Evans Scott R, Rubin Daniel, Follmann Dean, Pennello Gene, Huskins W Charles, Powers John H, Schoenfeld David, Chuang-Stein Christy, Cosgrove Sara E, Fowler Vance G, Lautenbach Ebbing, Chambers Henry F
Harvard University, Boston, Massachusetts.
Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring.
Clin Infect Dis. 2015 Sep 1;61(5):800-6. doi: 10.1093/cid/civ495. Epub 2015 Jun 25.
Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use.
比较优化抗生素使用策略的临床试验至关重要,但受到竞争风险的限制,这些风险会扭曲结果解读、非劣效性试验的复杂性、大样本量以及在患者层面上对利弊评估不足。抗菌药物耐药性领导小组努力通过创新试验设计来克服这些挑战。根据抗生素风险持续时间调整的反应(RADAR)是一种新颖的方法,采用优效性设计和两步法:(1)将患者分为总体临床结局(基于利弊),(2)根据结局排名的期望程度(DOOR)对患者进行排名。DOOR是通过为以下患者赋予更高排名来构建的:(1)总体临床结局更好,(2)在相似总体临床结局下抗生素使用持续时间更短。比较抗生素使用策略之间的DOOR分布。估计随机选择的患者如果被分配到新策略中会有更好DOOR的概率。DOOR/RADAR代表了评估优化抗生素使用新策略风险和益处的新范式。