new methods against the best current method: ethical decisions in science. Paper Presented at Revised Declaration of Helsinki: Implementing and Interpreting Ethical Principles in Biomedical Research 27-28, March 2001.
6. IJsselmuiden C. B. Ethics of placebo-controlled trials of Zidovudine to prevent the perinatal transmission of HIV in the Third World N Engl J Med 1998; 338: 836-841. Correspondence http://content.nejm.org/cgi/content/full/338/12/8
7. Ijsselmuiden C. Research design as a focal point for science and ethics. Paper Presented at Revised declaration of Helsinki: Implementing and Interpreting Ethical Principles in Biomedical Research 27-28, March 2001.
8. Singer P. A., Benatar S. R. A new look at international research ethics BMJ 2000; 321: 824-6
9. D'Alessandro U., Boelaert M. Editorial : The 5th Amendment of the Declaration of Helsinki: Implications for medical research in developing countries Tropical Medicine and Interantional Health 2001; 6: 245-7
10. Nuffield Council on Bioethics (1999).The ethics of clinical research in developing countrieshttp://www.nuffield.org/bioethics/publication/download.html
11. Wazana A. Physicians and the pharmaceutical industry. JAMA 2000; 283: 373- 380.
12. Benatar S. R. Avoiding exploitation in clinical research. Cambridge Quarterly Healthcare Ethics 2000; 9 (4): 562.
13. Lansang M.A., Crawley F. P. The ethics of international biomedical research BMJ; 321: 777-8
14. Bhutta Z. A. Why so little has changed in maternal and child health in South Asia? BMJ 2000; 321: 809-12
Dr Raja's essay originally appeared as: 'Universality of care: myth or reality?' in the Pakistan Journal of Medical Ethics 2001; 4: 3-7. It is reprinted here with some changes, with the permission of the editor and author.
1. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the Human Immune Deficiency Virus in developing countries. N Engl J Med 1997; 337: 853-55
2. Angell M. The ethics of clinical research in the third world. N Engl J Med 1997; 337: 847-49
3. Varmus H., Satcher D. Ethical complexities of conducting research in developing countries. N Engl J Med 1997; 337: 1003-5
4. Koski G. Issues concerning the October 2000 version of the Declaration of Helsinki. Statement at Revised Declaration of Helsinki: Implementing and Interpreting Ethical Principles in Biomedical Research March 27-28, March 2001.
5. Levine R. The testing of new methods against the best current method: ethical decisions in science. Paper Presented at Revised Declaration of Helsinki: Implementing and Interpreting Ethical Principles in Biomedical Research 27-28, March 2001.
6. IJsselmuiden C. B. Ethics of placebo-controlled trials of Zidovudine to prevent the perinatal transmission of HIV in the Third World N Engl J Med 1998; 338: 836-841. Correspondence http://content.nejm.org/cgi/content/full/338/12/8
7. Ijsselmuiden C. Research design as a focal point for science and ethics. Paper Presented at Revised declaration of Helsinki: Implementing and Interpreting Ethical Principles in Biomedical Research 27-28, March 2001.
8. Singer P. A., Benatar S. R. A new look at international research ethics BMJ 2000; 321: 824-6
9. D'Alessandro U., Boelaert M. Editorial : The 5th Amendment of the Declaration of Helsinki: Implications for medical research in developing countries Tropical Medicine and Interantional Health 2001; 6: 245-7
10. Nuffield Council on Bioethics (1999).The ethics of clinical research in developing countrieshttp://www.nuffield.org/bioethics/publication/download.html
11. Wazana A. Physicians and the pharmaceutical industry. JAMA 2000; 283: 373- 380.
12. Benatar S. R. Avoiding exploitation in clinical research. Cambridge Quarterly Healthcare Ethics 2000; 9 (4): 562.
13. Lansang M.A., Crawley F. P. The ethics of international biomedical research BMJ; 321: 777-8
14. Bhutta Z. A. Why so little has changed in maternal and child health in South Asia? BMJ 2000; 321: 809-12
Dr Raja's essay originally appeared as: 'Universality of care: myth or reality?' in the Pakistan Journal of Medical Ethics 2001; 4: 3-7. It is reprinted here with some changes, with the permission of the editor and author.
Dr Asad Jamil Raja, department of surgery, Aga Khan
University, Karachi, Pakistan. Email:caringair@yahoo.com