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.

项目摘要/摘要 1阶段试验的道德行为都在两者之间的条件下，潜力之间有合理的比率 风险和利益和研究候选人在为潜在的关键信息提供 知情同意程序。 IRB必须仔细评估支持评估的科学信息 为了满足这些条件，潜在的风险和收益。几个障碍阻碍了这样的评估。尽管 FDA仔细VET与第1阶段试验相关的临床前安全数据，临床前的情况并非如此 支持利益潜力所需的功效数据。此外，IRB没有获得有关的具体指导 在临床前疗效数据中寻找什么，或者应该如何审查第1阶段的科学主张 方式。缺乏指导是在给定广泛的研究记录特征的情况下，令人不安 许多临床前效力研究使得难以对新的 治疗方式最终可能能够证明临床功效。这样的推论是 在采用新颖的研究技术等临床前疗效研究方面尤其具有挑战性 CRISPR-CAS9和脑器官。知道可以可靠地推断出有关潜在功效的推论 关于采用新型临床前工具的新治疗方式将是我们项目的主要重点。这些 如果IRB能够确定存在合理比率，是否需要推断 在使用新的期票技术的第1阶段试验中的福利和风险之间。在这个挑战 设置，IRB可以从结构化的风险/福利评估方法中受益。该项目旨在 开发和试行这种方法。为此，我们将进行定量和定性研究以学习 关于IRB 1阶段研究的当前优势和劣势。我们将完成全国调查 IRB椅子。然后，我们将通过以下方式进行3组半结构化访谈 调查人员，（b）审查第一阶段审判申请的IRB成员，以及（c）过去的参与者或其法律 1阶段试验的代表。我们将使用这些发现来完善现有的概念框架 评估临床前研究功效数据的质量和可靠性。从这个精致的概念上 框架，我们将开发IRB和调查员清单，旨在（a）促进高度结构化称重 IRB在第1阶段试验中的潜在利益和风险以及（b）协助1阶段研究者提交更多 从道德上健壮的第1阶段试用申请。我们还将开发一个新颖的数据分析和决策支持 交互式软件平台可帮助1阶段研究者和IRB成员评估证据环境 围绕给定的1阶段试验。这些决策辅助工具还将用于确定有关的关键披露 1阶段试用研究候选人的潜在风险和收益。看看我们的决策辅助工具是否可能产生 这些期望的好处，在我们项目的最后一年中，我们将与他们一起使用第一阶段调查人员和IRB进行试验 成员。