The National Gene Vector Biorepository's Pharm/Tox Database

Abstract

The National Center for Research Resources has funded a new program to support preclinical and clinical gene therapy efforts. The National Gene Vector Biorepository (NGVB) will bring a variety of programs online during the next year. One of the resources will be a continuation of the Pharmacology/Toxicology (Pharm/Tox) Database formerly maintained by the National Gene Vector Laboratory. The purpose of the database is to provide gene therapy investigators with a catalog of gene therapy biodistribution and toxicology studies on file with the US Food and Drug Administration (FDA). Pharm/tox refers to any in vitro or animal study that seeks to determine the therapeutic or toxic effect of a drug product (including gene therapy). Pharm/tox studies are designed to estimate the dose and dosing schedule as well as to identify the potential toxicity of drug products before they are administered to humans. These studies, which are required by the FDA, are submitted in an Investigational New Drug (IND) application—the established mechanism for FDA oversight of investigational drug development. The IND application must outline what is known about the drug, how the drug will be manufactured, the clinical protocol under which the drug will be administered, and how the patients will be informed about potential risks; in addition, it must include the results of pharm/tox studies. The type and scope of a pharm/tox study will depend on several factors, including the product itself, the route of administration, the disease being treated, and the availability of suitable animal models. Given the complexity of products and disease indications, a customized pharm/tox plan is usually required. Therefore, investigators are well advised to draft a detailed pharm/tox plan, then engage the FDA via a Pre-Pre-IND or Pre-IND meeting before initiating the study, to minimize the chance that the study will be inadequate or insufficient to support the IND application. Why is the Pharm/Tox Database needed? There are at least three reasons to provide a public catalog of pharm/tox studies. First, the results of such studies are generally not available. Many go unpublished because they are not viewed as hypothesis-driven research, and studies that support clinical trials generally have no significant findings. The second need for the database is financial. These studies, especially when done in nonhuman primates, are expensive and use valuable animal resources. Because the costs of the studies can exceed the cost of vector production and testing, there is a financial incentive for academic investigators and the National Institutes of Health (NIH) to avoid unnecessary duplication of studies. Third, the time needed to admit new products into clinical trial may be shortened if duplicative pharm/tox studies are avoided. How can the database decrease costs? To protect the proprietary information of commercial sponsors, the FDA is prohibited by law from disclosing or using pharm/tox data submitted by one investigator for the benefit of another. An exception can be made when the FDA is given permission by the individual who submitted the original data. This is done with a “letter of cross-reference” written by the owner of the pharm/tox data. The letter authorizes the FDA to utilize the data in its deliberation of a specified IND application. By allowing the FDA to consider studies it has on file, it is hoped that subsequent gene therapy IND applications will not be viewed in isolation but can build on existing pharm/tox data and provide more focused (and less expensive) studies. Generally, an individual who obtains a letter of cross-reference from a commercial or academic institution is not shown the primary data contained in the referenced file. Because it is ultimately the FDA that decides whether existing data can be used in support of an IND application, not sharing the primary data protects confidentiality and proprietary information while still accomplishing the goal of permitting the FDA to reference the data. The NGVB Pharm/Tox database was designed with similar considerations; primary data are not contained in the database, but detailed information is provided to investigators so that they can identify studies of relevance to their IND application. What is contained in the database? It contains information regarding the study design and methodology, dose level, assessment vector type and manufacturing grade, species used in animal studies, route of administration, and detailed lists of analyses performed. For each study there are details on the number of animals evaluated and the dosing, as well as summary information about the results and implications of the study. The site and sponsor of the study are also listed. Who should use the database? Investigators who have not previously submitted a pharm/tox study to the FDA will find the database an excellent educational resource. The studies can serve as examples and help identify the scope of work required for previous studies that had similar routes of administration, vector systems, and/or transgenes. A tutorial is being developed to provide additional guidance on study design and interacting with the FDA. The database should be reviewed by anyone submitting an IND application to determine whether prior work can be used to decrease the scope (and cost) of the pharm/tox studies. For example, a review of the database may identify an existing study using a different transgene but a similar vector, manufacturing methodology, and route of administration. Although the FDA may require a toxicological assessment of the transgene, it might allow a limited biodistribution study based on information already on file in another IND application. The NGVB can facilitate the letter of cross-reference, and it is the expectation of NIH that letters will be provided to academic investigators for studies supported with NIH funds. For commercial entities that participate in this resource, the decision about whether to share this information is at their discretion. The database can also serve as a resource for grant reviewers and NIH program officers to determine whether grant applicants are seeking funds for duplicative work. A list of current and pending studies recorded in the database is provided in Table 1 . The database search site can be viewed at http://www.ngvl.org/include/tox/index.php, where short abstracts of the studies can be accessed. Access to the full contents of the database can be obtained by registering with the NGVB Coordinating Center. Academic, commercial, or other interested parties are welcome to register and view the database. The NGVB also requests that anyone involved with important gene therapy pharm/tox studies contribute to the database. The Coordinating Center can assist in uploading the information and will make the process as easy as possible. Contact information is provided on the NGVB website, https://www.ngvbcc.org. Finally, over the next year the NGVB will be developing a variety of other support resources for gene therapy investigators, including a reagents repository, assistance with vector insertion site assays and analysis, and archiving services for FDA-monitored samples and products.