Validation and qualification of an ex vivo human cardiac tissue-based assay for t
基于离体人体心脏组织测定的验证和鉴定
基本信息
- 批准号:8715622
- 负责人:
- 金额:$ 20.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-06-24 至 2015-12-23
- 项目状态:已结题
- 来源:
- 关键词:8 year oldAction PotentialsAddressAdverse eventAreaArrhythmiaBiological AssayBiological MarkersCardiacCardiotoxicityCardiovascular systemClinicalClinical ResearchClinical TrialsDataDevelopmentDoseDrug EvaluationDrug ExposureDrug IndustryEarly identificationElectrocardiogramEvaluationEvaluation ResearchExperimental ModelsExposure toGoalsHeartHumanIn VitroIncidenceIndustryKidneyLaboratoriesLeadershipLettersMeasurementMeasuresMethodologyNoiseOrgan DonorOutcomePatientsPharmaceutical PreparationsPharmacologic SubstancePhasePreclinical Drug DevelopmentProcessRiskSafetyServicesSignal TransductionSilverSystemTechnologyTestingTimeLineTissue SampleTissuesValidationbaseclinically relevantcommercializationcostcost effectivedrug developmentdrug discoveryexposed human populationhuman subjecthuman tissueimprovedin vivomanmeetingsnovelpre-clinicalpublic health relevanceresponsescreening
项目摘要
DESCRIPTION (provided by applicant): Drug-induced cardiac toxicity and adverse events remains a major challenge for both industry as well as regulators. The current strategies for early identification of these potential liabilities in the drug discovery and development process involves a combination of in vitro and in vivo assays, followed by an extensive ECG-based cardiac repolarization study which is conducted on human subjects during Phase II. These latter studies are known as "Thorough QT" studies (TQT) since they have specifically focused on drug-related changes in the QT interval, a biomarker for cardiac repolarization and the induction of pro-arrhythmic cardiac activity. While these strategies have undoubtedly contributed in the early identification of potentially dangerous pro-arrhythmic molecules, it is also becoming apparent that this approach, now over 8 years old, is amenable to significant improvements. Recently, both leaders in the pharmaceutical industry as well as regulators from the FDA, have expressed concerns related to: a) The costs associated with the current approach, in particular the TQT studies; b) The prolonged timelines involved in TQT studies; c) The false positive rate due to the utilization of biomarkers (like QT prolongation) that do not completely correlate with the occurrence of arrhythmias; d) The risks involved in exposing patients to high doses of drugs still in development, as required by the TQT studies. Based on these concerns, the leadership at the Division of Cardiovascular and Renal Products of the FDA Center for Drug Evaluation and Research has facilitated a number of initiatives aimed at soliciting the development and validation of novel experimental models for assessing cardiac safety of new drugs and, in particular, their pro-arrhythmic potential. As explicitly stated by the regulators, the goal is "to
replace the TQT clinical studies with one or more pre-clinical assays, by July 2015" (Dr. Norman Stockbridge, CSRC-HESI-FDA Meeting, July 24, 2013, Silver Spring, MD). AnaBios has recently developed a novel human heart-based drug safety evaluation platform, which is currently undergoing formal Biomarker Qualification at the FDA. The technology relies upon the utilization of viable human donor hearts in the laboratory for conducting ex-vivo measurements of cardiac function. This approach will be utilized to test human cardiac responses to novel drug in a pre-clinical assay, providing the next best kin to a human clinical cardiac study, but avoidin the risks related to drug exposure in man, the high costs and extended timelines which come with the clinical studies. The present proposal focuses on the validation of this ex-vivo heart platform in order to demonstrate its feasibility, robustness and overall value in predicting human clinical responses.
描述(由申请人提供):药物引起的心脏毒性和不良事件仍然是行业和监管机构面临的主要挑战。目前在药物发现和开发过程中早期识别这些潜在危险的策略包括体外和体内分析相结合,然后在第二阶段对受试者进行广泛的基于心电图的心脏复极研究。这些第二阶段的研究被称为深入的QT研究(TQT),因为它们专门关注QT间期的药物相关变化,心脏复极的生物标志物和诱发心律失常的心脏活动。虽然这些策略无疑对早期识别潜在危险的促心律失常分子做出了贡献,但也变得明显的是,这种方法现在已经超过8年,可以进行重大改进。最近,制药行业的领导者以及FDA的监管机构都表达了对以下问题的担忧:a)与当前方法相关的成本,特别是TQT研究;b)TQT研究涉及的时间较长;c)使用与心律失常的发生并不完全相关的生物标记物(如QT延长)导致的假阳性率;d)TQT研究要求患者暴露于仍在开发中的大剂量药物所涉及的风险。基于这些担忧,FDA药物评估和研究中心心血管和肾脏产品部的领导层推动了一系列倡议,旨在征求开发和验证新的实验模型,以评估新药的心脏安全性,特别是它们的促心律失常潜力。正如监管机构明确表示的那样,目标是“
到2015年7月,用一种或多种临床前分析取代TQT临床研究“(诺曼·斯托克布里奇博士,CSRC-HESI-FDA会议,2013年7月24日,马里兰州银泉)。AnaBios最近开发了一种新型的基于心脏的药物安全性评估平台,目前正在接受FDA的正式Biomarker资格认证。这项技术依赖于利用实验室中可存活的人类捐赠者心脏进行体外心脏功能测量。这种方法将被用于在临床前测试中测试人类心脏对新药的反应,为人类临床心脏研究提供下一个最好的亲缘关系,但避免了与人类药物暴露相关的风险、临床研究带来的高成本和延长的时间线。本提案侧重于对这一体外心脏平台的验证,以证明其在预测人类临床反应方面的可行性、稳健性和总体价值。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Andrea Ghetti其他文献
Andrea Ghetti的其他文献
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Development of a novel analgesic for mixed inflammatory and neuropathic pain states
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- 批准号:
10082913 - 财政年份:2021
- 资助金额:
$ 20.07万 - 项目类别:
Validation and qualification of an ex vivo human cardiac tissue-based assay for the assessment of the potential cardiotoxicity of pharmaceutical compounds
用于评估药物化合物潜在心脏毒性的离体人体心脏组织测定的验证和鉴定
- 批准号:
9312909 - 财政年份:2014
- 资助金额:
$ 20.07万 - 项目类别:
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