Dual Submissions

As illustrated in Fig. 2, there is a parallel path of submissions required prior to initiation of a gene therapy clinical trial. Sponsors of a gene therapy clinical trial must submit an IND application to the CBER, FDA for review under a 30-day review cycle and may not proceed until the IND is found to be acceptable. In addition, the FDA requires that a sponsor receive the approval of the institutional review boards (IRBs) and institutional biosafety committees (IBCs) affiliated with the institutions at which the trail will be conducted. Concurrently or prior to submission of an IND to the FDA, investigators conducting the clinical trial must also submit their protocol and information specified in Appendix M of the NIH Guidelines to the NIH OBA for review by the RAC. Based on recent changes to the NIH Guidelines for Research Involving Recombinant DNA Molecules (May 2002), all investigators/ sponsors who receive or who are sponsored by an entity that receives NIH support for recombinant DNA research must submit their clinical protocol to the RAC for review. Failure to follow the NIH Guidelines can result in withdrawal of NIH funding to the investigator and any supporting institutions. Although an investigator may submit the protocol to the FDA and the IRB prior to submittal to the RAC, review by the RAC is required before final IBC approval, so the committee can be informed of the RAC recommendations before making its final determination. The OBA submission must be received no less than 8 weeks prior to the next scheduled RAC meeting. A gene therapy clinical trial will be judged as exempt from, or in need of, full RAC/public discussion based on the following factors: novelty of the vector or gene delivery system, special disease concerns, unique applications of the gene therapy research or important social or ethical issues raised by the proposed research. Recommendations and comments resulting

Figure 2 Overview of parallel processes for submission of documentation related to initiation of human gene therapy clinical trials to the RAC and the FDA.

from discussion at the RAC meetings are forwarded to the investigator, the IRB, IBC, and FDA.

Due to timing and regulatory requirements, there are situations where the FDA decision to allow a clinical trial to proceed must be made before public discussion can occur. In this situation the investigator/sponsor is reminded by the FDA of the need to comply with NIH Guidelines regarding DNA recombinant research and that enrollment of subjects into the clinical trial may not begin until review and, if selected, public discussion of the protocol by the RAC has taken place. In general, public discussion of gene therapy clinical trials has been highly beneficial because it allows for consideration of societal and ethical issues surrounding the field of gene therapy and ensures the continued public acceptance and progression of the field.

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