Gene therapy has tremendous power to reverse genetic conditions, deliver vaccines and other treatments, and combat tissue-specific disorders. As the technology is still being developed, there are significant risks of infection and other adverse reactions to gene therapy. To manage these risks, the Center for Biologics Evaluation and Research (CBER) within the Food and Drug Administration (FDA) regulates gene therapy trials in humans. This FDA Guidance for Industry on “Recommendations for Microbial Vectors used for Gene Therapy” (MVGT) provides recommendations on the types of test results and other information investigational new drug (IND) sponsors should provide to the FDA regarding MVGT production, preclinical animal testing and early clinical trials in humans. The final guidance was announced via the Federal Register in September 2016.

Under the final guidance, FDA recommends that IND sponsors provide detailed information about product manufacturing and characterization in their IND submissions. This information includes:

• MVGT components:
  • Description of the MVGT bacterial strain, including its growth and storage conditions, the reagents used to grow it, and details about the bacterial and inserted genetic material.
• Production and isolation of the Drug Product:
  • Description of how the MVGT Drug Product is produced, isolated, purified and formulated for administration to humans;
  • Description of the product containers; and
  • Manufacturing process qualifications (such as current Good Manufacturing Processes (cGMP) requirements) for Phase 1, Phase 2 and Phase 3 clinical trials, as appropriate.
• Product testing:
  • Results from appropriate product testing for identity, purity, viability and potency at each stage of production, including:
    • Test results and specifications of the isolated Drug Substance and final Drug Product, including safety, purity, potency, presence of DNA plasmids, viability, and cell number;
    • Stability testing protocol information and results under the proposed storage and shipping conditions relevant to all phases of the clinical investigation;
    • Antibiotic sensitivity for two first line therapy and two second line therapy antibiotics;
    • Residual moisture content; and
    • Environmental assessment (or exclusion request).

(Note: In addition to information included in the initial IND submission, testing results for all manufactured lots should be included in required annual IND reports).

Building on general guidance for “Preclinical Assessment of Investigational Cellular and Gene Therapy Products,” the Guidance provides the following recommendations for preclinical studies using animal models for MVGT products:

• Choose animal species and models that are most relevant to the target disease or clinical population and the MVGT mechanisms in humans;
• Use preclinical studies to understand the nature and severity of potential toxicity, with special scrutiny of immune responses;
• Study whether the MVGT can continue to replicate and spread in the body after treatment, including to non-target tissues, especially considering that MVGTs will likely be used in immunocompromised/immunosuppressed patients; and
• Study the MVGT activity and distribution with and without antibiotics to guide antibiotic use in human trials.

Finally, the Guidance provides the following recommendations for early-phase clinical trials of MVGT in humans:

• Establish risk management, safety monitoring and treatment modification plans that specifically address MVGT infection risks, long-term safety after MVGT administration, and risks related to other conditions and medications relevant to the patient population;
• Design the trial, including dosing levels and dose escalation schedules, based on prior pre-clinical and clinical evidence and on expected MVGT risks; and
• Include participants who are most relevant to the target disease, but minimize risks by excluding patients who have specific susceptibility to potential harms from the MVGT being used.