Discussion

Chapter 15: Independent Review of Proposals

Katz's review complements and strengthens the findings of the Research Proposal Review Project. Whereas the RPRP sought to investigate several basic issues regarding the conduct of human subjects research, including balance of risk to potential benefit, justice in the selection of subjects, the involvement of people with diminished decisional capacity, and the consent process, Katz focused exclusively on informed consent. In doing so, he asked himself two interrelated questions: (1) What can be learned about the contemporary informed consent process? and (2) How adequately does the process protect the rights and interests of research subjects? Although Katz appreciated that there was more to the IRB process than could be ascertained from the protocols and consent forms submitted to the IRB, he felt that consent forms constituted written documentation not only of what subjects ultimately agreed to but also what IRBs considered to be adequate written disclosure for purposes of consent. With respect to these signed informed consent forms, he echoed a fellow Committee member's observation that, if such forms are not clearly written or are otherwise flawed in significant ways, it is likely that the oral interactions are similarly flawed.

Of the 93 proposals Katz reviewed, he identified 41 that posed greater than minimal risks to subjects and therefore that also raised significant and complex informed consent issues.[28] Of these 41 proposals, Katz found that 11 (26%) raised no or only minor ethical concerns and were analogous to those warranting a Committee rating of 1 or 2. Thirty protocols, however, raised ethical concerns about the informed consent process (analogous to a Committee rating of 3, 4, or 5). Of the 30 (74%) protocols that raised serious problems, Katz felt that 10 were "borderline" (analogous to a Committee rating of 3), and 20 raised serious ethical concerns of the sort analogous to those warranting a rating of 4 or 5 in the RPRP. Katz detailed the results of his review of these 20 problematic proposals for the Committee, and a summary of his findings specific to those proposals is presented here.

Physician-Investigators

In his review, Katz was struck by evidence of the dedication physician-investigators brought to their task. They were concerned, and so informed IRBs, about current treatments that were inadequate in eradicating disease or, at least, in prolonging life. Moreover, physician-investigators emphasized the importance of finding cures and not merely temporary or prolonged remissions.

Katz also noted that a number of the troublesome research proposals appeared to be part of an underlying "grand scientific design" to gain basic knowledge in such areas as cellular immunology or molecular biology, which might eventually lead to more clinical research about therapeutic effectiveness. The primary purpose of these studies was to advance knowledge for the sake of future patients, not to benefit present patients.

As investigators declared war on cancer and other ills, they often employed highly toxic agents to treat patients whose prognosis was grave. In their scientific protocols, the use of such agents was justified by arguing that only such aggressive approaches would ultimately lead to cure, although often only for future patients rather than present patient-subjects.

Katz, like the full Committee, was concerned that, at the same time, documents from these proposals were devoid of any discussion of the impact of the research on patient-subjects' quality of life, particularly in situations of terminal illness. He speculated that in their ultimate quest for finding cures, physician-investigators often paid more attention to increased longevity for present patient-subjects than to the quality of remaining life.

Patient-Subjects

To Katz, the ancient but questionable proposition that physicians and patients share an identity of interest in medical decision making becomes even more questionable in research settings where physician-investigators have dual allegiances: to their subject-patients and to their research objectives. As did those in the RPRP, Katz noted that consent forms for the troublesome proposals were often written in ways that made it difficult, if not impossible, for patient-subjects to come to a meaningful decision as to whether they wished to participate in research. Thus, patient-subjects seemed obliged to fall back on uninformed trust, based on a belief that physician-investigators will act only to ensure a patient-subject's therapeutic benefit.

Katz identified five specific problems with the informed consent process: (1) unclear purpose, (2) incomplete information regarding the consequences of participation in randomized studies, (3) confusing or incomplete discussion of risks, (4) exaggerated benefits, and (5) insufficiency of information in consent forms provided to IRBs. His concerns are elucidated below.

Specific Problems With the Informed Consent Process

Unclarity About Purpose

Katz found that the most striking element of the troublesome consent forms was the lack of a forthright and repeated acknowledgment that patient-subjects were invited to participate in human experimentation. All too quickly the language shifted to treatment and therapy when the latter was not the purpose and was only, at best, a by-product of the research. Like the other reviewers in the RPRP, Katz was particularly concerned with Phase I trials. As documented in some of the protocols in his examination, patient-subjects may suffer life-threatening toxicities that may, though rarely, kill them. Nevertheless, such studies are important for subsequent clinical trials and more widespread use in an attempt to save lives in the future. Katz's examination of consent forms revealed that investigators often did not take sufficient care to apprise patient-subjects of the purpose of Phase I studies. Although the dangers of the research are often mentioned, this information was often compromised when the "treatment" dimension of the research was emphasized. Katz concurred with a fellow Committee member who observed, through his participation in the RPRP, "Perhaps the consent form should not repeatedly emphasize that it is treatment, but I believe that it is the way it is perceived by the researchers themselves." Katz pointed out that the controversy over when, if ever, Phase I trials are to be regarded as potentially therapeutic has not been satisfactorily resolved with respect to the question: What must patient-subjects know? The President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research,[29]the adequacy and uniformity of the federal rules and policies for the protection of human subjects in biomedical and behavioral research, as well as the adequacy and uniformity of their implementation. when addressing Phase I trials, recommended that "patients not be misled about the likelihood (or remoteness) of any therapeutic benefit they might derive from such participation."[30] Katz's review of consent forms revealed that the Phase I purpose is often dismissed and the therapeutic benefits are highlighted. Thus, he was concerned that patient-subjects are likely to be confused about what is being asked of them.

The Consequences of Participation in Randomized Studies

A number of the troublesome proposals identified by Katz involved randomized clinical studies in which patient-subjects were assigned to two different experimental regimens to assess their comparative merits. These two procedures were generally described adequately in the consent forms. Patient-subjects, however, were generally not apprised of the already accumulated knowledge about possible therapeutic benefits to be derived from each regimen. Although protocols submitted to the IRB contained some, but often incomplete, information about the greater promise of one procedure over the other, patient-subjects rarely received such information.

In one protocol, for example, investigators clearly indicated that clinical experiences with the combined administration of chemotherapy and radiation had demonstrated its effectiveness against cancer. But since no scientific randomized clinical study had as yet been conducted, the investigators intended to submit half of the subjects to radiation alone. Consent forms provided no clues about what had already been learned from clinical experience and nonrandomized trials.

In another randomized trial, the research objective required that half of the patient-subjects submit to a mild treatment regimen, and the other half to a more intensive one. Katz noted that quality-of-life impairments imposed by random assignment to one research arm over another were not addressed in the consent forms. The consent forms also failed to address the fact that more intensive treatment regimens went counter to customary clinical practice of "watching and waiting," as the often slowly progressive nature of the cancers under investigation had led practitioners to recommend, in most cases, doing nothing or administering chemotherapy or radiation therapy only in low doses. Moreover, the risks inherent in both the mild and aggressive regimens were lumped together in the consent forms as if they were one and the same. The history of clinical experience with these particular cancers also was not discussed in the consent forms.

Discussion of Risks

The troublesome consent forms identified by Katz customarily listed an extremely detailed and separate discussion of all risks of the drugs, surgery, and/or radiation to be administered. Although he felt that federal regulations can be interpreted to require such detail, Katz, like the Advisory Committee as a whole, was concerned that such exhaustive treatment may serve only to overwhelm and numb patient-subjects. Only rarely were risks summarized or were risks of particular relevance to the research project highlighted. In almost none of the troublesome consent forms was there any comparative discussion of the impact on quality of life and toxic consequences of what investigators sometimes term total therapy (or of the physical and financial hardships imposed by countless research tests) on the one hand and of less toxic therapeutic alternatives that promise less but at least provide greater comfort for remaining life on the other.

For example, one study sought to explore the toxicity/efficacy of a new drug that may cause irreversible brain damage. That crucial piece of information, however, was not highlighted as a specific risk of the particular drug under investigation.

Another research project was designed to treat a cancer with a highly toxic drug, which had an expected mortality of up to 10 percent when used in a dosage greater than customary, as was contemplated in this "total therapy" research project. This fact, however, was not mentioned in the consent form. Although the patient-subjects had limited life expectancies, they probably would live longer than when a lethal drug toxicity would occur. Katz noted that another investigator simultaneously submitted the identical study to the same IRB (utilizing the same drug to combat the same disease), but with an exemplary protocol and consent form that discussed the expected 10 percent mortality rate without equivocation.

Presentation of Benefits

Like the RPRP reviewers, Katz found that benefits were often exaggerated in the troublesome consent forms. One consent form, for example, stated, "It is possible that the treatment [emphasis added] will cause the tumor to shrink or disappear or eliminate any symptoms and thus increas[e] life expectancy." Although this statement conveys a promise of benefit to the patient-subject, the protocol clearly indicates that any benefits would be fortuitous since they were neither an aspect of the research objective nor supported by evidence so far accumulated.

One consent form for a research project that was designed solely to establish the maximum tolerated dose of an intensive chemotherapy schedule stated, "It is not possible to predict whether or not any personal benefit will result from the use of the treatment program. A possible benefit could be the achievement of a remission." There was, however, no therapeutic intent in this proposal; physician-investigators were interested only in learning if it could be used safely in a subsequent randomized clinical trial. The subjects, however, could easily be led to believe that there was probable therapeutic benefit. Katz was particularly alarmed about the overstatement of benefits because patient-subjects so desperately long for such benefits.

Insufficiency of Information Provided to IRBs

In many cases, Katz found discrepancies between information provided in the protocol and that provided in the consent forms. This finding was not unlike that of the full Advisory Committee. Thus, an important question must be posed and eventually answered: Why was information that was available to IRBs not disclosed to patient-subjects?

According to the documents received, it seemed that even IRBs were often inadequately apprised of crucial information. In some cases, Katz noted that proposals were deficient in explicating the available knowledge about standard treatments, therapeutic effectiveness, and the impact of experimental procedures on quality of life. Although research is often a voyage into the unknown, investigators do possess preliminary guiding data that must be transmitted to IRBs. Only then can IRBs accurately evaluate consent forms and make certain that patient-subjects are provided with necessary information in order to make decisions about participation.

In one research project, for example, IRBs and, in turn, parents were insufficiently informed that the combination of radiation treatment and highly toxic chemotherapeutic agents used in the project exposed children to considerable risks that deserved careful scrutiny. The parents or guardians had two choices: to enroll their children in the study or to opt for standard treatments of either radiation or chemotherapy alone (depending also on the location of the cancer), with or without one of the chemotherapeutic agents that had considerable carcinogenic potential within five years. This example highlighted another, more general concern: that some patient-subjects may become part of inflexible research protocols when considerable clinical experience suggests that a patient-subject's medical condition may deserve an individualized treatment approach.