Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee by Rebecca N. Koehler

Author:Rebecca N. Koehler
Language: eng
Format: epub
Publisher: The National Academies Press
Published: 2014-01-23T00:00:00+00:00

Food and Drug Administration IND Review

Although NIH provides funding for gene transfer research and has broad authority to oversee research involving rDNA and therefore gene transfer research, the agency ultimately responsible for the regulation and approval of gene transfer technologies is FDA (which refers to these technologies as “gene therapy products”). An unapproved drug or, in this case, an unapproved gene therapy product, must undergo FDA review as an IND prior to human use.2 Gene therapy INDs3 are regulated by the Office of Cellular, Tissue, and Gene Therapies (OCTGT) in FDA’s CBER. A key purpose of IND review is to ensure the safety and rights of subjects. The purpose of reviews of phase II and III clinical trials specifically is to help ensure that the quality of the scientific evaluation is adequate to permit determination of drug efficacy and safety. FDA receives approximately 40 to 60 gene transfer INDs each year. FDA’s review follows a regulatory framework in which FDA and the sponsor interact throughout the product’s life-cycle, from pre-IND to post-marketing surveillance. Since 1996, FDA has reviewed 840 gene transfer IND submissions, of which 370 are still active (Takefman, 2013). To date, none of the INDs has progressed to approval for marketing.

CBER regulates cellular transfer products, human gene therapy products, and certain devices related to cell and gene transfer. Within CBER, oversight of gene therapy research and products is the responsibility of the OCTGT. FDA defines gene therapy products as products that “mediat[e] their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome … and [that] are administered as nucleic acids, viruses, or genetically engineered microorganisms” (FDA, 2006, p. 4). The general types of gene therapy products that FDA has reviewed to date are non-viral vectors (plasmids), replication-deficient viral vectors (e.g., adenovirus, adeno-associated virus), replication-competent oncolytic vectors (e.g., measles, reovirus), replication-deficient retro and lentiviral vectors, cytolytic herpes viral vectors, genetically modified microorganisms (e.g., Listeria, Salmonella, E. coli), and ex vivo genetically modified cells (FDA, 2013a). According to a statement by Jay Siegel to the U.S. Senate (U.S. Congress, 2000), CBER uses both the Federal Food, Drug and Cosmetic Act of 19384 and the Public Health Service Act of 19445 as enabling statutes for oversight. FDA regulates “all products that mediate […] genetic material by integration into the host genome, and that are administered as nucleic acids, viruses, or genetically engineered microorganisms” (FDA, 2006, p. 4). FDA also maintains a federal advisory committee, the Cellular, Tissue and Gene Therapies Advisory Committee, which reviews and evaluates available data related to the safety, effectiveness, and appropriate use of human cells, human tissues, gene transfer therapies, and xenotransplantation products that are intended for transplantation, implantation, infusion, and transfer in the prevention and treatment of a broad spectrum of human diseases and in the reconstruction, repair, or replacement of tissues for various conditions (Statement of policy for regulating biotechnology products, 1986).

The FDA approval process for new biologic drugs involves an investigator’s obtaining permission from the agency to commence human subjects research by filing an IND application.

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