Cover Image

PAPERBACK
$34.00



View/Hide Left Panel

15
Review Of "Report To The Advisory Committee To The Director, National Institutes Of Health"

On April 29, 1994, a subcommittee of the Advisory Committee to the Director of the NIH presented its report on review of the FIAU studies to the Director of the NIH, Harold Varmus. This report was presented to the IOM Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials on July 26, 1994, with an oral briefing by the subcommittee's co-chairs, David Challoner, Vice President for Health Affairs at the University of Florida, and David Kipnis, Distinguished University Professor at Washington University of St. Louis School of Medicine (NIH, 1994b).

OBJECTIVE OF THE NIH REVIEW

In October 1993, the then Acting Director of NIH asked a subset of his standing advisory committee of outside experts to conduct an independent, fact-finding review of the FIAU studies conducted at NIH. The charge to the committee was "to conduct a fact-finding review of all aspects of the FIAU studies carried out at the NIH, from concept to protocol development and implementation ... to consider whether the FIAU studies were conducted in full conformance to NIH policies." The subcommittee's task was further specified by four questions:

  1. Why were the FIAU studies conducted?

  2. How well were the FIAU studies conducted?

  3. How well were the adverse events in the FIAU studies handled?

  4. Could the adverse events have been avoided, particularly in the last study?

The subcommittee was asked to formulate recommendations for changes in regulations and procedures to enhance the intramural NIH conduct of clinical research.

The focus of the study was the design and execution of the NIDDK protocol 93-DK-0031 (Lilly study H3X-MC-PPPC [PPPC trial]) entitled "A Six-Month Course of FIAU for Chronic Hepatitis." In addition, the committee reviewed NIAID protocol 91-AI-0031 (Oclassen study R90-001-01) entitled "The Tolerance of HIV Infected Patients to Oral Doses of FIAU" and the joint NIAID-NIDDK protocol 91-DK-AI-0213 (Oclassen study R91-010-01) entitled "A Four-Week Course of FIAU for Chronic Hepatitis B.''



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials 15 Review Of "Report To The Advisory Committee To The Director, National Institutes Of Health" On April 29, 1994, a subcommittee of the Advisory Committee to the Director of the NIH presented its report on review of the FIAU studies to the Director of the NIH, Harold Varmus. This report was presented to the IOM Committee to Review the Fialuridine (FIAU/FIAC) Clinical Trials on July 26, 1994, with an oral briefing by the subcommittee's co-chairs, David Challoner, Vice President for Health Affairs at the University of Florida, and David Kipnis, Distinguished University Professor at Washington University of St. Louis School of Medicine (NIH, 1994b). OBJECTIVE OF THE NIH REVIEW In October 1993, the then Acting Director of NIH asked a subset of his standing advisory committee of outside experts to conduct an independent, fact-finding review of the FIAU studies conducted at NIH. The charge to the committee was "to conduct a fact-finding review of all aspects of the FIAU studies carried out at the NIH, from concept to protocol development and implementation ... to consider whether the FIAU studies were conducted in full conformance to NIH policies." The subcommittee's task was further specified by four questions: Why were the FIAU studies conducted? How well were the FIAU studies conducted? How well were the adverse events in the FIAU studies handled? Could the adverse events have been avoided, particularly in the last study? The subcommittee was asked to formulate recommendations for changes in regulations and procedures to enhance the intramural NIH conduct of clinical research. The focus of the study was the design and execution of the NIDDK protocol 93-DK-0031 (Lilly study H3X-MC-PPPC [PPPC trial]) entitled "A Six-Month Course of FIAU for Chronic Hepatitis." In addition, the committee reviewed NIAID protocol 91-AI-0031 (Oclassen study R90-001-01) entitled "The Tolerance of HIV Infected Patients to Oral Doses of FIAU" and the joint NIAID-NIDDK protocol 91-DK-AI-0213 (Oclassen study R91-010-01) entitled "A Four-Week Course of FIAU for Chronic Hepatitis B.''

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials In addition to the co-chairs, the members included Richard Corlin, Physician and Vice Speaker of the Delegates Committee of the American Medical Association, Santa Monica, Calif.; Suzanne Oparil, Director, Vascular Biology and Hypertension Program, University of Alabama, Birmingham; Robert E. Handschumacher, Professor of Pharmacology, Yale University, New Haven, Conn.; Rudi Schmid, Dean Emeritus, University of California, San Francisco; and Marguerite Kinney, Professor of Nursing University of Alabama, Birmingham. An expert consultant to the committee was Paul S. Lietman, Wellcome Professor of Clinical Pharmacology, Johns Hopkins University, Baltimore, Md. The committee held three meetings in closed session on December 20, 1993, and January 4 and 5 and February 16, 1994. An extensive list of documents and information from personal interviews was made available to the subcommittee and are listed in the report. Question 1—Why Were The Fiau Studies Conducted? Was The Scientific Rationale For The Studies Sufficiently Strong? The IOM committee agrees with the NIH subcommittee that there was a strong, justifiable, scientific, rational argument for evaluating FIAU for the therapy of HBV infection. The sequence of drug protocol development was logical and rational and occurred at an appropriate pace with an appropriate transfer in focus from AIDS to HBV infection. There was an appropriate interaction between the NIDDK IRB and investigators as new information became available, and the protocol was modified appropriately. The IOM committee also agrees with the concurrent review by NIH staff and the later subcommittee review that the critical evaluation of the death of the patient (patient 4D) from study R91 was rigorously undertaken using all of the information then available and can only retrospectively be assigned to a novel, delayed adverse reaction to FIAU. The decision to proceed with the 6-month study despite this death was not unreasonable at that stage of knowledge. Were the Patients with Hbv Infections Appropriate Candidates for the Second and Third Nih Trials of Fiau? The IOM committee agrees with the subcommittee's conclusion that the justification for developing Phase I/II studies directly with patients with HBV infection was appropriate. Furthermore, the entry criteria of including only patients with compensated liver disease was appropriate, because a temporary flare-up of acute transient deterioration in liver function, even if it was associated with the clearance of the virus, could be dangerous for a patient with decompensated liver disease. A further consideration is that failure to metabolize FIAU because of impaired liver function might make such patients more susceptible to other toxicities such as neuropathy. Thus, an appropriate consideration and review of the entry criteria were made.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials Were the Preclinical Toxicology, Kinetic, and Safety Data Adequate? The subcommittee reviewed the preclinical toxicology data available to FDA and Eli Lilly from studies performed with FIAU in animals before protocol 93-DK-0031 was conducted to determine whether there was an indication of potential hepatic or pancreatic toxicity. An extensive review concluded that the range and duration of testing were appropriate for the proposed studies and that there was no prior evidence to suggest targeted hepatic or pancreatic toxicity. In a subsequent study reported by Eli Lilly on January 14, 1994, a three-times-daily, oral gavage dosing study with 100 times the human dose in Fischer rats provided the first evidence of hepatotoxicity associated with lactic acidosis in a nonhuman test subject, but no elevations in AST or ALT levels were noted. The histopathology of this model was different from that in humans and the model was not replicated in the mouse. There was also a suggestion of diffuse fatty infiltration of the liver obtained in 1992 in the woodchuck hepatitis model. The subcommittee gave emphasis to the fact that animal models at the time did not raise cautions about hepatic toxicity. The subcommittee received information pertaining to FIAU incorporation into DNA. They noted that analytical techniques were not available to the sponsor to permit investigation of this hypothesis which, at the time of the report, still remained to be confirmed. The subcommittee reviewed information on the kinetics of FIAU obtained with high-performance liquid chromatography (HPLC) methodology and concluded that the early kinetic studies did not indicate a deep pool suggestive of DNA binding. The IOM committee concurs with the NIH subcommittee that a detailed review of preclinical toxicity data available at the start of the third study complied with existing regulations and provided no indication of the liver and pancreatic toxicity later observed in humans. The subsequent and ongoing research on FIAU integration into nuclear and mitochondrial DNA is critical to understanding the mechanism of toxicity and predicting the potential of new chemical entities to pose a similar risk in the future. Once models have been validated, they will become part of an elective screen. However, this information was not available before the onset of the third study and is still only suggestive. It can be anticipated that novel drug toxicity appearing for the first time in humans and not predicted by animal models will occur again in the future because it is an inherent risk of all new drug development programs. An appropriate response to such an event is to learn the mechanism of the toxicity and devise new predictive models. Should the Deaths That Occurred After the First and Second Trials Have Precluded the Use of Fiau in the Third Hepatitis B Trial? Clinical problems were identified in four of 14 HIV-positive patients subsequent to their participation in the first NIH trial (R90); These problems led to three deaths and one case of pancreatitis that resolved. One of the 24 patients in trial R91 also died within a few months of completing the study. The subcommittee provided an in-depth review of clinical information provided by the principal investigator's in both studies, Stephen Straus for the first study and

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials Jay Hoofnagle for the second study. Information available only to the FDA was not made available to the committee. The IOM committee concurs with the subcommittee's review of the deaths of trial R-90 subjects 401,406, and 408, well after completion of their FIAU treatment and their conclusion that ''even in retrospect, these deaths could not be attributed to FIAU." A fourth death (patient 4D) from the R91 trial was problematic for both the investigators and the NIH subcommittee. Patient 4D received FIAU for 28 days in August 1992. In November 1992 the patient had a laparoscopic removal of his gallbladder in response to persistent abdominal pain. No stones were found, and the patient developed intractable ascites and lactic acidosis. On evaluation by NIH investigators in December 1992, his liver enzyme levels were normal, but he was in liver failure. He died while awaiting a liver transplantation. Microvesicular steatosis was identified at autopsy. At the time of death, the cause of his syndrome was unknown, but it was not attributed to FIAU because of the long delay between the end of therapy and the onset of his syndrome. There were, however, in-depth internal discussions of possible underlying pathophysiology. The syndrome of metabolic acidosis, normal serum liver enzyme levels, and microvesicular steatosis that would later characterize the syndrome in the victims of FIAU toxicity in the PPPC trial was identified. In retrospect, the NIH subcommittee and the IOM committee consider this patient (patient 4D in trial R91) to be the first real case of the delayed FIAU toxicity syndrome responsible for the five deaths in the PPPC trial (93-DK-0031). Did the Investigators Adequately Consider All Data Available to Them in the Design and Conduct of the Protocols, or Were Important Data Ignored? The IOM committee concurs with the subcommittee's report that the study design was carefully considered and that all steps of the study had been appropriately revised. There is no evidence that any information was overlooked. The death of patient 4D was discussed, but there was insufficient information to ascribe the syndrome to any one cause. Hoofnagle was enthusiastic about the potential of FIAU providing an effective therapy for HBV infection. However, his approach was careful. There was evidence that information available in the investigator's brochure and from preclinical studies had been reviewed and discussed with both the sponsors and FDA. Clinical events in patients from the second trial (e.g., neuropathy) were incorporated into the trial design and information provided at the time of obtaining informed consent. Was The Third Study Prematurely Implemented or Put on A "Fast-Track"? The NIH subcommittee raised the question of whether transferring the focus of drug development from HIV- to HBV-infected patients led to an inappropriate fast-track initiation of clinical studies before full conventional animal toxicology studies were performed. In reviewing the sequence of events for the IOM committee, FDA officials (Feigal, 1994) indicated that the time frame for the development of FIAU was within the normal range for

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials an antiviral drug (being on the conservative side). It was noted that the second (R91) and third (PPPC) protocols were delayed to permit completion of studies in animals and safety evaluation. The IOM committee concurs with the NIH subcommittee that the sequence of development of FIAU was within existing guidelines and there is no evidence to suggest that fast-track development was a contributing factor to the untoward events induced by FIAU. Was The Third Study Accelerated By Pressure From Eli Lilly & Company? The subcommittee noted that the impetus for the third drug trial was investigator initiated and driven. There was every indication of close and full collaboration between the investigators and the sponsor and between the sponsor and the Antiviral Drug Division of FDA. The IOM committee concurs with the subcommittee that there was no evidence of undue haste or coercion from Eli Lilly. Question 2—How Well Were The Fiau Studies Conducted? The subcommittee further subdivided this issue to address the following specific aspects. Compliance With Nih Multiple Project Assurance And The Quality and Thoroughness of Irb Review of Protocols The subcommittee reviewed each protocol in depth and found each had received prior clearance from respective clinical directors of NIH. All IRB stipulations and reviews were met, including incorporation of amendments. The minutes of the IRB review accurately reflected the review proceedings, and the principal investigator promptly reported adverse events to the IRB. The subcommittee was satisfied that the two IRBs had provided a comprehensive, thoughtful and rigorous review and were in compliance with NIH and federal regulations. The Design of Clinical Studies with Particular Reference To The Third Protocol (Lilly Pppc/Nih 93-Dk-0031 Trial) The rationale, design, entry criteria, study measurements, safety monitoring, definition of stop points if toxicity occurred, and duration of follow-up of the third protocol were reviewed and were considered to be not only appropriate but of exceptionally high quality. In the words of the subcommittee report, the protocols were "meticulously prepared and implemented." The IOM committee concurs with the subcommittee critique.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials Quality and Content of The Consent Process The subcommittee undertook an exhaustive review of the process of enrolling subjects in FIAU studies. This included review of patient records and direct interviews with all 10 surviving patients, the investigators, the research nurses, the chairs of the two involved IRBs, the institute directors, and the acting director of the Clinical Center. The subcommittee was satisfied that the patients were provided full, informed consent and were impressed by the teamwork between investigators and staff. There was no evidence to suggest that pressure was exerted on the patients to enroll in the study. The IOM committee concurs with the subcommittee's report that all appropriate reviews and protections for human subjects were followed. One of the more unusual features of the third protocol was the close relationship between the patient volunteer group and the investigators at NIH. The patients tended to be well educated, well informed and highly motivated to participate, in many instances, in more than one study. Reporting to The IND Sponsor and FDA The subcommittee did not have the results of the investigations of the Compliance Office of FDA at the time of presentation of their report. The subcommittee was informed of a review of case report forms submitted by NIH investigators to Eli Lilly. On the basis of that and other reports, the subcommittee saw "no reason to believe that compliance reporting was not in order." The NIH subcommittee's task was not to provide a detailed audit of compliance with regulatory authorities, and it did not have all of the information available to FDA. It would therefore be inappropriate to relate their conclusions to the FDA audit process or review. It was clear, however, that the subcommittee, like the IOM committee, considered the investigator-sponsor relationship and the exchange of information to be of high quality. Clinical Care of Patients The NIH subcommittee reviewed the objectives and procedures of the NIH Clinical Center. Several specific points were raised: Patients attend the NIH Clinical Center only as participants in clinical research. The caliber of physicians and nurses is first rate. There was an exceptional, interactive, and well-informed relationship between staff and patients. Routine patient data and symptoms were carefully monitored and accurately reported. Side effects were given serious attention, and patients were carefully evaluated to ensure that anticipated and unanticipated events were properly addressed.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials Excellent concordance was observed in a comparison symptom reports prepared by the patients with the reports in the charts prepared by staff. In reviewing the files of 10 surviving patients, there was no single instance in which recorded complaints from the patients were not addressed. The IOM committee concurs with the favorable review of the NIH subcommittee on the quality of patient care provided by Hoofnagle and staff in the FIAU studies. A publicized incident between one patient in the study and Dr. Hoofnagle was addressed in the subcommittee report, in which it was considered to be a patient-specific incident. In the opinion of the IOM committee, there is no evidence that a lack of quality of patient care contributed in any way to the events that took place in patients receiving FIAU. Question 3—How Well Were The Adverse Events in The Fiau Studies Handled? As stated above, in the opinion of the subcommittee the three deaths in the R90 trial were thought to be unrelated to FIAU, and the death of a subject in the R91 trial "was considered but could not be proved to be drug related." The subcommittee therefore focused on the investigator responses to events occurring in subjects in the third protocol (PPPC trial), particularly in June 1993. On June 25, 1993, a patient was admitted in an emergency to a Virginia hospital with lactic acidosis. The clinical picture was identified as being similar to that of the patient from the previous protocol who had died with lactic acidosis and liver failure. Within 12 hours of recognition of an FIAU-related severe hepatotoxicity, the trial was terminated and the patients in the trial were urgently admitted to a hospital for evaluation. It was noted that Eli Lilly paid the expenses for transplantations, and all surviving patients continue to be followed on a regular basis at the NIH Clinical Center. The NIH subcommittee noted that the presentation of the patient with acute liver decompensation with lactic acidosis was immediately recognized as probable FIAU toxicity. This terminated the administration of FIAU and led to intensive efforts involved in managing the care of patients who still developed evidence of toxicity, despite discontinuation of the drug. Even in retrospect there was no time before this hospital admission, when evidence of adverse effects was sufficiently compelling, to warrant stopping this study of a very promising and sorely needed therapy. The IOM committee is in agreement with the conclusions drawn by the NIH subcommittee. Question 4—Could The Adverse Events Have Been Avoided, Particularly in The Last Study? The subcommittee considered it unlikely that changes in the research protocol or additional testing in animals or humans would have provided signals that would have delayed or prevented use of FIAU in patients with chronic HBV infection.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials Could The New, Highly Sensitive Ria Method Have Alerted The Attending Physicians to The Possibility of Hepatic and Pancreatic Failures? The initial HPLC assay lacked sensitivity in defining the terminal half-life of FIAU in humans. Following licensure to Eli Lilly, a 100-fold more sensitive assay, the RIA, was developed in June 1993 and was used to estimate a half-life of 29 hours rather than the 1-4 hours estimated previously. The IOM committee concurs with the NIH subcommittee that even if information from the RIA had been available before implementation of the final protocol, it would not have changed the study design or focused attention on hepatic or pancreatic toxicity. The information needed to anticipate this delayed selective toxicity would have been evidence of either differential uptake into liver and pancreatic tissue or differential effects on these two organs. It should be noted that neuronal, not hepato-pancreatic, toxicity was the primary danger anticipated. Could Damage to Mitochondria Be Responsible for The Delayed Toxicity Seen in The Extended Fiau Trial? The subcommittee reviewed what was known and speculated on the potential for FIAU to be incorporated into mitochondrial and nuclear DNA, particularly the incorporation into mitochondrial DNA in cell culture preparations. They concluded that too little information was available to influence study design on the basis of these considerations. At the time of review by the IOM committee substantial progress had been made, but there is still insufficient information to influence study design of drug development or even to recommend one strategy in preference over another. There is an intensive investigative effort being made by researchers at Eli Lilly and other laboratories to understand the mechanism of FIAU toxicity, learn the structure-activity relationships of different molecules to induce similar events, and develop a predictive in vitro model to anticipate and prevent similar toxicity in the future. There is a clear imperative to more clearly understand the pathophysiology of this syndrome. Would New Knowledge Concerning The Delayed Clearance of Fiau Have Changed The Daily Regimen Used in The Third Trial? Modification of the dosing interval in the third protocol in light of the longer half-life was discussed by the subcommittee. Specifically, was there a potential for drug accumulation during chronic therapy? It is evident that the kinetics of incorporation of FIAU into DNA are still unclear; just as importantly, the functional consequences of incorporation are also unknown. The IOM committee agrees that too little information is known relating the kinetics of FIAU to any dynamic effect, and knowledge of the longer half-life per se does not provide sufficient information to influence the study design.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials What Effect Might An HBV Infection Have on The Hepatic Toxicity of FIAU? The subcommittee report speculates on the potential additional variable of the presence of HBV in the hepatocytes of the treated patients. The IOM committee agrees that there is a potential for a disease-specific contribution to the adverse effect profile of a drug. For example, a modification caused by a virus in a target cell might induce changes only in infected cells. As indicated in Chapter 13 of this report, to the extent that the woodchuck hepadnavirus model allows hypothesis to human HBV infection, this extrapolation seems unlikely with FIAU. In any case, insistence on developing a convincing animal model for each human disease before attempting human drug trials would drastically impede the development of new drug therapies. Would A Different Accrual Pattern of Recruitment in The Final Protocol Have Affected The Outcome? In some clinical trials, the rate of accrual is defined and staggered for safety concerns. In most studies with small sample sizes, staggering of accrual is not preplanned but tends to occur naturally because of the limited availability of subjects. In the PPPC protocol, a 6-month delay in implementing the study led to the identification of most candidates from a previous trial. Furthermore, the initial study design was planned as a retreatment program. Thus, when the study started, 10 of the 15 subjects (all of the ones with prior FIAU exposure) were entered into the study within 1 month and had already received prolonged FIAU therapy when the first toxicity was noted. The subcommittee recommended that when short-term trials are extended to 6 months or more that accrual should be staggered (for example, only 20 percent to 25 percent of the patients started each month) to reduce the incidence of unexpected long-term or delayed toxicity. The IOM committee concurs with this recommendation to avoid the simultaneous enrollment of large groups of patients, at least in Phase I and II trials. SUMMARY AND RECOMMENDATIONS The NIH subcommittee concluded: "The FIAU studies represent the best of current practice in clinical investigations and exceeded regulatory requirements ... and that Dr. Hoofnagle and Dr. Straus were among the leading researchers in their fields and well qualified to conduct this research." An unfortunate sequence of events does not constitute the failure of a system. Conversely, if the studies had proceeded along less rigorously controlled conditions, it is probable that a major disaster involving large numbers of subjects would have occurred in the Phase III studies that were about to be implemented. "Delayed, fatal human toxicity due to FIAU represents a novel type of toxic reaction not previously encountered." The subcommittee could find no example of either clinical judgment or research process in which a change could have been expected to influence the outcome. In the words of the subcommittee, "It could not see itself having concluded or acted differently from the

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials investigative team or the patients, given the information available at each step." The IOM committee concurs with this assessment. Recommendations from The Nih Subcommittee Mechanisms of Toxicity It was recommended that all drugs that have potential for entering or modifying DNA should be considered for their abilities to damage not only nuclear DNA but also mitochondrial DNA. They recommended support of research to provide new and early measures of mitochondrial DNA damage. The IOM committee strongly endorses the need for further research to more clearly understand the mechanisms involved in FIAU toxicity. This is clearly vital not only for antiviral drug development but also for gene transfer studies. There is an urgent need to define drug incorporation into DNA (a pharmacokinetic description) and relate such changes to changes in function (i.e. a pharmacodynamic response). This issue merits financial support for research and given the high profile of AIDS and gene transfer research, it should have a high priority. The potential for extended reutilization or recycling of a nucleoside analog in and out of DNA must be considered. Support for further research in this area would be valuable. The IOM committee strongly endorses this recommendation. The identification of a new type of drug-induced toxicity in which prolonged therapy is associated with late-onset toxicity but rapidly progressive and fatal toxicity suggests long-term drug incorporation into DNA. Recent reports now suggest that a similar syndrome may also be induced on rare occasions by other nucleoside analogs, including those, like AZT, used extensively in the treatment of HIV infection. If this occurs for a variety of drugs, this mechanism has major implications in drugs with acute, delayed, mutagenic, and carcinogenic toxicity, and the factors involved are currently unknown. This underscores the urgent need to take advantage of this adverse sequence of events to positively identify currently unknown pharmacologic mechanisms of drug action. Preclinical Tests in Animals The subcommittee recommended that preclinical testing in animals should mimic as nearly as possible the route and dosage regimen proposed for use in humans and the disease state that occurs in humans. This is particularly important for orally administered drugs if first-pass clearance occurs in the liver. The IOM committee endorses the approach, but emphasizes that the current lack of knowledge makes it difficult to implement this recommendation. There are substantial differences in the activities and specificities between related drug-metabolizing enzymes in different species. Thus, experiments in animals must be shown to relate to human drug metabolism in humans before drawing inferences of relevance to toxicity and disease in

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials humans. There will always be the possibility of unexpected adverse events that are identified only in or that are identified first in humans. The comment on the need for models of disease is an appropriate plea for more research. However, there needs to be clear recognition that it is extraordinarily difficult to develop models of disease in animals truly analogous to disease in humans. At present there is insufficient evidence to justify the regulatory requirement of a model of disease in animals. FDA should not hold up drug development in the absence of such models. Conversely, FDA should encourage the positive development of such models to facilitate decisionmaking. The subcommittee recommended that vigorous preclinical screening is indicated for a suitable time period, particularly in patient populations whose lives are not imminently threatened by this disease. The IOM committee is concerned that translation of this recommendation into restrictive regulatory requirements would be counterproductive to the intent of this statement and would place an inappropriately heavy burden on the investigator. It does not in any way address the major difficulties of Phase I and Phase II trials with small sample sizes: differences in the extent or severity of disease process or the presence of confounding variables. The IOM committee recommends exploration of new approaches to comparative control groups for Phase I and Phase II studies. A variety of alternative approaches are available, and large amounts of potentially useful information have already been provided to FDA. The IOM committee recommends that the development of new methods be sponsored independently of FDA, to emphasize the research nature of such matters. It is recognized that issues of confidentiality would have to be addressed to permit full access to information. Patient Enrollment As noted previously, the subcommittee recommended that when patients were entered into Phase I or Phase II clinical trials of drugs with the potential for entering or modifying nuclear or mitochondrial DNA, there should be a delay between recruitment of each cohort to minimize the chance that many patients would be at risk of delayed toxicity if it should occur. The IOM committee suggests extending this recommendation of staggered entry to any study that involves prolonged therapy (i.e., 6 months or more) to humans. This should not be restricted to drugs that have a potential to modify DNA, because the mechanism of FIAU toxicity remains uncertain. The IOM committee does not recommend an inflexible rate of staggering, but suggests that a stipulated maximal rate of accrual should take into account the available information about the drug and the clinical context of its use. In retrospect, in the third FIAU trial, an entry criterion of 25 percent of the projected study group per month would have reduced the duration of exposure in half of those patients who suffered FIAU toxicity, although this half would still have had substantial, albeit 1 month less, exposure.

OCR for page 121
Review of the Fialuridine (FIAU) Clinical Trials Patient Follow-Up One of the recommendations of the FDA Task Force is that all patients in Phase I or II trials of any new drugs should be monitored for 6 to 9 months after the cessation of therapy. The NIH subcommittee recommended that this recommendation should apply only when there are scientific reasons for suspecting the possibility of long-term or delayed toxicity. The differences between the two sets of recommendations reflect a somewhat predictable difference in the relative weighing of risk and benefit by the two groups. A 6- to 9-month detailed follow-up on every patient in a Phase I study of an anti-cancer or anti-HIV drug will substantially increase the time and cost of new drug discovery. It will also very substantially increase the difficulty in establishing causal relationships. The net result is likely to be a trade-off in which a few drugs with dangerous toxicities are uncovered at the cost of stopping the development of at least some safe drugs that would have benefited large numbers of patients. The IOM committee recommends that the duration of follow-up be stated explicitly in each protocol along with a rationale. The IOM committee anticipates that because of the FIAU case, the potential for the delayed onset of toxicity after stopping therapy will influence follow-up protocol designs. There is a need to maintain flexibility in study design and tailor protocols for specific drugs to specific clinical situations.