Part IV

DISCUSSION OF PART III

Compared with what we have learned about the 1940s, 1950s, and 1960s, there have been many changes in the climate and conduct of human subject research. The most obvious change is the regulatory apparatus described in chapter 14, which was not in place in that earlier time. The rules of research ethics are also more articulated today than they were then, as exemplified by the evolution of the concept of informed consent. Although the basic moral principles that serve as the underpinning for research ethics are the same now as they were then, some of the issues of greatest concern to us today are different, or have taken on a different cast, from those of earlier decades.

In our historical inquiry, for example, we concentrated on cases that offered subjects no prospect of medical benefit; they were instances of "nontherapeutic research" in the strictest sense. That is, these were experiments in which there was never any basis or expectation that subjects could benefit medically--both the design and the objectives precluded such a possibility. Most of the human radiation experiments that were public controversies when the Advisory Committee was appointed were of this type. The basic moral concern they raised was whether people had been used as mere means to the ends of scientists and the government; this would have occurred if the subjects could not possibly have benefited medically from being in the research and they had not consented to this use of their person.

As we noted in chapter 4, the ethical issues raised by research that is nontherapeutic in this strict sense are stark and straightforward. Because risks to subjects cannot be offset by the possibility that they might benefit medically, there is rarely justification for nontherapeutic research that puts subjects at significant risk. Participation in such research is always a burden and never a benefit to the individual subject, making questions of justice straightforward as well. And, at least theoretically, there are no subtleties involved in disclosing to potential subjects that they cannot possibly benefit medically from participating in the research, although problems do emerge concerning what incentives are appropriate to induce people to become research subjects when, considerations of altruism aside, it is otherwise not in their interests to do so.

Today, we still conduct nontherapeutic medical research on human subjects. Much research in physiology offers subjects no prospect of medical benefit, as does every protocol that calls for "normal controls." Although nontherapeutic research frequently involves subjects who are healthy, it also often involves patient-subjects as well. It is, of course, still appropriate to be concerned about the ethics of such research, as it is with all research. For example, we were particularly troubled in our Research Proposal Review Project by documents that suggested that adults of questionable competence were being used as subjects of research from which it appeared they could not benefit medically and where the authorization for this use was unclear.

Much research involving human subjects does not, however, fit this nontherapeutic paradigm. Many of our most pressing ethical questions concern research that raises at least the specter of potential medical benefit to the patient-subject. For example, unlike the plutonium experiments with hospitalized adults or the iodine 131 experiments with hospitalized children, in which there was no possibility that the patient-subjects could have benefited medically, in the modern Phase I trial, which is conducted to establish toxicity, there is at least the possibility of therapeutic benefit, however slim. Thus, although Phase I trials often impose significant burden and risk on subjects, they are not nontherapeutic in the strict sense. And, in contrast with Phase I trials, in much research involving patient-subjects there is a real prospect that subjects will benefit medically from their participation. In many of these cases, being a research subject is clearly in the medical best interests of the patient.

As Otto Guttentag observed in the 1950s (see chapter 1), it is the possibility of medical benefit that creates much of the moral tension in human subject research. Physician researchers are often torn between the demands of a research project and the needs of particular patients. Today this tension has taken on special significance, with the immense growth of research at the bedside and the frequency with which the medical care of seriously ill patients is intertwined with clinical research. In our Subject Interview Study, for example, at least a third of the patients interviewed had some contact with medical research.

It is these considerations that led us to focus the efforts reported on in part III, and particularly the SIS, on research involving patient-subjects. The Committee regrets that we did not have the resources to conduct a similar study with subjects who are not also patients. It would have been particularly useful to have conducted such a study with subjects who are military personnel not currently in medical care. This would have allowed us to investigate other important sources of tension in the ethics of research, including the tension between giving orders and soliciting consent and between occupational monitoring and research.

Although the SIS and the RPRP employed radically different methodologies and were directed toward different research questions, both projects speak to the ethical issues raised by the conduct of human research in a medical context, a context dominated by the human needs to be healed and to heal.

The findings of the SIS underscore what other, smaller studies also have identified--that patient-subjects generally decide to participate in medical research because they believe that being in research is the best way to improve their medical condition.[1] In the SIS, we could not determine whether the patients had unrealistic expectations about how likely it was that they might benefit from being in research, or in what form that benefit might take. Other empirical studies suggest that some subjects do have an inadequate, sometimes exaggerated understanding of the potential benefits of the research in which they are participating.[2] In the RPRP, we reviewed consent forms that appeared to overpromise what research could likely offer the ill patient and underplay the effect of the research on the patient's quality of life. These were the kinds of disclosures that could easily be interpreted by a patient desperate for hope as offering much more than realistically could be expected. Not surprisingly, this problem was the most acute in certain Phase I trials that, while not being nontherapeutic in the strict sense, appeared to offer only a remote possibility of benefit to the patient-subject. In oncology, for example, it is estimated that in only about 5 percent of subjects enrolled in Phase I chemotherapy studies does the tumor respond to the drug,[3] and it is often unclear even then what the tumor response means from a patient's point of view.[4] To say that there is no prospect that the patients might benefit medically is questionable; there are enough cases of patients being helped in Phase I trials to make such a stark claim problematic. Beneficial effects of Phase I trials have a very low probability, but do occur.[5] At the same time, however, any suggestion of the possibility of benefit has the potential to be magnified many times over by patients with no good medical alternatives. It is understandable that physicians, faced with the prospect of little or nothing to offer seriously ill patients, may sometimes impart more hope than the clinical facts warrant. At the same time, however, desperate hopes are easily manipulated.

Consider, for example, a recent report of a small study of patient-subjects participating in Phase I clinical oncology trials.[6] Despite the predictably low likelihood of medical benefit for subjects in Phase I trials, all of the patient-subjects surveyed about their reasons for participating said their decision was motivated in large part by the possibility of therapeutic benefit, and nearly three-quarters cited trust in their physician as motivating their decision to participate. Only one-third listed altruism as a major motivating factor. These results support what we found in the SIS--that patient-subjects view research participation as a way of obtaining the best medical care, even when participating in research holds out very little prospect of direct benefit. This phenomenon, which is especially relevant when some subjects receive a placebo as a part of the research, has been dubbed the therapeutic misconception.[7] This phenomenon is not confined to patient-subjects' perceptions of benefit from research; at least one study has shown that physician-investigators also overestimate the potential benefits to subjects participating in Phase I oncology trials.[8]

One of the most powerful themes to emerge from the SIS is the role of trust in patients' decisions to participate in research, a finding that has been observed in other studies as well.[9] It was common for patients in the SIS to say that they had joined a research project at the suggestion of their physician and that they trusted that their physician would never endorse an option that was not in their best interest. This trust underscores the much-discussed tension in the role of physician-investigator,[10] whose duties as a healer and as a scientist inherently conflict. This trust that patients place in their physicians often is generalized to the medical and research community as a whole. Some patients expressed faith not only in their doctors but also in the institutions where they were receiving medical care. These patients believed that hospitals would never permit research to be conducted that was not good for the patient-subjects. The trust that patients have in physicians and hospitals underscores the importance of the Committee's concern, based on our review of the documents in the RPRP, that IRBs may not always be properly structured to ensure that the medical interests of ill patients are adequately protected. In some cases, the scientific information to make such judgments was not included in the documents we received. Even with adequate information, IRBs may lack sufficient expertise to evaluate the science or implications for medical care of particular proposals. As we heard from some IRB chairs, they may also lack the staff or the respect and authority within their institutions to function adequately to protect subjects.

The theme of trust discerned in the SIS also has implications for how properly to view the role of informed consent in protecting the rights and interests of human subjects. For many of the patients who based their decision to be in research on their trust in their physicians, the informed consent process and the informed consent form were of little importance. IRBs can serve the interests of these patients best by being vigilant in their review of risks and benefits and attending to questions of fairness in the selection of subjects. On the other hand, we also found in the SIS that sizable numbers of patients had refused offers to participate in research and that some patients who had consented to be research subjects had made efforts to learn what they could about the research opportunity. For these patients, the informed consent process likely served an important moral function.

From these seemingly conflicting results we can conclude both that the informed consent requirement is crucial to protect the autonomy rights of those potential subjects who choose to exercise them, but that it is naive to think that informed consent can be relied upon as the major mechanism to protect the rights and interests of patient-subjects. Taken together, the results of our two projects suggest that it is important to correct the deficiencies identified in the RPRP with respect to informed consent. Our results also underscore, however, the importance of an IRB review that focuses on whether the proposed research is a reasonable, ethically acceptable option to offer the patient, in light of available alternatives and the risks and potential benefits of the proposed research for the subject, including impact on quality of life. An alternative, the practice of adding detail to consent forms as a way of further informing potential subjects who often have a difficult time understanding risks, benefits, and purposes of research,[11] is unacceptable; by confusing subjects, it offers less, rather than greater protection. For the many patients who continue to rely on the expertise and good will of physicians and hospitals in deciding whether to participate in research, rigorous review on the part of IRBs and rigorous commitment on the part of physicians to honor the faith entrusted to them are the important protections.

The SIS and the RPRP also both speak to the current confusion between research and "standard care" in medical practice.[12] The same therapy that is part of a research protocol, and therefore must receive IRB approval, can proceed outside of the research setting and not be subject to IRB oversight. This leads to understandable confusion on the part of subjects as to whether they are participating in research, receiving standard care, or some combination. It is thus perhaps not surprising that research subjects occasionally seem unaware of their participation in research, even when there is evidence they have signed consent forms.[13] This finding was observed in the SIS, though the methodology of the study did not allow us to probe the reasons some subjects appeared unaware of their participation.

The confusion between research and alternative medical interventions is mirrored in the language used to communicate to patients in the informed consent process and in the language of patients themselves. In the SIS, the patients surveyed viewed experiments as involving unproven treatment of greater risk, while clinical investigation or study conveyed less uncertainty and were perceived as offering a greater chance of personal benefit. None of the consent forms we reviewed in the RPRP used the term experiment.

CONCLUSION

In addition to the role they played in helping the Advisory Committee come to our conclusions, the RPRP and SIS should be understood as adding to the body of research undertaken to try to understand the strengths and weaknesses of the system to protect the rights and interests of human subjects.

In the end, patients' reasons for participating in research must more accurately reflect the benefits they may reasonably expect. Altruistic motivation can be more fruitfully tapped, both for the benefit it provides to the advancement of science and to underscore for patients that the primary objective of some research is to create generalizable scientific knowledge rather than to offer personal benefit to them. Subjects are much more likely to have a positive view of biomedical research if they feel they understand what prospects research holds for them. The good news in the endeavor of human subject research is that subjects are willing to participate, and in the process entrust their care to researchers; however, that trust cannot be taken for granted as it sometimes has been in our history.

Increasingly it is being argued that it is generally advantageous for patients to participate in research; the distinction between standard care and research, if it was ever clear, is viewed as growing dimmer all the time.[14] As a consequence, the debate over subject selection has changed entirely. As we discussed in parts I and II, in the past a central concern was that certain populations, considered vulnerable to exploitation because of their relative powerlessness, were inequitably bearing the burdens of the risks of research. Today, the concern is that the same populations may have inequitable access to research and therefore individuals and the communities of which they are a part may be denied a fair share of the benefits of research participation. While this is a valid moral concern, the results of the SIS and the RPRP suggest that it remains important to be attuned to issues of vulnerability. While patients with serious illnesses may stand to gain the most from participating in medical research, they also are among the most vulnerable to its risks.

It also is important to underscore the finding in the RPRP that in both studies involving minimal risk and those involving greater risk, research with ill patient-subjects can proceed ethically and consent can be properly obtained. The research enterprise is too important to jeopardize by inadequate protections for subjects. Tensions and potential conflicts exist throughout the research process, and so we must be sure to acknowledge and address them squarely. This is the goal of the next and final part of the Advisory Committee's report.