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17
Ancillary Issues Raised During The Period Following The H3x-Mc-Pppc Trial

The tragic events that occurred in June to September 1993 in the group of ambulatory patients participating in the NIH trial (H3X-MC-PPPC) of FIAU therapy of chronic hepatitis B virus infection has been the principal focus of this committee's review. The tragedy that occurred, in which 7 of the 15 study participants developed sudden, rapidly progressive liver failure and 5 died (2 other lives were saved by liver transplantation), is heartbreaking. Our feelings go out for these patients and to the families and friends who suffered these irreparable losses, although we recognize that no amount of sympathy can compensate for the lives lost and for the shock and grief that these events induced. The committee is also cognizant of the sadness felt and expressed by the physicians and nurses who cared for these patients during this trial (and, in many instances, during earlier drug trials). Accordingly, the primary concern in this report has been to determine (1) whether investigators, sponsors, FDA, and NIH acted appropriately in the clinical trials of FIAC and FIAU, and (2) whether the rules or procedures governing the clinical trial process need to be changed to address problems identified in the FDA and NIH reports and in the review of all the FIAU/FIAC trials carried out by this committee. These have been considered in the earlier sections of this report. In many instances we agree with changes recommended by the FDA Task Force report or the report of the Advisory Committee to the Director of NIH. In other instances we have disagreed with some of the recommendations and have stated why (see Chapters 14 to 16). Our overall conclusions and recommendations are summarized in Chapter 18. In all instances the committee's concern has been to reduce as far as possible the chance of such an unanticipated misfortune ever occurring again in the course of a clinical drug trial. This is done with the acknowledgment of the benefits that can accrue to society as a whole by the performance of clinical trials in the drug discovery process, and with the recognition that the measures recommended here cannot provide absolute assurance against the appearance of an unanticipated type of toxicity during the course of early clinical trials of some yet untested class of promising drugs in the future.

In the course of the committee's review and deliberations several ancillary issues came to our attention, represented by events transpiring over the year subsequent to the catastrophic events that immediately followed termination of the PPPC trial at NIH. The committee considers these issues to be clearly very secondary in importance to the principal, unfortunate events that form the basis of this report. However, since these issues bear directly on the regulatory control of clinical trials, the committee believes that it would be reasonable to acknowledge these issues and add a commentary on them in the following paragraphs.



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Review of the Fialuridine (FIAU) Clinical Trials 17 Ancillary Issues Raised During The Period Following The H3x-Mc-Pppc Trial The tragic events that occurred in June to September 1993 in the group of ambulatory patients participating in the NIH trial (H3X-MC-PPPC) of FIAU therapy of chronic hepatitis B virus infection has been the principal focus of this committee's review. The tragedy that occurred, in which 7 of the 15 study participants developed sudden, rapidly progressive liver failure and 5 died (2 other lives were saved by liver transplantation), is heartbreaking. Our feelings go out for these patients and to the families and friends who suffered these irreparable losses, although we recognize that no amount of sympathy can compensate for the lives lost and for the shock and grief that these events induced. The committee is also cognizant of the sadness felt and expressed by the physicians and nurses who cared for these patients during this trial (and, in many instances, during earlier drug trials). Accordingly, the primary concern in this report has been to determine (1) whether investigators, sponsors, FDA, and NIH acted appropriately in the clinical trials of FIAC and FIAU, and (2) whether the rules or procedures governing the clinical trial process need to be changed to address problems identified in the FDA and NIH reports and in the review of all the FIAU/FIAC trials carried out by this committee. These have been considered in the earlier sections of this report. In many instances we agree with changes recommended by the FDA Task Force report or the report of the Advisory Committee to the Director of NIH. In other instances we have disagreed with some of the recommendations and have stated why (see Chapters 14 to 16). Our overall conclusions and recommendations are summarized in Chapter 18. In all instances the committee's concern has been to reduce as far as possible the chance of such an unanticipated misfortune ever occurring again in the course of a clinical drug trial. This is done with the acknowledgment of the benefits that can accrue to society as a whole by the performance of clinical trials in the drug discovery process, and with the recognition that the measures recommended here cannot provide absolute assurance against the appearance of an unanticipated type of toxicity during the course of early clinical trials of some yet untested class of promising drugs in the future. In the course of the committee's review and deliberations several ancillary issues came to our attention, represented by events transpiring over the year subsequent to the catastrophic events that immediately followed termination of the PPPC trial at NIH. The committee considers these issues to be clearly very secondary in importance to the principal, unfortunate events that form the basis of this report. However, since these issues bear directly on the regulatory control of clinical trials, the committee believes that it would be reasonable to acknowledge these issues and add a commentary on them in the following paragraphs.

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Review of the Fialuridine (FIAU) Clinical Trials Officials in the Office of Compliance in the Center for Drug Evaluation and Research of FDA began an investigation of the FIAU and FIAC trials within a month of the deaths of the PPPC trial subjects. The investigation apparently continues to this day, although it has already resulted in the public censure of four scientists and two drug companies (Schwartz, 1993; Hilts, 1994). Part of the mission of the Division of Scientific Investigations of the Office of Compliance is to perform on-site audits of sponsors and investigators performing research under INDs. The division carries out hundreds of such audits every year. Most of them are routine and performed as part of the ongoing activities of the Division in relation to its general mission of assuring compliance with federal guidelines for research performed under INDs. A small fraction of them are performed because of suspected problems, because of complaints from investigators or patients as to possible wrongdoing, or because of publicity surrounding a study. The audits in the case of the FIAU trials were prompted via the last of these and were initiated by the division after publicity in the media and the threat of hearings in Congress. Most audits conclude with an oral briefing of the findings and the provision of a list of problems or violations to the investigator or sponsor being audited. On other occasions this is followed up with letters notifying investigators or sponsors of problems or violations noted in the audit. Letters conveying such information are broadly referred to as warning letters and in terms of action indicated are classified as no action indicated (NAI), voluntary action indicated (VAI), or official action indicated (OAI). Letters of the first type, as implied by the name, do not require a response from the recipient. VAI letters request a response within 30 days of receipt with a proposal for correcting or preventing the cited problems or deviations in the future. OAI letters are intended to warn of an impending action such as disqualification from future drug research or even criminal prosecution and require a response within 15 working days. The committee was unable to determine exactly how the decision on what type of letter to send is reached, but it would appear to be a subjective decision based on some combination of the number of violations and their perceived seriousness. The division has issued a total of 3,731 such letters since beginning the practice in 1977 (20 percent NAI, 74 percent VAI, and 6 percent OAI). The number issued in fiscal year 94 was 187 (31 NAI, 91 VAI, and 8 OAI, with 57 remaining to be classified at the time of the testimony [July 25, 1994]). Letters were sent by the division pursuant to FIAC and FIAU trials to four scientists and two sponsors: Stephen E. Straus, Douglas Richman, Lawrence Corey, Jay Hoofnagle, Oclassen Pharmaceuticals, Inc. (Terry L. Johnson addressee), and Eli Lilly & Company (Randall Tobias addressee). These letters were generated as a result of on-site audits carried. out in the latter half of 1993 (all were started in August or early September). All letters were dated May 11, 1994 and were sent out by fax and overnight mail on May 13. The letters to Richman, Corey, Hoofnagle, Oclassen, and Lilly were OAI letters. The letter to Straus was a VAI letter. Technically, the letters are intended simply to note violations of protocol or procedure, devoid of judgment as to the relevance of the citations to patient care or treatment, as indicated below in testimony before the Committee:

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Review of the Fialuridine (FIAU) Clinical Trials But I want to emphasis to all of you very strongly that the letters issued by the Office of Compliance were issued primarily based upon violations, documented failures by the clinical investigators and/or the sponsors/monitors to comply to the regulations. There is no place in our letters, nor should there have been, and we did not allude to or present any insinuation that was a direct criticism of patient care or of lack of concern or that in any way the ultimate unfortunate results of the deaths of those patients should have been prevented. That never entered our review. (Richardson, 1994b) That intent was certainly not obvious to many readers of the letters, illustrated best perhaps by a news release from the Chairman of the House Government Operations Subcommittee on Human Resources and Intergovernmental Relations issued Friday, May 13, 1994 (before actual receipt of the warning letters by the letters' addressees). Over a headline alleging ''lethal science fiction used in the death of FIAU patients,'' it reads, in part, as follows: the Food and Drug Administration (FDA) warning letters to the two drug companies and three clinical investigators involved in the flawed fialuridine (FIAU) experiments confirm that the patients involved were neglected and mistreated. FDA's letters document that the clinical investigators and the drug companies consistently misinformed and misled the patients. It goes on to say: FDA's warning letters show that the drug companies and the investigators repeatedly and flagrantly violated FDA regulations, study protocols and good medical practice. In view of the death and suffering their negligence caused innocent victims their behavior and actions are reprehensible, unconscionable and inexcusable. In their self-serving rush to bring this drug to market, the overzealous researchers and drug companies lost sight of their primary duty to "do no harm" to their patients. (Congress of the United States, 1994) The communique concludes: "It appears this whole tragedy could and should have been prevented." The actual citations in the letters fall in four general categories: (1) protocol violations (e.g., You failed to reduce the dosage and/or stop FIAU in subjects when they demonstrated moderate toxicity); (2) informed consent document violations (e.g., You failed to state in the ICD that a purpose of the study was a determination of the safety of FIAU); (3) recordkeeping violations (e.g., You failed to complete several case report forms by not identifying significant clinical and laboratory experiences); and (4) reporting violations (e.g., You failed to assure that all safety reports of severe, unexpected laboratory adverse experiences [elevations in liver enzyme values and others] in subjects were promptly reported to the sponsor or IRB). The number of violations cited in the letters ranged from 5 to 25, and many were indeed "devoid of judgment about patient care." A number of very serious sounding charges however revolved around the issue of elevated liver enzyme levels in the blood (AST or ALT). As we

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Review of the Fialuridine (FIAU) Clinical Trials have discussed in earlier sections, the investigators and sponsors, with at least the tacit approval of the FDA's Antiviral Drug Division, considered such elevations evidence of a successful effect of FIAU therapy and therefore did not include such elevations in their protocols as a basis for stopping therapy or changing dose. The Office of Compliance, however, decided that the elevations should have instead been viewed as serious and unexpected adverse events and reported as such in writing within 10 days of their occurrence. The committee believes that the NIH investigators' view was a legitimate one, and is supported by the minimal enzyme elevations which characterized the toxic syndrome of the PPPC victims. The committee recognizes nonetheless that there is room for reasonable persons to disagree with that position. In contrast, a problematic pattern in the warning letters has to do with their declarative nature in matters of judgment and opinion. Nowhere is this more apparent than in citations regarding the content of consent statements used by Richman. The letter to him, in the section on informed consent documents (ICDs) used in the R89 study, indicates that: You failed to describe adequately and clearly foreseeable risks of central nervous system toxicity, myasthenia, myopathy, rhabdomyolysis, and liver toxicity in ICDs. You failed to provide in the ICDs complete and clear information regarding who to contact for answers to questions regarding research subjects' rights, information regarding compensation, and information on whether any medical treatments are available if injury occurs. The question is what is adequate and clear? According to Richman's response, the statements provided to patients included the following (see Appendix D for a copy of the statement): Some other side effects that I may experience include nausea and perhaps vomiting. It is also possible that confusion, jerking, and even seizures may occur while I am taking this medication, although this is unlikely on the doses I will receive. In animal studies there was evidence of heart damage in those animals receiving very high doses of FIAC. That statement was considered adequate and appropriate by Richman's institutional review board (IRB) when the trial was undertaken. That it no longer seems so, 3 years after the trial was done, is not, in our opinion, grounds for censure. The second of the two citations also raises questions as to what is to be considered complete and clear. Richman's response in regard to injury and compensation indicates that the consent statements used included the following: If I am injured as a result of participation in this research, the University of California will provide any medical care that I may need to treat those injuries—except when they are the consequence of research designed to benefit

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Review of the Fialuridine (FIAU) Clinical Trials me directly. The University will not provide any other form of compensation to me if I am injured. I may call (619) 534-4520 for more information about this. Participation in research is entirely voluntary. I may refuse to take part or withdraw at any time without jeopardy to my medical care at this institution. I have received a copy of this consent document to keep and a copy of "The Experimental Subject's Bill of Rights." The above mentioned Bill of Rights includes the following: If you have any questions regarding a research study, the researcher or his/her assistant will be glad to answer them. You may seek information from Human Subjects Committee—established for the protection of volunteers in research projects—by calling (619) 534-4520 from 8 am to 5 pm, Monday through Friday, or by writing to the above address. A additional flaw in the letter process, at least as practiced in this case, has to do with the absence of any appeal, or independent review process, for resolution of differences of opinion or of interpretation of fact. Seemingly, the only recourse open to an investigator or sponsor on receipt of an OAI letter is to suggest "remedies" until they are considered "adequate," and to do so without recourse. Furthermore, there are no guidelines as to the length of time an investigator or sponsor remains under the cloud of a warning letter once one is received. As of the committee's last meeting on November 17, 1994, none of the original addressees had received any response from FDA to their rapidly crafted responses of the previous Spring. The review process carried out by the FDA and culminating in warning letters leaves much to be desired. The nature of the review, with emphasis on mechanics rather than substance, is troubling, especially since there is a tendency on the part of the media and the public, including lawmakers, to equate mechanical faults with faults of substance. At the very least, if the focus in future reviews is to remain on mechanics, the warning letters in which they are summarized should also include some qualitative judgment as to their importance in regard to conclusions about safety and efficacy. For example, the issue in regard to consent is not whether there is evidence in the file that an investigator witnessed and dated a subject's signature on a consent statement but rather whether the subject was adequately informed. We believe, as well, that the compliance audit was not as informed or balanced as it should have been as a result of the decision to exclude from participation those at FDA in the best position to judge the conduct of the trial, namely, the Antiviral Drug Division. The view of the investigators in regard to ALT and AST flares, for example, was well known to the reviewers in that division assigned to the FIAU IND. In fact, the Antiviral Drug Division was a well-informed participant in the planning and evaluation of each of the Oclassen-and Lilly-sponsored studies, offering suggestions to the protocols and consent forms orally (by phone and in meetings with the sponsors and principal investigators) and in writing, and giving explicit or implicit approval of each study in turn. The fact that at times they were not informed of the

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Review of the Fialuridine (FIAU) Clinical Trials death of a former subject within 10 days of its occurrence or discovery in no way meant that they were not informed of the death well in advance of subsequent trials. If the Antiviral Drug Division was consulted by the Office of Compliance in the course of their investigation it is surprising that there is no acknowledgment in the warning letters that communication among investigators, sponsors, and the Antiviral Drug Division had been frequent and extensive. The Office of Compliance should at least acknowledge that there was a basis for inferring FDA approval on the part of investigators, even when the office later disagrees with actions subsequently taken by the investigators. The committee is troubled, as well, by a system of communication in regard to warning letters that makes them available to the media and others before their receipt by the parties being cited. There were newspaper accounts of the letter to Richman that appeared before he received it. We recognize and respect the need of the public to be informed and we recognize that the FDA is obligated to respond to requests for information under the Freedom of Information Act. In cases involving drugs already on the market, alerting the public should be the primary concern. That said, the committee nonetheless believes that it is well beyond the requirements of that act to release letters like those in this case to the public before the addressees have received the communications. The committee also believes that review of existing procedures for the preparation, release, and resolution of OAI letters would be appropriate. The review should be undertaken with the aim of providing a written description of the processes used for generating such letters and to ensure that they are fair and accurate. It should also outline due process procedures for sponsors or investigators wishing to challenge citations. Those processes might reasonably include provision for a hearing before parties independent of FDA. The rules and regulations regarding INDs are many and complex and are open, in many cases, to various interpretations. It seems apparent that investigators undertaking trials under INDs would benefit from courses or workshops having to do with their responsibilities and with procedures for complying with the guidelines. Ideally, every person engaged in such trials should be required to show proficiency before being allowed to proceed. Institutions have been required of late to set up courses on research ethics to qualify for training grants. The same should apply for investigators engaged in IND work. A reduction in the perceptual gap between investigators and FDA compliance personnel may be accomplished by a continuing dialogue between interested parties, perhaps in the form of an annual workshop jointly sponsored by FDA, the pharmaceutical industry, and members of the academic community. Expectations regarding the usefulness of the treatment protocol as a blueprint for a trial are viewed from differing perspectives. Investigators responsible for caring for patients in the context of a treatment trial know that their protocol, in spite of their best efforts, of necessity leaves room for judgment. They know that it has the potential of being viewed as "flawed" by themselves or others with the perspective of hindsight and that it is likely to be found lacking as a detailed blueprint. The personnel in the FDA responsible for assessing compliance, on the other hand, desire something more akin to a blueprint, used much as a building inspector uses a building plan to determine whether or not a builder is guilty of code violations. Testimony offered by representatives of the Office of Compliance of FDA suggests that the view from that vantage point is that a protocol submitted in a specified IND for a particular

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Review of the Fialuridine (FIAU) Clinical Trials trial is, in effect, a contract with FDA, and that violations of it are violations of FDA regulations and, hence, of federal law, and, ergo, are criminal offenses (Richardson, 1994). This view is disturbing from the perspective of an investigator, if for no other reason than that it seems apparent that given variation in patient needs there is no trial, regardless of how meticulously performed, capable of passing muster if it is subjected to sufficient retrospective scrutiny.