Recent estimates indicate that there is a 10 percent prevalence of chronic insomnia in the adult population of the United States, with an associated annual cost of $90 billion to $107 billion. Since its approval in 1982 for use in the treatment of insomnia, an estimated 11 billion prescriptions for Halcion1 (triazolam) have been filled worldwide. Its widespread use is attributed, at least in part, to the fact that as a benzodiazepine, Halcion was considered safer in terms of overdose, drug interactions, and addictive potential than the barbiturates and other hypnotic drugs that were often previously used for this purpose. In addition, Halcion had a relatively short plasma elimination half-life that afforded it the additional benefit of less morning grogginess compared to that from the use of other, longer half-life benzodiazepings.
Concerns about the safety of Halcion began to emerge when a Dutch physician reported a possible link between this drug and a syndrome that included depression, amnesia, hallucinations, and anxiety. In the United Kingdom, a decision to evaluate the safety of Halcion was made in response to a report from the manufacturer, Upjohn, in 1991 that "errors had been identified in a report of one of the clinical studies included in the original" application for approval. Since that time and for various reasons, the United Kingdom, Brazil, Argentina, Norway, and Denmark have removed Halcion from the market; Upjohn withdrew Halcion from the market in The Netherlands. Other countries, including the United States and Canada, modified the labeling to reduce the recommended dose and duration of treatment and to heighten awareness regarding possible side effects affecting behavior and cognition. The labeling changes raised questions regarding the hypnotic effectiveness of these lower doses of Halcion.
In 1996, a U.S. Food and Drug Administration (FDA) task force looking into the medical, procedural, and legal aspects of the drug's approval process concluded that Halcion was "safe when prescribed according to current labeling" and "effective in the treatment of insomnia at doses and durations currently recommended in the labeling." The task force also recommended that a separate reassessment of the safety and efficacy of Halcion be conducted by a panel of experts. To that end FDA requested that the Institute of Medicine (IOM) assess the following:
the adequacy of the study designs and quantitative endpoints used in the major clinical trials of Halcion;
the quality and quantity of postmarketing data with respect to adverse drug reactions;
the overall confidence in the data on the effectiveness, adverse events, and side effects of Halcion at different doses and for different durations, including those specified in the current product labeling; and
the need for additional studies to clarify and characterize the risk and efficacy profiles of Halcion.
The committee evaluated numerous sources of data to provide a broad perspective on the efficacy and safety of Halcion. These sources are listed in detail in Appendix. E. An abbreviated list appears in Box 1.
BOX 1 RESOURCES REVIEWED BY THE COMMITTEE
Premarketing clinical trial data (from the New Drug Application)
Information from FDA Psychopharmacological Drug Advisory Committee meetings
Integrated summaries of safety and efficacy
Postmarketing surveillance data
Spontaneous report data
Use, sales, and prescription data
ASSESSMENT OF EFFICACY DATA
The primary purpose of a hypnotic agent is to improve the quality of sleep. The efficacies of hypnotic agents are assessed through subjective evaluations that involve the use of questionnaires or interviews and also through objective (polysomnographic) measurement of endpoints that include time to onset of sleep, duration of sleep, and number of awakenings.
Because there is ample evidence of Halcion's efficacy at 0.5 mg, and because this is no longer a recommended dose level, the committee focused much of its attention on data related to the efficacies of the 0.25- and 0.125-mg doses, including the possibility of the development of tolerance over time.2 The committee examined the study designs from premarketing and postmarketing clinical trials and, having judged the study designs to be sufficient to produce reliable data, used statistical methods and analyses to evaluate the data across studies, grouping them by those that measured polysomnographic endpoints and those that measured subjective endpoints. The committee also reviewed the published literature.
Conclusions and Recommendations
The following conclusions and recommendations are based on the committee's review and analysis of various types of data, including randomized, controlled (dose and duration) clinical trials, spontaneous reports of adverse events, and survey data.3 The postmarketing trials met current standards for a well-controlled clinical trial; the premarketing trials were adequate for the time and were sufficient to provide data of adequate quality to judge the effects of the drug. A statistical reanalysis of the data from trials using questionnaires to evaluate the subjects' sleep clearly supports the previous analyses that Halcion positively affects the quality of sleep. Polysomnographic data did not exhibit evidence of tolerance over time. Additionally, the committee found that a dose-response relationship does exist, and the literature generally supports the claim that the drug is efficacious.
Based on review of the original studies, FDA's reanalysis, and the IOM committee's own reanalysis of 20 studies, the questionnaire and polysomnographic dam are adequate to support the conclusion that Halcion is effective in achieving the defined endpoints in the general adult population with insomnia when used as directed (in the current labeling) at doses of 0.25 mg for up to 7-10 days. In addition, polysomnographic data from clinical trials support the efficacy of Halcion at 0.25 mg in non-geriatric adults for 2 Weeks or more.
The questionnaire data are limited but adequate to support the conclusion that Halcion is effective in achieving the defined endpoints at the 0.125-mg dose in the geriatric population. Two studies (one for 2 days' duration; one for 7 days' duration) support this conclusion; one
Tolerance is the pharmacological term indicating a waning effect with the continuing use of the same dose of a drug, or the ability to endure or be less responsive to a stimulus, especially over a period of continued exposure. See Appendix C.
It is important to note that the conclusions and recommendations are based on a review of publicly available information. The committee did not review original, raw data or case reports but, rather, reviewed the data that were summarized in the New Drag Application and other sources and data that have been reviewed by FDA. The committee's analyses were based on these publicly available summary data.
study in the literature did not. Although there are no polysomnographic clinical trials in the New Drug Application for the 0.125-mg dose in geriatric subjects, nor in the postmarketing clinical trials or published literature for this dose in geriatric subjects with insomnia beyond 3 days of treatment, the committee's reanalysis of the combined data clearly shows statistically significant drug-related effects at the 0.125-mg dose in the geriatric population.
Although analysis of the questionnaire data supports the efficacy of Halcion at a dose of 0.125 mg in the geriatric population, inadequate data are available to establish the effect of this dose on sleep architecture in the elderly insomniac.
Recommendation 1: Improve Confidence in Lowest Dose. Definitive short-, intermediate-, and long-term polysomnographic studies are needed in a geriatric population to determine the sleep architecture of elderly insomniacs using the 0.125-mg dose.
Clinical Trial Design
The study designs and quantitative endpoints (i.e., sleep latency, duration, awakenings, and global assessment) used in the major clinical trials of Halcion in the past are of sufficient quality to yield adequate and reliable data for the determination of efficacy. The modem standards for the conduct of clinical trials have become more rigorous.
Recommendation 2: Update Guidelines. FDA should revise and update its Guidelines for the Clinical Evaluation of Hypnotic Drugs (U.S. Department of Health, Education, and Welfare, 1977) to include clinical trials on the intermediate- and long-term efficacies of hypnotic drugs. Future studies comparing Halcion with other drugs should use multiple doses of both Halcion and the comparator drugs to permit the determination of relative clinical potency.
Recommendation 3: Improve Outcomes Measures. Research is needed to identify the most valid and reliable endpoints for determination of the clinical efficacies of hypnotic agents. Most importantly, this should include endpoints that are nested in a 24-hour day-night cycle (e.g., to evaluate amnesia and daytime sedation). This should also include better integration of the subjective and objective (polysomnographic) response measures.
The committee's analysis of questionnaire data from studies of the efficacy of Halcion taken for up to 43 days indicates that there is no evidence to support the development of tolerance to the hypnotic effects of Halcion; that is, the difference in the effects between drug versus placebo was consistent over time (0.5 mg for 43 days, 0.25 mg for 28 days, 0.125 mg for 8 days, and 0.25 nag for 12 weeks). In addition, polysomnographic data from clinical trials
do not provide evidence of tolerance. In contrast to the clinical trial data, the polysomnographic literature suggests that tolerance may develop. However, available data suggests that tens of thousands of prescriptions are being obtained by patients for much longer periods of time (e.g., the Evaluation of Medications for Insomnia in Canada study reports a mean duration of 1.7 years of use in Canada). No data indicating the efficacy (or safety) of such long-term use of Halcion for chronic insomnia exist.
Recommendation 4: Determine Tolerance. Controlled clinical trials of a duration of Halcion use beyond that recommended in the current labeling are needed to determine whether tolerance to Halcion develops with long-term use.
ASSESSMENT OF SAFETY DATA
The committee also considered the quality and the adequacy of the data (e.g., clinical trial data and spontaneous reports of adverse events) with regard to the safety of Halcion, particularly the concerns that the drug (1) produces a unique profile or syndrome of adverse events, and (2) produces adverse effects that are qualitatively similar to but quantitatively more frequent or severe than the adverse effects associated with drugs in the benzodiazepine class of drugs or drugs with benzodiazepine-like activity.
Conclusions and Recommendations
The data from premarketing clinical trials, postmarketing studies, and the published literature do not support clearly the existence of a unique profile or syndrome of adverse events associated with Halcion relative to those associated with other drugs of its type. Furthermore, reanalysis of 25 parallel-group, placebo-controlled studies and a review of the published literature did not provide clear evidence of a greater risk of adverse events associated with Halcion relative to the risk of adverse events associated with comparator drugs of its class.
On the other hand, there are some gaps in the data regarding safety. For example, despite reports of amnesia, no study has been conducted to evaluate rigorously the effects of Halcion on autobiographical memory. Studies addressing this shortcoming would be an important addition to the understanding of the effects of triazolam. Also, because it is clear that Halcion is frequently used at higher doses and for longer durations than those recommended by FDA, studies of the long-term use of high-dose Halcion should be considered.
Clinical Trials and Surveillance
The committee is confident in the quality and adequacy of the data from the clinical trials (pre- and postmarketing) supporting the safety of using Halcion within the current labeling guidelines. The committee recognizes, however, that the lack of significant adverse
events reported from clinical trials appear to conflict with the numbers and types of adverse events (e.g., anterograde amnesia and confusion) that have appeared in the Spontaneous Reporting System of FDA and in some case reports in the literature. Many factors contribute to this apparent conflict, including the nature and design of clinical trials and external events that can affect the reporting of adverse events.
It is important to note that the statistical power to detect rare events is necessarily limited in controlled clinical trials because such trials include a small number of subjects compared with the number of patients using the drug in the postmarketing period, and subjects admitted to the trials must conform to carefully defined inclusion and exclusion criteria, narrowing the likely range of adverse events; rare events are unlikely to be detected in sample populations of a few hundred subjects. In addition, the treatment regimens in these trials are purposely chosen to avoid untoward or adverse events that might be expected to occur with higher doses or with dose dependent or duration-dependent use.
With respect to surveillance and reports of adverse events, the committee notes that apparent inconsistencies in the data from clinical trials and spontaneous reports are likely to occur for the reasons stated above, and concludes the following:
The popularity and consequent widespread use of Halcion produced large at-risk populations from which spontaneous reports of adverse events emerged.
Many people take Halcion (and other hypnotic drugs) for more than a year and at dosages above those recommended in the labeling.
In general, the types and frequencies of reported adverse events are subject to many external influences, including media attention, marketing, litigation, differential reporting rates, ability to connect drug use to a health event, and other factors, all of which affect the accuracy of interpreting the results.
Recommendation 5: Improve Surveillance, Analysis, and Integration of Findings. The committee recommends that FDA develop improved methods for integrating the findings of clinical trials and postmarketing surveillance, and for resolving discrepancies in the interpretation of data from spontaneous reports, clinical case reports, and controlled clinical trials. This would include the reestablishment of a biostatistics and epidemiology advisory committee (in addition to having biostatistics and epidemiology expertise on the other advisory committees) that would be charged with the rapid and thorough assessment of the potential health risks suggested by reports of adverse events, identification and resolution of conflicts that may arise in the review of clinical trial and surveillance data, and the provision of expert advice on the maintenance and operation of effective postmarketing surveillance systems.
During the course of the study, the IOM committee was led by the data and other information to consider some important, broader implications of its findings. The committee's
concluding remarks in this report therefore address, first, the need for additional research to expand and improve the fundamental understanding of sleep and the related condition of insomnia. Second, but not less important, is an issue that arose from information that was collected in an attempt to reconcile the apparent discrepancy between the clinical trial data and the reports of adverse events related to the use of Halcion. It seemed that at least some of the adverse events that were being reported through the Spontaneous Reporting System of FDA were similar to those that had been reported in some of the early clinical trials with higher doses and longer durations of use of Halcion. This, combined with survey data that indicate that many people use hypnotic agents for very long periods of time (the Evaluation of Medications for Insomnia in Canada reported average use of 1.7 years), led the committee to consider the possibility that the adverse events that were being reported for Halcion might be due, at least in part, to the use of Halcion for longer periods of time and at higher doses than those currently recommended in the labeling.
The committee believes that this type of use may be a problem common to all hypnotic medications and is complicated by incomplete understanding of insomnia and its clinical management. Although prescription of hypnotic drugs at higher doses and for longer durations than those recommended in the product labeling may provide benefit to some patients, the magnitude of Halcion use at higher doses and for longer durations than those that are recommended also suggests that alternatives (e.g., other medications or diagnoses) are not being fully explored, to the potential detriment of patients.
Spontaneous reporting of adverse events provides a "signal" to FDA of the possibility of serious unintended threats to the health of the patient. The pharmacoepidemiolgist, among others, then has the task of deciding which signals should be followed up and which can be ignored. The severity of the events, the size of the at-risk population (and the potential for larger numbers of adverse events), and information concerning use at higher doses or for longer durations than those that are recommended are all important factors in the decision to pursue the spontaneous report(s) further.
Postmarketing surveillance requires the collection and assessment of at least two very different types of information: (1) data from controlled trials, and (2) data from spontaneous reports of adverse events. These two types of data vary significantly in their quality, and, thus, their interpretation as a body can be quite complicated. This was true for Halcion, because some of the clinically significant adverse events (e.g., memory impairment, nervousness) were detected not in the clinical trials but only in the spontaneous reports. In such circumstances and in those instances in which adverse events are difficult to detect—but are clinically significant in terms of the health and well-being of the patient—the need for objective, critical assessments, better methods for detecting behavioral or psychological adverse events, and integrated evaluations of the entire body of information is critical.
Recommendation 6: Improve Postmarketing Data Collection and Analysis . The committee recommends that additional effort be dedicated to the postmarketing surveillance and monitoring of hypnotic agents and other drug products and that this effort include objective and critical evaluations of integrated sets of data on adverse events, on actual patient use, and from clinical trials. Special emphasis should be placed on developing improved methods for (1) collecting and
integrating evaluations of patient use data and Clinically significant adverse events, and (2) responding effectively when there appear in the spontaneous reports signals that correlate with data indicating patient use at higher doses and for longer durations than those that are recommended.
Recommendation 7: Educate Health Care Providers. The committee recommends that FDA establish an independent task force with the charge of reviewing and developing mechanisms for improving prescribing practices and patient use of hypnotic medications. This task force should pay special attention to issues raised by the actual use of these agents and, for physicians, to the issues of appropriate differential diagnosis when addressing the problem of insomnia in their patients. It would be useful to provide physicians with efficacy and adverse effects dose-response curves for durations comparable to those being used in practice, even if they are greater than those recommended in the labeling.
In addition, the committee recommends that professional societies of primary care and other health providers increase their members' attention to the need for caution in prescribing hypnotic drugs at higher doses and for longer durations than those that are recommended. Efforts in this area should include increased attention to this issue in medical education and in residency programs, including the addition of questions about the use of hypnotic drugs on medical specialty examinations.
FDA should identify ways to disseminate information on the diagnosis and management of insomnia more effectively to medical students and in training programs for primary care physicians.
Table 1 presents the individual tasks that were addressed by the Committee and a summary of the relevant conclusions and recommendations.
TABLE 1 Committee Tasks and Summary of Relevant Conclusions and Recommendations