An ethical dilemma: Moving medical research to the developing countries. By: Qianyao Qiu

Transcription

1 An ethical dilemma: Moving medical research to the developing countries By: Qianyao Qiu Collaboration among peoples from different nations, whether in the form of engaging in trade, providing material assistance, or participating in cultural interchange, can substantially benefit all parties involved. However, these kinds of collaboration do not always proceed smoothly, particularly when controversy emerges regarding the nature of the collaboration and/or the distribution of the benefits. In recent years, the increasingly global collaboration in health research, particular the conduct of clinical trials in developing countries has highlighted a number of new ethical issues. Some ethical issues are raised by these collaboration, such as using placebo-controlled versus standard care trials; and the post trial obligations of the sponsors to provide continuous benefit to the trial participants and the host community after the trials end. 1 There are several reasons for these collaborations. First, the host country might desire information about effective and affordable interventions for an indigenous health problem. For example, researchers from many other countries have collaborated with U.S. researchers and received NIH support for investigations of malaria or dengue, diseases that rarely occur in the United States, as well as for treatment of infectious diseases, such as tuberculosis, HIV/AIDS or cancer, which are common in the United States. Second, in order to be marketed in some developing countries, drugs and biologicals even if already tested and approved in other countries must be approved by national regulatory authorities. In some countries, this may require domestic testing. Third, it is more efficient to conduct research in a country in which the condition being studied is more prevalent. Certain diseases associated with particular environmental conditions such as a tropical climate can only be studied in locations where those conditions exist. Fourth, it might be less expensive and faster to conduct research in developing countries. Enrollment of participants, for example, can occur more quickly, or procedural requirements can be less burdensome (and protections for participants may not be as comprehensive). Whatever the reason, there are increasing number of these collaboration during the past decade. And the long standing ethics of designing, conducting, and follow up on clinical trials have re-emerged. 2 First ethical dilemma is the using placebo-controlled trial versus the standard care. In this case, concerns focused on two areas. First, using placebocontrolled trials when an effective treatment exist, means that individuals in the 1

2 controlled group are being treated differently than those in the controlled groups in developed nations (where the control is an established effective treatment). This may imply that they are not considered equally worthy. Second, some have claimed that an alternative research design could have addressed the health needs of those in the host country without using a placebo control. 3 The example of the AIDS trials is only one of the known cases of the international research that has heightened ethical concerns. In 1997, controversy arose over a series of placebo-controlled trials aimed at finding an affordable and implementable treatment to lower the rate of maternal-to-infant transmission of HIV in developing countries. The controversial studies followed an earlier National Institutes of Health (NIH)-sponsored study conducted in the United States) called ACTG 076, after the number of the NIH protocol), which demonstrated that maternal-to-infant transmission of HIV could be reduced by two-thirds when AZT is administrated continuously to women as early as the 14 th week of pregnancy. This treatment became the standard of care in the United States and other developed countries. But the treatment is impossible to be promoted in the developing countries because of several reasons, primarily cost and the lack of a health care infrastructure to administer the regimen. As a result, some of the clinical trials in some developing countries, such as Thailand and Africa were designed to test a lower dose of AZT in HIV-positive women, which was much cheaper than the standard dose, in a placebo-controlled trial. In addition, these studies initiated the treatment much later in pregnancy because women in these countries do not receive early prenatal care. And the AZT was administered orally rather than intravenously because of the limitation of the medical facilities. Moreover, newborns did not receive full treatment. These differences from the proven ACTG 076 regimen aimed to establish a course of treatment that could reasonably be implemented for HIV-positive pregnant women in resource scarce countries. For ethical reasons, placebo-controlled trials testing this regime can not be conducted in the United States and other developed countries once the efficacy of the ACGT 076 regimen had been established. In other words, it would be considered unethical to withhold women in a research study from an effective treatment that they could obtain as part of their routine medical care. In an effort to obtain the fastest and most useful results, researchers often conduct placebo-based trials. In these trials, some research subjects receive the experimental new drug while others receive a placebo treatment, which is no treatment at all. By administering the new technology to some patients, and no treatment to others, the researchers are able to gauge the success, safety and efficacy of the technology quickly and accurately. In these HIV placebo-controlled trials, research subjects are permitted to continue to suffer, despite the availability of the proven effective treatment, for the benefit of scientific research. 2

3 Critics of the study argued that it is wrong for researchers who come from a country where an effective treatment is used to withhold that treatment from any study participant and that infants in the study, who could be prevented from acquiring HIV, would become infected and die unnecessarily. They argued that the experimental treatment should have been compared with the standard treatment rather than with the placebo, thereby avoiding these unnecessary deaths. Subsequently, such a study design was adopted in another NIHsponsored study in another location in Thailand at the same time that the placebo-controlled trials were being carried out elsewhere in the same country. Defenders of the placebo-controlled studies agued that there were four reasons to support the use of placebo-controlled studies. First, the standard of care for HIV-positive women in these developing countries is no treatment at all. So they are left no worse off as a result of participating in the study. Second, a placebo-controlled trial can be conducted with fewer participants and completed in a much shorter time than an AZT-controlled study, so useful information and effective interventions pertinent to host community or country will be available much sooner. Third, the ACTG 076 treatment regimen that has become standard in the west is not now, and will not in the foreseeable future, is available to this population because of the cost. Therefore, use of this active control would render the results of very little relevance to the health needs of the developing country. Fourth, if it is proven to be effective, the less expensive and more appropriate regimen can be made available by governments to all HIV-positive pregnant women in these countries. These placebo-controlled trials did succeed in showing that the cheaper, short-course AZT regimen was significantly better than a placebo. But the controversy of the ethical principles relevant to these researches has not abated. All research involving human subjects should be conducted in accordance with three basic ethical principles, namely respect for persons, beneficence and justice. 4 Respect of persons including two concepts, which are respect for autonomy and protection of persons with impaired or diminished autonomy. Respect for autonomy requires that those who are capable of deliberation about their personal choices should be treated with respect for their capacity for selfdetermination. Protection of persons with impaired or diminished autonomy, which requires that those who are dependent or vulnerable be afforded security against harm or abuse. The research trials participants in the developing countries are the group of people who are vulnerable. They might not be able to afford the expensive treatment; they might not understand the ongoing research. Researchers should respect their autonomy and protect those people. Beneficence refers to the ethical obligation to maximize benefits and to minimize harms. The goal of conducting human trials is to test a hypothesis that 3

4 one technique or treatment is better than another. So we can apply the proven better technique or treatment to the practice. Final goal is to help the patients to combat the diseases. It is very important to carry the concept of beneficence in the clinical trials involving developing country participants. The research design should be sound, and that the investigators be competent both to conduct the research and to safeguard the welfare of the research subjects. Justice refers to the ethical obligation to treat each person in accordance with what is morally right and proper; to give each person what is due to him or her. In the ethics of research involving human subjects the principle refers primarily to distributive justice, which requires the equitable distribution of both the burdens and the benefits of participation in research. The trial participants in developing countries are vulnerable to injustice. "Vulnerability" refers to a substantial incapacity to protect one's own interests owing to such impediments as lack of capability to give informed consent, lack of alternative means of obtaining medical care or other expensive necessities, or being a junior or subordinate member of a hierarchical group. Special provision must be made for the protection of the rights and welfare of vulnerable persons. Sponsors of research or investigators should not take advantage of the relative inability of low-resource countries or vulnerable populations to protect their own interests, by conducting research inexpensively and avoiding complex regulatory systems of industrialized countries in order to develop products for the lucrative markets of those countries. Many international societies have been aware of the problem and started to address the problem. The Declaration of Helsinki, issued by the World Medical Association in 1964, is the fundamental document in the field of ethics in biomedical research and has influenced the formulation of international, regional and national legislation and codes of conduct. The declaration of Helsinki (2000) states that 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 a placebo, or a no treatment, in studies where no proven effective method exists. In Paragraph 32 of the Declaration of Helsinki, it states "In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed." 5 Although not clearly specified in the Helsinki Declaration, the standard of care can be interpreted in the context of the study location. It can be interpreted as the global standard of care rather than a locally existing standard, or a general 4

5 standard of care in the research setting. Others have expanded the definition of standard of care to include additional aspects such as provision of care by a research team with equivalent qualifications, training, and expertise as those in industrialized countries, and research carried out by a team with the same culture and language as the study subjects, to assure effective communication and informed consent. It can be difficult to determine whether an intervention constitutes an established effective treatment. In a setting where research subjects would have access to the best current methods of prevention, treatment, or diagnosis, a placebo may not be used. But is it ethically acceptable to use a placebo in settings where the standard of care does not include the best current methods? Standard of care need not be the best current method anywhere in the world when sponsor shows that to be impossible for the host countries. Treating people fairly does not require treating them exactly the same. It can be balanced by alternative methods that, though longer and more expensive, are ethically sound. The CIOMS (Council for International Organizations of Medical Sciences) has the guideline for the choice of control in clinical trials. It states: As a general rule, research subjects in the control group of a trial of a diagnostic, therapeutic, or preventive intervention should receive an established effective intervention. In some circumstances it may be ethically acceptable to use an alternative comparator, such as placebo or "no treatment". 4 The placebo may be used when there is no established effective intervention; when withholding an established effective intervention would expose subjects to, at most, temporary discomfort or delay in relief of symptoms; when use of an established effective intervention as comparator would not yield scientifically reliable results and use of placebo would not add any risk of serious or irreversible harm to the subject. So we can see that using placebo control rather than an effective established effective intervention is ethically acceptable if there are only minimal, temporary risks to the placebo group. In the condition of cancer or HIV/AIDS, it will be too serious to deprive control subjects of an established effective intervention. But in the situation that established effective intervention is not generally available or affordable, and unlikely to become available or affordable in the foreseeable future, there may then be less reason for concern that a placebo design is unethical. In such circumstances, an ethical review committee will need to engage in careful analysis of the situation to determine whether the use of placebo rather than an established effective intervention is ethically acceptable, provided that the rights and safety of subjects are protected. Second ethical dilemma is the post trial obligations of the sponsors to provide continuous proven benefit to the trial participants and the host countries after the trial ends. The trial participants, they made contribution to the trial. And in many cases, the research yields a beneficial treatment, but the treatment is not 5

6 available to the research subjects who contribute to its success after the trial ends. The example is the HIV trials. Given the high prevalence of HIV infection, the multinational drug companies are carrying out trials in some developing countries. The trial protocols usually provide free supply of trial drugs for a specific time, usually about two to three years for the patients enrolled in the trials. There is no guarantee that the treatment will be continued after the trial ends. If the intervention is proven to be beneficial to the trial participants, is it ethical to stop intervention after the trial ends? This is particular of a problem if the patients are receiving life-sustaining intervention in the study. And they lack access by other means after the study. The discontinuation of the proven beneficial treatment would cause immediate (perhaps lethal) harm to the trial participants. 6 The governments and most people in the developing countries where new medical interventions have been tested cannot afford them. The host communities take the risk in conducting the trials, but they can t share the benefit from those trials because proven beneficial treatment might be too expensive for them to afford. How can we balance the equal distribution of burden and benefit from those trials? 7 Here we need to talk about the three basic ethical principles in the human trials again. They are the respect of person, the beneficence and the justice. The respect of person means that we need to respect the person s autonomy and protect the person with diminished and impaired autonomy. The trial participants and host communities take the risk of conducting a trial. If a treatment is proven beneficial to them, they should have the right to have access to it. But with the limited resources and prevalent poverty in the developing countries, it is very difficult for the residents there to share the benefit from the trial. As sponsors and researchers, they should try hard to respect the autonomy of those patients and try to provide the post trial access to the treatment. Beneficence means to do better. It is good that the treatment is proven effective. But what can be done to make it better? Some argue that the trials at least do no harm to the trial participants in the developing countries, because they would otherwise have no access to the treatment. But is it ethical to stop the proven effective treatment after the trial ends? The most concern about the post-trial obligations to the trial participants and host communities is the justice. One concept of the justice is distributive justice, which deals with the fair allocation of society s benefits and burdens. In the research context, distributive justice requires that no group or social class be disproportionately exposed to the risks and inconveniences of serving as participants in research that aims to develop medical interventions to benefit the entire population. Justice as reciprocity, on the other hand, is concerned with what people deserve as a function of what they have contributed to an enterprise 6

7 or to society. In the context of clinical trials, justice as reciprocity could mean that something is owed to research participants even after their participation in a trial has ended, because it is only through their acceptance of risk and inconvenience that researchers are able to generate findings necessary to advance knowledge and develop new medical interventions. The contribution is especially strong at the completion of a successful trial, which establishes the efficacy and safety of an intervention. In recent years, a number of international organizations and national research regulators have addressed the obligations to the trial participants after the trial ends. For the first time, the Declaration of Helsinki contains a provision concerning the need for some benefits to research participants. It states, At the conclusion of the study, every patient entered into the study should be assured of access to the proven prophylactic, diagnostic, and therapeutic methods identified by the study. In addition to the declaration of Helsinki, other international documents make recommendations that would impose post-trial obligations. The UNAIDS (The Joint United Nations Program on HIV/AIDS) was the first organization to make recommendations that explicitly focus on resolving drug access problems as part of international collaborative research. Guidance Point 2 states that Any HIV preventive vaccine demonstrated to be safe and effective should be made available as soon as possible to all participants in the trials in which it was tested. Plans should be developed at the initial states of HIV vaccine development to ensure such availability. Researchers also support the obligation to care for research participants after a clinical trial has been completed. The Kass/Hyder survey revealed that a substantial percentage of the researchers surveyed had plans to distribute interventions that were proven effective to some participants at the conclusion of the research. 43 percent of U.S. researchers surveyed and 32 percent of developing country researchers surveyed planned to distribute the intervention to the entire study population at the conclusion of the study. About 33 percent of the researchers surveyed planned to provide the intervention to participants for two to five years, and another third for more than five years. Then what should be provided to the host communities and countries? The relevant distinction between research participants and the rest residents in the host communities is that research participants are exposed to the risks and inconveniences of the study. In addition, a relationship of trust and care exists between participants and researchers that do not exist for the others. On what basis can one justify an ethical obligation to make the unaffordable effective interventions available to members of the broader community or host country? The global inequities in wealth and resources are so vast; expecting 7

8 governmental or industrial research sponsors to seek to solve the problem is unfair and unrealistic. But some have argued that the sponsor are obligated to provide effective interventions after a study is completed to the population from which the research participants were drawn. They argued that research is designed to create general knowledge and is legitimate in a developing country only if its purpose is to create general knowledge that will benefit the citizens of that country. If the research only has the potential to benefit the limited number of individuals who participate in the study, it cannot offer the benefit to the developing country that legitimizes the use of its citizens as research subjects. It should be emphasized that research s goal is to prevent or treat large populations, and it make no sense if its benefits are limited to the small population of research subjects. A number of international and national guidelines recognize and make recommendations to the post-trial obligations to host communities and countries. The CIOMS International Ethical Guidelines document states that before undertaking research involving subjects in underdeveloped communities, whether in developed or developing countries, the investigator must ensure that the research is responsive to the health needs and the priorities of the community in which it is to be carried out and any intervention or product developed, or knowledge generated, will be made reasonably available for the benefit of that population or community. This requirement is echoed in Ethical Considerations in HIV Preventive Vaccine Research: UNAIDS Guidance Document, recently issued by the joint United Nations Program on HIV/AIDS (UNAIDS): HIV vaccine development should ensure that the vaccines are appropriate for use among such populations, among which it will be necessary to conduct trials. The WHO (World Health Organization) s Operational Guidelines for Ethical Committees that review Biomedical Research refers to the consideration of the availability of successful interventions in the host community in the ethics review process. The document states a description of the availability and affordability of any successful study product to the concerned communities following the research should be considered as part of the ethical review process. The Belmont Report s concept of justice encompasses the prospect of making effective interventions available to a population that is larger than that of the research participants, whether the population is a poor group within a wealthy society or one that lives in a developing country and is participating in a study sponsored and/or conducted by a developed country. The ethical requirement that research be responsive to the health needs of the population or community in which it is carried out calls for decisions on what is needed to fulfill the requirement. It can be fulfilled only if successful 8

9 interventions or other kinds of health benefit are made available to the population. This is especially important to the research conducted in countries where governments lack resources to make such a beneficial treatment widely available. Even when a product to be tested in a particular country is much cheaper than the standard treatment in some other countries, the government or individuals in that country may still not be able to afford it. If the knowledge gained from the research in such a country is used primarily for the benefit of populations that can afford the tested product, the research may be unethical. The researchers are also aware of the problems. Some scientists state that research should only be conducted in a country if the results will be available (affordable) in the host country. Who should provide post-trial benefits? Determine who should be responsible for providing post-trial benefits to research participants and host communities or countries is an especially difficult problem. Majority of people support the idea that the sponsors and researchers should be responsible to deliver the benefits. Although individual researchers do not usually have either the resources or the authority to directly provide post-trial benefits to participants or host countries, they can play an important role in helping to ensure that such arrangements are in place. The researcher s basic and generally accepted responsibility is to respect the participants (and the community they represent) by informing them about the research and their role in it, obtaining meaningful consent, enrolling participants in clinical trials only when there is a reasonable balance between risk and potential benefits, and designing the study in such a way that it addresses a health concern of the host country. Researchers can further fulfill their ethical obligation to participants and host countries by ensuring that the issue of access to effective interventions and other post-trial benefits is considered at each stage of the trial, especially the planning and design stages. The burden of delivering post-trial benefits fall mostly on research sponsors because most researchers are not able to ensure that research participants and others in the host community can obtain post-trial benefits. An absolute requirement to provide effective interventions to host countries would impede the funding sponsors s willingness to support the research and thus might harm developing countries by delaying or preventing beneficial research. It has been pointed out that expecting industrial sponsors to provide expensive drugs free of charge after a trial is over might curtail interest among companies in developing interventions specifically for diseases that are prevalent in developing countries. If companies do not anticipate a fair return on their investment, they might be less like to support the research. So the obligation of researchers and sponsors to provide post-trial benefits cannot be absolute. The availability of effective interventions will depend on 9

10 many factors that are often beyond the control of researchers and sponsors. But they should make good faith efforts to secure the continued benefit of effective interventions by ensuring that the issue of their availability is discussed during trial planning. The result of these negotiations should be included in the protocol submitted for IRB (Institutional Review Board) review, and potential participants in the trial should be told during the consent process what arrangements have been made for making effective interventions available after the trial is completed and that availability of the intervention will cease when it becomes available as standard care in the host country. In some situations, researchers and others involved in negotiating post-trial benefits may conclude that there is impossible for an effective intervention become available to the participants in the trial or to the population. In these situations, the parties need to reconsider whether the study should be carried out or not. 8 In conclusion, it is a very complicated ethical issue of the conducting the medical research (especially the clinical trials) in developing country. The main ethical dilemma is the using the placebo control instead of the standard care, and the post-trial benefit to the trial participants and host communities. International society has aware of the dilemma and is making the effort to solve them. But with the unequal wealth distributed in the world, the dilemma will continue to exist. 10

11 References: 1. Ethical and policy issues in international research: clinical trial in developing countries. National Bioethics Advisory Commission (NBAC), Chapter 5, Anup Shah. Pharmaceutical corporation and medical research Zulfiqar Ahmed Bhutta. Ethics in international health research: a perspective from the developing world. Bulletin of the world health organization, 2002, Vol 80, P International Ethical Guidelines for Biomedical Research Involving Human Subjects. Council for International Organizations of Medical Sciences (CIOMS) 5. Bebe Loff and Jim Black. The declaration of Helsinki and research in vulnerable populations. MJA, 2000; 172: When research is concluded-access to the benefits of research by participants, communities, and countries. National Bioethics Advisory Commission (NBAC), Chapter 4, Ethical issues in international research setting the stage.. National Bioethics Advisory Commission (NBAC), Chapter 1, Ruth Macklin. Double standards in medical research in developing countries. Cambridge, UK; Cambridge University Press,