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What it does 

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.
Relevant Science 

MVGTs are bacteria that have been modified to include genetic material for transfer into human cells. The purpose of the gene transfer is to influence the activity of the human cells, for example adding a missing function in a person with a genetic condition, adding a new function not typical of that cell type, or causing tumor cells to stop growing or die. The process of transferring genetic material from bacteria to mammalian cells is called “bactofection.”

The FDA guidance relates to the production of MVGT drug products to be administered to patients in clinical trials. This process begins with a bacterial culture from which a single colony is selected and grown. The gene of interest is inserted into that bacteria, usually in the form of a small circular DNA molecule called a plasmid; growing the bacteria therefore expands the number of copies of the engineered plasmid. These modified bacteria are then processed for administration to patients. The processing of the MVGT sometimes includes killing or weakening the bacteria to limit its ability to cause a serious infection. When the bacteria are introduced into the body, they target a specific site and are killed (lysed), releasing the gene of interest into the human cells where it can perform its intended function.

Aside from MVGT, there are other methods of gene delivery, including viral vectors and chemical gene transfer. Viral vectors are very efficient at transferring DNA to human cells, but they carry risks of inflammation and toxicity to target and non-target tissues. Chemical gene transfer methods avoid the infection risks of viral or bacterial vectors, though they are much less efficient at transferring DNA to target cells. MVGT products are less efficient than viral vectors, and like viral vectors, they have the potential to cause infections or immune responses (this risk is a clear focus of the current guidance). Despite these drawbacks, MVGT products have significant advantages over alternative viral vectors and chemical gene transfer methods, the most prominent being the simplicity of the technique and the ability to target specific cells or tissues in the body.

One of the most promising applications of MVGTs is in fighting cancer. The ability of MVGTs such as Salmonella to travel specifically to tumors has made it possible to target cancer tumor cells without harming other non-tumor cells. The approaches to fighting tumor growth with MVGTs currently include activating genes that increase the host’s immune response against tumor cells, and cutting off blood flow to the tumor. Genetically modified MVGTs can also be used to help doctors find tumors by using radio-tracer genes that can be seen in positron emission tomography (PET) scans. MVGTs are being tested in clinical trials in humans, however there are currently no FDA approved treatments using MVGTs or other gene therapy methods.

See webpages by National Institutes of Health, The American Medical Association and the Mayo Clinic for general information about gene therapy.

Endorsements & Opposition 

At present, there have not been publicly reported endorsements or opposition to this guidance.

Status 

This is final FDA guidance, released September 16, 2016. 

Primary Author 
Kate Saylor, M.S.
Editor(s) 
Allison Roder, PhD Candidate, & Aubrey Incorvaia, MPP
Recommended Citation 

Duke SciPol, “FDA Guidance on Microbial Vectors for Gene Therapy” available at http://scipol.duke.edu/content/fda-guidance-microbial-vectors-gene-therapy-final-guidance (10/19/2016).