Regulation and Oversight of Gene Therapy Products

REGULATION AND OVERSIGHT OF GENE THERAPY PRODUCTS

Experimental use of gene medicines is initiated only after careful review of the approach and trials monitored to protect the patient. The process to obtain approval for clinical testing from regulatory agencies in the United States is summarized in Figure 20. The Center for Biologics Evaluation and Research (CBER) of the FDA reviews gene therapy Investigational New Drug (IND) applications sub-mitted by an investigator or sponsor. The National Institutes of Health (NIH) establishes guidelines for genetic research and implements policies through thescientific concern about the ethical, scientific and safety aspects of genetic research. Scientific and ethical review by the RAC is mandatory for clinical trials occurring at or sponsored by institutions receiving NIH funding for recombinant DNA research. Other protocols not meeting these criteria may also be submitted voluntarily for RAC review. The Office for Human Research Protections (OHRP) is responsible for monitoring and implementing compliance and supplying educational materials protecting human

research subjects. The Institutional Biosafety Committee (IBC) and the Institutional Review Board (IRB) at each investigative site must also review and approve protocols and consent forms for any gene therapy clinical trial. Enrollment of patients for the trial begins only after attaining an IND, RAC review, and IBC and IRB approval (Mendell, 2004). Other countries also have a number of committees that must approve gene therapy protocols and address other scientific and ethical concerns asso-ciated with clinical trials (Kong, 2004).

Vectors for clinical trials must be produced according to strict Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) principles. General requirements are described in 21 CFR and guidelines for the production and qualification of cell and gene therapy products can be found in Points toConsider or Guidance documents (www.fda.gov). ICHguidance documents for quality-related issues also have application to gene therapy products. Some of these documents are reproduced as chapters in the United States Pharmacopeia (USP) (Seaver, 2000). Reference standards for gene therapy vectors to assist manufacturers in characterizing raw materials, pro-cess components and process impurities and for comparative analysis among agents used in different clinical trials are needed. To date, an adenovirus reference standard has been produced and is available through the American Type Culture Collection (ATCC) (Hutchins, 2002). Reference standards for AAV and lentivirus vectors are currently under development (Kiermer, 2005; Flotte, 2006).