MRC Clinical Trials Unit at UCL, London, UK.
Clin Trials. 2024 Apr;21(2):162-170. doi: 10.1177/17407745231206261. Epub 2023 Oct 31.
A 2×2 factorial design evaluates two interventions (A versus control and B versus control) by randomising to control, A-only, B-only or both A and B together. Extended factorial designs are also possible (e.g. 3×3 or 2×2×2). Factorial designs often require fewer resources and participants than alternative randomised controlled trials, but they are not widely used. We identified several issues that investigators considering this design need to address, before they use it in a late-phase setting.
We surveyed journal articles published in 2000-2022 relating to designing factorial randomised controlled trials. We identified issues to consider based on these and our personal experiences.
We identified clinical, practical, statistical and external issues that make factorial randomised controlled trials more desirable. Clinical issues are (1) interventions can be easily co-administered; (2) risk of safety issues from co-administration above individual risks of the separate interventions is low; (3) safety or efficacy data are wanted on the combination intervention; (4) potential for interaction (e.g. effect of A differing when B administered) is low; (5) it is important to compare interventions with other interventions balanced, rather than allowing randomised interventions to affect the choice of other interventions; (6) eligibility criteria for different interventions are similar. Practical issues are (7) recruitment is not harmed by testing many interventions; (8) each intervention and associated toxicities is unlikely to reduce either adherence to the other intervention or overall follow-up; (9) blinding is easy to implement or not required. Statistical issues are (10) a suitable scale of analysis can be identified; (11) adjustment for multiplicity is not required; (12) early stopping for efficacy or lack of benefit can be done effectively. External issues are (13) adequate funding is available and (14) the trial is not intended for licensing purposes. An overarching issue (15) is that factorial design should give a lower sample size requirement than alternative designs. Across designs with varying non-adherence, retention, intervention effects and interaction effects, 2×2 factorial designs require lower sample size than a three-arm alternative when one intervention effect is reduced by no more than 24%-48% in the presence of the other intervention compared with in the absence of the other intervention.
Factorial designs are not widely used and should be considered more often using our issues to consider. Low potential for at most small to modest interaction is key, for example, where the interventions have different mechanisms of action or target different aspects of the disease being studied.
2×2 析因设计通过随机分配至对照组、仅 A 组、仅 B 组或 A 和 B 联合组来评估两种干预措施（A 与对照和 B 与对照）。扩展析因设计也是可能的（例如 3×3 或 2×2×2）。析因设计通常比替代的随机对照试验需要更少的资源和参与者，但它们并未广泛使用。在将其用于后期阶段之前，我们确定了考虑这种设计的研究人员需要解决的几个问题。
我们调查了 2000 年至 2022 年发表的与设计析因随机对照试验相关的期刊文章。我们根据这些文章和我们的个人经验确定了需要考虑的问题。
我们确定了使析因随机对照试验更可取的临床、实际、统计和外部问题。临床问题是（1）干预措施可以容易地共同给予；（2）共同给予的安全性问题的风险低于单独干预措施的个别风险较低；（3）需要关于联合干预措施的安全性或疗效数据；（4）相互作用的可能性（例如，给予 B 时 A 的作用不同）较低；（5）比较与其他干预措施平衡的干预措施而不是允许随机干预措施影响其他干预措施的选择很重要；（6）不同干预措施的纳入标准相似。实际问题是（7）测试许多干预措施不会损害招募；（8）每种干预措施及其相关毒性不太可能降低对另一种干预措施的依从性或整体随访；（9）容易实施或不需要盲法。统计问题是（10）可以确定合适的分析尺度；（11）不需要调整多重性；（12）可以有效地进行疗效或缺乏益处的早期停止。外部问题是（13）有足够的资金可用，（14）试验不是为了许可目的。一个总体问题（15）是析因设计应比替代设计要求更低的样本量要求。在具有不同不依从性、保留率、干预效果和相互作用效果的设计中，当与不存在另一种干预措施相比，一种干预措施的效果降低不超过 24%-48%时，2×2 析因设计比三臂替代设计需要更低的样本量。
析因设计并未广泛使用，应根据我们确定的问题更多地考虑使用。最大小到适度相互作用的潜力低是关键，例如，干预措施具有不同的作用机制或针对正在研究的疾病的不同方面。
