背景:根据FDA的Optimus计划,在早期发现剂量的肿瘤学试验中,利用患者报告的结果(PRO)数据来增强对研究性治疗的耐受性评估,引起了新的兴趣.通常,在大多数试验设计中,剂量递增完全依赖于临床医生评估的不良事件.研究表明,在评估研究性治疗是否可以耐受时,患者和临床医生之间存在差异。导致建议在后续试验中进一步研究可能无法耐受的剂量.人们也越来越认识到,患者和公众的参与和参与(PPIE)在丰富试验设计和实施方面发挥着关键作用。然而,根据我们的知识,在早期剂量发现肿瘤学试验的高级统计试验设计的开发中,没有PPIE探索了PRO的最佳整合.
方法:2023年10月18日与9名参与者举行了虚拟PPIE会议,讨论在剂量发现试验设计中纳入PRO的问题。这个跨学科的会议是由一个统计学家团队开发和领导的,临床专家,定性专家,和试验方法学家。会议结束后,两名积极参加PPIE会议的患者倡导者提供了深入的观点.我们讨论了PPIE在塑造先进的剂量发现试验设计中的重要性,分享患者对整合PRO的见解,以告知治疗耐受性,并为有意义的患者参与试验设计开发提供模板。
结果:参与者普遍支持在剂量发现试验中引入PRO,但对PRO如何减少推荐剂量的大小(以及潜在的有效效果)表现出一些担忧。一些参与者分享说,如果这意味着他们将不得不停止治疗,他们可能不愿意通过PRO记录他们症状的真正严重程度。他们讨论了PRO可用于评估耐受性而不是剂量的毒性。
结论:在开发以患者为中心的剂量发现试验设计中,增强患者的声音现在至关重要。本文提供了一个示例性说明,说明测试人员和方法学家如何在未来的先进剂量发现试验设计的开发中有效地纳入患者的声音。
肿瘤试验的目的是确保治疗是安全的,了解它的副作用,并为未来的临床试验推荐正确的剂量(或多个剂量)。传统上,患者对治疗的耐受性由评估毒性(副作用)的医生使用既定的分级指南进行评估.研究表明,医生可能无法识别患者在试验期间实际经历的所有副作用。在剂量发现试验中引入患者报告的结果(PRO)越来越感兴趣。Pros是患者的健康和幸福经历的报告,直接来自患者自己,通常使用问卷进行评估。在剂量发现试验中,我们从低剂量的药物开始,然后增加剂量,直到太多患者出现严重的副作用。然后在后期阶段试验中研究最高安全剂量。我们正在建议一种新的方法来进行这些试验。我们想看看医生认为严重的副作用和病人说的话。这使我们能够推荐平衡两种观点的剂量。我们还想询问患者对严重副作用的风险水平。在本文中,我们强调让患者参与创建先进的剂量发现试验设计的重要性,特别是与PRO,以帮助确定剂量是否为患者耐受。我们还分享了患者和公众参与和参与会议的结果,并为有意义的患者参与开发试验设计提供了指导。
BACKGROUND: In light of the FDA\'s Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials. It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials.
METHODS: A virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development.
RESULTS: Participants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose.
CONCLUSIONS: Amplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs.
The aim of dose-finding oncology trials is to make sure a treatment is safe, understand its side effects, and recommend the right dose (or doses) for future clinical trials. Traditionally, a patient’s tolerance to treatment is assessed by doctors who evaluate toxicities (side-effects) using established grading guidelines. Research has shown that doctors might not identify all the side effects that patients actually experience during a trial.There is growing interest in the introduction of patient-reported outcomes (PROs) within dose-finding trials. PROs are reports of a patient’s health and well-being experiences which come directly from the patient themselves, usually assessed using a questionnaire.In a dose-finding trial, we start with a low dose of a drug and increase it until too many patients have severe side effects. The highest safe dose is then investigated in a later phase trial. We are suggesting a new way to do these trials. We want to look at both what doctors see as severe side effects and what patients say. This enables us to recommend a dose that balances both perspectives. We would also like to ask patients what level of risk they are comfortable with regarding severe side effects.In this paper, we highlight the importance of involving patients in creating advanced dose-finding trial designs, particularly with PROs to help decide whether a dose is tolerable for patients. We also share findings of a patient and public involvement and engagement session and provide a guide for meaningful patient involvement in developing trial designs.