Consensus and Controversy in Clinical Research Ethics

An international consensus for protecting the rights and interests of research subjects has emerged in a process that began with the Declaration of Helsinki¹ and continues in the development of official guidelines² as well as a growing scholarly literature.³ Despite this consensus, legitimate ethical controversies persist. This article discusses points of consensus and controversy in clinical research ethics, focusing on substantive, rather than procedural, concerns.

The consensus system requires independent review of research protocols and informed consent of subjects or their surrogates. Independent review examines such issues as adequacy of study design, minimization of risk, risk-benefit ratio, protection of confidentiality, promotion of informed decision making by subjects, potential conflicts of interest, and equitable selection of subjects. Through the informed consent process, potential subjects decide for themselves about enrolling.

This system, which draws its strength from foundations in such ethical principles as autonomy, beneficence, and justice, has been refined by 3 decades of experience and enhanced by increasing professionalization of system administrators. Three enduring challenges in this system concern the definition of research, process of independent review, and process of informed consent.

Defining Research. Research is “a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.”⁴ This definition raises the problem of distinguishing research, which is subject to regulation, from innovative therapeutic intervention, which is not. This issue has been discussed in connection with surgical interventions but also occurs in innovative uses of other therapies. One response focuses on whether the physician’s primary intent is to develop generalizable knowledge or treat an individual patient. This response assumes that only one intention is primary and can be clearly distinguished from other intentions. Another response focuses on the intent to present or publish results, which distinguishes research from innovation. This response falters because such plans may emerge only after innovative interventions have been completed and innovative treatments may be published without systematic investigation.⁵

An adequate definition of research must also distinguish research from quality improvement activities, because both involve rigorous data collection and analysis. Attempts to distinguish them have not been fully successful, although some guidance has been offered.⁶

Independent Review. In the United States, independent review traditionally involves local review by a committee of institutional peers, both scientists and nonscientists, and community representatives.⁷ This system recognizes that different institutions with distinct local demographics require resolutions of ethical problems best identified and managed locally. In recent years, commentators have criticized this system as (1) not making provision for national or regional review of specialized research by a committee of subject-matter experts; (2) unduly burdensome on investigators in multicenter studies who must secure approval from multiple, often conflicting, institutional review boards (IRBs); (3) not taking advantage of well-designed commercial IRBs that can complete quality reviews quickly; and (4) wasting resources in duplicate reviews by IRBs and data and safety monitoring boards of the protocol and interim data.⁸ One strategy manages these problems by innovative techniques within the system (eg, retaining local review by IRBs but encouraging deference to a central protocol review committee, such as the National Institutes of Health’s Recombinant DNA Advisory Committee for gene transfer research).⁹ Another strategy advocates alternatives to the current system, such as the national IRB for reviewing cancer protocols.¹⁰

Informed Consent. Consensus has emerged that informed consent involves not just disclosing information, but also promoting subjects’ understanding and voluntary decision making. Many studies question the effectiveness of common disclosure practices, as measured by subjects’ level of understanding. They cast particular doubt on understanding in cases in which subjects mistakenly believe a study may offer substantial clinical benefit, an example of “therapeutic misconception.”¹¹ When subjects desperately believe a study offers their last hope, the voluntariness of their decision making can be questioned. Attempts have been made to improve understanding and enhance voluntariness but the results are mixed.¹²

The system involves 3 parties in the protection of subjects: investigators, subjects, and independent reviewers. Some cases may require involvement of a fourth party, the community from which subjects are recruited. The community may serve as a surrogate decision maker for individual subjects, protector of community interests as distinct from individual interests, or claimant regarding the fair distribution of research benefits and burdens. The community serves these roles by advising on, or participating in, the design, approval, and oversight of research.

Consulting the Community When Individual Consent Is Impossible. Sometimes informed consent from individual subjects or surrogates cannot play its usual role, either because it is difficult to obtain consent in a timely manner or because the research subjects are communities. Research on emergency interventions is an example of the first and research on community-wide public health interventions is an example of the second.

Emergency interventions, such as the administration of artificial blood or agents for severe head injury, must often be studied on subjects incapable of consenting and for whom surrogates often cannot be found in the required timeframe. One option is to enroll only those subjects for whom surrogates can be found, but this requires longer recruitment periods and increased cost. A second option is to obtain prospective consent from at-risk individuals, but identifying such potential subjects is usually not realistic. A third option, recently adopted by the federal government, is to allow such research without individual consent under specific conditions, including community consultation.¹³ This can be understood as a kind of surrogate consent or as a process to protect subjects who cannot protect themselves. Questions remain about the nature of the community that should be consulted, appropriate forms of consultation, and appropriateness of decisions to change or retain a protocol in light of the results (B.A.B., unpublished data, 2005).

Public health research on such interventions as community-wide smoking cessation programs or programs to reduce the incidence of sexually transmitted disease are targeted, not to identifiable individuals, but to entire communities by such means as public service announcements and distribution of educational materials. The unit of analysis and the research subject are a community. Community approval is the process through which the community protects itself. There are unanswered questions about the form of the approval, as well as about the moral need and significance of community approval.¹⁴

Protecting the Community From Collective Risk. Research may pose potential risk for a community, distinct from potential risks to individual research subjects. The conduct of a research project or its results may cause significant social disruption within a community. Results may be used to rationalize discrimination against or within a community or to reinforce negative social perceptions.¹⁵ These risks are particularly salient for research involving historically disadvantaged communities, both domestic and international. The consent of some community members to participate does not address collective risk.

In addition to problems of identifying communities and designing a culturally sensitive consultation process, community consultation raises difficult problems about the rights of individuals and the representation of those rights in the consultation process. For example, research on women’s health may be rejected by male leaders of a patriarchal society because the research would be socially disruptive, but women in the community may want to participate. Should such leaders be able to veto the research project?¹⁶

The Community as Claimant on Fair Distribution of Resources. Often, research studies are conducted with economically disadvantaged or socially vulnerable populations domestically and internationally. A research study may unfairly divert social resources from more urgent community priorities as defined by the community. A research study also may unfairly burden subjects who lack the means to access its benefits later. These 2 problems become especially urgent when, after the research ends, validated interventions will not be available in that community or the research infrastructure will not be preserved as a community resource. Although these concerns have been raised about international research on human immunodeficiency virus prevention and treatment, they apply across diseases.¹⁷

Community consultation provides the community an opportunity to prioritize proposed research, protect its health care infrastructure from unfair diversion, negotiate the availability of validated interventions, and obtain other gains from the value of new discoveries. This proposal does not clarify who has the resulting economic obligation to the community and how the scope of such an obligation should be understood and enforced.

The system presents rules for research on all human subjects without recognizing ethically significant heterogeneity that justifies rules for special populations that are vulnerable to exploitation or that have been underrepresented. Vulnerable populations may require additional protections, while underrepresented populations need to be included.

Populations Vulnerable to Exploitation. Exploitation in research means that some subjects experience an unfair distribution of the benefits and burdens of research. This may occur when subjects are unable to negotiate a fair distribution either because of inadequate understanding due to cognitive limitations or because of inadequate bargaining power due to their needs.

Two groups of subjects present issues of inadequate understanding, minor children and cognitively impaired adults.^{18 - 19} A 2-part strategy has won international consensus: consent by a surrogate decision maker and subject assent (ie, the positive agreement of a subject who is incapable of providing informed consent). There are questions about when assent should be required and what weight should be given to subjects’ assents or dissents. Other questions involve the extent of risk to which surrogates may consent, for both therapeutic and nontherapeutic research, and about potential conflicts between the interests of the subject and the surrogate. A distinctive issue for research on cognitively impaired adults is the acceptability of prospective consent to future research obtained when potential subjects are cognitively intact, although they exhibit early stages of cognitive disorders.²⁰

Other populations present issues of need-generated vulnerability, especially the economically disadvantaged and the desperately ill. Because they may lack access to health care, the economically disadvantaged are vulnerable to being exploited by those offering health care and other incentives in the context of research. Because research may be seen as their only hope, subjects who are desperately ill are vulnerable to exploitation by those offering research that might be beneficial. Some commentators deny that there is an ethical problem in such cases, as long as the subjects or surrogates adequately understand the study and voluntarily choose to participate. Others describe such cases as involving undue inducements that threaten understanding or the ability to refuse participation. They propose various protections for such subjects, such as limits on payment to subjects and consent monitors/advocates for the desperately ill.²¹

Previously Underrepresented Populations. Specific populations have been underrepresented in research and therefore deprived of the full benefits of research directed to their health care needs. Children have been underrepresented because the economics of drug development favor conducting research and obtaining approval in adult populations and leaving pediatricians to prescribe off-label drugs. Women of childbearing potential have been underrepresented because of legal fears of liability for injury to future children. Racial and ethnic minorities have been underrepresented because of perceptions that they are difficult to recruit and retain. A strong consensus has emerged that such underrepresentation should end. Congress and federal agencies have instituted measures to address these disparities.²² A major controversy concerns whether incentives or penalties are the better way to encourage enrollment of these groups, but there is consensus that research priorities should better reflect the health care needs of these groups, leading to targeted research such as the Women’s Health Initiative.²³

The system fails to recognize ethically significant heterogeneity among types of research. Specific rules have been proposed for special types of research, notably clinical trials and research involving stored human tissues.

Clinical Trials. The launching of clinical trials raises several ethical issues. First, there is consensus that clinical trials should be launched only when there is sufficient promise for the new intervention but insufficient evidence to justify broad use, a condition called equipoise.²⁴ Ambiguity exists about defining equipoise. Equipoise may be defined descriptively by reference to beliefs and practices in the relevant clinical community or defined normatively by reference to available evidence. Second, there is growing agreement that a national registry should be created in which all clinical trials would be included from initiation, to promote attention to the total body of evidence and thus lessen publication bias favoring published positive results.^{25 - 26} Third, although there is consensus that the various kinds of financial conflicts of interest should be managed before trial initiation, disagreement persists about how to do so when research is increasingly funded by industry. Some believe disclosure is sufficient but others believe divestiture is also required in some cases.²⁷

There is consensus that the optimal study design for comparing interventions is the randomized controlled trial, but problems persist about randomization and choice of control group. Randomization is scientifically crucial, but subjects may not understand it and think they are receiving treatment chosen by their physician, or may resist randomization because they do not want their treatment chosen randomly. The use of a control group is scientifically crucial but choosing an appropriate control group is ethically challenging. Commentators question placebo-control groups when proven, approved therapies already exist, and question active control groups when they might receive suboptimal treatment. Others defend both choices when such controls are scientifically needed and adequate measures are adopted to protect control subjects from serious long-term harm. Choosing an appropriate control group has been particularly controversial in psychopharmacological research.²⁸

Research Involving Stored Human Tissue. There is consensus that human tissue research, especially genetic research and research on disease pathology, is very important and that its value increases by joining tissue analyses with information from patients’ records. For prospective tissue collection, ethical concerns focus on the interrelated issues of the content of the required consent, protection of confidentiality, and possibility of follow-up. It has been proposed that global consent for use of research data combined with reversible delinking of research data from patient identifiers provides sufficient protection of subjects’ confidentiality, preserves latitude in subsequent use, and allows for follow-up. Others suggest that more is required (eg, specific consent to use tissue for a particular research project or type of research plus anonymization [irreversible delinking of research data from identifiers]), although these measures limit possibilities for future research and prevent follow-up. For research on already collected tissue, where consent may not have been obtained and has become impractical, opinions range widely. Some believe that delinking is sufficient, some require anonymization, and some believe that such research is unethical because consent cannot be obtained.²⁹

The state of research ethics reflects consensus on many issues but substantive controversies persist about the foundations of the consensus system and the need to supplement it with community involvement, rules for special populations, and rules for special types of research. These involve both conceptual and empirical components. Further studies focusing on these substantive controversies are required to better define and promote the ethical conduct of clinical research.