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Executive Summary

INTRODUCTION

In June 1993 a clinical trial of a promising new medication for hepatitis B was abruptly terminated when one of the 15 out-patients participating in the National Institutes of Health (NIH) study was suddenly hospitalized with liver failure. Although all the remaining patients were contacted and told to stop taking their medication, six more developed severe toxicity in the next few weeks. Five patients died, and two others were probably saved from death only by liver transplantation.

All of these patients had been taking the experimental drug fialuridine (FIAU) for at least 9 weeks. During the first 8 weeks of therapy, patients had reported only relatively mild side effects—and the levels of hepatitis B virus (HBV) in their blood had dropped precipitously. After the 9-week mark, however, the severity of side effects increased; the dosage of FIAU was decreased in 4 patients and eventually discontinued in three. After thirteen weeks one of these patients, who had stopped taking FIAU 17 days earlier, was admitted to his local hospital with a failing liver, shock, and acidosis. At this point all patients still taking FIAU were told to stop taking it, but this did not prevent serious additional toxicity. In retrospect, we can identify the distinctive characteristics of this severe toxicity: hepatic (liver) failure, despite only mild jaundice and minimal changes in the aminotransferase measures which generally signal liver damage; severe and rapidly progressing accumulation of lactic acid in the blood (lactic acidosis); inflammation of the pancreas to varying degrees (pancreatitis); and a marked accumulation of fat within the cells of the liver (microvesicular steatosis). All seven patients also developed signs of myopathy and/or peripheral neuropathy (damage to the muscles or nerves in the arms and legs). More recent studies indicate that FIAU is incorporated into mitochondrial DNA in the liver and other tissues. In vitro work suggests this may be related to the toxicity seen in the NIH patients, but in vivo studies will be necessary to fully understand the mechanism. An animal model employing the woodchuck shows great promise in this regard.

The Secretary of the Department of Health and Human Services (DHHS) told Congress she would commission an objective and independent study by the National Research Council's Institute of Medicine (IOM), and in June of 1994 a contract for such a study was signed. In it the IOM was tasked to assemble a committee of experts in a variety of fields (clinical research, pharmacology, toxicology, and medical ethics as well as hepatology) to perform a thorough analysis of all the FIAU clinical trials, as well as those of FIAC (a related compound, rapidly converted to FIAU in the human body). The group was to focus on whether any rules



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Review of the Fialuridine (FIAU) Clinical Trials Executive Summary INTRODUCTION In June 1993 a clinical trial of a promising new medication for hepatitis B was abruptly terminated when one of the 15 out-patients participating in the National Institutes of Health (NIH) study was suddenly hospitalized with liver failure. Although all the remaining patients were contacted and told to stop taking their medication, six more developed severe toxicity in the next few weeks. Five patients died, and two others were probably saved from death only by liver transplantation. All of these patients had been taking the experimental drug fialuridine (FIAU) for at least 9 weeks. During the first 8 weeks of therapy, patients had reported only relatively mild side effects—and the levels of hepatitis B virus (HBV) in their blood had dropped precipitously. After the 9-week mark, however, the severity of side effects increased; the dosage of FIAU was decreased in 4 patients and eventually discontinued in three. After thirteen weeks one of these patients, who had stopped taking FIAU 17 days earlier, was admitted to his local hospital with a failing liver, shock, and acidosis. At this point all patients still taking FIAU were told to stop taking it, but this did not prevent serious additional toxicity. In retrospect, we can identify the distinctive characteristics of this severe toxicity: hepatic (liver) failure, despite only mild jaundice and minimal changes in the aminotransferase measures which generally signal liver damage; severe and rapidly progressing accumulation of lactic acid in the blood (lactic acidosis); inflammation of the pancreas to varying degrees (pancreatitis); and a marked accumulation of fat within the cells of the liver (microvesicular steatosis). All seven patients also developed signs of myopathy and/or peripheral neuropathy (damage to the muscles or nerves in the arms and legs). More recent studies indicate that FIAU is incorporated into mitochondrial DNA in the liver and other tissues. In vitro work suggests this may be related to the toxicity seen in the NIH patients, but in vivo studies will be necessary to fully understand the mechanism. An animal model employing the woodchuck shows great promise in this regard. The Secretary of the Department of Health and Human Services (DHHS) told Congress she would commission an objective and independent study by the National Research Council's Institute of Medicine (IOM), and in June of 1994 a contract for such a study was signed. In it the IOM was tasked to assemble a committee of experts in a variety of fields (clinical research, pharmacology, toxicology, and medical ethics as well as hepatology) to perform a thorough analysis of all the FIAU clinical trials, as well as those of FIAC (a related compound, rapidly converted to FIAU in the human body). The group was to focus on whether any rules

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Review of the Fialuridine (FIAU) Clinical Trials or procedures governing the clinical trials process need to be changed, and what burdens or costs such changes might place on future clinical trials. CLINICAL TRIALS Clinical trials are of vital importance in the development of new drugs for use in humans. Preliminary animal experimentation is important in identifying potentially effective interventions in animal models with simulated human diseases and in identifying efficacious and non-toxic amounts of a pharmaceutical to be given. However, no amount of animal testing can substitute for carefully planned and carefully conducted human studies. The process is a lengthy one (4-7 years) and one which involves many study subjects. One of the things that sets clinical trials apart from other scientific experiments is the obligation for care. Investigators undertaking them have obligations to ensure that patients enrolled are adequately cared for, even if doing so conflicts with or is at odds with required data collection and treatment procedures, as set forth in the protocol for the trial. Evaluation of the treatment is relatively straight forward in randomized controlled trials involving comparison of one or more test treatments vs a control treatment (a placebo, standard medical treatment, or another test treatment). Judging the safety or efficacy of a treatment is much more problematic in the case of trials not involving a designed comparison group often the case in early evaluations of a new drug. In those settings, one is often left in a quandary as to what to make of isolated cases of morbidity indicated by observed clinical events or intimated by changes in specified laboratory tests. Are the changes due to the disease itself or to the drug? Ethical justification of research involving human subjects requires responsiveness to ethical norms or rules that are embodied in six general behavior-prescribing statements: there should be 1) good research design, 2) competent investigators, 3) a favorable balance of harms and benefits, 4) informed consent, 5) equitable selection of subjects, and 6) in some ethical codes but not in US federal regulations, compensation for research-induced injury. In addition to these six substantive norms there are various procedural rules designed to ensure responsiveness to the substantive rules. Most important for the present considerations are: there should be 1) review and approval by an institutional review board and 2) written documentation of informed consent. HEPATITIS B AND OTHER VIRAL DISEASES Viruses, composed of DNA or RNA inside a protein shell or ''envelope'', include the influenza virus that causes the common "flu," the human immunodeficiency virus (HIV) responsible for AIDS, and the hepatitis B virus (HBV) resulting in a hepatitis infection with variable symptoms. With acute HBV infection patients are frequently fatigued, jaundiced, and complain of abdominal pain. The vast majority of 300,000 persons infected with HBV each year in the U.S. recover completely and only about five percent of infected adults develop chronic liver disease. Although such disease often results in only minor complaints of fatigue,

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Review of the Fialuridine (FIAU) Clinical Trials joint pains, poor appetite and abdominal pain, chronic infection results in scarring of the liver (with consequent impairment of flow of blood through the liver, back-pressure into the veins of the intestine and an increased propensity for life-threatening bleeding episodes). Other complications include retention of fluid in the abdomen (ascites), increased susceptibility to life-threatening bacterial infections, and mental confusion (encephalopathy). Once these complications occur, the life expectancy of the patient is very limited, and liver transplantation the only therapeutic option. HBV infection has also been linked epidemiologically to the development of liver cancer; in males with perinatally acquired infection, life-long risk of development of hepatocellular carcinoma is 40 to 60 percent. An important feature of chronic HBV infection involves the spontaneous loss of viral replication seen in 2.5 to 25% of patients. Viral clearance is believed to be immune-mediated and is frequently associated with a transient rise in serum aminotransferases (AST, aspartate aminotransferase, and ALT, alanine aminotransferase, enzymes present in liver cells whose appearance in quantity in blood is generally taken to indicate liver damage). This enzyme increase, or so-called "flare" phenomenon, is also seen in patients with a positive response to interferon therapy. It may thus be difficult to distinguish, on the basis of aminotransferase alone, drug-induced hepatotoxicity from a positive response to antiviral therapy. Indeed, because of this flare phenomenon it is easy to understand why investigators like those conducting the FIAU trials might well have been encouraged by a rise in liver enzymes that in other circumstances would have been cause for alarm. Successful treatment of chronic HBV infection has been limited. Interferon effectively inhibits viral replication in only one third of patients, it must be given by injection, and it is associated with significant toxic effects. Approaches to treatment of viral diseases have generally been either to stimulate the natural host defenses against infection with drugs like interferon or to inhibit the way viruses divide and multiply with nucleoside analogs, molecules which are similar to the building blocks of deoxyribonucleic acid, DNA, and which become incorporated into the viral DNA as the virus divides, inhibiting and interrupting this replicative machinery. Zidovudine (AZT), the commonly used treatment of HIV infection, is an example of this second approach. FIAU was another. EARLY CLINICAL TRIALS OF FIAC AT MEMORIAL SLOAN-KETTERING CANCER CENTER Although the toxic effects that led to the formation of this IOM committee were related to the administration of the drug fialuridine (FIAU), our review begins with studies of the parent drug fiacitabine (FIAC) which is metabolized to FIAU. FIAC is a pyrimidine nucleoside analog synthesized by Fox and his colleagues at Memorial Sloan-Kettering Cancer Center (MSKC) in the 1970s. It was found to be highly active, in vitro, against several of the clinically important human herpes viruses and shortly thereafter against hepadnaviruses, inhibiting, in its triphosphate form, the DNA polymerases of human and woodchuck hepatitis viruses. It was studied at MSKC in the early 1980s in the treatment of herpes simplex virus (HSV), varicella-zoster virus (VZV), and cytomegalovirus (CMV). These early trials of FIAC were carried out to a large extent in seriously ill patients suffering from underlying neoplastic

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Review of the Fialuridine (FIAU) Clinical Trials disease or immunosuppressive conditions. These pathogens are frequent and often serious complications in such patients. FIAC had a beneficial effect in treatment of VZV infections. Its efficacy against CMV was unclear because of the uncertainty of the diagnosis in many patients and the steady downhill course of many of the seriously ill patients. Toxicity appeared to be manifest primarily as hematopoietic suppression, i.e., depressed white blood cell and platelet counts. Whether FIAC may have contributed to any of the many deaths in that study is uncertain from the available information; the underlying disease with disseminated superimposed infections in these very ill patients seems likely to have been the main factor. Since dosing was only for short periods in these trials, the potential for toxicity with long term use would not have been discernible. Further clinical trials of FIAC were not carried out at the time, probably because of the emergence of an effective, relatively non-toxic nucleoside analog (acyclovir) for the treatment of HSV and VZV infections. Thus, the return to clinical study of FIAC in 1989 under the sponsorship of Oclassen Pharmaceuticals seems to have been reasonable in view of the drug's in vitro activity against CMV (an important viral infection in patients with HIV infection and for which there still was need of effective oral treatment). OCLASSEN CLINICAL TRIAL R89-001-01 This evaluation of the effects of FIAC for treatment of CMV infection in HIV-positive individuals was developed by Oclassen Pharmaceuticals in conjunction with the AIDS Clinical Trials Group (ACTG) of the National Institutes of Allergy and Infectious Diseases (NIAID). CMV is the most common infectious pathogen in HIV-positive patients, with the most frequent manifestation, chorioretinitis, occurring in 25-30 percent of HIV-positive patients. Other clinical manifestations include fever, malaise, arthralgias, pancytopenia, hepatitis, pneumonitis, and gastrointestinal ulcerations. Disseminated CMV disease is rare (less than 5 percent of CMV infections), but when it occurs it is usually fatal. The need to identify an effective oral drug to treat CMV disease in this patient population was one of the most important scientific priorities of the ACTG. This trial was conducted at two sites, the University of California at San Diego (Principal Investigator, Douglas D. Richman), and the University of Washington in Seattle (PI, Lawrence Corey). Both are established investigators with extensive experience in the study of antiviral agents in the treatment of other herpes virus infections as well as HIV. Trial R89 was a Phase I/II clinical trial designed to evaluate, simultaneously, the safety and relative anti-CMV activity of FIAC at doses roughly equivalent to the doses the MSKC found effective against VZV. Patients were HIV-infected, had CD4 counts of 500 cells/mm3 or less, and documented CMV in either their blood or urine. Therapy was limited to 4 weeks, because data from animal toxicity tests of more than 90 days duration were not available, but patients were followed for a total of 3 months. Gastrointestinal side effects, predominantly nausea and fatigue, were noted in the first dozen study patients, with no demonstrable anti-CMV effect, so the study team recommended discontinuation of the development of FIAC as an anti-CMV drug, and the study was stopped.

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Review of the Fialuridine (FIAU) Clinical Trials Because some later analyses of the FIAU tragedy put great emphasis on the post-trial deaths of patients from the early trials, including this one, the committee paid particular attention to the four participants in this study who died within six months of the termination of FIAC. Three clearly died of HIV-related complications not involving the liver. The fourth patient, 107, suffered liver failure and died 11 weeks after his last dose of FIAC. The 1993 FDA Task Force Report classifies this case as one in which FIAC should be considered a possible cause of death. The committee judged the trial well designed and conducted. In the case of one patient who died with liver failure 11 weeks after his last FIAC, the committee believes that even in retrospect the confounding variables of CMV infection, hepatitis B infection and continuing treatment of HIV with AZT clearly preclude unequivocal classification of the death as FIAC-related. OCLASSEN CLINICAL TRIAL R90-001-01 This study, the first involving FIAU, the primary metabolite of FIAC, grew out of the hope that it was responsible for the strong in vitro anti-CMV activity of both compounds, but would not produce the dose-limiting toxicity of FIAC seen in the R89 trial. Richman and Corey planned a traditional Phase I, dose-escalating study of FIAU with the emphasis on safety. During protocol development, several reviewers suggested evaluating the potential role of FIAU in the treatment of hepatitis B virus (HBV) infection, so an amendment was created which allowed investigators to enroll HBV infected patients after an initial cohort of non-HBV infected individuals had been enrolled. As in the previous trial (R89) there was no evidence of anti-CMV activity even at doses associated with clinically significant gastrointestinal symptoms. The team then turned to patients coinfected with HIV and HBV. A new co-investigator and site, Stephen Straus of the National Institute of Allergy and Infectious Diseases, were recruited for this phase of the study. Like Richman and Corey, Straus had been integrally involved in the development of drugs designed to treat human herpes virus infections, such as vidarabine and acyclovir. Striking reductions in circulating hepatitis B DNA were noted in most patients, with the majority of patients showing decreases in their circulating HBV DNA values to less than the lower limits of the measurement technology. More importantly, the level of virus remained suppressed for up to 4 to 6 weeks after the drug was discontinued. The experience with other nucleoside analogs had resulted in only a partial reduction of circulating HBV and rapid reversal upon cessation of the drug. Thus, FIAU represented the most potent anti-HBV agent studied to date. Several patients in the R90 study developed significant elevations in liver function enzyme levels while on treatment. Based on the dramatic fall in HBV DNA and the frequent observation of a "flare" in transaminases associated with successful treatment of hepatitis B, the investigators judged the elevations not to be "serious or unexpected adverse events," but indications of successful therapy. The very modest elevations in the enzymes of the non-HBV patients were consistent with this interpretation. Nevertheless, three patients died within 6 months of receiving FIAU. All three had received a second 14-day course of FIAU treatment

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Review of the Fialuridine (FIAU) Clinical Trials when their HBV DNA levels recovered from the decreases associated with their initial FIAU therapy. One patient died of pancreatitis and two suffered liver failure, but in each case severe underlying disease and/or other more recent medications led the investigators to attribute the two deaths they were told about to causes other than FIAU toxicity. The committee concluded that this was a carefully performed study which underwent extensive internal and external review, employed a novel real-time data monitoring system and produced convincing evidence of anti-HBV activity at doses of FIAU producing few adverse effects. Although the deaths of three of the four patients receiving two courses of FIAU treatment caused the committee concern, we concluded that even in retrospect underlying disease and/or more recent medications were more plausible causes of death than FIAU toxicity in each case. OCLASSEN CLINICAL TRIAL R-91-010 The encouraging findings in the R90 study generated plans for instituting an evaluation of more prolonged administration of FIAU. This study was conducted solely at the NIH Clinical Center with Dr. Jay Hoofnagle as the Principal Investigator. Dr. Hoofnagle is a gastroenterologist and hepatologist who is Director of the Division of Digestive Diseases and Nutrition at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the NIH. He was the Principal Investigator on the major studies that established the therapeutic benefit of interferon in patients with chronic active hepatitis B. It was the opinion of both Hoofnagle and Straus that ultimate control of hepatitis B virus disease would require some degree of prolonged chronic suppression for durable effect. The standard treatment regimen for the only approved drug therapy, interferon, for example, calls for 16 weeks of subcutaneous injections. Therefore, this study was initially designed to evaluate several low doses of FIAU which would be administered over a prolonged period. Duration of therapy was ultimately limited to 28 days because there was only limited animal toxicity data to support longer term courses of treatment. Fatigue, nausea, skin rash, bone marrow suppression, seizures, and "pains in the arms and legs due to irritation of the nerves or the muscles" were all described as potential side effects in the informed consent document. The first patient was dosed in April, 1992 and by February 1993, all 24 subjects had completed therapy and the 6-month followup stipulated by the protocol. Hepatitis B virus DNA was suppressed 70 to 95 percent in the three highest dosing groups and to a lesser degree in the lowest dose group. Side effects during therapy were mild and transient. No patients developed side effects severe enough to modify dose or interrupt therapy. A total of 9 patients became HBV DNA negative, and AST/ALT "flares" were noted in 8. However, a year later, 6 of the 9 patients showed evidence of circulating HBV DNA. Several patients in the R91 study experienced significant health problems in the months following their participation in the R91 trial. In each case, a long delay between FIAU and symptom development, preexisting problems and/or inconclusive lab results led the investigators to assign causes other than FIAU. This determination of cause of death was clearly most difficult in the case of patient 4D, a 59-year-old man who died 4 months after completion of his 28-day FIAU therapy. Although interpretation was complicated by an

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Review of the Fialuridine (FIAU) Clinical Trials intervening cholecystectomy, it is now apparent that this patient's experience was very similar to that later seen in the victims of FIAU toxicity in the subsequent six-month trial (H3X-MC-PPPC, or simply PPPC) with systemic lactic acidosis, pancreatitis, and hepatic steatosis. The investigators discussed this death extensively with the sponsor, the NIDDK institutional review board (IRB), NIH Senior Staff, pathologists at the Armed Forces Institute of Pathology, and the FDA before initiating further study of FIAU in trial PPPC. In fact, their acute awareness of the peculiar nature of this patient's presentation was no doubt responsible for their rapid termination of that trial when a patient presented with a similar syndrome on June 26, 1993. In conclusion, the committee believes this study clearly established FIAU as promising treatment for chronic HBV infection. Although the antiviral effect was most often temporary, the relative absence of serious toxicity during treatment suggested that longer treatment would be possible. Post-treatment health problems in several patients were again difficult to interpret in the context of underlying disease, preexisting conditions, other medication, and long intervals since FIAU therapy. With our current knowledge of FIAU toxicity we can now identify patient 4D in this trial as the first unequivocal FIAU death, but we note that the investigators were suspicious at the time and in our view acted appropriately in incorporating that suspicion into the planning and conduct of the subsequent trial. ELI LILLY CLINICAL TRIAL H3X-MC-PPPA This study, one of three begun in late winter or early spring of 1993, was sponsored by Eli Lilly and Company, which entered into a licensing agreement with Oclassen in August of 1992 and assumed responsibility for further development of FIAU. A straightforward followup to trial R91, the study plan called for subjects to receive the drug two or three times per day for 90 days. Patients were entered at 2 study centers: University of Texas Galveston (PI, David Paar) and Tufts New England Medical Center Hospital (PI, Marshall Kaplan). A total of only 5 patients received FIAU before the trial was discontinued promptly upon receipt of information concerning adverse events in subjects in the H3X-MC-PPPC trial at NIH. The 3 patients in the clinical trial at Galveston took FIAU for periods of 16, 19, and 43 days. The committee feels that no toxicity clearly attributable to FIAU occurred in these 3 patients. At the New England Medical Center Site FIAU was administered to a total of only two patients, for periods of 28 and 55 days. One patient noted leg pain and numbness beginning 3-4 months after stopping FIAU therapy. Evidence of a primary sensory neuropathy was found on neurological consultation, and electrophysiologic studies were confirmatory. The committee feels that although this patient may possibly have been predisposed by virtue of his prior history of alcohol abuse, his documented peripheral neuropathy should be considered a neurotoxic effect of FIAU. ELI LILLY TRIAL H3X-LC-PPPG This study, conducted at the Lilly Laboratory for Clinical Research (PI, David Hyslop) in Indianapolis in March and April of 1993, was the only one of those reviewed by this

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Review of the Fialuridine (FIAU) Clinical Trials committee which utilized normal healthy subjects rather than patients infected with HIV and/or HBV. It was also the only one which kept the subjects on-site all day every day during the study. The primary objectives were to determine the relative bioequivalence of a syrup formulation and two tablet formulations of FIAU, and to determine the pharmacokinetic profile of each (i.e. how much of the dose is absorbed, how fast, how quickly is it eliminated, and in what form). Sixteen subjects each received five doses of FIAU, separated by 3 to 7 day intervals. The study ultimately utilized a newly developed radioimmunoassay (RIA) highly specific for FIAU and far more sensitive than the high-performance liquid chromatography (HPLC) assay that had previously indicated a half-life of 1-4 hours for FIAU. The RIA technique was not perfected until mid-June however, so blood and urine samples from this trial were simply frozen for later analysis. Pharmacokinetic measurements performed on blood and urine samples after the RIA was validated in June revealed more rapid absorption of FIAU in syrup than in tablet form, with food generally decreasing the rate of absorption, and a prolonged elimination phase with a terminal half-life of 28-30 hours. Adverse events noted included diarrhea, headache, transient myalgia, and in two cases, transaminase elevations. Although both subjects with these elevations were asymptomatic, dosing was discontinued for one (subject 1203) after his serum ALT quadrupled and his AST tripled after the second dose. This subject was encouraged to stay at the lab despite being dropped from his dosage group, while the investigators worked him up for hepatitis and other possible causes of his ALT/AST elevations, which continued to rise to peaks of 137 and 60 respectively a week after his last dose of FIAU. His transaminase levels returned to baseline 5 weeks after his second and last dose of FIAU. The second subject (subject 508), also asymptomatic, showed 3-5 fold increases in ALT and AST after dose 2 as well, but levels of both enzymes decreased on each of the following three days and the subject was continued in the study. AST and ALT measures gradually returned to baseline despite 3 additional 5 mg doses of FIAU. Since neither of these subjects was infected with hepatitis B, there is no possibility that these rises were "flares" associated with the destruction of infected hepatocytes, a fact given great importance by some critics, who argue that these data should have been sufficient grounds for Lilly to stop not just these patients but all ongoing clinical trials with FIAU, including the PPPC trial at NIH. At the time, however, several pieces of information were available which argued against such an action. The total dose received by each subject, 10 mg, was minuscule compared to the doses apparently well tolerated by the presumably less robust patients in previous trials, whose total doses ranged from 100 to more than 1000 mg. Perhaps more importantly, neither subject with elevated liver enzymes had any clinical signs or symptoms. We believe it would be a mistake to eliminate clinical judgement from clinical trials, and in this case we believe that dropping subject 1203 from the trial while continuing to observe him carefully was appropriate and sufficient. Similarly, had the revised estimate of FIAU half life been available to the NIH researchers earlier they may have been more wary of the drug accumulating in tissue, but in the absence of any clinical indications it is difficult to imagine halting an apparently successful therapy solely on this basis.

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Review of the Fialuridine (FIAU) Clinical Trials ELI LILLY TRIAL H3X-MC-PPPC (NIH PROTOCOL #93-DK-0031) This study was conducted at the Liver Diseases Section of the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) at NIH. Principal Investigator was Dr. Jay Hoofnagle. In the previous trial (R91) 4 weeks of FIAU therapy was shown to inhibit HBV replication strongly and consistently, but this inhibition was transient. The rationale for this new trial (PPPC), an open-label, randomized study of FIAU with two treatment groups (0.10 and 0.25 mg/kg/day), was that treatment for 24 weeks would result in short-term inhibition of viral replication, normalization of serum aminotransferases, and potentially long-term viral remission. Eleven patients previously treated with FIAU in R91-010 met all entry criteria, and were quickly enrolled. Four patients who had never received FIAU were enrolled two months later. Review of the informed consent document by the IOM committee found that it was written clearly in language understandable to the layman and was not misleading in minimizing potential side effects of FIAU. After discussion with the NIDDK IRB, death was not included as a possible adverse event in the consent form itself since at that date the death of patient 4D from the R91 trial was not attributed to FIAU. Nevertheless, patients were informed verbally of the possibility of death, and that the death of patient 4D could have been FIAU-related. In early June 1993, it became apparent that the ten patients who had been started on FIAU in late March and April were having increasing side effects (mainly nausea, vomiting, diarrhea and abdominal cramps). HBV DNA levels had decreased in all patients and six of ten patients had become HBV DNA negative, but by mid-June three patients were no longer receiving drug because of side effects. When one of these three developed lactic acidosis, hepatic failure and renal failure on June 25th, prior experience with a single puzzling patient from trial R91 (patient 4D) made the investigators consider FIAU a likely cause. The trial was halted on June 26th and all fifteen patients were seen within a few days at the NIH. Seven of the ten patients who had received more than 2 months of FIAU had evidence of FIAU toxicity (lactic acidosis, hepatic failure, pancreatitis, neuropathy and/or myopathy). Despite stopping drug, seven patients had progressive hepatic failure and were transferred to other hospitals for possible liver transplantation. Although the outcome was tragic, after careful study the IOM committee believes that there was sufficient justification for initiating the PPPC trial, that the protocol and consent form were appropriate, and that the conduct of the trial was equal to or above prevailing standards of care. There is no evidence that there was information available at the initiation of PPPC or at any time during the trial itself that would have or should have reasonably been interpreted to have averted the ultimate disaster. PATIENT INTERVIEWS A total of 19 FIAU patients were interviewed over the telephone on issues of informed consent and attention to possible side effects. The subjects were drawn from the three studies testing FIAU in HBV positive subjects without concomitant HIV infection: the 28-day NIH

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Review of the Fialuridine (FIAU) Clinical Trials trial (R-91), the aborted 6-month NIH trial (PPPC), and the 3-month Galveston/Boston trial (PPPA) terminated along with the NIH study. Perhaps the most important generalization that can be drawn is that the patients' reports of the informed consent process and their satisfaction with their treatment by the study staff are closely associated with their current health. The 3 subjects interviewed who reported currently suffering from peripheral neuropathy, two of whom were in the R-91 trial and the other in PPPA, all felt that the risk of side effects had been minimized in their discussion of the informed consent documents. The pattern of response by the rest of our interview subjects suggests that the studies on the whole were characterized by good to excellent rapport between patient and staff, frank discussion of potential risks, close attention to signs of FIAU toxicity, prompt action when it seemed indicated, and a general feeling by the patients that they had been informed to the best of the investigators' abilities and treated conscientiously throughout. OVERALL ASSESSMENT OF THE TRIALS The overall impression of the IOM committee is that the entire series of trials reviewed was an ethically sound clinical research project 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. REVIEW OF THE FDA TASK FORCE REPORT In November, 1993, the Food and Drug Administration (FDA) released a retrospective assessment of three FIAU and FIAC trials by a 3-member internal task force formed "to determine what data and what analyses of data were available to sponsors and the FDA at the start of the H3X-MC-PPPC study, and whether improvement in the rules governing design, analysis and reporting of data from clinical trials is warranted." The report evaluated preclinical animal studies and three clinical trials (R89, R90, and R91) for information suggestive of hepatic or pancreatic toxicity comparable to that observed in trial PPPC. The IOM committee has serious reservations about the Task Force approaches to both the laboratory data and the clinical events. In summary, we believe the suggested "worst-case" attribution of all possibly adverse laboratory findings and adverse hepatic and pancreatic clinical events to FIAC or FIAU inappropriately ignores other potentially important information. The FDA Task Force made a series of recommendations on a) clinical design and execution; b) reporting requirements; c) FDA record-keeping; and d) further review of FIAU toxicity. These recommendations have since become the basis for a number of proposed changes to the Code of Federal Regulations (CFR) governing the IND process. The IOM committee agrees in principle with nearly all of the recommendations, although we note that many of the practices they would promote were in fact observed in the FIAU trials and others are likely to make very small contributions to trial safety if they can be implemented at all. We disagree strongly with the Task Force call for worst-case analyses; i.e. assuming that all

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Review of the Fialuridine (FIAU) Clinical Trials adverse health events in trial patients, and more importantly in former trial patients, are drug-related. REVIEW OF THE NIH REPORT In April 1994, a seven-member subcommittee of the [NIH] Director's Advisory Committee issued a report on their review of FIAU studies conducted at NIH. The IOM committee agrees with the NIH subcommittee that there was a strong, justifiable, scientific, rational argument for evaluating FIAU for the therapy of hepatitis B. We agree as well with the conclusions of their review of the preclinical toxicology data that the range and duration of testing was appropriate for the proposed studies and that there was no prior evidence to suggest hepatic or pancreatic toxicity. Like the IOM committee, the NIH subcommittee found no evidence that important data were ignored or overlooked in planning for the PPPC trial, nor did they find any evidence to suggest that pressure for fast-track development was a contributing factor to the untoward events of that trial. The subcommittee was satisfied that the two IRBs involved had provided comprehensive, thoughtful and rigorous reviews and were in compliance with the NIH and federal regulations. The subcommittee was also satisfied that patients provided full, informed consent and were impressed by the teamwork between investigators and staff. The IOM committee concurs with these judgments as well as with the favorable review of the NIH subcommittee on the generally high quality of patient care provided during and after the FIAU trials. FDA-PROPOSED CHANGES TO THE CODE OF FEDERAL REGULATIONS The FDA has recently issued a series of proposed changes to existing regulations regarding adverse experience reporting. The proposed changes related to INDs are largely derived from and closely follow the recommendations of the FDA Task Force report. We question the wisdom of some of the observations and recommendations contained in the FDA Task Force Report in this report, but there are also elements of the proposed changes that we endorse on general principle. Foremost among them are the desirability of formal ongoing monitoring and use of designed comparison groups in all stages of testing, starting with Phase I and II trials. We believe that investigators need to abandon the case report form of data collection and plan for real-time monitoring of trials, regardless of size, sponsor, or funding source, preferably in the form of some independent person or group. This is obviously no panacea, since the FIAU studies reviewed here all had formal or informal real-time monitoring systems as well as the mandated case report forms, but it is a change that would help insure that all investigators will be as alert to developing problems as these were. The use of controls and randomization is also suggested as highly desirable. Although we concur, we are under no illusions as to the power of small trials like the ones reviewed here to detect drug-induced toxicity. Most adverse effects caused by treatments will go undetected

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Review of the Fialuridine (FIAU) Clinical Trials in the typical Phase I or II trial involving 20 to 40 patients and treatment and followup over a short time period. We also endorse the concept of longer followup on its general merit, but it is difficult enough to determine whether or not morbid or fatal events are treatment related when they occur while patients are under direct observation and being managed according to a specified protocol. Interpretation of such data becomes profoundly more problematic when the events occur long after treatment ends. The FDA also recommends requiring pre-trial estimates of expected mortality in the patient populations from which the subjects are to be drawn and combined with information from related trials. We tested the likely efficacy of these suggestions by conducting a statistical analysis of available information from the FIAC/FIAU trials of 1989-93. We investigated a range of underlying mortality rates for the analyses (from 10 to 20 percent per year for the HIV patients in the R89 and R90 trials and from 2 to 4 percent per year for the HBV patients in R91 and PPPC). The number of deaths ''expected'' in each group of patients was calculated and compared to the number of deaths actually observed. The only trial that produced any convincing statistical evidence of drug toxicity is PPPC and all of the deaths in that trial occurred after the investigators had already stopped the trial based on morbidity. To summarize, it is unlikely that the FDA-recommended procedures of estimating expected deaths and following up for 6 months would have resulted in cancellation of trial PPPC. In regard to the proposed changes requiring a marked increase in safety reporting, we remain skeptical that the benefits from such added efforts will outweigh the increased expense, added time for drug development, delays in access for general use, and so called type II errors—abandoning work on a drug because it is believed to be ineffective or harmful when, in fact, with further testing and development it would have been shown to be both effective and safe. ANCILLARY ISSUES Although the committee's focus throughout this review has been on reducing as far as possible the chance of a tragedy like that of trial PPPC ever occurring again in the course of a clinical drug trial, several ancillary issues came to our attention in the course of the review, clearly very secondary in importance to the principal, unfortunate events that form the basis of this report, but bearing directly on regulatory control of clinical trials. Foremost among these were the "warning letters" sent to investigators and sponsors by the FDA in May of 1994. The committee analyzes some misunderstandings surrounding these letters and offers some suggestions on improving the process. CONCLUSIONS On review of the FIAU trials, the IOM committee finds no evidence of negligence or carelessness on the part of the investigators or sponsors. The committee is not aware of any preclinical tests available prior to the outcome of this trial that could have been done to

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Review of the Fialuridine (FIAU) Clinical Trials anticipate this unfortunate event. We would nevertheless urge the readers of this report to put this tragedy in a proper perspective as a distinctly rare occurrence, related to a previously unrecognized form of late drug toxicity, in a field with an otherwise exemplary safety record. On the basis of its review of the FIAU studies, the IOM committee will make some recommendations on the future conduct of early phase drug trials. Although the IOM committee's recommendations are focused on Phase I and Phase II trials, they do not stem from perceived deficiencies in the conduct of the investigators or sponsors in the FIAU studies; as already noted, none were identified. The IOM committee believes that implementation of its recommendations may reduce the already very low probability of occurrence of toxicity of the sort there was in the fialuridine studies, particularly when studying drugs that are similar to fialuridine in structure or action. In many instances the effect will be to insure the continued and consistent use of procedures and practices employed in the FIAU trials reviewed here. RECOMMENDATIONS Generic Issues Proceed cautiously in revision of the current drug development system. The current system has evolved checks and balances that have benefited new drug development and patient safety, and no single component can undergo a major revision without endangering the system as a whole. The committee is doubtful that any of the changes reviewed above and/or proposed below, had they been in effect prior to the initiation of the FIAC/FIAU trials reviewed here, would have substantially altered the tragic outcome. All clinical researchers engaged in trials should be exposed to explicit training not only on the design and conduct of clinical trials and their ethical obligations to patients but also on their legal and regulatory obligations to both the sponsor and the FDA. We urge the establishment of a system of no-fault compensation for research injury by government, sponsor or some combination of both. Trial Design Some form of independent safety monitoring would be a valuable component of any clinical trial in which patients are treated for extended periods, but they are especially important for all double-blind trials and in any trial in which there is reason to anticipate that evidence of adverse reactions could be confused with evidence of disease progression or therapeutic response. For other types of trials the sponsor should bear the burden of demonstrating that a monitor is unnecessary. We support in principle the desirability of controls in Phase II studies, even while recognizing that statistical power will generally be inadequate to detect all but the most common of adverse drug effects, and among those, only those that rarely occur in untreated subjects. Nevertheless, particularly in trials involving extended treatment of patients, the use

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Review of the Fialuridine (FIAU) Clinical Trials of some concurrent comparison group should help focus attention on the importance of differentiating drug effects from the underlying disease(s). Research into the development of a database from which to construct historical control groups should also be supported. Such control groups may be needed as comparison groups when suitably matched concurrent control groups are not feasible. The extensive data submitted to the FDA through the IND process are a potentially valuable resource to custom match patients in new drug trials with controls from previous trials, matching not only for entry criteria but also for disease extent and severity, concomitant medications and other confounding variables. Concerted efforts should be made to include in all clinical trial protocols explicit prospective criteria to help distinguish between adverse events related to drug treatment and changes in the underlying disease, for better or worse, whether or not controls are employed. Clinical protocols should also have a section explicitly addressing the determination of the followup period, based on preclinical data and clinical data from other drugs thought to be similar in structure and action. Drugs suspected of modifying DNA or associated macromolecules demand a minimum of 6 months followup. At the outset of extended Phase II trials, consideration should be given as to whether there is sufficient evidence of safety to justify simultaneous enrollment of a substantial group of patients, or whether the patients' disease is so serious that access to the drug seems warranted. Adverse Event Reporting Data should ideally be analyzed (by the investigators or independent safety monitor in Phase I and Phase II trials, and by data safety monitoring committees or data coordinating centers in multicenter Phase III studies) on a continuing real-time basis rather than only after all case report forms are complete for all patients. This will ensure that the fewest possible patients are exposed to possible hazards, and that rapid intervention will prevent or limit injury to individual patients. We concur with the suggestion of the FDA Task Force that some form of cumulative adverse event reporting should be provided by the sponsor, in a form which includes not only those events previously reported as serious, unexpected and drug related, but also any events judged to have met only the first or the first two of those conditions, along with the sponsor's explanation of the event. A careful analysis of all available information rather than a "worst case" assumption should then determine further actions. We believe that requiring a cumulative and all-encompassing report of the sort referred to in the previous recommendation every six months will prove to be a substantial impediment to development of drugs to combat life-threatening diseases (e.g., cancer) where adverse events are frequent because of the often progressive nature of the underlying disease. Some judgement will always be necessary, by the investigators deciding the most likely cause of adverse events, and by the FDA, in deciding for which drugs and at what intervals a cumulative safety summary is necessary. Ideally the investigators and the FDA would work together in making both of these determinations.

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Review of the Fialuridine (FIAU) Clinical Trials Compliance Audits Given the intense publicity surrounding the issue of FDA "warning letters," regard for due process would seem to require some modifications in procedure. A fairer process, for example, might be for the FDA to refrain from public release of the letters until receipt of the mandated reply from the addressees. Some sort of appeal process, independent of the Office of Compliance, and including scientific peers expert in the area should also be available in the event of intractable disagreement. Where retrospective evaluation by the Office of Compliance is at odds with a prior evaluation by the responsible FDA review division, that fact should at least be acknowledged in the letter. Further Research Into FIAU Toxicity We urge continued support for research into the mechanism of FIAU toxicity, including development of animal models and other test procedures that could be used to screen drugs with potential to alter DNA prior to clinical trials. Preclinical testing in animals is especially important in the case of FIAU-like drugs with a potential for long-term effects on nuclear or mitochondrial DNA. Toxicology studies in at least two different species, using the route of administration intended for use in patients, with dosing for at least as long as intended for clinical trials, and extended followup on at least a subsample of animals should all be key considerations in preclinical testing. Wherever feasible and reasonable, the preclinical assessment should include testing in an animal model of the disease being targeted.