Current global regulatory landscape for biodistribution & shedding assessment of rAAV gene therapies & recommendations of the IMI ARDAT consortium on future directions

An understanding of the biodistribution and shedding profile of a gene therapy product following in vivo administration is an important element of the development program. Recommendations for biodistribution studies have been issued by various regulatory authorities with the most recent draft International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline S12 ‘Nonclinical biodistribution considerations for gene therapy products’ released for public comment on 3 June 2021. In this paper the Innovative Medicines Initiative, Accelerating Research & Development for Advanced Therapies consortium provides an overview of the current regulatory landscape for conducting shedding and biodistribution studies and makes a call for harmonization across regions. In addition, over the last three decades, a significant body of literature on biodistribution and shedding of AAV-based gene therapies has amassed, and we describe herein the initial stages of construction of a formal database of published biodistribution and shedding data. The outputs from the database could be leveraged by Sponsors of AAV programs in regulatory submissions. This would reduce the need for unnecessary duplicative studies, streamline nonclinical development and expedite the arrival of this important class of novel medicines into clinic.