“We consider an assessment of the vector integration pattern to be relevant in subjects enrolled in gene therapy clinical studies when the vector has the potential for genomic integration (e.g., integrating retroviral vectors).

An assessment of integration sites may be useful if subjects demonstrate evidence of clonal expansion (e.g., a dominant clone representing a substantial proportion of the integration profiles).

Sponsors should test for vector sequences in surrogate samples (e.g., peripheral blood) by PCR at predetermined intervals during the long-term follow-up period. Depending on the nature of the product and the expected risks, sampling intervals may be no greater than every six months for the first five years and no greater than annually for the subsequent ten years.”

< Guidance for Industry: Long Term Follow-Up After Administration of Human Gene Therapy Products >

“If integration is being confirmed, copy number determination, integration site identification, and monitoring for any subsequent adverse biological effects and changes in cell behaviour should be performed.

Depending on the nature of the vector used, extended in vitro and in vivo assays addressing insertional oncogenesis may be warranted prior to first administration in humans.”

<Guideline on the quality, non-clinical and clinical aspectsof gene therapy medicinal products>

“For gene therapy products involving genome-editing tools such as CRISPR–Cas9, given that current scientific understanding and available detection methodologies remain limited, a more comprehensive safety evaluation should be conducted during development.

This evaluation should include safety considerations in upstream design and construction, such as selection of the editing system and sequence design; assessment and verification of potential off-target sites and related detection data; evaluation of risks associated with tumorigenicity or pro-tumorigenic selection of edited cells; and assessment of the immunogenicity of the components of the editing system.

Appropriate risk-mitigation strategies and corresponding safety control and testing methods should be established to address these potential risks.”

<Technical Guidelines for Pharmaceutical Research and Evaluation of In Vivo Gene Therapy Products (Trial) >