The use of a clinical utility index to compare insomnia compounds: a quantitative basis for benefit-risk assessment.
The use of a clinical utility index (CUI) was proposed in order to compare two calcium channel alpha2delta ligands that were in development for the treatment of insomnia. The important attributes included in the CUI were two measures of residual sedation and five measures of efficacy (wake after sleep onset, sleep quality, sleep latency, and sleep stages (stage 1 and stages 3-4)). Dose-response analyses were conducted on each end point, and a sensitivity analysis was conducted to determine a clinically meaningful difference in CUI. Nonparametric bootstrap parameters were used to build confidence intervals (CIs). Peak CUI (80% CI) was 0.345 (0.25-0.43), observed at a dose of approximately 30 mg with the lead compound and 0.436 (0.35-0.52) observed at >600-mg dose for the backup. Although CUI was slightly greater for the backup, peak CUI values were observed at doses that were not considered viable, and therefore development of the ligand was discontinued. The use of the CUI allowed an efficient, quantitative, and transparent decision.
Ouellet
D
D
Pfizer Global Research and Development, Ann Arbor, Michigan, New London, Connecticut, USA. daniele.x.ouellet@gsk.com
Werth
J
J
Parekh
N
N
Feltner
D
D
McCarthy
B
B
Lalonde
R L
RL
D015220:Calcium Channels / Q000378:metabolism; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006801:Humans; D006993:Hypnotics and Sedatives / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008024:Ligands; D017286:Polysomnography / Q000379:methods; D018570:Risk Assessment; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy* / Q000378:metabolism; D012894:Sleep Stages / Q000187:drug effects / Q000502:physiology; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology
C425903:CACNA2D1 protein, human; D015220:Calcium Channels; D006993:Hypnotics and Sedatives; D008024:Ligands