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.
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