11
Summary of Patient Interviews
A total of 19 patients who received FIAU were interviewed over the telephone by the IOM committee study director. The focus of the interview was on issues of informed consent and attention to possible side effects. The subjects were drawn from the three studies testing FIAU in hepatitis B virus-positive subjects without concomitant HIV infection: the 28-day NIH study (R91), the aborted 6-month NIH study (PPPC), and the 3-month study in Galveston and Boston (PPPA) were terminated along with the NIH study. All five subjects enrolled in the PPPA trial were contacted by the principal investigators and were asked if they were willing to participate in a telephone interview for the IOM committee reviewing all of the FIAU trials. All agreed and consented to provision of their names and phone numbers to IOM, although they were given the option of calling the IOM study director if they preferred to remain anonymous. A similar procedure was followed with the NIH patients, except that the NIH Clinical Center's patient representative, rather than the principal investigators, made the initial contact with the patients. Since 10 of the 24 patients in the 28-day trial (R-91) subsequently became subjects in the 6-month trial (PPPC), and 5 of the 15 patients in the PPPC trial died, only 24 NIH patients were potentially available for interview (24 + 15 - 10 - 5). Of these, 15 indicated that they were willing to be interviewed, and 14 were successfully contacted and interviewed. Eight of these 14 participated only in the R91 trial, four were subjects in both the R91 and PPPC trials, and 2 participated only in the PPPC trial.
Although the numbers of patients from each study are far too small to allow any meaningful quantitative analysis, the committee felt that some firsthand information from the patients themselves was necessary to properly evaluate both the possibly self-serving accounts of the scientists and drug companies on the one hand and the often sensational media accounts charging or implying systematic negligence, indifference, or even willful misrepresentation on the other hand.
Several generalizations are in fact possible from an examination of the answers of the group as a whole to a few of the questions. For example, only 3 of the 19 subjects reported that their current health was worse than that before their exposure to FIAU. This is at least partially a result of bias in the sample. Five subjects died, of course, and it is quite possible that others who might have reported poor health declined to be interviewed for that reason or because of concern about pending legal action against the government and the drug companies. Nevertheless, all of those interviewed reported that they had been encouraged to read the ICD carefully and had done so. Some had been given a copy of the protocol as well. All of the subjects interviewed reported being fully aware that participation was entirely voluntary and
that they were free to withdraw at any time (although two subjects also reported that it was made clear that they were lucky to be accepted and should be very grateful; no one interviewed ever considered dropping out of the study). Surprising, only four subjects sought advice from another physician once they had the consent form or protocol in hand (all four were encouraged, to a greater or lesser degree, to sign the form).
All of the interview subjects reported that the study staff had been very attentive to their reports of side effects at every appointment, pointing out that they were always quizzed not only on the symptoms from a long written list but about any other changes in their health of any sort. When they reported new symptoms or increased severity of previously reported symptoms to nonphysician staff, the latter were quick to call in a physician. Four of the 19 patients (3 with current injuries they attribute to FIAU) interviewed reported that they would not consider volunteering for further drug trials with their previous investigators under any circumstances.
An important commonality among the six patients in the PPPC trial was their universal recall of discussion during the informed consent process about the death of one of the patients in the PPPC trial 4 months after completing FIAU therapy, following surgical removal of his gallbladder. Although the PPPC protocol discussed the death in some detail, along with the rationale behind the investigators' judgment that the death was not FIAU related, the ICD actually given to the subjects for signature contained none of this information. All of the subjects interviewed recalled being told about this patient, as well as another patient in the R91 trial who developed peripheral neuropathy some months after his course of FIAU treatment. All of them also recalled, in varying detail, that the investigators did not believe that FIAU was responsible for the death and that nerve conduction tests had been added to detect neuropathies. The Boston/Galveston (PPPA) trial, which began at roughly the same time as the PPPC trial, did not include such a discussion, and as a result one of the patients from that trial, who was otherwise quite satisfied with his treatment by the study staff expressed disappointment that he "didn't get full disclosure." As he put it, "Even if they thought it was irrelevant it should have been my call." This patient was one of the four who told the interviewer that they would not volunteer for another drug trial (in this subjects' case, ''anywhere'').
Perhaps the most important generalization that can be deduced from this small sample of 19 interviews is that the subject's reports of the informed consent process and their satisfaction with their treatment by the study staff are closely associated with their current health. The three subjects interviewed who reported currently suffering from peripheral neuropathy, although two were in the R91 trial and the other was in the PPPA trial, were insistent that the risk of side effects had been minimized in their discussion of the ICD. One reported being satisfied with the answers to his many questions at the time, but he now feels that significant pieces of information were withheld or denied; the second reports that his only question, directed at one of the associate principal investigators sometime after signing the ICD, earned him a scolding for his lack of faith. The third patient reported a painful neuropathy that developed, like that of the others, sometime after halting FIAU and complained of indifference or disbelief by the study staff (see chapter 7 above). Although NIH continued to provide evaluation and consultation to the patient's private physician (the patient had moved to the Far West in the interim), relations became increasingly adversarial. Difficulties initially centered upon the apparent reluctance or inability of NIH to provide for pain treatment, but
escalated sharply when the tragic events of the PPPC trial unfolded. The patient felt that the trial should never have been undertaken in view of his neuropathy and adverse effects noted in other patients during and after the previous trials. The doctor-patient relationship finally ruptured with the patient's very strongly worded testimony to this effect to the FDA Antiviral Advisory Committee in September of 1993 and a subsequent letter to him from Hoofnagle informing him that in view of those remarks he did not think it appropriate for NIH to continue providing medical care or advice. Upon appeal to the Acting Director of NIH the patient was extended a formal apology, assured that he would receive the same opportunities for assistance as other former trial participants, and given a new point of contact at NIH, the Clinical Director of NIDDK. He subsequently received a thorough clinical evaluation which included assays for FIAU in blood and urine (negative). He has declined to participate in a formal long-term study of FIAU patients at NIH.
The committee cannot and does not see it within its charge to make judgments on the veracity of every patient's complaint. Accordingly, the unhappiness of these three patients may be completely justifiable. The overall pattern of response by the interview subjects, however, suggests that the studies on the whole were characterized by good to excellent rapport between patients and staff, frank discussion of potential risks, close attention to signs of FIAU toxicity, prompt action when it seemed indicated (leaving aside the question of whether the investigators should have known more than they did about toxicity at the time), and a general feeling by the patients that although they would certainly never have volunteered for a study that they believed involved a serious risk of death or permanent injury, they felt that they had been informed to the best of the investigators' abilities and had been treated conscientiously throughout the trials.
