Gene Transfer Clinical Core Unit

基因转移临床核心单元

基本信息

批准号：
7688331
负责人：
Paul E Monahan
金额：
--
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688331
关键词：
Accident and Emergency department Address Adherence Adverse event Advertisements Advisory Committees Advocacy Amendment Animals Annual Reports Area Attention Authorization documentation Back Basic Science Benefits and Risks Bioethics Biological Biological Assay Biological Products Biology Biotechnology Canavan Disease Caring Case Report Form Cessation of life Charge Classification Clinical Clinical Investigator Clinical Protocols Clinical Research Clinical Research Protocols Clinical Trials Clinical Trials Data Monitoring Committees Clinical Trials Design Code Coercion Collaborations Collection Committee Members Communication Communities Competence Complement Complex Conflict (Psychology)Consent Consent Forms Consult Consultations Continuing Education Continuity of Patient Care Coupled Critiques Cyclic GMP Cystic Fibrosis Data Data Analyses Data Collection Data Quality Databases Development Disease Disease Vectors Doctor of Medicine Doctor of Philosophy Documentation Dose Duchenne muscular dystrophy Early identification Education Enrollment Ensure Epidemiologist Epidemiology Ethics European Evaluation Evaluation Research Evaluation Studies Event Exclusion Criteria Familiarity Fanconi&apos s Anemia Fellowship Florida Follow-Up Studies Forcible intercourse Frequencies Funding Future Gender Gene Delivery Gene Transfer Genes Genetic Genetic Recombination Goals Grant Guidelines Hand Head Health Health Professional Hemophilia A Hemostatic function Hospitals Human Human Resources Human Rights Human Virus Individual Infection Control Informed Consent Institutes Institution International Intervention Journals Knowledge Laboratories Life Liposomes Maintenance Master of Public Health Measures Medical Medicine Methods Minority Mission Modeling Modification Molecular Molecular Biology Monitor Monitoring Clinical Trials Nasal cavity National Heart, Lung, and Blood Institute Nature Notification Nursing Staff Office for Protection from Research Risks Oncogenic Outcome Pamphlets Participant Pathway interactions Patient Care Patient Recruitments Patient Selection Patients Peer Review Pennsylvania Performance Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Physicians Plasmids Play Population Population Study Preparation Principal Investigator Private Sector Procedures Process Processed Genes Progress Reports Protocols documentation Public Health Schools Reagent Recombinant DNA Recombinant DNA Research Recombinants Recommendation Records Recruitment Activity Registered nurse Registries Regulation Regulatory Pathway Relative (related person)Report (document)Reporting Research Research Design Research Ethics Research Ethics Committees Research Personnel Research Proposals Research Subjects Research Training Resolution Resources Review Committee Rights Risk Role Running Safety Schedule Science Scientist Screening procedure Series Serious Adverse Event Services Site Social Medicine Societies Source Specific qualifier value Speed Structure Study Subject Support Groups System Techniques Technology Testing Therapeutic Therapeutic Agents Therapeutic Studies Thrombosis Time TimeLine Tissues Toxic effect Toxicology Training Training Activity Training Programs Translating Translational Research Translations Travel Trypsin United States United States Food and Drug Administration United States National Institutes of Health Universities Update Viral Vector Virus Visit Voting Work World War II Writing adeno-associated viral vector authority base clinical application clinical care clinical efficacy clinical practice computerized data management design drug development experience follow-up gene replacement gene therapy gene therapy clinical trial gene transfer vector human subject improved institutional biosafety committee interest medical schools meetings member multidisciplinary novel patient safety pre-clinical preclinical study programs prospective protocol development research clinical testing research study response safety testing symposium tool training project vector virology volunteer working group

Accident and Emergency department Address Adherence Adverse event Advertisements Advisory Committees Advocacy Amendment Animals Annual Reports Area Attention Authorization documentation Back Basic Science Benefits and Risks Bioethics Biological Biological Assay Biological Products Biology Biotechnology Canavan Disease Caring Case Report Form Cessation of life Charge Classification Clinical Clinical Investigator Clinical Protocols Clinical Research Clinical Research Protocols Clinical Trials Clinical Trials Data Monitoring Committees Clinical Trials Design Code Coercion Collaborations Collection Committee Members Communication Communities Competence Complement Complex Conflict (Psychology)Consent Consent Forms Consult Consultations Continuing Education Continuity of Patient Care Coupled Critiques Cyclic GMP Cystic Fibrosis Data Data Analyses Data Collection Data Quality Databases Development Disease Disease Vectors Doctor of Medicine Doctor of Philosophy Documentation Dose Duchenne muscular dystrophy Early identification Education Enrollment Ensure Epidemiologist Epidemiology Ethics European Evaluation Evaluation Research Evaluation Studies Event Exclusion Criteria Familiarity Fanconi&apos s Anemia Fellowship Florida Follow-Up Studies Forcible intercourse Frequencies Funding Future Gender Gene Delivery Gene Transfer Genes Genetic Genetic Recombination Goals Grant Guidelines Hand Head Health Health Professional Hemophilia A Hemostatic function Hospitals Human Human Resources Human Rights Human Virus Individual Infection Control Informed Consent Institutes Institution International Intervention Journals Knowledge Laboratories Life Liposomes Maintenance Master of Public Health Measures Medical Medicine Methods Minority Mission Modeling Modification Molecular Molecular Biology Monitor Monitoring Clinical Trials Nasal cavity National Heart, Lung, and Blood Institute Nature Notification Nursing Staff Office for Protection from Research Risks Oncogenic Outcome Pamphlets Participant Pathway interactions Patient Care Patient Recruitments Patient Selection Patients Peer Review Pennsylvania Performance Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Phase III Clinical Trials Physicians Plasmids Play Population Population Study Preparation Principal Investigator Private Sector Procedures Process Processed Genes Progress Reports Protocols documentation Public Health Schools Reagent Recombinant DNA Recombinant DNA Research Recombinants Recommendation Records Recruitment Activity Registered nurse Registries Regulation Regulatory Pathway Relative (related person)Report (document)Reporting Research Research Design Research Ethics Research Ethics Committees Research Personnel Research Proposals Research Subjects Research Training Resolution Resources Review Committee Rights Risk Role Running Safety Schedule Science Scientist Screening procedure Series Serious Adverse Event Services Site Social Medicine Societies Source Specific qualifier value Speed Structure Study Subject Support Groups System Techniques Technology Testing Therapeutic Therapeutic Agents Therapeutic Studies Thrombosis Time TimeLine Tissues Toxic effect Toxicology Training Training Activity Training Programs Translating Translational Research Translations Travel Trypsin United States United States Food and Drug Administration United States National Institutes of Health Universities Update Viral Vector Virus Visit Voting Work World War II Writing adeno-associated viral vector authority base clinical application clinical care clinical efficacy clinical practice computerized data management design drug development experience follow-up gene replacement gene therapy gene therapy clinical trial gene transfer vector human subject improved institutional biosafety committee interest medical schools meetings member multidisciplinary novel patient safety pre-clinical preclinical study programs prospective protocol development research clinical testing research study response safety testing symposium tool training project vector virology volunteer working group

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项目摘要

The UNC Core clinical gene transfer group has had extensive experience with gene transfer clinical trials. These include for CF a 12 subject, dose-ranging, safety/efficacy Phase I trial of Ad-CFTR in the nasal cavity, and a subsequent 11 patient, dose-ranging, safety/efficacy Phase I liposomal-plasmid DMA trial in the nasal cavity (16; 17). These trials in CF have been complemented by two (retroviral/high capacity AdV) trials for hemophilia, and another trial for Fanconi's anemia. In addition, the UNC Vector Core and Human Applications Laboratory have produced cGMP adeno-associated virus vector for human clinical trials of Canavan's Disease and Duchenne Muscular Dystrophy with appropriate FDA (Office of Cellular Tissue and Gene Therapies, OCTGT) and NIH RAC oversight (14). Thus, we have experience with regulatory aspects (pre- and post-trial, including a formal FDA audit) as well as the practical performance of gene therapy trials. In addition, we have accrued 'special' experience. The tragic death of the University of Pennsylvania volunteer highlighted the topic of "informed consent". Guidelines for informed consent for human clinical research have been established by the NIH, based on a series of standards that evolved after World War II. However, these guidelines were reviewed and revised by a group from UNC in the context of "gene therapy", based on the premise that clinical studies involving gene transfer are different from other studies involving humans (18). Subsequently, an NIH-supported study was performed at UNC to examine the perceived benefit of gene therapy studies in the context of informed consent (Gail Henderson, Ph.D., Dan Nelson, MS, UNC Department of Social Medicine) (19;20). The Office of Research Subject Advocacy was established in 2001. It is headed by David Weber, M.D., M.P.H., Co- Chair of the Biomedical IRB, and coordinated by Associate Director Marie Rape, R.N., B.S.N. This office ensures the safety of research subjects involved in protocols in the GCRC, which is involved in all gene transfer protocols at UNC. A critical function is oversight and education to avoid misconceptions or misrepresentations during the clinical trial consent process. Infection control in the context of viral vectors for gene therapy is also an important new ethical and functional issue. Most of the vectors for gene transfer are derived from naturally-occurring human viruses, and there is great concern that these vectors might become "replication-competent" and spread/recombination with other viruses might occur. To date, there are no widely available recommendations from Federal or private organizations to guide infection control. Dr. Weber developed infection control guidelines for the UNC adenoviral gene transfer study in cystic fibrosis (16;21). Dr Weber subsequently called for the development of infection control strategies for gene transfer vectors, leading to the first multidisciplinary conference recommendations for such clinical application in gene transfer (22;23). The UNC Clinical Core group, headed by Paul Monahan, M.D., works with the Executive Committee of the CF and Gene Therapy Centers to identify vectors that should be moved toward clinical testing in humans. Working with the prospective Principal Investigators of clinical projects, the Clinical Core helps to devise plans for testing of the safety, as well as biological and clinical efficacy, of new vectors for gene transfer. This assessment includes appropriate pre-clinical studies in animals for biological efficacy and toxicity. In addition, the Clinical Core group is instrumental in helping prospective investigators develop clinical protocols that identify pertinent endpoints for gene transfer efficacy and generate information of high quality to advance knowledge about the vector and the disease of interest. The Clinical Core group works with the GCRC, the Gene Transfer Subcommittee and the Office of Research Subject Advocacy of the GCRC, and the Office of Clinical Trials (OCT) to ensure that clinical protocols are rigorously monitored and meet all regulatory, ethical, and infection control issues. The Clinical Core group also works closely with the OCT to guide gene therapy clinical trials through complex regulatory pathways, develop the necessary tools, e.g.; Case Report Forms and flow sheets for clinical projects, ensure human subject compliance, monitor individual projects, and create a registry for UNC gene therapy patients. The UNC Clinical Core also works collaboratively with the GCRC and the Office of Clinical Trials to provide functional training for clinical trial coordinators, GCRC staff, and clinical investigators. This 'hands-on' clinical research training parallels successful models in basic science laboratories as well as the GCRC and CAP fellowships of recent years that have produced productive and independent clinical investigators in more traditional pharmacology areas. In the next section we describe the human and institutional resources available at UNC CH to meet these critical tasks.

UNC核心临床基因转移组在基因转移方面具有丰富的经验临床试验。其中包括CF A 12主题，剂量范围，AD-CFTR的安全/功效I期试验在鼻腔和随后的11例患者，剂量范围，安全/功效阶段I脂质体质量药物鼻腔中的DMA试验（16; 17）。 CF中的这些试验已由两个（逆转录病毒/高）补充血友病的容量副本试验，以及Fanconi贫血的另一项试验。另外，UNC向量核心和人类应用实验室已经生产了与CGMP腺相关的病毒载体的 Canavan病和Duchenne肌肉营养不良的人类临床试验，适当的FDA （OCTGT的细胞组织和基因疗法办公室）和NIH RAC的监督（14）。因此，我们有具有监管方面的经验（预审和包括正式FDA审计）以及基因治疗试验的实际性能。此外，我们还获得了“特殊”经验。大学的悲惨去世宾夕法尼亚州的志愿者强调了“知情同意”的主题。知情同意指南 NIH已建立了人类的临床研究，基于一系列发展的标准第二次世界大战后。但是，这些准则已由UNC的一组审查和修订基于涉及基因转移的临床研究不同的前提，“基因疗法”的背景是不同的来自其他涉及人类的研究（18）。随后，在 UNC在知情同意书的背景下检查基因治疗研究的感知益处（盖尔亨德森（Henderson）博士，丹·尼尔森（Dan Nelson），MS，UNC社会医学系（19; 20）。办公室研究主题倡导成立于2001年。它由M.D.，M.P.H. 生物医学IRB主席，由副主任玛丽·强奸公司（Marie Rape）协调这个办公室确保GCRC中涉及协议的研究对象的安全，该方案参与了所有基因转移协议在UNC。关键功能是监督和教育，以避免误解或在临床试验同意过程中的错误陈述。在基因疗法的病毒载体的背景下感染控制也是一个重要的新伦理和功能问题。基因转移的大多数向量源自天然人类病毒，非常担心这些媒介可能会成为“能够复制的”和可能会发生与其他病毒的扩散/重组。迄今为止，尚无广泛可用的联邦或私人组织的建议指导感染控制。韦伯博士发展了囊性纤维化中UNC腺病毒基因转移研究的感染控制指南（16; 21）。博士韦伯随后呼吁开发基因转移载体的感染控制策略，导致第一个针对这种临床应用的多学科会议建议转移（22; 23）。由医学博士保罗·莫纳汉（Paul Monahan）领导的UNC临床核心小组与高管合作 CF和基因治疗中心的委员会，以识别应转向临床的向量在人类中进行测试。与临床项目的潜在主要研究人员合作，临床核心有助于制定新的计划测试计划以及新的生物学和临床功效的计划基因转移的向量。该评估包括在动物中进行适当的临床前研究生物疗效和毒性。此外，临床核心组有助于帮助潜在研究人员开发了临床方案，以确定基因转移功效相关的终点和生成高质量的信息，以提高有关载体和感兴趣疾病的知识。临床核心组与GCRC，基因转移小组委员会和办公室合作研究主题的倡导GCRC和临床试验办公室（OCT），以确保临床协议受到严格监控，并满足所有监管，道德和感染控制问题。这临床核心组还与OCT密切合作，以指导基因治疗通过复合物进行临床试验监管途径，开发必要的工具，例如；病例报告的表格和流程表的临床表格项目，确保人类主题合规性，监控单个项目并为UNC创建注册表基因治疗患者。 UNC临床核心还与GCRC和临床试验办公室合作为临床试验协调员，GCRC工作人员和临床研究人员提供功能培训。这 “动手”临床研究培训与基础科学实验室的成功模型以及最近几年的GCRC和CAP奖学金产生了生产性和独立的临床传统药理学领域的研究人员。在下一部分中，我们将描述UNC CH可用的人类和机构资源满足这些关键任务。