FDA Pushes Risk-Based Patient Selection for Microbial Vector Therapies

The FDA is calling for risk management plans for clinical development of microbial vectors for gene therapy, focusing on the potential for vectors to germinate, regerminate or reseed.

The use of genetically modified bacteria such as salmonella, listeria or E. coli can provide inherent and “substantial” risks of viruses and sepsis, especially in the patient bases often targeted with these types of treatments, the agency says in newly issued guidance. “Such concerns derive from the infectious nature of the product, the risks of necessary concomitant medications, and the risks of the study procedures.”

To reduce these concerns, firms bringing MVGTs to clinical trials should create risk management plans in early phases of development. Assessments can and should be altered throughout the course of the trials as researchers learn new information about the drug. Researchers studying the microbial vectors should take special, pre-specified care with patient selection, as well as dosing and tracking plans.

Choosing patients least likely to develop complications and severe side effects from an MVGT is paramount. For these gene therapies, some of which can treat severe, rare and fatal conditions, the FDA says to “consider selection of a population with relatively reduced risks from the intrinsic or allergenic properties of the MVGT product.”

That includes, for example, avoiding those with dead tissue (such as patients with brain abscesses) in spore-based products that thrive in that environment or those with liver damage or disease in MVGTs that can cause organs to turn.

Other drugs may be necessary to make MGVTs work as intended. Antibiotics can help to mitigate the likelihood of infection; meanwhile, immunocompromising drugs could keep them viable against immune systems attempting to ward off the bacteria.

Researchers are asked to conduct antibiotic testing including sensitivity to determine which ones to use in trials, at which frequency and length. For suppressants, reasoning behind their use should be justified and documented in INDs with safety protections against infection built in. And for all cross-medicating, data should be provided defending the firm’s dosing regimen throughout the trial – taking into account both drug risks and delivery method risks.

The amounts of biologics delivered to patients in early-phase trials can pose some of the greatest risks in this type of development, so sponsors should work in tandem with the agency early on to develop acceptable preclinical data to help with dosing decisions. Past clinical data may also suffice depending on justification for its use.

During trial design, the FDA recommends sponsors consider all past human experience with the drug or similar products, evaluating whether they apply to the investigational study. That includes comparing preclinical records: seed stock history, genetic and physical makeup, growth properties and microbial cell bank systems – along with detailed information on manufacturing from culturing steps to harvesting conditions, pH adjustments, cell inactivation if any and timetables. Using in-depth safety information from past human interactions with the drug can replace extra dosing studies, but sponsors should contact CBER to discuss the possibility.

In INDs, the FDA recommends paying close attention to detail in language used for dose-limiting toxicities and maximum tolerated dose, with an eye toward including MVGT-specific designations that can be used as new markers for FDA adverse-event reporting, DLTs or trial-stopping rules:

  • Septicemia symptoms;
  • Fever and positive blood culture without hospitalization; and
  • Unexpected extension, delay or severity of known side effects like fever.

Tracking these risks and side effects can include plans built around blood cultures and imaging studies when questionable symptoms arise and long-term safety monitoring for biologics with suspected toxicities. Monitoring in early-phase trials for shedding of MVGTs is recommended, the agency says.

The trial suggestions are in keeping with the guidance’s larger IND strategy for microbial vectors, stressing detailed composition records and testing to ward off health concerns.

The guidance also outlines chemistry, manufacturing and controls information that it wants drugmakers to include in gene therapy INDs. For example, it suggests stability testing through each step for all gene-therapy applications to evaluate the MVGT’s microbial independence, watching for invasive bacterial pathogens, environmental agents and — in early-phase trials when drug manufacturing shares laboratory space — any surrounding microbial products in development.

It is meant to supplement the FDA’s 2008 Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Controls (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs).

Comments are due Dec. 13. Read the draft guidance here: www.fdanews.com/10-13-Gene-Therapy-Guidance.pdf. — Victoria Pelham

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