Nonclinical Toxicology in Support of Licensure of Gene Therapies

Abstract

and discussed their relevance to biologic products. Elesperu stated that genotoxicity assays are designed as surrogate assays to detect rare occurrences of genetic damage, and noted that although no single test alone will detect all types of mutagenic effects, a positive result in any one test is considered evidence for genotoxic potential. Elesperu emphasized that these assays are properly used for hazard identification and not risk translation, and that additional testing to evaluate the risk to humans of insertional mutagenesis by gene therapy vectors will need to be developed in support of eventual licensure. Marion Gruber (FDA) presented the purpose and design of reproductive and developmental toxicity studies. The relevant guidelines, ICH S5a, can be found online at http://www.ich.org/pdfICH/s5a.pdf. Reproductive toxicity studies focus on the effects of a product in pregnant animals, to identify potential developmental defects that might result from fetal exposure to the product. The target population for genetic vaccines and gene therapeutics often includes women in their reproductive years, and the label must have a statement describing the potential risk of using the product during pregnancy. Gruber noted that the evaluation of reproductive and developmental risk of gene therapy vectors should be done on a case-by-case basis, taking into account any evidence for insertional mutagenesis by the vector, the particular target patient population, and any potential for the transgene product to induce disease. Rick Irwin (National Institutes of Environmental Health and Safety) detailed the standard rodent carcinogenicity studies as conducted by the National Toxicology Program (http://ntp.niehs.nih.gov), emphasizing that these studies are designed to evaluate the occurrence of both benign and malignant growth. Irwin noted that carcinogenicity studies are both time-consuming and costly, and that they therefore must be carefully planned and implemented, and that the requirements for the testing of gene transfer vectors in rodents should be determined by risks associated with the specific gene transfer agent. Leslie Recio (Merck Research Laboratories) discussed alternative models for carcinogenicity testing that make use of genetically modified animals that have been ‘primed’ for tumor development. Potential advantages of such systems are greater sensitivity that could lead to earlier detection of malignant potential using a smaller number of animals. Richard D. McFarland (FDA) next discussed the timing of nonclinical studies of therapeutic MEETING REPORT