Interpreting Helsinki in a Pluralistic World
Ann Boyd and Denise Hise
“We live today in a world densely populated by human beings living in close communication with one another all over the surface of the planet. Viewed from a certain distance it has the look of a single society, a community, the swarming of an intensely social species trying to figure ways to become successfully interdependent. We obviously need at this stage, to begin the construction of some sort of world civilization.”
-- Lewis Thomas [1]
Environmental, cultural and individual influences have contributed in significant ways to the complexity of human societies and the shape of the modern world. [2] Global wealth and resources are unevenly distributed and the poor and marginalized segments of societies continue to bear the greatest burdens of disease as a result of the vast disparities in resources committed to disease control. Long chains of causation have led to this state of affairs and inequalities of access to care and outcome of disease increasingly characterize our world. The fundamental insights and social transformations required to rectify this profound global injustice will not come quickly, if at all, yet it is critical to bring the necessary resources to bear on the ‘plagues of the poor’ and to diminish worldwide disparities in health care. Given these disparities what does it mean to have clinical trials with human subjects conducted by developed country agents in developing countries? Two revisions in Helsinki 2000 deserve closer scrutiny: the articles dealing with standard of care and reasonable availability.
Plagues of the Poor
Collectively Malaria, Acquired Immune Deficiency Syndrome (AIDS) and Tuberculosis (TB) kill at least six million people a year, the majority in resource-poor countries, and constitute major public health challenges undermining development in these countries. [3] A brief review of the plight of persons in sub-Saharan Africa and South East Asia regarding these infectious pathogens reveals the severity of the situation.
Two-thirds of the global population is at risk for malaria. Nearly 90% of deaths from malaria occur in sub-Saharan Africa where an estimated one million children die annually. [4] The incidence of malaria is increasing in part due to resistance of parasites and mosquitoes to drugs and insecticides, respectively. The absence of a reliable animal model for vaccine and prophylaxis testing, as well as treatment of active disease, means that human subjects are the only universally recognized way to design research aimed at preventing or treating malaria. [5] A small percentage of persons from the developing world are at risk for malaria due to travel or work in endemic regions.
Nearly 40 million people live with HIV/AIDS worldwide, including 2.2 million children under the age of 15. HIV has entrenched itself amongst the world’s poor and marginalized, predominantly in sub-Saharan Africa and South-East Asia, while incidence is declining in wealthy countries. Three million people die each year from AIDS, totaling 30 million since the beginning of the epidemic. [6] There is an urgent need to create and systematically evaluate more candidate vaccines and human clinical trials are ultimately required to define vaccine/drug effectiveness. No single regimen is likely, at least initially, to provide the optimal balance of efficacy, safety and cost for all regions of the world. [7]
One-third of the global population is infected with Mycobacterium tuberculosis. Eight million people become sick with TB each year, 95% of them reside in the developing world and half of these cases occur in Bangladesh, China, India, Indonesia, Pakistan, the Philippines and Thailand. TB kills two million people each year, including over 100,000 children. TB is completely curable with short-course treatment. [8,9] However, multidrug-resistant TB strains have emerged making treatment much more difficult and expensive, essentially translating to a death sentence for the poor. In addition, 14 million people are co-infected with TB and HIV, and TB is the leading infectious cause of death in HIV-positive individuals. [10] Clearly TB, especially drug resistant strains, poses a threat to people everywhere, but the vast majority of cases occur in zones already compromised by poverty.
Lower socioeconomic status has been linked to poorer health throughout history, with impoverished individuals having the highest rates of morbidity and mortality within human populations of any culture. [11] Impoverished populations continue to bear the brunt of disease but lack the health care infrastructure to cope with the burden. They are therefore dependent on wealthy nations or global health initiatives to intervene on their behalf. In ethical terms then, these populations are vulnerable.
Many of the urgent health problems that remain to be solved in the world necessitate further research to find new ways to prevent and treat illness and develop more effective interventions with fewer side effects that can be more universally accessible. Conducting such research in developing countries introduces the risk of exploitation when access to regular health care is limited. The formal agreement between pharmaceutical industries and governments represents both the interest in development of new and improved treatments while simultaneously risking at the least, the perception of exploitation. Individuals in any culture may fail to achieve a clear distinction between research and clinical care. In conditions where access to care is limited, the clinical trial becomes all the more attractive. Informed consent derived from the principle of autonomy deserves serious review when the choice is simply research trial or nothing. There are circumstances in pockets of poverty in wealthy nations where unequal access may lure a person to enter a research trial. It may not necessarily be wrong to respect the individual’s choice where options are severely limited. Doing something is often preferable to doing nothing, but it is not justification for exploitation or doing harm.
Autonomy, beneficence and justice provide ethical norms for review of human subjects research but as western philosophical principles are subject to diverse pluralistic interpretation within the diverse local culture as well as the international community. Whether or not these three principles are the right choice for international research with human subjects is open to question. Minimally, autonomy does not stand alone as the icon of ethical approval but works best in tension with beneficence and justice. These principles however provide the lens through which Helsinki guidance in human subjects research regarding standard of care and fair benefits is subject to interpretation and application.
Helsinki 2000 Concerns
Standard of care refers to the optimal treatment for a given diagnosis, but the question is whether that treatment is the best anywhere in the world or locally defined. Defining the standard of care for clinical trial participants is at the heart of the debate as we continue to refine our approach to trans-cultural research. The debate centers in particular on two paragraphs of the 2000 revision of the World Medical Association Declaration of Helsinki, which provides guidance on the ethical conduct of medical research involving human subjects.
The Nuremberg Code created a universal expectation that all research involving human subjects be deemed scientifically worthy and all subjects voluntarily choose to participate. Ascent did not yield compliance [12] and thus, the Declaration of Helsinki added the normative step of independent ethical review for all clinical research involving human subjects. Experience and critique discovered cases in which the intent of both Nuremberg and Helsinki were inadequately applied. The latest and sixth revision of Helsinki Declaration (2000) challenges the concept and practical interpretation of the principle of beneficence in terms of risk-benefit, justice as fair access, and autonomy as informed consent.
The Helsinki Declaration version VI of 2000 contains two paragraphs of particular relevance to international clinical trials with prophylactic drugs. Paragraph 29 reads, “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 those studies where no proven prophylactic, diagnostic or therapeutic method exists.” Paragraph 30 reads: “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.” Several interpretations of the wording of these two guidelines deserve reflective consideration in regard to any international clinical research trial with human subjects.
Following prolific writing in response to Helsinki 2000, the WMA added a note of clarification to paragraph 29 in 2002: “The WMA hereby reaffirms its position that extreme care must be taken in making use of a placebo-controlled trial and that in general this methodology should only be used in the absence of existing proven therapy. However, a placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:
where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or
where a prophylactic, diagnostic or therapeutic method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk or serious or irreversible harm.” [13]
Placebo controls and “Best current” method
Ethically, the debate continues on whether the standard of care ought to refer to a global context as anywhere in the world, or to the standard available in the host country, or to the standard of care in the sponsoring country and whether placebo-controlled trials in developing countries would be deemed unethical if an effective prophylactic treatment existed, even if it was not available in the prospective host country as a standard of care at the time of the pending trial. [14,15] The “best current” provision and the rejection of placebo controls may be unreasonable and unrealistic in the context of developing nations and an impediment to developing new therapies for medical conditions for which there is any existing proven therapeutic benefit. [16,17] The Helsinki Declaration itself risks losing “its moral authority” [18], if guidelines derived from it are too ambiguous. Alternatively if the Declaration is too directive and strident, the risk is that the norms will simply be ignored. Nevertheless, the effort to recognize the potential for exploitation and injustice requires elimination of the insidious double standard in medical research that rejects for the rich what is acceptable for the poor. In an ideal situation, the value of individual human beings would no longer be ignored in the pursuit of scientific knowledge and the standard of care would be the same for everyone. Lacking agreement about who will bear the expense of absolute equality leads to the stalemate of applying the Helsinki 2000 revisions. The pendulum swing is extreme in the demand for radical change that establishes a firm egalitarian equality by literal adherence to the revisions and the resistance that fears a collapse of medical progress in the inhibitions inferred for clinical trials. The fundamental tenant of Helsinki is however to offer guidance not to dictate protocol.
Change as process
Viewed from a certain distance this has the look of a society reacting to the introduction of a new idea. New ideas threaten the existing order and are generally met with resistance. Initiated as speculative suggestions, new interpretations to “standard of care” and “placebo-control designed trials” invite heated debate – the traditionalists citing all the harms of change and the proponents of greater equality cite harms of current practice. The suggested changes deserve debate, and ought to be seasoned by reflection and dialogue, allowing time for adaptation and application, even if in limited ways. [19] The pace of progress is slow. But, at times, seemingly impractical ideals can be a program for reform. The Helsinki Declaration describes an ideal, an ethical framework that we know ought to be imposed to eliminate the risks of exploitation of persons in the developing world, something to strive for in our dystopia. Every society tolerates certain blots, at that stage inevitable. [19] At this particular stage in our history, given the worldwide disparities in health care, our inability to implement a literal interpretation of this ideal appears to be our blot. Yet within this framework, many possibilities can be imagined to set us on the path toward gradually attaining this ultimate ideal, and in this way is not restrictive at all.
The Helsinki Declaration is offered for international guidance without the force of law or sanctions for noncompliance. However, if the language of the guidelines is taken literally, the risk may be that research in developing countries is eliminated from consideration. If guidelines are considered unreasonable or unrealistic, they may simply be ignored or displaced by local or national legal alternatives. Retreating into regional or national regulations loses sight of the global community in which human health and flourishing are as integrated as are economic or environmental issues.
Rather than the provisions being taken literally and imposed as ultimatums, perhaps a progressive view of the standards as a goal for clinical research with human subjects could parallel the current practice of autonomy in informed consent. Autonomy is derived from the western philosophical notion of free rational choice, but autonomy in some cultures may mean adherence to the communal good rather than individual priority. To impose any one understanding of autonomy can hamper achieving the intent of informed consent as much as insisting that a document signed by the participant is all that autonomy means. Although it is natural to seek consensus or highly general principles underlying our codes of ethics, there is always more than one way to proceed and no regulative notion can be defined precisely enough to prescribe details of conduct for all circumstances. [19] Ambiguity can be a source of strength, providing avenues for negotiation and compromise. Flexible, alternative solutions that will allow research with the potential to benefit host communities without exploiting them can be found.
A few months ago, one of us (Boyd) was in Kenya reviewing the clinical trials sponsored there as a collaboration between the Kenyan Ministry of Health and the Walter Reed Army Institute of Research (WRAIR) in Washington D.C. The nurses in one clinic described the impact of the clinical center built in the community and the increased availability of routine medical care as well as the opportunity to participate in clinical trials as a transition from “despair to hope.” Prior to the availability of testing for HIV status with subsequent delivery of antiviral drugs, very few people would consent to be tested. Once aware that if tested, and HIV positive, drugs would allow a person to live longer and return to work, a dramatic increase in surveillance and treatment occurred. Her elaborated meaning gave me a new sense of what it means to work toward equality in a culturally sensitive way. Does this example mean that once the clinical trials sponsored by WRAIR began, that all Kenyan nationals had access to testing or to antiviral therapy? Certainly not, but the improved participation, education, and economic impact of the work has encouraged the Kenyan government to invest in healthcare in a new way. If the modest improvement of infrastructure and availability of treatment options for some percentage of the population is acceptable to the leaders and citizens of Kenya in terms of Helsinki normative standards, I think respect of persons encourages us to accept their interpretation.
The Helsinki Declaration has been regularly revised, attempting to incorporate current thoughts and ideals. [20] Perhaps this time it is our turn to broaden our interpretative lens, to recognize that there is more than one ethically acceptable approach and imagine some effective alternatives that can be made available to communities with limited resources. Thus we begin a process so badly needed of addressing standing global inequalities in health care and work toward allaying the unnecessary suffering they cause. Poverty is a central fact of life in many areas of the globe and remains a primary cause of disease prevalence in those regions. The burden of disease has increased rapidly in severely affected countries and failure to intervene effectively could undermine past progress and threaten public health in general. [21] The formulation of appropriate policies and interventions is a matter of particular urgency; our fellow beings can ill-afford to wait for reality to catch up to our ideals. Our reaction will be a measure of what we judge to be worthwhile, our capacity for compassion and our commitment to social justice. Seeking common ground between the best standard being the best anywhere and the best being merely what is locally offered provides a way to respect the international guidance of Helsinki and promote ethical research with human subjects. [22]
Common Ground
Perhaps it would help to consider the standard of care and best-proven treatment concept in parallel with a culturally sensitive approach to obtaining informed consent. Both processes ought to mutually respect the collaboration between sponsor and host country participants (scientists, government authorities, ethicists, and community representatives from the proposed trial area). Developing culturally appropriate ways to meet the standard of voluntary informed consent includes culturally appropriate methods of disclosing information, seeking permission for research participation from a community representative or family member, and assessing participants’ understanding of information relevant to the trial. These cultural sensitivity steps neither seek to assure that individuals are forced to comply with western ethical principles e.g. autonomy, justice and beneficence, nor are they necessarily exploited. The requirement of individual informed consent is not to be ignored or waived but amended in process and language to fit the situation.
Likewise, reaching an objective conclusion about what constitutes ethical international research between a sponsor and a developing nation requires an understanding of the context in which the research will be done. The challenge centers on the validity of applying ethical principles for medical research in diverse cultures and even whether such research is ethically justified in areas without adequate access to basic health care. If the reference point for the standard of care judgment is deemed to be anywhere in the world then, practically speaking, research in developing countries risks being eliminated from consideration. Alternatively, if the standard of care is determined on that available in the host country, then the risk of exploitation remains without corrective. The extreme poles of the interpretation delineate the ethical need to assess the situation regarding the local standard of care and seek to understand it within the social, economic, and cultural framework of the host country without neglecting awareness of what is globally most effective.
Fair Benefits
Standards of care often refer to specific products or interventions, ignoring larger interpretations of benefit that may include the overall care in a health system. [23] It would seem that the best way forward at this time would be to adopt a flexible, pragmatic approach that enlisted the full participation of the host country in finding an acceptable balance between the burdens and benefits of the ensuing research initiative, making provision for them to receive a fair level of benefits as determined by their standards.
The fair benefits framework relies on four foundational principles: a) that the research would have social value, b) that it will address a health problem in the developing country, c) that the location proposed for the research is chosen for valid scientific reasons, and d) the risk-benefit ratio is favorable. [24] An advantage to the conceptual phrase “fair benefit” is the interpretative flexibility. A population in a developing country could consider a diverse range of benefits from research appropriately “fair,” for example, the construction of health care facilities, training of nationals, public health infrastructure improvement. Benefits could be directly associated with participation in the research, or to the population during the research, or to the participants and population after completion of the research. Capacity development or enhanced training in ethics review could thereby be considered community benefit, as could the acquisition and dissemination of generalizable knowledge that may improve health for others. [25]
The perspective of the putative host country on the merit of the proposed research is essential. [26, 27, 28] The local government, community representatives and ethical review should determine the value of the trial benefits for its own people. Outsiders will likely not clearly understand the health care system or the cultural norms of a host population. Transparency in the negotiation of the trial is necessary in order to gain consensus within the host country and among concerned collaborators. [29] Respect for local opinion and appreciation of cultural values, social practices and traditions will promote mutual understanding and encourage the establishment of trusting, collaborative partnerships between host countries, industry, government, research, and ethical oversight that are necessary if effective preventive and therapeutic interventions are to impact the current devastating effects of disease. Each protocol should be subject to the judgment of all relevant parties in the research effort and ethical principles should be thoughtfully balanced against each other to determine what can to be done in a given situation. The relevant parties to address the risk-benefit ratio of the trial for the participants and the after-trial benefits to the host community should negotiate agreement. Thus, interpreting beneficence multiculturally ought to parallel a pluralistic interpretation of autonomy.
A flexible interpretation and cultural sensitivity to plurality of normative standards will allow the most practical and realistic approach to being faithful to the intent of the Helsinki Declaration so that scientists may continue the development of prophylactic and therapeutic drugs to treat diseases of the poor. If the leaders of the research enterprise in the United States take Helsinki seriously, universal health care within the nation will become a higher priority. Taking care of one’s own house has a validity that a pronouncement of ideal values fails to accomplish. It is clear from the current lack of health care coverage in the United States that absolute equality as a norm of justice challenges our applied ethics universally.
Interdependence
Ethical guidelines for international research are important because values and beliefs differ between individuals and across cultures. Are the principles of autonomy, beneficence and justice the right norms for international, multicultural research using human subjects? While they remain the basis of research ethical assessment, we are right to set the standard high in order to propel us in the direction of global equity, and yet, it seems paramount that we retain a flexible interpretation that will allow us to work gradually toward a more fair distribution of resources for public health. Acknowledgment and acceptance of our diversity and interdependence may enable us to approach the ethical issues of our time with renewed clarity of vision and to choose paradigms that will accommodate our continued growth and evolution. We are dynamic beings, capable of changing our attitudes consciously and at will. We can exercise our judgment and call for certain measures because they are the best that can be done. We are not yet so morally bereft as to require our hand held while absolute instructions are read aloud. We can act on our own vision of the future and begin the construction of some sort of world civilization.
References
Thomas, Lewis. Late Night Thoughts on Listening to Mahler’s Ninth Symphony. Penguin Books. 1983.
Diamond, Jared. Guns, Germs, and Steel, The Fates of Human Societies. W.W. Norton & Company, Inc. 1999.
http://www.rbm.who.int/cmc_upload/0/000/015/370/RBMInfosheet_3.htm.
Vernick, K.D.; Waters, A.P. Genomics and Malaria Control, N Engl J Med 351 (2004): 1901-1904.
Klausner, R.D., et al. The Need for a Global HIV Vaccine Enterprise. Science 300 (2003): 2036-2039.
http://w3.whosea.org/EN/Section10/Section186/Section189.htm.
http://w3.whosea.org/EN/Section10/Section186/Section191.htm.
http://w3.whosea.org/EN/Section10/Section186/Section1805.htm.
Mann, J.M.; Gruskin, S.; Grodin, M.A.; Annas, G.J. Health and Human Rights. Routledge. 1999.
Beecher, Henry K, “Ethics and Clinical Research,” New Engl J Med 274 (1966): 1354-1360.
World Medical Association (WMA) Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Ferney-Voltaire, France: Adopted 18th WMA General Assembly, Helsinki, Finland, June 1964; amended: 29th WMA General Assembly, Tokyo, Japan, October 1975; 35th WMA General Assembly, Venice, Italy, October 1983; 41st WMA General Assembly, Hong Kong, September 1989; 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996; and 52nd WMA General Assembly, Edinburgh, Scotland, October 2000, http://www.wma.net/e/policy/17-c_e.html.
Angell, M. The Ethics of Clinical Research in the Third World. N Engl J Med 337 (1997): 847-849.
Lurie, P.; Wolfe, S.M. Unethical Trials of Interventions to Reduce Perinatal Transmission of the Human Immunodeficiency Virus in Developing Countries. N Engl J Med 337 (1997): 853-856.
Levine, R.J. The “best proven therapeutic method” standard in clinical trials in technologically developing countries. J Clin Ethics 9 (1998): 167-172.
Levine, R.J. The need to revise the Declaration of Helsinki. N Engl J Med 34 (1999): 531-534.
Lie, R.K.; Emanuel, E.; Grady, C.; Wendler, D. The Standard of Care Debate: The Declaration of Helsinki versus the international consensus opinion. J Med Ethics 30 (2004): 190-193.
Whitehead, Alfred North. Adventures of Ideas. The Free Press. 1967.
Forster, H.P.; Emanuel, E.; Grady, C. The 2000 revision of the Declaration of Helsinki: a step forward or more confusion? Lancet 358 (2001): 1449-1453.
Farmer, Paul. Infections and Inequalities, The Modern Plagues. University of California Press. 1999.
Macklin, R. After Helsinki: Unresolved Issues in International Research. Kennedy Inst Ethics J Vol 11 no. 1 (2001): 17-36.
Bhutta, Z. Standards of Care in Research. BMJ 329 (2004): 1114-1115.
The Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Fair Benefits from Research in Developing Countries. Science 298 (2002): 2133-2134.
Emanuel, E.J., Wendler, D., Grady, C. What Makes Clinical Research Ethical? JAMA 283 (2000): 2701-2711.
Varmus, H.; Satcher, D. Ethical Complexities of Conducting Research in Developing Countries. N Engl J Med 337 (1997): 1103-1105.
US. National Bioethics Advisory Commission. Ethical and Policy Issues in International Research: Clinical Trials in Developing Countries. Vol. 1. Report and Recommendations of the National Bioethics Advisory Commission. Bethesda, MD: 2001, http://bioethics.gov/clinical/Vol1.pdf.
Joint United Nations Programme on HIV/AIDS (UNAIDS). Ethical Considerations in HIV Preventative Vaccine Research. Geneva, May 2002.
The Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries. Moral Standards for Research in Developing Countries: From ‘Reasonable Availability’ to ‘Fair Benefits’. Hastings Cent Rep 34 (2004): 17-27.