Fleming Thomas R, DeGruttola Victor, Donnell Deborah
Department of Biostatistics, University of Washington, Seattle, WA, USA.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Stat Commun Infect Dis. 2019;11(1). doi: 10.1515/scid-2019-0001. Epub 2019 Jul 18.
While much has been achieved, much remains to be accomplished in the science of preventing the spread of HIV infection. Clinical trials that are properly designed, conducted and analyzed are of integral importance in the pursuit of reliable insights about HIV prevention. As we build on previous scientific breakthroughs, there will be an increasing need for clinical trials to be designed to efficiently achieve insights without compromising their reliability and generalizability. Key design features should continue to include: 1) the use of randomization and evidence-based controls, 2) specifying the use of intention-to-treat analyses to preserve the integrity of randomization and to increase interpretability of results, 3) obtaining direct assessments of effects on clinical endpoints such as the risk of HIV infection, 4) using either superiority designs or non-inferiority designs with rigorous non-inferiority margins, and 5) enhancing generalizability through the choice of a relative risk rather than risk difference metric. When interventions have complementary and potentially synergistic effects, factorial designs should be considered to increase efficiency as well as to obtain clinically important insights about interaction and the contribution of component interventions to the efficacy and safety of combination regimens. Key trial conduct issues include timely enrollment of participants at high HIV risk recruited from populations with high viral burden, obtaining 'best real-world achievable' levels of adherence to the interventions being assessed and ensuring high levels of retention. High quality of trial conduct occurs through active rather than passive monitoring, using pre-specified targeted levels of performance with defined methods to achieve those targets. During trial conduct, active monitoring of the performance standards not only holds the trial leaders accountable but also can assist in the development and implementation of creative alternative approaches to increase the quality of trial conduct. Designing, conducting and analyzing HIV prevention trials with the quality needed to obtain reliable insights is an ethical as well as scientific imperative.
虽然已经取得了很大成就，但在预防艾滋病毒感染传播的科学领域仍有许多工作要做。设计、实施和分析得当的临床试验对于获取有关艾滋病毒预防的可靠见解至关重要。在我们基于以往科学突破的基础上，将越来越需要设计临床试验，以便在不损害其可靠性和普遍性的前提下高效地获得见解。关键设计特征应继续包括：1）使用随机化和基于证据的对照；2）规定采用意向性分析以保持随机化的完整性并提高结果的可解释性；3）直接评估对临床终点的影响，如艾滋病毒感染风险；4）使用优效性设计或具有严格非劣效界值的非劣效性设计；5）通过选择相对风险而非风险差值指标来提高普遍性。当干预措施具有互补且可能协同的效应时，应考虑采用析因设计以提高效率，并获得有关相互作用以及组成干预措施对联合治疗方案疗效和安全性贡献的重要临床见解。关键的试验实施问题包括及时招募来自病毒载量高的人群中艾滋病毒感染风险高的参与者，达到被评估干预措施 “现实世界中可实现的最佳” 依从水平，并确保高保留率。高质量的试验实施通过主动而非被动监测来实现，使用预先设定的目标绩效水平和明确的方法来实现这些目标。在试验实施过程中，对绩效标准进行主动监测不仅能让试验负责人负责，还能协助开发和实施创造性的替代方法，以提高试验实施质量。设计、实施和分析具备获得可靠见解所需质量的艾滋病毒预防试验，既是道德要求，也是科学要求。
