Preclinical development strategies for novel gene therapeutic products

With over 220 investigational new drug applications currently active, gene therapy represents one of the fastest growing areas in biotherapeutic resea rch. Initially conceived for replacing defective genes in diseases such as cystic fibrosis or inborn errors of metabolism with genes encoding the norm al, or wild-type, gene product, gene therapy has expanded into other novel applications such as treatment of cancer or cardiovascular disease, where t he risk:benefit profiles may be more acceptable in relation to the severity of the disease. Different types of vectors, including modified retroviruse s, adenoviruses, adenovirus-associated viruses, and herpesviruses and plasm id DNA, are used to transfer foreign genetic material into patients' cells or tissues. Developing a toxicology program to determine the safety of thes e agents, therefore, requires a modified approach that encompasses the phar macology and toxicity of both the gene product itself and the vector system used for delivery in the context of the application for the clinical trial . In general, the issues involved in designing and developing appropriate p reclinical testing to determine the safety of these products are similar to those encountered for other recombinant molecules, including protein bioth erapeutics. Limitations to some of the typical toxicology studies conducted for a traditional drug development program may exist for these agents, and nontraditional approaches may be required to demonstrate their safety. Man y factors may affect the safety and clinical activity of these agents, incl uding the route, frequency, and duration of exposure and the type of vector employed. Other safety considerations include quantitation of the duration and degree of expression of the vector in target and other tissues, the ef fects of gene expression on organ pathology and/or histology, evaluation of trafficking of gene-transduced cells or vector after injection, and intera ctions of the host immune system with the transduced cell population. Becau se of the unique concerns regarding each of these therapies, the Center for Biologics Evaluation and Research encourages sponsors to obtain toxicity d ata whenever possible while evaluating the pharmacologic activity of the ve ctor in a species or animal model relevant to their clinical indication. Sp onsors are encouraged to discuss preclinical study design and results with the Center during product development to facilitate early identification of safety concerns prior to entry of these novel agents into the clinical set ting and to ensure an uninterrupted course of development while addressing issues required for licensure.