Background Phase 2 trials are instrumental for designing definitive efficacy trials or attaining accelerated approval. However, high attrition of drug candidates in phase 2 raises questions about their supporting evidence. Methods We developed a typology of supporting evidence for phase 2 cancer trials. We also devised a scheme for capturing elements that enable an assessment of the strength of such evidence. Using this framework, we content analyzed supporting evidence provided in protocols of 50 randomly sampled phase 2 cancer monotherapy trials starting between January 2014 and January 2019, available on ClinicalTrials.gov. Results Of the 50 protocols in our sample, 52% were industry funded. Most invoked supporting evidence deriving from trials against different cancers (n = 28, 56%) or preclinical studies (n = 48, 96%), but not from clinical studies involving the target drug-indication pairing (n = 23, 46%). When presenting evidence from models, only one protocol (2%) explained their translational relevance. Instead, protocols implied translatability by describing molecular (86%) and pathophysiological (84%) processes shared by model and target systems. Protocols often provided information for assessing the magnitude, precision and risk of bias for supporting trials (n = 43, 93%, 91%, 47%, respectively). However, such information was often unavailable for preclinical studies (n = 49, 53%, 22%, 59%). Conclusion Supporting evidence is key to justifying the commitment of scientific resources and patients to a clinical hypothesis. Protocols often omit elements that would enable critical assessment of supporting evidence for phase 2 monotherapy cancer trials. These gaps suggest the promise of more structured approaches for presenting supporting evidence.

中文翻译：

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2 期癌症试验方案中的支持证据：内容分析


背景 2 期试验有助于设计确定性疗效试验或获得加速批准。然而，第 2 阶段候选药物的高流失引发了对其支持证据的质疑。方法 我们为 2 期癌症试验开发了支持证据的类型学。我们还设计了一个方案来捕捉能够评估此类证据强度的要素。使用这个框架，我们分析了从 2014 年 1 月开始的 50 项随机抽样的 2 期癌症单一疗法试验方案中提供的支持证据，可在 ClinicalTrials.gov 上获得。结果在我们样本的 50 个协议中，52% 是企业资助的。大多数援引的支持证据来自针对不同癌症的试验 （n = 28， 56%） 或临床前研究 （n = 48， 96%），但不是来自涉及目标药物-适应症配对的临床研究 （n = 23， 46%）。在提供来自模型的证据时，只有一个方案 （2%） 解释了它们的转化相关性。相反，协议通过描述模型和目标系统共享的分子 （86%） 和病理生理学 （84%） 过程来暗示可翻译性。方案通常提供用于评估支持试验的量级、精密度和偏倚风险的信息（分别为 n = 43、93%、91%、47%）。然而，此类信息通常无法用于临床前研究 （n = 49， 53%， 22%， 59%）。结论支持证据是证明科学资源和患者对临床假设的承诺的关键。方案通常省略了能够对 2 期单药治疗癌症试验的支持证据进行关键评估的要素。这些差距表明，有望采用更结构化的方法来提供支持证据。