Taking Informed Consent Seriously in Global HIV Vaccine Research

In 1997, the New York Times front page featured a report about women who had participated as subjects in a research study of zidovudine to prevent perinatal HIV transmission in Ivory Coast. Many were confused about research. One woman believed that she received medicine to cure malaria, fever, or AIDS. Another said, “If scientists say that it has to be this way, then I can only agree with them” (1). Did these women understand what the study meant or what they were doing? If not, would they still have agreed to participate if they fully understood the study's implications? Will they distrust research in the future? We simply do not know, because no valid and reliable method was available to ensure the subjects' voluntary, informed consent. The process of obtaining human subjects' consent to participate in research generally is developed on an ad hoc basis for each research study (2). This ultimately haphazard approach to consent is no longer tenable in the face of heightened public awareness—and federal regulatory sanctions—of recent research scandals, both in the United States and abroad (3–6). The good news is that a positive, effective response appears to be within reach. There is a growing body of empirical research on subject comprehension of information about research studies (7–11). The next step, I believe, should be to develop a valid and reliable methodology to ensure the voluntary, informed, and understanding consent of research subjects (I use the terms subjects instead of participants for clarity, to distinguish those who participate as the subject of analysis from those who participate as investigators and analysts, for example). The study by Coletti et al. in this issue (12) represents a new milestone in progress toward this goal. It demonstrates not only that it is possible to implement an informed consent process that most people can understand, but also that informed subjects are not disproportionately scared away from vaccine trials to prevent HIV infection. Most important, it provides the seed for developing a methodology for an effective consent process—as an essential component of well-designed, ethical research. It is time to take that step for all HIV vaccine trials, both here and in the developing world, where phase 3 efficacy trials will be conducted. After years of alternately promising and disappointing results, several vaccine candidates to prevent HIV infection are poised for testing in clinical trials of efficacy (13) (summaries of clinical trials of investigational HIV vaccines can be found at http://www.clinicaltrials.gov, http://www.niaid.nih.gov/vrc/clintrials/clin_current htm, and at http://www.hvtn.org.trials.) This means that formerly hypothetical questions about how to obtain consent to participation in HIV vaccine clinical trials must now be answered—correctly and soon—if we are not to waste the chance to find a safe and effective means of preventing HIV infection. Foundations of Informed Consent to Research Once it is determined that a candidate vaccine is ready for testing and that a trial is worth doing, an essential element in the design of an HIV vaccine trial is how to identify and enroll people who are willing to volunteer as human subjects. Consent to become a research subject is a prerequisite of research in several different senses—practical, scientific, legal, and ethical. Clinical research is obviously not possible without the participation of human subjects. They provide the data necessary to determine whether a vaccine (or other intervention) is safe and effective. Because no one has any obligation to become a research subject, research depends on individuals' voluntary participation as research subjects. The fundamental legal and ethical principles of informed consent to research are well established: no competent adult may be used as a research subject without his or her voluntary, competent, and understanding consent (14–18). The most authoritative written statement of these basic legal requirements—the Nuremberg Code—is reflected in the federal regulations governing federally funded research (19–22). It has also become an ethical principle and part of all subsequent codes of research ethics (23–25). In the most comprehensive government-sponsored review of ethical issues in research since the President's Commission in the early 1980s, the National Bioethics Advisory Commission (NBAC) reconfirmed in 2001 that research requires the voluntary, informed consent of all human subjects (14). Moreover, in a separate Report, the NBAC concluded that the same principle applies to research in developing countries, where HIV vaccine efficacy trials will be conducted: “Recommendation 3.1: Research should not deviate from the substantive standard of voluntary informed consent. Researchers should not propose, sponsors should not support, and ethics review committees should not approve research that deviates from this substantive ethical standard” (26) (v). Gaps in Carrying Out the Ethical Obligation Until the 1970s, physicians commonly objected to the legal and ethical obligation to provide information sufficient to enable their patients to make a knowledgeable decision about treatment, claiming that patients would refuse “necessary” medical care (14,27,28). That fear proved unfounded, and, although the doctrine of informed consent is not always perfectly implemented, there is no longer any serious objection to the principle that competent patients may not be treated without their voluntary and informed consent (29). The main concern today is how to obtain informed consent. Likewise, today, no responsible researcher would argue for participation in research without consent (30). Nonetheless, some researchers fear that prospective subjects will refuse to enter a study if they are fully advised of the risks and uncertainties, or even the absence of personal benefit. There may even be resistance to pursuing the research needed to develop effective consent processes. Yet not doing so risks conducting research to which subjects have not consented. Among the public at large, the most common criticism of research is that subjects did not know that they were in a research study or did not understand the possible risks or consequences of participation (31,32). The consent process in research studies is often poorly understood and implemented, both in this country and abroad. Recent, rapid expansion of research in developing countries may exacerbate both the extent of this problem and negative reactions to research in general if effective methods to ensure informed consent are not developed and used (33–36). Mistrust of research may have influenced U.S. postal workers exposed to anthrax in 2001, to whom the CDC offered an investigational anthrax vaccine; only 2 percent of the 10,000 people eligible accepted. The CDC reportedly decided not to study the postal workers' reasons because it was hesitant to seek consent for another study (37). A recent national survey of attitudes toward research reports that 79.2% of African Americans and 51.9% of white Americans believed that “someone like them would be used as a guinea pig without his or her consent” (38). This is consistent with research indicating that African Americans are less trusting of research than other ethnic groups (39). This magnitude of distrust is distressing and calls for taking informed consent seriously. Empirical Research on Informed Consent to Vaccine Trials Lawyers, ethicists, and most researchers understand that consent is not a form, but a process (4). Nonetheless, empirical research on how to provide information and ensure that consent is voluntary, informed, and understanding remains scattered and incomplete. This is especially true for preventive vaccine trials, and HIV vaccine trials in particular, which are more complicated and difficult to understand than studies using potentially therapeutic agents to treat disease, and expose healthy volunteers not only to the uncertainties of medical risks, but also to the risk of discrimination, and the possibility of increased risk of HIV infection if they engage in risk behaviors in the mistaken impression that they are protected from infection (40–46). Investigators, scholars, and commissions have urged the development of better methods to convey appropriate comprehensible information to prospective research subjects before large-scale clinical trials begin (8,47–50). The Coletti study is a major step forward in empirical research on the consent process because it compared a fairly typical procedure for obtaining consent with an intensive experimental process in a large (4892 subjects), multisite, randomized, controlled study of the consent processes themselves. The experimental process appears to have applied lessons from prior research and anticipated others (10,11). For example, the experimental process group was encouraged to review and discuss more extensive information with study staff, friends, and family and to consider what joining the study might mean to them. They were not tested on comprehension and did not decide whether to participate in the hypothetical vaccine trial until a subsequent visit, and then only after discussing their understanding of the study again with trained staff. This approach appears responsive to the concern that most people have difficulty understanding or remembering complex or detailed new information when first presented (7). The experimental consent process appears to have gone beyond typical explanations to make sure that prospective subjects understood the contingent, experimental nature of research and the special complexities of HIV vaccine trials. This is a welcome effort to avoid the therapeutic misconception, where subjects believe that the investigational agent is actually therapy that will benefit them by preventing disease, for example (51–53). Subjects who received the more intensive experimental process demonstrated significant increases in understanding compared with controls who received the standard information. This improved understanding is especially encouraging because those tested included members of groups that are at risk for HIV infection and sometimes, perhaps mistakenly, assumed to be less likely to understand research protocols (54–56). Over time, subjects did not appear to forget what they had learned in the process. Subjects were also able to correct their earlier misunderstandings, a notable finding because erroneous first impressions are hard to correct. Unlike single procedure studies (or medical treatments), vaccine trials entail participation over months or years, which means that subjects must continue to understand the study and the consequences of their own role in it in order to agree to continue their participation. The study adds to the growing body of evidence suggesting that traditional procedures for obtaining consent to research, like a single description of a proposed study, are not sufficient to ensure subjects' voluntary and understanding participation (7–9,57–60). It goes beyond most studies by elucidating the differences in understanding achieved with the two processes. It is disquieting, however, that only 65% of the experimental process subjects understood “once a large-scale HIV vaccine study begins,” they cannot assume that the vaccine is completely safe, and that only 45% understood that the vaccines being tested were not “known to be at least 50% effective at preventing HIV.” As the authors recognized, there is still work to be done in designing education materials that prospective subjects understand. One suggestion is to consult members of the prospective group of subjects in designing the consent process (61). People living with AIDS in the United States have contributed a great deal to educating researchers about the capabilities of individuals who participate as subjects of clinical trials, such that investigators often consult patient and community groups on trial design and counseling techniques. Coletti and colleagues took advantage of this resource to refine the experimental consent process for use in an actual phase II HIV vaccine trial (62). With the advice of a community advisory board, they used videos to introduce the study to all prospective subjects, expanded the information booklet, and added more questions to the test of comprehension. To their credit, the researchers decided not to enroll anyone who could not answer 14 of the 15 questions correctly, and yet no one had to be turned away for this reason. Subjects undergoing this more intensive process with additional information demonstrated greater levels of comprehension than those in the first study. This suggests that it is indeed practical to provide sufficient, comprehensible information to permit informed consent across a diverse population. It also raises questions about whether subjects who are enrolled in other clinical trials without demonstrating their understanding can be said to have consented. The Need for a Methodology of the Consent Process A good informed consent process not only helps individuals make good decisions about participation in research, it also helps investigators avoid accusations of exploitation. After all, it is the investigators and their institutions who are responsible for ensuring that human beings who participate in their studies have voluntarily consented to participate as subjects. However, investigators, most of whom have limited training in the legal and ethical requirements for informed consent in research, are typically left to their own devices to create a consent process for each study on an ad hoc basis. Institutional review boards (IRBs) have neither the time nor the resources, nor perhaps the expertise, to perform this task for investigators (63,64). What is needed is a valid and reliable methodology for the consent process, comparable to the methodologies used in other aspects of research design. Investigators use accepted methodologies to design studies to answer research questions because these methods have been shown to be effective in producing valid data. The randomized clinical trial design that will be used to test HIV vaccine candidates will be selected because it is a reliable way to collect valid data. The same is true of methodologies for randomizing a study population into intervention and control groups, as well as statistical methodologies for analyzing different types of data. Investigators now take for granted the need to justify the methods used for each aspect of research, and rightly so. I think the same should be true for the informed consent process. We should develop a standard methodology for the consent process. This should include identification of the elements of research and the elements of a specific study which are material to prospective subjects; educational processes for presenting essential information in culturally relevant and usable ways; measures of subject competence to make decisions about participating in research; measures of voluntariness in entering a study; and measures of understanding of the concept of research, specific study goals and procedures, and the subject's role therein, as well as risks and uncertainties. The advantages of a valid and reliable methodology for the consent process are obvious. Investigators need not reinvent the wheel each time they initiate research. With a tested methodology, they can reasonably assume that subjects who meet the standards for consent are willing to participate (65). The public may even be more willing to participate in research if they are persuaded that there are valid and reliable measures in place to ensure that they will not be misled or exploited. Of course, this does not mean that the consent process for every study will be exactly the same, any more than all clinical trials are the same. Investigators should select the components—from among several methodologies—that best fit each study and its study population. Nonetheless, there is an overarching and defined set of tasks that can be performed to identify which methods should be used for the components of the consent process. Some component methods, like the test of subject comprehension in the Coletti study, can serve as a model. Others remain to be developed. For example, we lack suitable measures to assess voluntariness in prospective subject populations. Subjects must be able to make a voluntary decision, as freely as possible from external constraints, yet few studies have examined whether subjects' participation was voluntary (66). This is especially important in developing countries where poverty, political and sexual inequality or limited access to health care can distort perceptions of research. In addition, the content of the information provided to prospective subjects merits closer analysis (67). Studies rarely report what subjects were told, so it is difficult to determine whether subjects' failure to answer questions correctly resulted from their own lack of understanding or the input they received. Researchers may provide more information about the investigational agent being tested than about the concept of research, the goals of the study, and subject's role in the research. This might explain why some subjects fail to grasp that the study is an experiment and not an offer of personal medical benefit. Investigators should pursue the development and testing of screening tools to identify the knowledge educational and attitudes of the population to determine what they and need to know, as well as how to them In addition, more should be to who should provide information and to prospective subjects. Researchers have a to ensure that all consent is competent, voluntary and informed, but this does not mean that other people cannot do the or subjects may be more questions of trained people who are not Most important is that the consent process be on valid and reliable methods that serve the goals of informed than on about what and how to prospective subjects. 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