AAV serotype IVDs for patient selection in gene therapy development: Technical and regulatory considerations by ARDAT consortium

Currently, most clinical trials for adeno-associated virus (AAV)-based gene therapy (GT) exclude patients with pre-existing anti-AAV antibodies (AAV Abs) due to potential impact on treatment efficacy and safety. Diagnostic regulations require sponsors to define pre-existing AAV Ab level cutoffs and validate patient selection assays before beginning clinical studies. In the absence of robust clinical outcome data early in development, sponsors often rely on thresholds derived from literature or preclinical studies, or default to assay detection limits. The transferability of these thresholds to actual clinical outcomes remains uncertain, leading sponsors to use conservative cutoffs to avoid costly revalidations and development delays. This may prevent some patients from accessing potentially beneficial treatments. We advocate for more flexible validation approaches based on current understanding of antibody characteristics and the commonly used assay formats. We propose an AAV serotype-specific in vitro diagnostic (IVD) assay, an “AAV serotype IVD,” with pragmatic analytical validations for single AAV serotypes. This approach would allow sponsors to establish clinically meaningful cutoffs through adaptive clinical trials that progressively include patients with escalating pre-existing AAV Ab levels by implementing multiple cutoffs during clinical development. These measures could expedite AAV GT development while expanding access for patients with elevated pre-existing AAV Ab levels.