Yang Felix, Bousnina Imein, Madej Anne, Kalamegham Rasika
Genentech, A Member of the Roche Group, South San Francisco, USA.
Howard University, Washington D.C., USA.
Ther Innov Regul Sci. 2025 May 4. doi: 10.1007/s43441-025-00790-2.
The Drug Development Tools (DDTs) Qualification program creates a pathway to evaluate Clinical Outcome Assessments (COAs) that capture a specific concept of interest (COI) in a specified Context of Use (COU). If successfully qualified, a COA can be relied upon to measure a COI that has an application in drug development and regulatory decision-making. Thus, qualified COAs are important DDTs. This analysis aims to assess the Food and Drug Administration's (FDA's) performance reviewing applications in the COA Qualification Program, as well as the uptake of qualified COAs in drug development to date.
In order to assess the use of qualified COAs in drug development, we analyzed the Summary Basis of Approvals (SBA) retrieved from Drugs@FDA and the COA compendium. The submission and review dates for the Letter of Intent (LOI), Qualification Plan (QP), and Full Qualification Package (FQP) steps were retrieved from Center for Drug Evaluation and Research (CDER) & Center for Biologics Evaluation and Research's (CBER) database, as well as the FDA COA Qualification Program website.
Our analysis showed that 86 COAs were listed on the FDA COA website, with a majority of them being Patient Reported Outcomes (PRO). Completeness Assessment (CA) for each portion of submission, as well as review times for the LOI, QP, and FQP steps vary widely, with 46.7% of submissions having a review time exceeding the published targets. To date, 7 COAs (8.1%) have achieved qualification, and one (1.1%) has been denied after undergoing all steps for qualification. On average, it takes 6 years for a COA to be qualified. Our analysis of FDA's approval documents shows that the Agency has relied on qualified COAs to support benefit-risk assessment of 11 medicines. Only three of the seven qualified COAs have been used to support benefit-risk assessment of medicines. The three qualified COAs that have been used are KCCQ, E-RS, and EXACT. Each of these has been used to support multiple indication claims. KCCQ - cardiomyopathy for 2 medicines, heart failure for 6 medicines; E-RS - chronic obstructive pulmonary disease (COPD) for 1 medicine; and EXACT - COPD for 3 medicines. Note: E-RS and EXACT were both used in aclidinium bromide/formoterol/fumarate. In each case they were used as secondary or exploratory endpoints, none as primary endpoints. Only 1 qualified COA was included in drug labels.
The lengthy and unpredictable nature of the COA Qualification Program review timelines poses a risk for tool developers and sponsors intending to qualify a new COA, to use an existing COA or sponsors intending to qualify and use a new COA in the drug development process. Our findings show that, to date, the DDT Qualification Program has not significantly improved the inclusion of qualified COAs in clinical development plans to support regulatory decision-making and label claims, and therefore the impact of the pathway to facilitate the use of innovative tools has been limited. To improve the utility of this program, FDA should publicly share the timelines so participants can be better prepared to integrate into their development programs. Furthermore, FDA should clearly articulate how and when COAs can be used in drug development.
药物开发工具（DDT）资格认证计划创建了一条评估临床结局评估（COA）的途径，这些COA在特定的使用背景（COU）中捕捉特定的感兴趣概念（COI）。如果成功获得资格认证，COA可用于衡量在药物开发和监管决策中有应用价值的COI。因此，获得资格认证的COA是重要的DDT。本分析旨在评估美国食品药品监督管理局（FDA）在COA资格认证计划中审查申请的表现，以及迄今为止获得资格认证的COA在药物开发中的应用情况。
为了评估获得资格认证的COA在药物开发中的使用情况，我们分析了从Drugs@FDA和COA汇编中检索到的批准总结依据（SBA）。意向书（LOI）、资格认证计划（QP）和全面资格认证包（FQP）步骤的提交和审查日期从药物评估和研究中心（CDER）及生物制品评估和研究中心（CBER）的数据库以及FDA的COA资格认证计划网站中获取。
我们的分析表明，FDA的COA网站上列出了86个COA，其中大多数是患者报告结局（PRO）。提交材料各部分的完整性评估（CA）以及LOI、QP和FQP步骤的审查时间差异很大，46.7%的提交材料审查时间超过了公布的目标。迄今为止，7个COA（8.1%）已获得资格认证，1个（1.1%）在完成所有资格认证步骤后被否决。平均而言，一个COA获得资格认证需要6年时间。我们对FDA批准文件的分析表明，该机构已依靠获得资格认证的COA来支持11种药物的获益 - 风险评估。7个获得资格认证的COA中只有3个被用于支持药物的获益 - 风险评估。已被使用的3个获得资格认证的COA是堪萨斯城心肌病问卷（KCCQ）、欧洲呼吸学会问卷（E - RS）和炎症性肠病问卷（EXACT）。每个都被用于支持多种适应症声明。KCCQ - 用于2种药物的心肌病评估，用于6种药物的心力衰竭评估；E - RS - 用于1种药物的慢性阻塞性肺疾病（COPD）评估；EXACT - 用于3种药物的COPD评估。注意：E - RS和EXACT都用于阿地溴铵/富马酸福莫特罗。在每种情况下，它们都用作次要或探索性终点，没有一个作为主要终点。只有1个获得资格认证的COA被纳入药品标签。
COA资格认证计划审查时间长且不可预测，这给工具开发者、打算对新COA进行资格认证或使用现有COA的申办者，以及打算在药物开发过程中对新COA进行资格认证并使用的申办者带来了风险。我们的研究结果表明，迄今为止，DDT资格认证计划并未显著提高在临床开发计划中纳入获得资格认证的COA以支持监管决策和标签声明的情况，因此促进创新工具使用的途径的影响有限。为了提高该计划的效用，FDA应公开分享审查时间线，以便参与者能更好地准备将其纳入开发计划。此外，FDA应明确说明COA在药物开发中如何以及何时可以使用。
