Draft Guidance for Microbial Vectors Used for Gene Therapy Outlines FDA Safety Concerns

Issues for Sponsors with INDs and CMC concerns

FDA recently released a draft guidance entitled “Recommendations for Microbial Vectors Used for Gene Therapy” as a supplemental guidance to “Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs),” dated April 2008.

The new recommendations suggest that FDA foresees a great deal of risk associated with microbial vectors used for gene therapy (MVGTs). As such, there are several questions raised by the Agency in the draft guidance. These questions, which may pose challenges to biological product manufacturers throughout the IND process, include the following:

1. Does the MVGT activate a proinflammatory immune response?
2. If the MVGT product replication is dependent on special nutrient requirements or a specific microenvironment, what happens to the MVGT in the absence of these requirements?
3. The administration of MVGTs is not typically performed via its natural route, therefore there is a question of how this will affect the bio-distribution/shedding in animal models?
   • The FDA has also raised this concern for virus or bacteria-based gene therapy (VBGT) and oncolytic products.

These three questions suggest that FDA is aware of the potential for increased risk during clinical trials, and imply that the Agency expects sponsors to include a detailed risk assessment study in IND submissions. In addition, the questions demonstrate that the threshold for safety in clinical trials for MVGTs appears to be extremely elevated.

The FDA will want to see a comprehensive summary of data from all previous human experiences. In the draft guidance, the Agency recommends that sponsors contact CBER to discuss dosing issues for new MVGTs before conducting additional pre-clinical studies. This will help eliminate the duplication of studies where data already exists on prior human experiences. Non-specific symptoms can cause increased risk of MVGT incubation in necrotic or abscess tissues and long-term safety monitoring protocols must be in place, especially in products that have re-germination potential. Because of this, additional blood cultures will be required. Long-term adverse effects related to MVGT specific to prior human exposure must be thoroughly vetted.

FDA advises sponsors to correspond with the Agency early in the development process due to the heightened awareness about the potential risks involved in MVGT. If previous human data is available, some preclinical studies may not be necessary. ProPharma Group can offer guidance in communicating with the FDA and CBER regarding preclinical development of MVGT products. We can also aid in the construction of an IND applications. For more information about how we can help you achieve a successful interaction with FDA, please contact us.

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