Ethics in Research and New Product Development
All new drugs and other medical products must be tested on human subjects before they are sold. Although participation in health research is often a valuable opportunity for participants, what happens to them is determined not only by their clinicians' therapeutic intent (if any) but also by the need to ensure that the research yields useful information. Managing the potential conflict between those motivations is often an ethically challenging task, and the issues become particularly contentious when research is conducted in developing countries.
Developing Consensus on Ethics and Human Subjects Research
The central ethical question in health research that involves human subjects is what may be asked of some individuals so that others may benefit. The question arises in any research in which human subjects are asked to participate, but is most pressing if the care that is offered to subjects provides no therapeutic benefit or if that care is compromised by the requirements of the study design. Informed consent, while in most cases a requirement for ethical justification of research involving risk, does not relieve the scientist of responsibility. The ethical question is what potential subjects may be recruited for, even if they do consent.
A rough consensus exists worldwide on the elements of research ethics and, increasingly, on the central role of the ethical review committee, or institutional review board (IRB). This consensus can be traced back to the post-World War II international determination to ensure that the kind of barbaric research practiced by Nazi scientists would not again stain the good name of medical science.1 Three advisory documents have been particularly influential. The Nuremberg Tribunal that conducted the postwar Doctors' Trial promulgated a code of conduct for medical research that stressed the requirement of informed consent. The World Medical Association issued the first version of its Declaration of Helsinki in 1964 and has revised it several times. A further set of guidelines, issued in 1993 and revised a decade later, was published by the Geneva-based Council for International Organizations of Medical Sciences. Although they lack the force of law, these documents are widely acknowledged as international standards. Indeed, the World Medical Association's periodic revisions of the Declaration of Helsinki have become focal points for international debates over outstanding issues in research ethics.
The most elaborate codification of research ethics is the so-called Common Rule of Conduct of the U.S. Code of Federal Regulations (title 45, section 46), which derived from the work of the National Commission for the Protection of Human Subjects of Biomedical and Behavior Research of the mid 1970s. In addition to proposing rules governing many aspects of research with human subjects, the commission proposed that the IRB be given the central role in research ethics and be responsible for prior review of research proposals.2 The IRB was a compromise, granting a measure of self-regulation to scientists and an assurance of ethical conduct to the government and the public for publicly funded investigations.
The basic elements of research ethics engender little disagreement. The research must never be brutal or inhumane, and all unnecessary risks should be eliminated. Any net risks to subjects must be justified by the prospect of potential benefits to others. Prospective participants must be told that they are in a study and must be informed of its nature and its risks and benefits. In the case of research that offers therapeutic benefit, scientists must explore the range of reasonable therapeutic alternatives with the patient. Potential subjects must understand that their participation is completely voluntary and that they may withdraw at any time and for any reason. Because they cannot voluntarily shoulder risks, further protection must be provided to those who cannot give consent. Such people include, among others, mentally incompetent or immature participants and those involved in research (chiefly in social psychology) that requires initial deception. Consent, however, is not sufficient to ensure fairness; there should be additional safeguards against unfair distribution of the burdens and benefits of research. Finally, all research that involves potential risks should be reviewed by an IRB acting on the basis of internationally recognized ethical principles.
The global acceptance of these principles and the rapid development of capacity for ethical review attest to the perceived validity of this system of rules and procedures of ethical review. However, there has been relatively little research on how IRBs actually perform. Many IRBs in smaller institutions lack the necessary expertise to review novel or complex proposals, and their institutional setting creates a potential conflict of interest. Government investigations of the adequacy of IRBs for the tasks that are now assigned to them have often been critical (for example, Office of the Inspector General 1998, 2000). IRBs are often overworked and understaffed, resulting in ever-lengthening delays between initial submission of protocols and final approval. Regardless of the value of IRBs, predicting what will pass through them and what might provoke delay or rejection has become a significant concern for medical researchers. The system thus has costs as well as benefits, a fact that lends additional gravity to the controversies that it must resolve.
Goals of Ethical Review of Research
Although the overall purpose of ethical review is to ensure that research with human subjects is ethically defensible, the international consensus specifies several distinct goals that are sometimes in tension with each other:
Protection. Ethical review committees can protect subjects by alerting investigators to unforeseen hazards and by suggesting research designs that can avoid unnecessary risk or reduce the number of subjects exposed to risk. By insisting that a clear explanation of risks and benefits be provided to potential participants, ethical review committees also help potential participants to protect themselves. Ethical review committees often take the name "Committee for the Protection of Human Subjects," reflecting a central preoccupation of research ethics today.
Assurance that participation is voluntary. Some research cannot be conducted without asking some participants to endure discomfort or pain, to delay relief from symptoms of their disease, or to risk other harm so that future patients may benefit. Permitting investigators to approach potential subjects in these cases requires an ethical judgment. In approving such a proposal, the function of the ethical review committee is not, strictly speaking, only to protect the subjects (the goal of protection would often be served more effectively by declining to do the research), but also to permit them to be enlisted in the effort to improve health care for others. Thus, a second function of ethical review is to ensure that those who agree to participate do so voluntarily and freely and that they understand what is being asked of them.
Equality and fairness. Although research ethics committees have little authority to address persistent social injustices, a third concern of research ethics is that the benefits and burdens of health research be distributed fairly. This function receives relatively little attention in the literature of research ethics, despite its prominence in such well-known documents as the Belmont Report of the National Commission for the Protection of Human Subjects (1979). Many of the most notorious abuses of research subjects, including the Nazi investigations in the concentration camps, the Japanese biowarfare experiments on Chinese and other civilians, and the Tuskegee research on African Americans suffering from syphilis, were committed on subjects chosen exclusively from disadvantaged groups.
Those three goals of ethical review—protecting subjects; ensuring voluntary, informed participation; and reviewing the fairness of recruitment—are promulgated in the international guidelines and in the Common Rule (and in the regulations of other countries), but they do not always point in the same direction. For example, a research project that asks participants to endure a burden or risk—thus failing to offer full protection—can still meet the requirement of equality if the burden is equally shared.
Ethical review, thus, is not a matter of applying a checklist, but it imposes an obligation of substantial ethical judgment. A key challenge for IRBs is to earn and retain the trust of participants and of the public, a task made more difficult by the unavoidable absence of explicit criteria for approval. This problem is exacerbated by the institutional conflict of interest inherent in the placement of the IRB within the research institution, which prompts concern that the committees will downplay risks to subjects for projects that profit or benefit the institution or its influential staff members. Conversely, IRBs that are fearful of institutional embarrassment or legal sanction in the event of any harm befalling research participants might lean too far in the direction of overprotection of subjects, at the expense of important scientific research initiatives. Both concerns have been raised about the IRB system.
Current Controversies in Research Ethics
Some of the most sharply disputed issues have arisen in international collaborative research involving scientists and sponsors from wealthy countries conducting experiments in developing countries. Some of the problems are procedural. For example, U.S. agencies have insisted on the same kind of recordkeeping for IRBs in developing countries that is required of IRBs in U.S. research institutions. IRBs in developing countries may accept the same principles of accountability, but they do not have the elaborate staffs and budgets that leading IRBs rely on.
The most difficult disputes involving the ethics of research in developing countries are, however, substantive rather than procedural.
Standard of Care
The international guidelines used in navigating the ethical dilemmas of research in developing countries were created for the very different purpose of ensuring that what happened at Dachau and Auschwitz would not recur. It is not clear whether those rules usefully resolve the kinds of dilemmas that arise in, say, Uganda or Peru.
The Declaration of Helsinki, following the Nuremberg Tribunal, requires informed consent of all competent research subjects, and in section 29 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."
To its supporters, any departure from the letter of the Declaration of Helsinki that would permit an experiment in a poor country that would be forbidden in a rich one would constitute a double ethical standard. In their view, this clause of the Declaration of Helsinki affirms the equal importance of human lives, regardless of wealth or nationality, and stands as a safeguard against exploitation of those made vulnerable by poverty, sickness, and absence of governmental protection.
Opponents, however, argue that this position seems to rule out the possibility of testing cheap new products that may be effective, although perhaps not as effective as other products that the population could not afford. If so, it would be difficult to understand whom the single-standard-of-care position would be protecting, for surely it is better for a seriously ill person to receive a good drug, even if it is not the best, than to receive no drug at all.3
Both points of view deserve respect. The single-standard approach is consistent with the postwar consensus on principles of research ethics, and it offers a bright line between research that amply respects human subjects and that which might result if sponsors and scientists were tempted to roam the globe in search of human subjects who could be used as experimental material with a minimum of expense or trouble.
Opponents of the universal-standard view, however, challenge its premise. It made sense to insist on a single, universal standard when the problem was Nazi barbarity, because the prevailing standard was high and the medical criminals in the death camps denied it to the imprisoned minority—people unjustly stripped of their entitlements. In Uganda or Nepal, however, care at the highest world standard is available, if at all, to only a small elite.
A full reconciliation of those points of view may not be possible. The authors suggest that a relativized standard should be considered only when the beneficiaries will include the impoverished, sick population. Even in those cases, however, the local standard of care could be adopted in the experiment only if it met or exceeded the standard provided by other countries at similar levels of development.
Placebo Controls and Other Issues Involving Research Design
For certain purposes, scientists use a placebo control even though a proven treatment exists. Patients in these control groups thus receive care that is inferior to what they would experience in good clinical care. Until very recently, the Declaration of Helsinki flatly condemned this practice (its current language is somewhat less restrictive), but the U.S. Food and Drug Administration (FDA) accepted results of these trials in applications for approval of new drugs. The FDA's justification for this acceptance rests on two claims, one scientific and one ethical. The first is that in certain contexts (for example, for conditions such as depression, in which eligibility criteria and outcomes are subjective, to an appreciable extent, and in which symptoms fluctuate in both treated and untreated patients), active controls may produce misleading indications of equivalency, yielding seemingly positive results that may be spurious. The second is that when only placebo controls can be informative, it is sometimes justifiable to ask participants to be randomized with placebo and thereby to risk discomfort and distress (but not any appreciable risk of death or long-term impairment).
Debates over placebo controls are often joined in the context of disputes over the appropriate standard of care that arise in the case of research in developing countries, but placebo controls are controversial in trials in high-income countries, too. Placebo controls are one instance of a large category of ethical issues in research that require weighing the importance of a scientifically ideal research design against the well-being of participants. For example, a study of long-term chemotherapy to prevent the recurrence of breast cancer was halted before the designated endpoints had been reached after the study's Data Safety and Monitoring Board decided that continuing the study after a strong trend had been established favoring the chemotherapy would be unfair to the control group. It is notable that in this instance severe criticism of this decision was voiced by an organization representing women at risk for breast cancer, as well as by the editorial board of the New York Times. Critics of the early termination of the trial were, in effect, aligning themselves with the interests of future beneficiaries of the research and possibly against the immediate interests of the women in the control group.
Rights of Host Communities
Ideally, research involving human subjects would be a cooperative endeavor for mutual advantage among free citizens who understand and endorse the need for research and who expect to share both in the burden of serving as research subjects and in the eventual benefit of improved health care. Societies that recruit subjects primarily from lower socioeconomic strata fall short of this ideal; those that do not offer new advances in care to all of their citizens fall even further short, raising serious questions about fairness. Furthest of all from this ideal are some instances of the increasingly common practice of recruiting research subjects among the poorest people in the poorest countries. The means for protecting human subjects in these countries are often nonexistent. Most of their citizens will be unable to afford new drugs developed by firms in industrial countries. It is not clear that these subjects participate voluntarily. Their lack of scientific education or even literacy limits their ability to understand the terms of the proposed agreement with the scientists and sponsors (particularly when consent forms, on legal advice, run to 20 dense pages), and poverty often deprives them of any alternative means of recovering their health.
Despite these potential ethical shortcomings, international collaborative research is assured of continued growth. Some of this research targets diseases affecting mainly poor people, who as a group suffer more from too little research on their populations than from too much. Even research intended to develop therapies that will be affordable only to much wealthier patients can be defended. Individual participants may receive better care than they would otherwise, and visiting scientists offer employment and technical training.
To right the perceived imbalance in what is asked of research subjects in poor countries and the value that is obtained by scientists who experiment on them, some have proposed that sponsors of research in the poorest countries compensate their hosts by offering a supplementary benefit (Glantz and others 1998). One much discussed option is access following the end of the study to any drugs or other therapies whose effectiveness is confirmed in the research. The most limited proposals would restrict this entitlement to individuals who were enrolled in the study (those who received placebo as members of a control group, for instance), and time limits (such as three years) have been proposed in the case of chronic diseases such as HIV/AIDS. More expansive community benefit proposals have called for lifetime access to the treatments by all participants, their families, other members of the local community, or even all citizens of the country. Other proposed benefits include a specified amount of technology transfer, including scientific training and the construction of clinics and laboratories, and cash payments earmarked for health care. A moderate proposal is to encourage these benefits but to require only that they be discussed and agreed on before investigations are initiated (National Bioethics Advisory Commission 2001).
These proposals are intended to restore fairness to the relationship between participants and those who benefit from research, including scientists and their sponsors and also future beneficiaries of advances in medical science. Among the potential drawbacks are the inability to specify, even roughly, how much is owed to host communities; the inability to determine whether community benefit should be required even of research funded by governments or philanthropists for the benefit of people living in the host communities; and the risk that placing these demands on proposed research projects will drive them away from these very needy sites. Some of these uncertainties may be resolved over time as a variety of approaches are attempted, particularly if they are studied and reported to officials in potential research sites.
These international collaborations would draw less scrutiny if it were clear that all subjects knew what they were getting into and participated of their own free will. Although evidence on this point is mixed, special circumstances in some countries introduce problems that will have to be addressed over the long run. Cultural differences between host populations and scientists may lead to conflicts over who has the authority to speak for the individuals invited to participate in a given study. Regulatory authorities in high-income countries have been reluctant to accept permission by a woman's husband or by a village chief on behalf of his people in lieu of individual consent. It is often unclear—particularly from the vantage point of an IRB in Europe or the United States—whether the cultural norms of the host population designate the husband or village chief as decision makers in these transactions and whether insistence on concurrent individual consent would be viewed as intrusive or insulting.
Another recurring issue is whether people enrolled in a trial of a promising therapy who are ill and very poor can rightly be viewed as volunteers. The prospect of a cure for a person who would otherwise die would seem to be irresistible, even if the treatment is not up to the standards that even less well-to-do citizens of richer countries would expect. Financial incentives, too, would predictably have a powerful effect on an individual who may always be looking for a day's wage to feed hungry children. Some IRBs limit payments to compensation for lost wages and travel expenses, but even at this level researchers are asked to change the amounts offered to avoid forcing a choice on the potential participant. As with alleged cultural differences regarding individual informed consent, IRBs operate with scant evidence on this point. It is difficult from a long distance to decide what amount of compensation undermines freedom of choice. It is also unclear whether the moral categories used in these disputes have been adequately thought through. The fact that a poor person finds an attractive offer irresistible will be viewed as evidence of coercion by some observers but nothing more than common sense by others.
Most of these controversies can be traced back to underdevelopment and the inequalities of wealth and education that prevail among and within nations today, but progress in resolving the ethical controversies that have become obstacles to badly needed health research must be made even as these disparities persist. Viewing health research in the context of development and emphasizing research that is targeted to the needs of the poor majorities in poor countries can provide a context in which trust rather than fear or suspicion is the default response in host countries. Efforts to build capacity for ethical review within the host countries, such as financial support for ethical review committees, can place the locus of decision making closer to the people who serve as subjects. Research on the effectiveness of current ethical and regulatory requirements and mechanisms might enhance the process of ethical review while reducing its bureaucratic burden. Meanwhile, the quality and appropriateness of ethical review of this research that takes place in the sponsors' countries would be enhanced by eliciting the views of officials in developing countries, clinicians, scientists, and community leaders.
1. Because our current system of ethical review and regulation of research with human subjects derives from our resolve to prevent the recurrence of earlier abuses, it deserves mention that the standard historical account of research ethics has been seriously incomplete. While the Allies sat in judgment of the Nazi scientists at Nuremberg, abuses of similar scope and savagery practiced by Japanese biowarfare researchers on Chinese and other civilians and prisoners of war were kept secret (and their perpetrators were unpunished) following a pact with the criminal scientists to exchange data for war crimes immunity. Moreover, the Allied governments did not always honor the Nuremberg principles. In the Soviet Union, scientists attempting to develop for clandestine operations poisons that would not be identified on autopsy practiced their craft, with predictably lethal results, on hapless prisoners (Birstein 2001). Abuses in the United States, such as the Tuskegee syphilis study (Brandt 2000), have been more widely publicized, but ethical lapses in large-scale Cold War-related studies, ranging from radiation studies on urban populations (Advisory Committee on Human Radiation Experiments 1995) to surreptitious administration of mind-altering drugs such as LSD (Rockefeller Commission 1975), were state secrets.
2. In the United States, the Office of Human Research Protections, an agency of the Department of Health and Human Services, has overall responsibility for oversight of IRBs administering research using U.S. government funds. Its Web site is http://ohrp.osophs.dhhs.gov/.
3. Supporters of the single-standard view might point out that, in its current version, the Declaration of Helsinki does not require that everyone in an experiment receive the best available care, but rather that new treatments be tested against the best available care. But this defense faces further objections. In some cases, testing against the best available care (rather than against the care currently provided to the population or against placebo) will fail to provide the evidence needed to convince the ministry of health or potential donors that funds should be provided. There is a potential contradiction in any view that claims both that all patients in experiments deserve the best care and that it is ethically acceptable to test a new treatment that is not expected to be quite as good as the best currently available.