Family Health International (FHI 360), Durham, NC 27713, USA.
Clin Trials. 2012 Aug;9(4):377-84. doi: 10.1177/1740774512445512. Epub 2012 May 18.
Vaginally and rectally applied microbicides are being developed to help prevent sexual acquisition of HIV. Due to the lack of surrogate outcomes, the path toward licensure typically moves directly from expanded safety studies to expensive Phase 2b/3 trials with rare incident infection outcomes. The need to confirm an initial trial's significant finding can lead to serious delays in implementing essential programs to reduce the spread of HIV.
To propose an adaptive design where a Phase 2b/3 study powered to detect a clinically meaningful effect with evidence of one trial (observing one-sided p < 0.025) is allowed to expand by a prespecified, feasible amount if interim data suggest the chance of further achieving a more robust evidence threshold (p < 0.001, potentially sufficient for licensure from a single trial) is promising.
As an example, prespecified conditional power criteria are used to determine whether a 90-event trial with 90% power to detect a 50% reduction in risk should be expanded to 130 events. Asymptotic results and simulations are used to assess false-positive error rates and other operating characteristics of the design.
False-positive error rates can be controlled at the desired 0.025 and 0.001 levels with appropriate choice of critical values or expansion criteria. The chance of achieving robust evidence can approach that of a 130-event trial with traditional stopping boundaries (controlling a = 0.001) but with substantially lower expected size for plausible effectiveness levels.
Conditional power calculations assume the interim estimate of effect is an unbiased estimate for the remainder of the trial, an assumption which may not hold if product adherence varies over time. Observing a measure of effect with p < 0.001 may not be sufficient for licensure. A decision to expand the trial would be informative to investigators regarding the interim effect size.
A moderate increase in trial size can make the difference between a study with good power to detect a clinically meaningful effect and one which may reasonably obtain the robust evidence required for regulatory bodies and public health programs to consider making a new microbicide available to persons at risk of HIV infection. The proposed design allows for this possibility while not requiring investigators to make an up-front commitment to a prohibitively large trial.
正在开发阴道和直肠应用的杀微生物剂，以帮助预防通过性行为感染艾滋病毒。由于缺乏替代结果，获得许可的途径通常直接从扩大安全性研究进入昂贵的 2b/3 期试验，这些试验的感染结果罕见。需要确认初始试验的显著发现可能导致在实施减少艾滋病毒传播的基本计划方面出现严重延误。
提出一种适应性设计，如果一项 2b/3 期研究有能力检测到具有一项试验证据的临床有意义的效果（观察到单侧 p < 0.025），并且如果中期数据表明进一步达到更有力证据阈值的机会（p < 0.001，可能足以从单一试验获得许可）有希望，则允许按规定的可行数量扩大。
作为一个例子，使用预定的条件功效标准来确定是否应该将 90 项事件试验扩大到 130 项事件，该试验有 90%的功效来检测风险降低 50%。使用渐近结果和模拟来评估设计的假阳性错误率和其他操作特征。
通过适当选择临界值或扩展标准，可以将假阳性错误率控制在所需的 0.025 和 0.001 水平。达到有力证据的机会可以接近具有传统停止边界的 130 项事件试验（控制 a = 0.001），但对于合理的有效性水平，预期规模要小得多。
条件功效计算假设中期效果估计是整个试验其余部分的无偏估计，如果产品依从性随时间变化，则该假设可能不成立。观察效果的度量值为 p < 0.001 可能不足以获得许可。扩大试验的决定将为研究人员提供有关中期效果大小的信息。
适度增加试验规模可以使具有良好检测临床有意义效果的能力的研究与可能合理获得监管机构和公共卫生计划考虑使新的杀微生物剂可供感染艾滋病毒风险的人使用的有力证据的研究之间产生差异。所提出的设计允许这种可能性，而无需研究人员对一项大到不可行的试验做出预先承诺。
