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Nonclinical AAV Biodistribution Study Consideration For Gene Therapy: ICH S12 Perspective

What is Biodistribution?

Biodistribution (BD) is the in vivo distribution, persistence, and clearance of a gene therapy (GT) product at the site of administration and in target and non-target tissues, including biofluids (e.g., blood, cerebrospinal fluid, vitreous fluid), in biologically relevant animal species. Nonclinical BD studies entail the use of analytical methods to detect the GT product and transferred genetic material in collected samples and can include methods to detect the expression product of the transferred genetic material.

Characterization of the BD profile following administration of a GT product in animals is a critical component of a nonclinical development program. BD characterization data are critical in:

  • overall interpretation of the study findings to enable a better understanding of the relationship of various findings (desired and undesired) to the administered GT product. 
  •  ascertaining a potential benefit: risk profile of the GT product before administration in humans. 
  • inform elements of a first-in-human trial and subsequent clinical trials, such as the dosing procedure (i.e., dosing intervals between subjects), the monitoring plan, and long-term follow-up assessment.

When BD studies should be conducted? 

BD studies should be conducted during the early stage of nonclinical development and prior to initiation of non-clinical studies. The BD data obtained may

  • aid in species selection for subsequent pharmacology and toxicology studies. 
  • help evaluating and interpreting the nonclinical pharmacology and toxicology findings. 
  • also inform design aspects of a first-in-human clinical trial
Is the GLP studies a requirement of BD studies?

In principle, nonclinical BD studies that are not conducted in compliance with Good Laboratory  Practice (GLP) are accepted; however, when BD evaluation is performed as part of a GLP compliant toxicology study, it is important that all in-life parameters and sample collection procedures remain in compliance with GLP

Does the Test Article needs to be the same used for clinical studies?
The test article administered in the nonclinical BD studies should be representative of the intended clinical GT product including:
  • manufacturing process, 
  • product characteristics (e.g., titre),
  • final clinical formulation. 
Nonclinical BD data generated with a GT product that consists of the clinical vector containing a different therapeutic transgene or an expression marker gene when 
  • e.g., adeno associated virus vector of the same serotype and
  • promoter with a fluorescent marker protein expression cassette 
What are the factors while selecting the animal model species? 
BD assessment should be conducted in a biologically relevant animal species or model that is permissive for transfer and expression of the genetic material. Selection factors may include 
  • species differences in tissue tropism.
  • gene transfer efficiency, and transgene expression in target.
  • and non-target tissues/cells. 
  • immunogenicity against the administered vector and/or expression product. 
How to determine the route of administration and dose? 
The ROA of the GT product can affect the BD profile, including the cell types that are transduced and the immune response. Therefore, the GT product should be administered using the intended clinical ROA, as feasible.
The selected dose levels of the administered GT product should provide adequate characterization of the BD profile to aid in interpretation of the pharmacology and toxicology assessments. The highest dose level administered should be the expected maximum dose level in the toxicology studies.

However, with appropriate justification, the anticipated maximum clinical dose level can also serve as the highest dose level for BD evaluation.

What sample specimen should be collected? 
The collected samples should include the following core panel of tissues/biofluids: blood, injection site(s), gonads, adrenal gland, brain, spinal cord (cervical, thoracic, and lumbar), liver, kidney, lung, heart, and spleen. 

Additional tissues (such as peripheral nerves, dorsal root ganglia, cerebrospinal fluid, vitreous fluid, draining lymph nodes, bone marrow, and/or eyes and optic nerve) may be collected depending on the following factors:
  • vector type/tropism 
  • expression product
  • route of administration, 
  • disease pathophysiology 
  • animal/sex and age

Reference 

https://www.fda.gov/media/151599/download

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