Halcion An Independent Assessment of Safety and Efficacy Data (1997) / Chapter Skim
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Assessment of Efficacy Data
Assessment of Efficacy Data
Pages 20-48
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From page 20... ...
~ ^~ To assess the quality and quantity of the available data regarding the efficacy of Halcion, the committee first examined the indications for the use of hypnotic drugs and the means of evaluating the efficacies of these types of drugs, including the requirements for approval by FDA. The committee then assessed the quality of the protocols and the designs of the pro- and postmarketing clinical trials investigating the efficacy of Halcion.
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From page 21... ...
The exclusion criteria should be such that large segments of the population who will be treated in good clinical practice will not be eliminated. However, because impairment of steep can be a clinical symptom associated with psychotic disorders, the standard of care is treatment of the psychotic disorder rather than prolonged use of hypnotic agents, and the exclusion of psychotic patients in clinical trials of an hypnotic agent is justified and appropriate.
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indeed, although not a specific objective, in a study comparing the effects of nefazodone and fluoxetine on mood and polysomnographic data for depressed patients complaining of insomnia, the patients and clinicians reported nearly equal improvement in subjective steep measures for both days, whereas polysomnographic data showed a progressive deterioration of some measures for fluoxetine (Gillin et al., 1997~. Finally, the nature of polysomnographic studies restricts them to small numbers of subjects who are unlikely to be a representative subset of the population at large.
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From page 23... ...
The committee also reviewed a final report of a study that FDA used in making its decision concerning the approval of Halcion at lower doses but that was not part of the Upjohn NDA (Lee, 19901. QUALITY OF PROTOCOLS AND STUDY DESIGN Before undertaking its review, the committee familiarized itself with the FDA publication Guidelines for the Clinical Evaluation of Hypnotic Drugs (U.S.
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Patient selection criteria did not include body weight, a factor that might affect the levels of a drug in the blood of subjects receiving the same dose. Analyses of statistical power, which are required to determine the appropriate number of subjects to be enrolled in the study (which requires identification of the minimal detectable difference)
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30 HALCION: AN INDEPENDENT ASSESSMENT TABLE 2-2 Results of TOM Committee Review of Low-Dose Protocols, Pivotal Protocols, and Postmarketing Protocols No. of Protocols Mewing the Cntenon/ Total No.
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From page 31... ...
Low-dose protocols included Protocols 2401, 6010, 6014 IV, 6020, 6033, 6034, 6035, 6056, 6060, 6060A, 6061, 6062, 6063, 6064, 6065, 6401, 6402, 6403, 6414, and 6417. Pivotal protocols included Protocols 6024, 6041, and 6045.
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From page 32... ...
The primary endpoint variables were polysomnographic sleep latency and total sleep time. For steep latency, Halcion was significantly more effective than placebo at both the beginning and the end of the treatment period (p = 0.015 and <0.0l, respectively)
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for subjects receiving Halcion at the 0.125-mg level. TABLE 2-3 Polysomnographic Data Results for Tolerance for 0.25-mg Dose in Controlled Clinical Trials Difference Protocol and Periods of Comparison Total Sleep Time (mint Sleep Latency (min)
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In addition, it is of critical importance to characterize the magnitude of both expected and observed effects (e.g., the size of the mean difference in overall sleep time between the Halcion and placebo groups divided by a pooled estimate of the standard deviation)
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1 1 BOX 2-1 FOUR PRIMARY ENDPOINTS AND THEIR RESPECTIVE RATING CATEGORIES USED IN THE QUESTIONNAIRES 1. Patient global rating: Did the medication help you sleep?
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By contrast, only 17 percent of the subjects receiving Halcion reported no help from the drug, whereas 5 ~ percent of the subjects receiving placebo reported no help from the drug. For onset, 64 percent of the subjects treated with 0.25 mg of Halcion reported "quicker sleep onset," whereas only 27 percent of the subjects receiving placebo reported such an effect.
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. In summary, reanalysis of the efficacy data obtained by questionnaire supports the earlier findings of FDA that demonstrated the efficacy of 0.25 mg of Halcion for the general adult population and 0.125 mg of Halcion for the geriatric population.
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From page 39... ...
is improved for subjects receiving the 0.25- and 0.5-mg doses relative to that for subjects receiving placebo; however, the observed proportions for 0.25 and 0.5 mg of HaTcion are identical. The results of the statistical analysis reveal significant linear doseresponse relationships for global ratings (p < 0.0001)
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From page 40... ...
Global Sleep Quality Rating HALCION: AN INDEPENDENT ASSESSMENT O- 1 1 1 None A Little Quite a Bit A Lot (b) Sleep Latency come (c} Sleep Duration 5-6 Hours 6.1-7 Hours 7.1-8 Hours (d)
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From page 41... ...
Secondary outcome variables were items on a morning questionnaire and the subjects' global clinical assessment. Halcion improved sleep latency and the duration of sleep compared with those for subjects receiving placebo, but not to a statistically significant degree.
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Polysomnographic Studies of Halcion in the Published Literature Polysomnographic studies provide the most detailed and quantitative measures of physiologic sleep. These measures include sleep latency, total sleep time, sleep efficiency, number of awakenings, wake time after sleep onset (WASO)
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From page 43... ...
Interestingly, subjective improvements showed tolerance for steep latency and sleep quality. In two studies with elderly subjects using Halcion at 0.25 mg for 2 weeks, the steep of subjects given Halcion showed statistical improvement over baseline when measured at the end of the study and compared to the sleep of subjects receiving placebo (Mouret et al., 1990; Scharf et al., 1990~.
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From page 46... ...
Except for the study with elderly patients with PEMS, the committee found no polysomnographic data for the 0.125-mg dose of the geriatric population for 7 to 10 nights of treatment. CONCLUSIONS AND RECOMMENDATIONS in summary, the TOM committee reviewed the protocols and study designs of clinical trials used to evaluate the efficacy of Halcion.5 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.
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From page 47... ...
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-realted 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.
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From page 48... ...
. In addition, polysomnographic data from clinical trials do not provide evidence of tolerance, but the polysomnographic literature suggests that tolerance may develop.
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