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: 10365163
• 负责人: JONATHAN M KIMMELMAN
• 金额: $ 64.53万
• 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/10365163
• 关键词: Authorization documentation; Benefits and Risks; Brain; CRISPR/Cas technology; Characteristics; Clinical; Clinical Research; Computer software; Data; Data Analytics; Decision Aid; 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; Risk-Benefit Assessment; 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 第一阶段试验的道德行为是以两者之间存在合理的比例为条件的 风险和收益以及研究候选人在 知情同意程序。IRBs必须仔细评估支持评估的科学信息 潜在的风险和利益，以满足这些条件。有几个障碍阻碍了这种评估。而当 FDA仔细审查与第一阶段试验相关的临床前安全数据，但对临床前试验并非如此 支持潜在受益所需的疗效数据。此外，IRBs没有收到关于以下方面的具体指导 在临床前疗效数据中应该寻找什么，或者他们应该如何审查关于第一阶段的科学主张 医疗模式。缺乏指导是令人不安的，因为广泛的研究记录了 许多临床前疗效研究使人们很难对新的 治疗方式可能最终能够证明临床疗效。这些推论是 尤其是当涉及到使用新的研究技术的临床前疗效研究时，如 CRISPR-Cas9和脑器官。知道关于潜在疗效的什么推论可以可靠地做出 关于新的治疗方式，采用新的临床前工具将是我们项目的主要重点。这些 如果IRBs要确定有一个合理的比率，就必须有这样的推论吗 在采用新的预期技术的第一阶段试验中，利益和风险之间的关系。在这个具有挑战性的 在这种情况下，IRBs可以受益于一种结构化的风险/效益评估方法。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的研究，以了解 关于IRB审查第一阶段研究的当前优势和劣势。我们将完成一项全国性的调查 IRB座椅。然后，我们将进行三组半结构化访谈：(A)过去的第一阶段试验 调查人员，(B)审查第一阶段试验申请的IRB成员，以及(C)过去的参与者或其法律 第一阶段试验的代表。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，我们将开发IRB和调查员检查表，旨在：(A)促进高度结构化的称重 评估IRBs在第一阶段试验中的潜在益处和风险，并(B)协助第一阶段调查人员提交更多 道德稳健的第一阶段试验应用程序。我们还将开发一种新的数据分析和决策支持 帮助第一阶段调查人员和IRB成员评估证据背景的交互式软件平台 围绕给定的第一阶段试验。这些决策辅助工具还将用于识别关于以下方面的关键披露 第一阶段试验研究候选人的潜在风险和好处。看看我们的决策辅助工具是否会产生 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调查人员和IRB一起进行试点 会员。