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12
Overall Assessment of the Trials

Although the committee has offered comments throughout the reviews of the individual trials, it will be useful to try to summarize the committee's overall impression of the conduct of these trials. In doing so the committee will return to the rules and norms for ethical research with human subjects described above in the section describing clinical trials.

PROCEDURAL REQUIREMENTS

The IOM Committee reviewed the various documents related to review and approval by the IRBs; it also interviewed the chairs of these committees. The IOM committee also reviewed the sample consent forms that were used in these studies. It is always possible to second-guess such documents, particularly the consent forms. It is rare that an IRB reviews a consent form that has already been reviewed and approved by another IRB without finding some way to improve it (Lipsett, Fletcher and Secundy, 1983). The IOM committee found these documents to be of generally very high quality.

In the opinion of the IOM committee, there were no clear departures from the requirements of relevant federal regulations. One omission detected by the IOM committee could be considered a possible deviation from the regulatory requirements, but members of the committee are uncertain about whether it should be so considered because earlier trials had not clearly established a cause-effect relationship between FIAU and peripheral neuropathy. The consent form for protocols PPPA and PPPG did not mention peripheral neuropathy or anything else that would enable a prospective subject to anticipate this adverse effect. It did mention muscle aches, but this does not suffice as disclosure of the possibility of peripheral neuropathy.

Both of these studies were initiated roughly contemporaneously with the 6-month PPPC trial at NIH, and the protocols were very likely written well after the PPPC protocol, which included not only a discussion of peripheral neuropathy, albeit somewhat atypical in its delayed onset in two patients who had participated in trial R91, but also included a provision for nerve conduction tests to help assess developing neuropathy.



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Review of the Fialuridine (FIAU) Clinical Trials 12 Overall Assessment of the Trials Although the committee has offered comments throughout the reviews of the individual trials, it will be useful to try to summarize the committee's overall impression of the conduct of these trials. In doing so the committee will return to the rules and norms for ethical research with human subjects described above in the section describing clinical trials. PROCEDURAL REQUIREMENTS The IOM Committee reviewed the various documents related to review and approval by the IRBs; it also interviewed the chairs of these committees. The IOM committee also reviewed the sample consent forms that were used in these studies. It is always possible to second-guess such documents, particularly the consent forms. It is rare that an IRB reviews a consent form that has already been reviewed and approved by another IRB without finding some way to improve it (Lipsett, Fletcher and Secundy, 1983). The IOM committee found these documents to be of generally very high quality. In the opinion of the IOM committee, there were no clear departures from the requirements of relevant federal regulations. One omission detected by the IOM committee could be considered a possible deviation from the regulatory requirements, but members of the committee are uncertain about whether it should be so considered because earlier trials had not clearly established a cause-effect relationship between FIAU and peripheral neuropathy. The consent form for protocols PPPA and PPPG did not mention peripheral neuropathy or anything else that would enable a prospective subject to anticipate this adverse effect. It did mention muscle aches, but this does not suffice as disclosure of the possibility of peripheral neuropathy. Both of these studies were initiated roughly contemporaneously with the 6-month PPPC trial at NIH, and the protocols were very likely written well after the PPPC protocol, which included not only a discussion of peripheral neuropathy, albeit somewhat atypical in its delayed onset in two patients who had participated in trial R91, but also included a provision for nerve conduction tests to help assess developing neuropathy.

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Review of the Fialuridine (FIAU) Clinical Trials SUBSTANTIVE NORMS The IOM Committee provides no comment in this section on compliance with the ethical norms calling for good research design and competence of investigators because these matters are discussed at length in other parts of this report. Favorable Balance of Harms and Benefits As discussed earlier, the ethical justification of research requires a determination that the balance of risks and anticipated benefits is—in the words of federal regulations—"favorable" or "reasonable." This determination, which must first be made by the investigators and then ratified by the IRB, must be accomplished at the outset, before the research is begun. These estimates of risk and anticipated benefits may turn out to be badly mistaken when the results are in, and all involved may regret doing the research, but the work should not be deemed unethical solely on that basis. In this case there were reasonable grounds for great optimism about FIAU. It often inhibited hepatitis B virus DNA replication very promptly and virtually completely; no other therapeutic agent that could accomplish this salutary objective so efficiently was (or is) known. Moreover, it was an easily administered oral medication, and there was no advance indication of any serious adverse events. In all research activities designed to evaluate a new drug, the initial estimation of risks must take into account the possibility of occurrence of novel injuries—harms that cannot be predicted on the basis of prior clinical or preclinical testing. Fortunately, injuries that are both serious and unanticipated are very unusual. In this case there occurred an injury that was both serious and unanticipated. This occurrence does not indicate that the research was ethically deficient. The IOM committee cannot—even in retrospect—suggest any tests that might have been done to anticipate this serious toxicity. Responsiveness to this norm also requires that there be careful monitoring of all events that have a bearing on the assessment of both risks and benefits. In this case there have been allegations that the monitoring of safety data may have been faulty and that findings of adverse events did not result in indicated changes either in the protocol or in the risk information divulged to subjects. On review of this matter, the IOM committee finds that the monitoring of such data was not merely adequate; when considered in the light of prevailing practices in the field, the monitoring activities of these research groups and the sponsors were exemplary. Interpretation of such data, particularly data indicating either damage to the liver or diminishing liver function, was not recognized promptly as indicating drug toxicity for at least three reasons. (1) Since the patients had chronic hepatitis some fluctuation in the results of liver function test results is expected as the activity of the disease waxes and wanes. (2) Some of the patients in whom changes in liver function tests were detected had other factors that could have contributed to such changes. (3) Some, although not all, experts believe that improvement in patients with chronic hepatitis is often heralded by flare responses during which laboratory test results that most commonly indicate damage to the liver (elevated serum aminotransferase) may be observed.

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Review of the Fialuridine (FIAU) Clinical Trials It should also be noticed that the PPPC trial (and the PPPA trial running concurrently in Boston and Galveston) was discontinued almost immediately after the sponsors and investigators became aware of the second instance of hepatic failure in a subject who had participated in the FIAU studies. Under the circumstances, this was a remarkably prompt response. Equitable Selection of Subjects These studies did not involve as subjects any members of the so-called special populations that have been identified in federal regulations or proposed regulations as requiring special protection. And yet, as discussed earlier, there are reasons to consider as vulnerable in relevant respects persons with serious and potentially disabling or deadly diseases. Such persons may not be "so situated as to be able to exercise free power of choice." The subjects of the FIAU studies can certainly be considered vulnerable in this regard. Ethical justification of the involvement of such persons requires determinations that the research goals are important and that they could not be realized with less vulnerable subjects and that the research is designed to develop knowledge or therapeutic products that (one reasonably expects) will be of benefit to the vulnerable class from which the subjects are recruited. Moreover, it is generally accepted that investigators should recruit subjects who have the capacity to consent for themselves before turning to those who cannot (Levine, 1986). These conditions seem to us to have been met by the studies under review. In consideration of the possibility that at least some of the subjects might have been relatively impoverished in that they would be unable to secure medical services of high quality without participation in these studies, there was a need to be especially careful to avoid offering "undue" material inducements in the form of cash payments. The IOM committee found no evidence of undue inducements. It must be acknowledged that the offering of excellent medical care and promising new therapies free of charge is a very substantial material inducement. Although many commentators in the field of medical ethics have identified and described the problems associated with this fact (Levine, 1986), the IOM committee is aware of none who have recommended a satisfactory resolution of these problems. It must be acknowledged that some persons with serious chronic diseases may enroll as research subjects as a consequence of desperation or in fear of retaliation for not cooperating. Investigators can respond to the fear of retaliation by informing prospective subjects of their right to refuse to participate or to withdraw at any time without the loss of any benefits to which they are otherwise entitled. Such advice is required by federal regulations and was provided to subjects of the FIAU studies. But, as noticed earlier, such information will not alleviate all fears of retaliation in all prospective subjects. The most constructive way that investigators can respond to the desperation and fears of some prospective subjects is to be sensitive to such feelings and to try to avoid exploiting those who experience them. The IOM committee, on the basis of its interviews with investigators, research nurses, and patients, found that most of them reported that the investigators were sensitive to such matters. This topic will be discussed in more detail in the section on informed consent.

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Review of the Fialuridine (FIAU) Clinical Trials In some respects, many of the subjects of these studies may be considered less vulnerable (more capable of informed consent) than typical subjects in early-phase drug trials in that many of them were experienced as research subjects, having previously served as subjects in other drug trials. Compensation for Research-Related Injury The consent documents for each of the protocols reviewed by the IOM committee were in compliance with the regulatory requirement to provide "an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained." There is no question that all possible steps were taken by the NIH investigators and Eli Lilly to insure that the patients injured in trial PPPC received whatever medical care was necessary. Eli Lilly in fact has spent over $2 million to date for services to these patients and their families. Obviously these efforts were largely in vain, and a number of victims or their families have turned to the legal system in search of compensation. As noted earlier in this report, several prestigious national advisory bodies have recommended to the federal government that it establish a no-fault system for compensation for injured research subjects. The IOM committee believes that the availability of such a system would have been very helpful in the aftermath of the FIAU studies. Among other things, it would have made possible an appropriate response to the just claims of injured patient-subjects and their families without the need for litigation with its attendant vexation, delay, and added financial burdens. Moreover, it would have made it unnecessary for the investigators and the patient-subjects who had grown accustomed to cooperation and mutual support in the pursuit of a common goal to become wary of one another and guarded in their communications as is customary in potential adversary proceedings. For these and other reasons, the IOM committee supports the development of a no-fault system of compensation for research-related injury. Informed Consent As noted earlier, the IOM committee found that the informed consent documents were of high quality and thoroughly responsive to the requirements of federal regulations. Now the report addresses the process of informed consent. The committee was presented with persuasive evidence that each of these investigators went beyond the requirements set forth by the IRBs. For one notable example, the IRB decided that it would not be necessary to divulge the fact that one subject had died following participation in an early trial of FIAU. The circumstances of that death were such that one could not state confidently that FIAU played any role in the unfortunate outcome. That point notwithstanding, investigators and subjects recalled that the investigators had, in fact, informed prospective subjects of that death and spoke candidly about their concern that it might be related to FIAU.

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Review of the Fialuridine (FIAU) Clinical Trials SUMMARY The overall impression of the IOM committee is that these trials were ethically sound clinical research projects designed and carried out by highly competent investigators who frequently went beyond the requirements dictated by regulations or imposed by IRBs to respond to the desires and needs of their patient-subjects. Indeed, with rare exceptions, their relationships with the patient-subjects appeared to have elements of the depth and sensitivity to which good primary care physicians aspire in their relationships with their patients.