Daniel Shepshelovich, Hadar Goldvaser, and Eitan Amir, Princess Margaret Cancer Centre and the University of Toronto, Toronto, Ontario, Canada; Daniel Shepshelovich and Hadar Goldvaser, Tel-Aviv University, Tel Aviv, Israel; Ariadna Tibau and Consolación Molto, Hospital de la Santa Creu i Sant Pau and Universitat Autònoma de Barcelona, Barcelona; Alberto Ocana, Castilla La Mancha University, Albacete, Spain; and Bostjan Seruga, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
J Clin Oncol. 2018 Jun 20;36(18):1798-1804. doi: 10.1200/JCO.2017.77.5593. Epub 2018 Apr 11.
Purpose Modifications in cancer drug indications, dosing, and related toxicities after Food and Drug Administration approval are common. It is unclear whether drug approval without a supporting randomized controlled trial (RCT) influences the probability of such modifications. Methods We searched the Drugs@FDA Web site for new drug indications for solid tumors approved between January 2006 and December 2016. Study characteristics, regulatory pathways, and label modifications from approval to October 2017 were collected from drug labels. Label modifications were considered to be major if defined as such in the drug label. Indications approved with and without supporting RCTs were compared using logistic regression. The Benjamini-Hochberg false discovery rate method was used to adjust for multiplicity. Results We identified 59 individual drugs for 109 solid tumor indications. Of these, 17 indications (15.6%) were not supported by an RCT, with no change over time. Indications not supported by RCTs were more likely to require companion diagnostic tests (odds ratio [OR], 3.90; P = .02), to include surrogate end points as primary outcomes (OR, 7.88; P < .001), and to receive breakthrough therapy designation (OR, 7.62; P = .006) or accelerated approval (OR, 17.67; P < .001). Indications not supported by RCTs were associated with significantly higher odds of postapproval modifications in common adverse events (71% v 29%; OR, 5.78; P = .002). A nonsignificantly higher odds of postapproval major modifications in warnings and precautions was also observed (88% v 62%; OR, 4.61; P = .051). Postapproval major modifications in indication and usage, dosing and administration, boxed warnings, and contraindications were comparable in the two groups. Conclusion Cancer drug indications not supported initially by RCTs are associated with more postmarketing safety-related label modifications. Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting RCT.
在获得食品和药物管理局批准后，癌症药物的适应证、剂量和相关毒性的修改很常见。尚不清楚没有支持性随机对照试验（RCT）的药物批准是否会影响此类修改的可能性。
我们在 Drugs@FDA 网站上搜索了 2006 年 1 月至 2016 年 12 月期间批准的用于实体瘤的新型药物适应证。从药物标签中收集了从批准到 2017 年 10 月的研究特征、监管途径和标签修改信息。如果药物标签中明确规定了，则认为标签修改是主要修改。使用逻辑回归比较有和没有支持性 RCT 批准的适应证。使用 Benjamini-Hochberg 假发现率方法进行多重调整。
我们确定了 59 种用于 109 种实体瘤适应证的药物。其中，有 17 种适应证（15.6%）没有 RCT 支持，且无时间变化。没有 RCT 支持的适应证更有可能需要伴随诊断测试（比值比 [OR]，3.90；P =.02），将替代终点作为主要终点（OR，7.88；P <.001），并获得突破性治疗指定（OR，7.62；P =.006）或加速批准（OR，17.67；P <.001）。没有 RCT 支持的适应证与常见不良事件的批准后修改的可能性显著增加相关（71%比 29%；OR，5.78；P =.002）。还观察到警告和注意事项的批准后主要修改的可能性也略有增加（88%比 62%；OR，4.61；P =.051）。两组适应证、用法、剂量和给药、框警告和禁忌证的批准后主要修改相似。
最初没有 RCT 支持的癌症药物适应证与更多的上市后安全性相关的标签修改相关。当开处方没有支持性 RCT 批准的药物时，医疗保健专业人员应警惕未被识别的不良反应。
