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February 2003, Volume 8, Number 2

An ethics-based approach to global child health research

Daniel Roth MD BSc

When the international health research community recently opened its eyes to the ethical dilemmas raised by clinical drug trials in developing countries, the focal point was the study of antiretroviral therapy to reduce the incidence of maternal-fetal transmission of human immunodeficiency virus (HIV) (1). A heated debate in the literature dealt mainly with the fact that the control arm of trials in Asia and Africa involved HIV-infected mothers who received a placebo, instead of an antiretroviral regimen that had already been proven to reduce vertical transmission of HIV and was the standard of care in the United States. Many were appalled by the implication that thousands of infants were knowingly left at high risk of becoming infected with a deadly virus (2). The fact that the health of children was at stake in this controversy should not be overlooked as an incidental detail. Children are a vulnerable population in even the richest parts of the world, yet the role of foreign-sponsored health research involving children in the poorest regions is a particularly pressing issue that should be addressed by the paediatric research community in a timely and meaningful manner.

Ethical considerations are integral to all health research throughout the world (3). Research involving children has historically been discouraged on ethical grounds, and was essentially barred by the Nuremberg Code (1949) (4). However, there is growing recognition of the ethical imperative to include children in research studies (5), particularly in light of evidence that child health research is not only beneficial, but that the absence of paediatric research can be harmful (6). There is likewise the obligation to adhere to ethical guidelines to protect the safety, human rights and cultural integrity of the children, their families and their communities.

However, simultaneously enhancing both the inclusion and protection of children in research may create an apparent dilemma for paediatric researchers (7). There is some evidence that paediatric researchers have not universally emphasized the importance of ethical considerations, suggested by the finding that 40% of paediatric research studies published in five major American journals in 1999 did not document ethical approval (8), with even lower rates of approval documented in recent surgical paediatric publications (9). Yet the reality is that ‘protection’ and ‘inclusion’ can be mutually supportive goals when they exist within the context of an ethics-based approach to global child health research. The current development of cross-national paediatric research initiatives should therefore be guided by a formal discussion of bioethics.

A proactive ethical approach to global child health research serves children in two broad ways. First, adherence to ethical principles leads to the development of a set of rational and relevant priorities and objectives. Second, promoting ethics ensures that observational or interventional methodologies are consistent with the customs and needs of the specific population with whom the investigators are working, and are mindful of the reality within which the community exists. Going beyond mere approval by an institutional review board or adherence to international guidelines (10), ethical research aims to reduce health inequities, by serving to benefit primarily the population from which the study participants are recruited, and benefit secondarily all children on a global scale through the transposition of the acquired knowledge.

Ethical Priority Setting in Global Child Health Research

In his famous treatise on clinical research ethics, Henry K Beecher wrote in 1966 that “an experiment is ethical or not at its inception” (11). He implied that the goals of research, not just the study methodology, have an ethical component. The ultimate objective of global child health research should be to achieve equity in child health, such that all children have the capability to attain health at the highest known standard, regardless of their socioeconomic status, race, religion or geographic location. The current state of global health is, in contrast, defined by deep inequities. Despite considerable progress in many areas of health development, millions of children in developing countries continue to die each year from preventable diseases, including those for which effective vaccines are available (12). Over the past two decades, the worsening HIV/AIDS epidemic has had a devastating impact on the world’s youngest generation, mainly in poor countries; last year, of the estimated 580,000 children younger than 15 years old who died from AIDS (20% of the total estimated three million people who died from AIDS in 2001), 500,000 were in Sub-Saharan Africa alone (13).

Children living in poverty have been doubly disadvantaged by historically unethical global research priorities: first, by a global research agenda that has neglected the poor; and second, by a relative lack of support for paediatric research, epitomized by the paucity of clinical trials of new pharmaceutical products that involve children.

A historically unethical global research agenda

For the past decade, it has been well-recognized that a global inequity in research efforts exists, dubbed the ‘10/90 gap’. This term represents the fact that less than 10% of the estimated US$70 billion spent annually on health research addresses the conditions that account for 90% of the burden of disease worldwide, as measured by the number of disability-adjusted-life-years (14). The implication is that the health of the poor, particularly in developing countries, has not been adequately addressed by the sponsors of health research. A review of randomized controlled trials published in a major paediatrics journal between 1982 and 1996 revealed that only eight (3%) of the 251 studies took place in Africa (15). The Global Forum for Health Research, based at the World Health Organization, was created in 1997 to work toward the reduction of the 10/90 gap, an endeavour that Canadian investigators are supporting (16) despite reports that progress has been slow (17).

There are trends suggesting that a shift toward equitable global paediatric research priority-setting may be underway. Within the past two years, the Child Health and Nutrition Research Initiative, organized under the banner of the Global Forum, has sought to coordinate global priority-setting for research in child health, nutrition, and development (18). By highlighting the contributions of research to major advances in global child health (eg, oral rehydration therapy, immunization), the Child Health and Nutrition Research Initiative stresses the need for further research efforts (19). There are encouraging reports of small-scale North-South partnerships that have capitalized on collaborative research projects to build sustainable and effective child health programs (20,21). These successes contrast with expensive, large scale vertical child health programs, typically dictated by international institutions such as the World Bank, whose contributions to long-term health improvements are debatable (22).

Children are still therapeutic orphans

The second factor underlying unethical priority-setting in child health research is that children have been notoriously ignored in the process by which new drugs are approved and brought to the market, a problem that has led investigators to characterize children as ‘therapeutic orphans’. In the United States, the American Academy of Pediatrics documented in 1995 that approximately 80% of approved therapeutic drugs were not adequately labelled for use in children (23), a situation that has similarly been noted in Europe (24). The initial American response was the inclusion of the ‘Pediatric Exclusivity Provision’ in the 1997 Food and Drug Administration (FDA) Modernization Act, which allows six months of extended patent rights for a drug whose manufacturer submits results of paediatric studies in compliance with FDA requests (25). Recognizing that such an incentive was insufficient on its own, the ‘Pediatric Rule’ was brought into effect in April 1999 to permit the FDA to request paediatric data from drug manufacturers as a condition of approval of a new pharmaceutical product (26). However, a United States Federal court decided in October 2002 that the FDA cannot legally enforce the Pediatric Rule (27), a judgement that threatens the viability of legislation designed to encourage paediatric clinical trials. Even if paediatric drug research were to expand, only 1% of new medicines developed over the past 25 years have been directed at tropical diseases (28), suggesting that there is unlikely to be an equitable benefit for those children who suffer from diseases that predominate in developing countries. In fact, a recent report by Médecins Sans Frontières (29) reveals that the ‘drug gap’ is widening due a virtual complete lack of interest of the major pharmaceutical corporations in diseases that afflict those who are poor.

Ethical Methodology in Global

Child Health Research

In addition to setting ethical priorities and objectives, an ethics-based approach to clinical research also has to incorporate epidemiological methods that respect the particular needs and characteristics of the population that is involved in the study (30,31). Investigators involved in the design of a paediatric research project should consider three levels at which a study may impact on a society: first, the direct effect of the specific research project on study participants and their families; second, the impact of the study in terms of expected health outcomes among children in the community or country in which the study is conducted; and last, the broad effect of intervention by foreign health professionals on the community or region.

The impact of research on the individual child

There has been considerable discussion of the methodological challenges of paediatric research, given the vulnerability of children as participants, the difficulty in establishing an acceptable balance of risks and benefits, and the obstacles encountered in carrying out a valid informed consent process (32,33). Methodological issues in developing countries have been widely debated, yet issues unique to paediatric populations in these settings have rarely been discussed.

Defining the acceptable balance of risks and benefits: The degree to which a child stands to benefit from a particular experimental intervention depends on the risk of morbidity or mortality resulting from the illness to which the intervention is targeted. Guidelines sponsored by the Canadian Paediatric Society state that exporting research to other countries to avoid placing our own children at risk neglects the social responsibility to protect and benefit all children (6). However, given the higher incidence of adverse outcomes of infectious diseases and nutritional deficiencies in impoverished regions, some interventions may have relatively greater benefits for participants in these settings (eg, zinc supplementation to reduce the incidence of pneumonia [34]). Therefore, a higher level of risk may be deemed to be acceptable if the overall risk-benefit ratio remains unchanged or improved. It is unethical, however, to locate children with greater ‘background risks’ with whom to conduct a study to justify higher-risk research (9).

Establishing a valid informed consent/assent process: A process of valid informed consent is necessary in almost all research settings, and assent from minors must accompany consent of a legal guardian where possible (10). The intricacies of proxy consent required in paediatric research is compounded by the challenge of obtaining valid informed consent in a non-Western context (35,36). The authors of a study of the informed consent process for a placebo-

controlled Hemophilus influenzae B vaccine trial involving children in The Gambia concluded that the Western model for obtaining proxy consent was valid despite cultural differences (37). However, only 10% of the parents of participating children were aware of the concept of a placebo, an especially worrisome observation given that 93% of parents reported having joined the trial to receive the active vaccine. Informed consent/assent is at risk of being undermined in developing countries because vulnerability or desperation may lead parents or children to disregard the risks of experimental interventions when deciding to join a study. A study is clearly unethical if its success in recruitment depends on taking advantage of low, poverty-driven standards of care. Therefore, at the very least, investigators and institutional review boards must ensure that every study is scientifically and ethically valid in its design, such that neither acceptance nor rejection of participation entails undue risk or disadvantage.

There are at least two ways in which we can increase the contextual suitability of informed consent/assent processes, without compromising universal ethical standards. First, we should conduct prospective, empirical studies of the informed consent process in developing countries such that our practices will reflect evidence-based ethics. Second, we should promote the routine creation of community advisory boards, which have been used successfully to facilitate the implementation of informed consent processes that reflect the needs and wishes of study participants (38).

The impact of research on paediatric care within the community

One of the most important ways in which ethical research methodology promotes health equity is by exemplifying the principle of distributive justice, which states that “studies should be designed to obtain knowledge that benefits the class of persons of which the subjects are representative” (39). Even if ethical priorities exist, it is not enough to simply conduct paediatric research within a developing country; rather, the design of every study must be such that the outcomes can be feasibly used to improve child health within that same region.

A major issue of discussion is whether placebo-

controlled studies in children are ethical if there already exists a proven effective treatment in adults. In developing countries, this dilemma may be confounded by the question of whether placebo-controlled trials are ethical if a proven effective treatment exists in developed countries, but is not normally available in the region where the study is being conducted – this was the controversy regarding the HIV trials discussed above. However, it is important to note that the reason that the randomized, placebo-controlled trials of short-course zidovudine for the prevention of perinatal HIV transmission in Africa and Asia were unethical was only partially related to the fact that control subjects were not provided with an active drug. As stated by Peter Piot (40), director of the Joint United Nation Programme on HIV/AIDS, UNAIDS program, “the real double-standard lies not in the way the trials are being conducted, but in the inequity in access to medicines in different countries”. Although the trials addressed an important aspect of the HIV crisis in the developing world, they were unethical because they ignored, if not mocked, the realities of health care available to the population from which the study sample was drawn. In fact, even trials that compared two active drug regimens were unethical because they made no provisions to ensure that the results, if scientifically valid, could be practically applied where the study was conducted. Because studies in the past have often ignored inequities in health, as well as disregarded the unique cultural and political features of developing countries that may not be shared by Northern partners, the translation of research into action has rarely occurred successfully in resource-poor countries (31). Developed countries and international health organizations should pledge financial support to allow their Southern partners to develop more effective health systems through which evidence-based child health policies can be implemented effectively. This requires a strong commitment to distributive justice before participant recruitment begins.

The broad impact of research on the community

The effect of research is not only in the application of the knowledge acquired by analyzing the collected data, but also results from the act of doing the study itself, and by the process of intervening as health professionals in a foreign country. A basic tenet of biomedical ethics, primum non nocere (do no harm), reminds us that sometimes doing nothing at all is better than doing something potentially damaging. Despite the ethical obligation to promote paediatric research abroad, investigators must consider the overall impact of intervening and/or interfering, given the endless list of examples of failed and even damaging development projects in the past (41).

In addition, paediatricians must always remain cognizant of the link between health and human rights (42). An investigator’s presence in a developing country entails his or her responsibility to take an interest in the general health and welfare of the population, emphasizing an awareness of nonmedical factors, such as war and drought, which clearly have an impact on the health of children. An understanding of the determinants of health in each unique community, combined with close collaboration with local health professionals, should guide the development of ethical health research agendas in the future.

Summary

Despite the increasing attention paid to ethical conduct in cross-border health initiatives, the ethical concerns arising specifically from paediatric research in developing countries have not been widely discussed in the medical literature. This does not necessarily imply that such issues are not being addressed by those who are involved with child health care and research in developing countries, but it does suggest that there is a lack of formal discourse or study in this area. An ethical approach to child health research should be formally incorporated into future North-South collaborative projects. This comprises a research agenda that promotes equity in child health, as well as research methodologies that are culturally sensitive yet adhere to universal ethical standards. Particular emphasis should be placed on distributive justice and a valid process for obtaining informed parental/guardian consent and child assent.

A tacit indifference toward global inequities is a frequent feature of unethical research studies in developing countries. Unethical research does not benefit children in developing countries, because it ignores the underlying causes of lower paediatric standards of care, namely social and economic inequity. Research priorities should reflect the health issues of developing countries, and should address, a priori, the challenge of implementing research findings in resource-poor settings. Child health research initiatives need to continue to be broadened in the developing world, but it must be recognized that their impact will only be truly beneficial for children if investigators promote an ethical approach in both the design and conduct of their research.

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