The RATIOS Study: Risk/benefit AssessmenT by IRB review of Phase One Studies

RATIOS 研究：IRB 对第一阶段研究进行审查的风险/收益评估

• 批准号: 10543557
• 负责人: JONATHAN M KIMMELMAN
• 金额: $ 55.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543557
• 关键词: Authorization documentation; Benefits and Risks; Brain; CRISPR/Cas technology; Characteristics; Clinical; Clinical Research; Computer software; Data; Data Analytics; Decision Aid; Decision Making; Disclosure; Disease; Enrollment; Ethics; Future; Health; Human; Informed Consent; Institutional Review Boards; Instruction; International; Interview; Investigational Drugs; Judgment; Learning; Legal; Life; Modality; Modeling; Morals; Occupations; Online Systems; Organoids; Participant; Persons; Phase; Process; Qualitative Research; Research; Research Ethics Committees; Research Personnel; Research Technics; Resources; Risk; Safety; Specificity; Structure; Surveys; Technology; Testing; Text; Translations; Uncertainty; United States Dept. of Health and Human Services; United States Food and Drug Administration; clinical efficacy; clinical translation; common rule; design; early phase trial; effective therapy; efficacy study; falls; improved; member; nervous system disorder; novel; phase 1 study; phase I trial; pilot test; pre-clinical; preclinical efficacy; preclinical safety; preclinical study; safety testing; therapeutic development; tool

PROJECT SUMMARY/ABSTRACT The ethical conduct of Phase 1 trials is conditioned on both there being a reasonable ratio between potential risks and benefits and research candidates being provided with key information about that potential during the informed consent process. IRBs must carefully assess the scientific information supporting the assessment of potential risks and benefits in order to meet these conditions. Several hurdles hinder such assessment. While the FDA carefully vets preclinical safety data that relate to Phase 1 trials, the same is not true for the preclinical efficacy data needed to support the potential for benefit. Further, IRBs receive no specific guidance regarding what to look for in preclinical efficacy data or how they should vet scientific claims made about Phase 1 modalities. This lack of guidance is disconcerting given extensive research documenting characteristics of many preclinical efficacy studies that make it difficult to make reliable inferences about whether a new treatment modality might eventually be capable of demonstrating clinical efficacy. Such inferences are especially challenging when it comes to preclinical efficacy studies that employ novel research techniques like CRISPR-Cas9 and brain organoids. Knowing what inferences about potential efficacy can reliably be made about new treatment modalities employing novel preclinical tools will be the primary focus of our project. These are the very inferences that are required if IRBs are to be able to determine that there is a reasonable ratio between benefits and risks in Phase 1 trials employing new promissory technologies. In this challenging setting, IRBs could benefit from a structured approach to risk/benefit assessments. This project is designed to develop and pilot such an approach. To do this, we will conduct quantitative and qualitative research to learn about current strengths and weaknesses in IRB review of Phase 1 studies. We will complete a national survey of IRB chairs. Then we will conduct 3 sets of semi-structured interviews with: (a) past Phase 1 trial investigators, (b) IRB members who review Phase 1 trial applications, and (c) past participants or their legal representatives of Phase 1 trials. We will use these findings to refine an existing conceptual framework for assessing the quality and reliability of efficacy data in preclinical studies. From this refined conceptual framework, we will develop IRB and investigator checklists designed to (a) promote highly-structured weighing of potential benefits and risks by IRBs in Phase 1 trials and (b) assist Phase 1 investigators to submit more ethically robust Phase 1 trial applications. We will also develop a novel data analytics and decision-support interactive software platform to help Phase 1 investigators and IRB members evaluate the evidentiary context surrounding a given Phase 1 trial. These decision aids will also be used to identify critical disclosures about potential risks and benefits to Phase 1 trial research candidates. To see if our decision aids might produce these desired benefits, in the final year of our project we will pilot them with Phase 1 investigators and IRB members.

项目总结/摘要 1期试验的伦理行为取决于潜在的 风险和收益，并在研究期间向研究候选人提供有关这种潜力的关键信息， 知情同意程序。IRB必须仔细评估支持评估的科学信息， 潜在的风险和收益，以满足这些条件。有几个障碍阻碍了这种评估。而 FDA仔细审查了与1期试验相关的临床前安全性数据，但临床前试验却并非如此。 需要有效性数据来支持潜在获益。此外，IRB没有收到有关以下方面的具体指导 在临床前疗效数据中寻找什么，或者他们应该如何审查关于1期的科学声明 方式。这种缺乏指导的情况令人不安，因为广泛的研究记录了 许多临床前有效性研究使得很难对新药物是否有效做出可靠的推断。 治疗方式最终可能能够证明临床疗效。这种推论是 尤其是在临床前疗效研究方面， CRISPR-Cas9和脑类器官。了解可以可靠地做出哪些关于潜在疗效的推断 关于采用新的临床前工具的新的治疗方式将是我们项目的主要重点。这些 如果IRB要能够确定存在合理的比率， 在使用新的承诺技术的1期试验中的获益和风险之间。在这个充满挑战 在这种情况下，IRB可以受益于风险/获益评估的结构化方法。该项目旨在 制定并试行这种办法。为此，我们将进行定量和定性研究， 关于IRB审查1期研究的当前优势和劣势。我们将完成一项全国性的调查 IRB椅子然后，我们将进行3组半结构化访谈：（a）过去的1期试验 研究者，（B）审查I期试验申请的IRB成员，和（c）既往参与者或其法律的 1期试验的代表。我们将利用这些发现来完善现有的概念框架， 评估临床前研究中疗效数据的质量和可靠性。从这个精致的概念 框架，我们将制定IRB和研究者检查表，旨在（a）促进高度结构化的权衡 IRB在I期试验中的潜在获益和风险，以及（B）协助I期研究者提交更多 伦理上稳健的第一阶段试验申请。我们还将开发一种新的数据分析和决策支持 交互式软件平台，帮助I期研究者和IRB成员评估证据背景 围绕着一个给定的第一阶段试验。这些决策辅助工具还将用于识别以下关键披露： 1期试验候选人的潜在风险和获益。看看我们的决策辅助是否能产生 这些预期的好处，在我们项目的最后一年，我们将与第一阶段的研究者和IRB进行试点 成员