Food and Drug Administration (FDA) (Laughren and Lee, 1992); both had been presented at a May 1992 meeting of the FDA Psychopharmacologic Drugs Advisory Committee (PDAC). The committee first analyzed the frequency of adverse events and then examined the frequency and nature of adverse events that led to the withdrawal of subjects from the trials (i.e., dropouts).

Adverse Events

In 1992 Upjohn created a new database of safety information by reentering the data from the case-report forms for the 116 clinical trials in the NDA. FDA oversaw this effort and verified that ''there was a highly accurate transfer of pertinent data" from the case reports to the new database (Laughren and Lee, 1992, p. 9). Upjohn also developed an ISS using results from 79 studies (from among the 116 studies from the NDA, but without the Phase I studies and including the available postmarketing clinical trials) comparing approximately 4,000 subjects treated with Halcion (0.1 to 1.0 mg), 1,300 subjects treated with flurazepam (Dalmane; 15 to 30 mg), and 2,100 subjects treated with placebo.

A subset of the 116 studies was selected specifically to compare Halcion with placebo and another benzodiazepine hypnotic drug. That subset consisted of the 25 studies that (1) involved subjects with insomnia, (2) had a parallel-group design, (3) were at least 1 week in duration, and (4) involved placebo or flurazepam as the comparator drug. Upjohn used this subset of 25 studies in its comparative analysis in the ISS, and FDA used this subset in its analysis of dropouts. The IOM committee first examined Upjohn's comparative analysis of the frequency of adverse events as described in the ISS.

Integrated Summary of Safety

Table 3-1 indicates the frequency of adverse events involving the central nervous system (CNS) from the 79 clinical trials in the ISS. Tables 3-2 through 3-5 present tabular summaries of the data from the subset of 25 studies using the following classifications: adult and geriatric insomniac populations, low and high doses, and shorter and longer durations. In reviewing these data, the committee made the following three observations.

Observation 1: Comparable Safety Profile

Halcion at the currently recommended doses (0.125 and 0.25 mg) and for the shortest durations of use (1 to 7 days) has a safety profile comparable to those of both placebo and the lowest dose of flurazepam (15 mg), even for those undesirable events associated with the pharmacologic activity of benzodiazepines, namely, restlessness, nervousness, drowsiness, impaired coordination, light-headedness, and dizziness (Tables 3-2, 3-4, and 3-5). Rates of response for the most frequently occurring CNS-related adverse event (sedation or drowsiness) were 16.7, 23.5, and 11.3 percent for the three groups (Halcion, flurazepam, and placebo), respectively (see Table 3-1), Dizziness and headache were second and third most common adverse events. Other events of interest described in the tabulated summaries were impaired memory (at rates of 0.7, 0.5, and 0.2 percent, respectively) and impaired coordination (at rates of 3.4, 4.6, and 1.5 percent, respectively).

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