Potthoff Richard F
a Cancer Statistical Center, Duke University Medical Center , Durham , NC , U.S.A.
J Biopharm Stat. 2018;28(4):633-644. doi: 10.1080/10543406.2017.1372773. Epub 2017 Oct 30.
Loss to follow-up (LTFU) in clinical trials represents a potential threat to their soundness that may not be adequately recognized. We consider a log-rank test in a trial with two arms, experimental and control, and with a single unfavorable binary endpoint such as death. Commonly, one applies censoring to patients with LTFU. That approach is valid if LTFU is independent of outcome, but can lead to bias otherwise. Unfortunately, there is no statistical test for independence, so the legitimacy of the approach rests on unverifiable assumptions. For two cases, we evaluate the impact of the approach based on simulations that use reasonable models for outcome-dependent LTFU. In each case, LTFU in one arm disproportionately suppresses recognition of relatively early deaths or other outcomes, thus producing bias favoring that arm. The first case has extra LTFU in the experimental arm and the treatment has no benefit. The second case has extra LTFU in the control arm and the treatment is effective. The simulation results show severe inflation of Type I error in the first case and major loss of power in the second case. Remedies for LTFU are scarce but include avoiding it in the first place where possible.
临床试验中的失访（LTFU）对试验的可靠性构成了潜在威胁，而这一点可能未得到充分认识。我们考虑在一个有试验组和对照组两个臂的试验中进行对数秩检验，且有一个单一的不良二元终点，如死亡。通常，人们会对失访的患者进行删失处理。如果失访与结局无关，那么这种方法是有效的，但否则可能会导致偏差。不幸的是，目前没有用于检验独立性的统计方法，所以这种方法的合理性依赖于无法验证的假设。对于两种情况，我们基于模拟评估该方法的影响，这些模拟使用了合理的依赖结局的失访模型。在每种情况下，一个臂中的失访不成比例地抑制了对相对早期死亡或其他结局的识别，从而产生有利于该臂的偏差。第一种情况是试验组有额外的失访且治疗无益处。第二种情况是对照组有额外的失访且治疗有效。模拟结果显示，第一种情况下I型错误严重膨胀，第二种情况下检验效能大幅损失。针对失访的补救措施很少，但包括尽可能首先避免失访。
