Department of Neurology, New York University, New York, New York, USA.
Epilepsia. 2010 Oct;51(10):1936-43. doi: 10.1111/j.1528-1167.2010.02650.x.
Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled "withdrawal to monotherapy" in treatment-resistant patients, which employs a so-called "pseudo-placebo" as a comparator arm. The authors submitted a white paper to the FDA advocating use of a virtual placebo historical control as an alternative to pseudo-placebo. Such an approach reduces patient risk that would result from exposure to pseudo-placebo. In this article, we present the data submitted to the FDA to justify a historical control.
We analyzed individual patient data from eight previously completed withdrawal to monotherapy studies, which we determined had similar design. All studies employed percent meeting predetermined exit criteria (denoting worsening of seizure control) as the outcome measure. Kaplan-Meier estimates of the percent exiting were calculated at 112 days.
The percent meeting exit criteria were uniformly high, ranging from 74.9-95.9%. The eight studies appear to meet the criteria set forth for use of historical control. The estimate of the combined percent exit based on the noniterative mixed-effects model is 85.1%, with a lower bound of the 95% prediction interval of 65.3%, and 72.2% for an 80% prediction interval.
There is justification for proposing that these data can serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo-placebo arm in trials intended to demonstrate the efficacy of approved drugs as monotherapy in treatment-resistant patients.
从美国食品和药物管理局 (FDA) 获得单药治疗批准一直很困难，几乎所有批准都是在耐药患者中使用一种名为“撤药至单药治疗”的试验设计获得的，该设计采用所谓的“假性安慰剂”作为对照臂。作者向 FDA 提交了一份白皮书，主张使用虚拟安慰剂历史对照作为假性安慰剂的替代方法。这种方法降低了患者因接触假性安慰剂而面临的风险。在本文中，我们展示了提交给 FDA 的数据，以证明历史对照的合理性。
我们分析了来自八项先前完成的撤药至单药治疗研究的个体患者数据，这些研究被确定具有相似的设计。所有研究均采用符合预定退出标准的患者百分比（表示癫痫控制恶化）作为主要终点。计算了 112 天时退出的百分比的 Kaplan-Meier 估计值。
符合退出标准的百分比均很高，范围为 74.9-95.9%。这八项研究似乎符合提出使用历史对照的标准。基于非迭代混合效应模型的联合退出百分比估计值为 85.1%，95%预测区间的下限为 65.3%，80%预测区间为 72.2%。
有理由提出这些数据可以作为未来单药治疗研究的历史对照，从而避免在旨在证明已批准药物作为耐药患者的单药治疗疗效的试验中需要安慰剂/假性安慰剂臂。
