The US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research this week issued final guidance for investigation new drug (IND) submissions for microbial vectors used for gene therapies (MVGTs) in early-phase clinical trials.
The 27-page final guidance follows a draft issued in October 2015 and is meant to supplement: “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),” from April 2008.
Focusing on manufacturing components and processes, as well as product and stability testing, the guidance also offers recommendations on preclinical and clinical studies for MVGTs.
MVGTs include bacterial vectors such as Salmonella, Listeria or E. coli genetically modified to express human tumor antigens, cytokines, growth factors, enzymes, therapeutic proteins or nucleotides. MVGTs may also be generated by the modification (deletion, truncation, or point mutation) of chromosomal or episomal genes and by the insertion of foreign genetic material into the chromosome or into naturally occurring episomes, FDA says, or by the introduction of one or more plasmids.
MVGTs may also be modified to alter their growth characteristics, as MVGTs may be live, dead or replication-restricted as a result of specific biochemical requirements or genetic modification.
Comments on Draft Guidance
Janssen Pharmaceuticals was the only commenter on the draft guidance, noting at the outset that the document may need to be expanded beyond initial INDs to include late stage development considerations.
Janssen also sought clarification on the need to do in vivo biological activity, safety and biodistribution/persistence profiles of the MVGT product in the presence and absence of antibiotics.
“This appears to be a new requirement (e.g., the draft guidance states ‘should be evaluated’) and goes beyond the traditional in vitro antibiotic sensitivity testing that has been sufficient in the past,” the company said. “Since this would be a new requirement, it would be useful for the Agency to provide additional rationale and methodology for this testing (e.g., species selection, endpoints, time points, etc.). In addition, as these characteristics could be microbial vector specific, would it be possible for a Sponsor to provide alternatives to conducting this testing (e.g., only assessing biodistribution and shedding in the absence and presence of antibiotics).”
The final guidance says antibiotic sensitivity tests “should contain at least two first line therapy and two second line therapy antibiotics normally used to treat infections with the microbial agent(s) for which the MVGT was derived,” and also notes, “Data obtained from these studies can help guide the selection of effective antibiotics, as well as appropriate timing of antibiotic administration in the clinical trial.”
Recommendations for Microbial Vectors used for Gene Therapy Guidance for Industry