Predictive Evidence Threshold Scaling: Does the Evidence Meet a Confirmatory Standard?

Making better use of evidence is one of the tenets of modern drug development. This calls for an understanding of the evidential strength of nonconfirmatory evidence relative to a confirmatory standard. Such inferential comparisons can be done via predictive evidence threshold scaling (PETS). Under PETS, the evidence meets a confirmatory standard if the predictive probability of a positive effect reaches the predictive evidence threshold from hypothetical confirmatory data. These probabilities require plausible assumptions about between-trial heterogeneity and potential biases. Two examples are discussed. The first is breakthrough designation, illustrated by a recent Food and Drug Administration approval of crizotinib for the treatment of non-small-cell lung cancer based on phase I and II data. The second is childhood Guillain–Barré syndrome, with sparse children data enriched with adult data. The examples suggest that the evidential strength of nonconfirmatory data can meet a confirmatory standard. This is reassuring for modern drug development, which exploits various types of evidence to inform adaptive licensing decisions. Supplementary materials for this article are available online.

更高效地利用证据是现代药物研发的核心原则之一。这要求我们明确相较于确证性标准，非确证性证据的证据强度。此类推断比较可通过预测性证据阈值缩放法（Predictive Evidence Threshold Scaling，PETS）实现：在PETS框架下，若阳性效应的预测概率基于假设性确证性数据达到预测性证据阈值，则该证据可符合确证性标准。此类概率的计算需针对试验间异质性与潜在偏倚作出合理假设。本文将讨论两个案例：其一为突破性疗法认定，以美国食品药品监督管理局（Food and Drug Administration，FDA）近期基于Ⅰ期和Ⅱ期临床试验数据批准克唑替尼用于治疗非小细胞肺癌为例进行阐释；其二为儿童吉兰-巴雷综合征，其稀缺的儿童病例数据通过纳入成人数据得以扩充。上述案例表明，非确证性数据的证据强度可达到确证性标准，这对于依托各类证据制定适应性审批决策的现代药物研发而言，无疑是令人安心的结论。本文的补充材料可在线获取。