4
Additional Comments on Broader Implications

During the course of this study, the Institute of Medicine (IOM) committee was led by the data and other information to consider some important, broader implications of its findings. The committee's concluding remarks therefore address, first, the need for more research to improve the fundamental understanding of sleep and the related condition of insomnia; and secondly, the need to improve both the integration of the various types of postmarketing information and the attention that is paid to the information that is collected.

Insomnia is often an acute, short-term disorder, but for many it is a chronic condition that requires longer-term attention. It is also a disorder that is poorly understood from a diagnostic perspective, and the available tools for the management of insomnia are fairly limited. Furthermore, little is known about the interaction of hypnotic drags with other drugs and substances in people of differing ages, gender, and diagnoses. Furthermore, large numbers of people take hypnotic drugs for longer periods of time and at higher doses than those that are recommended, despite limited knowledge of potential benefits or adverse events. A better understanding of the basic science of sleep and insomnia would facilitate the development of improved therapeutic agents as well as the clinical management of insomnia. The committee believes, therefore, that additional research is needed in this area, in conjunction with the development of improved guidelines for the evaluation of hypnotic agents (see Chapter 2).

The second broad implication 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 (triazolam). It seemed that at least some of the adverse events that were being reported through the Spontaneous Reporting System (SRS) of the U.S. Food and Drug Administration (FDA) were similar to those that had been reported in some of the early clinical trials with higher doses of Halcion and with longer durations of use. This, combined with survey data that indicates that many people use hypnotic agents for very long periods of time (a Canadian survey [the Evaluation of Medications for Insomnia in Canada (EMIC)] reported average use of 1.7 years) led the committee to consider the possibility that



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Halcion: An Independent Assessment of Safety and Efficacy Data 4 Additional Comments on Broader Implications During the course of this study, the Institute of Medicine (IOM) committee was led by the data and other information to consider some important, broader implications of its findings. The committee's concluding remarks therefore address, first, the need for more research to improve the fundamental understanding of sleep and the related condition of insomnia; and secondly, the need to improve both the integration of the various types of postmarketing information and the attention that is paid to the information that is collected. Insomnia is often an acute, short-term disorder, but for many it is a chronic condition that requires longer-term attention. It is also a disorder that is poorly understood from a diagnostic perspective, and the available tools for the management of insomnia are fairly limited. Furthermore, little is known about the interaction of hypnotic drags with other drugs and substances in people of differing ages, gender, and diagnoses. Furthermore, large numbers of people take hypnotic drugs for longer periods of time and at higher doses than those that are recommended, despite limited knowledge of potential benefits or adverse events. A better understanding of the basic science of sleep and insomnia would facilitate the development of improved therapeutic agents as well as the clinical management of insomnia. The committee believes, therefore, that additional research is needed in this area, in conjunction with the development of improved guidelines for the evaluation of hypnotic agents (see Chapter 2). The second broad implication 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 (triazolam). It seemed that at least some of the adverse events that were being reported through the Spontaneous Reporting System (SRS) of the U.S. Food and Drug Administration (FDA) were similar to those that had been reported in some of the early clinical trials with higher doses of Halcion and with longer durations of use. This, combined with survey data that indicates that many people use hypnotic agents for very long periods of time (a Canadian survey [the Evaluation of Medications for Insomnia in Canada (EMIC)] reported average use of 1.7 years) led the committee to consider the possibility that

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Halcion: An Independent Assessment of Safety and Efficacy Data the adverse events that were being reported for Halcion might be due, at least in part, to the use of Halcion for much longer periods of time and at higher doses than those currently recommended in the labeling.1 The committee believes that this type of use may be a problem common to all hypnotic medications and that it 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 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. Further investigations, if they are conducted, could include the following: Verification of possible adverse drug reactions (ADRs); Collection of estimates of drug use in a population; Search for more ADRs attributable to the suspect drug; Examination of in toxicology animal regarding the suspect drug; Examination and reanalyses of the data from clinical trials; Launching ad hoc case-control or cohort studies exploring the association of the drug and the suspected adverse event; Querying various drug surveillance systems under contract to FDA and regulatory bodies in other countries; Querying the drag company that markets the suspect drug; and Research studies with other designs, including rechallenge and withdrawing the drug (experiment in prevention). Postmarketing surveillance requires the collection and assessment of at least two very different types of information: data from controlled trials, and 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 1   The FDA task force also observed that "marketing data suggest that Halcion is sometimes prescribed by physicians for longer periods of time and at higher doses than is recommended in the labeling" (FDA, 1996, p. iii).

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Halcion: An Independent Assessment of Safety and Efficacy Data 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 include objective and critical evaluations of integrated data sets of adverse events, actual patient use, and clinical trials. This effort should include special emphasis on developing improved methods for (1) collecting and integrating evaluation of patient use data and clinically significant adverse events, including behavioral or psychological events, and (2) responding effectively when signals appear in the spontaneous reports 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 to the issues of appropriate differential diagnosis when addressing the problem of insomnia in 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 care 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.