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ICH S12 Guideline on nonclinical biodistribution considerations for gene therapy products

The guideline focuses on the development and regulatory considerations specific to gene therapy products that utilize genetic materials to mediate their therapeutic effects. It defines the scope of products covered by the guideline and clarifies exclusions, including prophylactic vaccines, chemically synthesized oligonucleotides, shedding evaluation, and certain aspects of genomic integration. It underscores the importance of regulatory oversight and safety assessment for gene therapy products.

Scope of BD Studies

BD studies can be conducted as stand-alone studies or in conjunction with other nonclinical pharmacology and toxicology studies. These studies are crucial for evaluating the distribution of the GT product in the body.

Choice of Animal Species or Model:

BD assessments should be performed in a biologically relevant animal species or model that mirrors the intended clinical use of the GT product. The selection should consider factors like tissue tropism, gene transfer efficiency, and transgene expression.

Test Article Selection:

The test article used in nonclinical BD studies should closely resemble the intended clinical GT product. This includes factors such as manufacturing process, product characteristics (e.g., titre), and final clinical formulation.

Group Size and Sex of Animals:

An appropriate number of animals per sex should be included in each BD study at predetermined sampling time points. Justifications should be provided for the number of animals, and in keeping with the 3Rs (Replacement, Reduction, Refinement), the total number can be an aggregate from multiple studies.

Route of Administration and Dose Levels:

The route of administration (ROA) should mirror the intended clinical ROA as closely as possible. Dose levels should provide adequate characterization of the BD profile. The highest dose level studied should reflect the expected maximum clinical dose, but it should not exceed the highest dose in toxicology studies.

Sample Collection:

Sample collection procedures should minimize the potential for contamination. Pre-specified processes should be followed, and samples should be retained for analysis. Time points for sample collection should be chosen to capture changes in GT product levels over time, including persistence and potential repeat administration. A variety of tissues and biofluids should be collected, with the specific panel depending on factors like vector type, tissue tropism, ROA, and more.

Replication Competent Vectors:

For vectors capable of replication, sample collection should also cover the detection of the second peak level due to vector replication and subsequent clearance phases.

Additional Considerations:

Depending on various factors, additional tissues and biofluids may need to be collected for analysis. These can include peripheral nerves, ganglia, cerebrospinal fluid, and more

Specific Consideration

Assay Methodologies:

BD assessment involves quantifying the genetic material (DNA/RNA) of the GT product and, if applicable, the expression products in tissues and biofluids. Quantitation is typically done using established nucleic acid amplification methods like qPCR or digital PCR. Spike and recovery experiments are performed as part of assay development to demonstrate the ability to detect the target nucleic acid sequence in different tissues and biofluids. Other techniques such as ELISA, immunohistochemistry, western blot, and imaging technologies can also be used.

Measurement of Expression Products:

While quantifying the genetic material is the primary focus of BD assessment, determining the level of expression products in tissues can provide valuable information about safety and activity profiles. The decision to measure expression products should be based on a risk-based approach considering factors like GT product levels, persistence, target population, and potential safety concerns.

Immunological Considerations:

Pre-existing immunity in animals, especially non-human primates, against the GT product may affect the BD profile. Screening for pre-existing immunity is recommended. Post-administration, a cell-mediated or humoral immune response can occur, potentially influencing the BD profile. Sampling for immunogenicity analysis may support BD data interpretation. Immunossupression for BD assessment is not recommended unless justified.

Ex Vivo Genetically Modified Cells:

BD assessment for GT products consisting of ex vivo genetically modified cells should consider factors like cell type, route of administration, and potential effects of expression products or gene modification on cell distribution. In cases of hematopoietic cells, widespread distribution is expected following systemic administration. For specific organ/tissue distribution, BD assessment of select tissues is recommended.

BD Assessment in Gonadal Tissues:

BD assessment of the GT product in gonadal tissues is crucial for both sexes, unless the clinical target population is restricted to one gender. Persistent presence in gonads may lead to further evaluation in germ cells or non-germline cells, informing the risk of inadvertent germline integration or germline cell genome modification.

Triggers for Additional Nonclinical BD Studies:

  • Significant changes in the clinical development program, such as alterations in the route of administration (ROA), higher doses exceeding the maximum tested in nonclinical studies, changes in dosing regimens, or inclusion of both sexes in clinical indications originally proposed for a single sex, can trigger the need for additional BD assessment.
  • Modifications to the vector structure, serotype, or other factors that may affect distribution or transgene expression can also necessitate additional BD studies.
  • Changes in the manufacturing process that could impact the final formulation or quality attributes of the gene therapy product, such as gene transfer activity or product titre, should be considered for potential effects on BD.

Considerations for Alternative Approaches:

  • Existing BD data from nonclinical studies conducted for a different clinical indication with the same gene therapy product may suffice in some cases. However, factors like dose levels, dosing regimens, ROA, and changes in promoters need to be considered when deciding whether additional BD studies are necessary.
  • BD data obtained from a previously characterized gene therapy product with the same vector structure and tissue tropism but a different transgene may support waiving additional nonclinical BD studies, provided proper justification is provided.
  • In cases where no biologically relevant animal species exists to inform the BD profile for the clinical population (e.g., due to the absence of the target molecule in animal cells), alternative approaches for BD evaluation should be discussed comprehensively and justified.

Application of Nonclinical BD Studies:

  • Characterizing the BD profile in animals is a crucial aspect of nonclinical development for gene therapy products. BD data help interpret study findings and understand the relationship between observed effects (desired and undesired) and the administered GT product.
  • Attribution of observed findings to genetic material (DNA/RNA) and/or expression products is essential for assessing the benefit-to-risk profile of the GT product before human administration.
  • The relevance of BD data to the clinical population should be considered, taking into account factors like ROA, dose levels, dosing regimens, and potential immune responses in animals.
  • BD data also inform aspects of first-in-human and subsequent clinical trials, including dosing procedures, monitoring plans, and long-term follow-up assessments.

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