Eligibility Antibody Assays in AAV Gene Therapy Trials: Toward Indication- and Stage-Proportionate Regulatory Oversight in Rare and Ultra-Rare Indications

Pre-existing antibody assays have become de facto gatekeepers to administered adeno-associated virus (AAV) gene therapy, shaping eligibility and enrollment across programs. Their scientific rationale is real, as neutralizing antibodies can suppress transduction and anticapsid antibodies promote complement activation. However, available clinical evidence has not established a consistent relationship between baseline antibody titers and therapeutic failure, immune-mediated toxicities, or other adverse safety outcomes across AAV programs. This uncertainty between laboratory plausibility and demonstrated clinical consequence is the central evidentiary problem that should inform how these assays are regulated. When antibody assays direct patient eligibility, they may qualify as medical devices under the Federal Food, Drug, and Cosmetic Act. Device status does not automatically require Investigational Device Exemption (IDE) oversight. Significant risk (SR) classification demands a case-by-case determination reflecting actual incremental risk in the specific protocol context, not merely that an eligibility decision is involved. That distinction matters enormously in rare and ultra-rare disease development, where IDE-level validation requirements can represent a genuine and disproportionate barrier to programs serving limited patients. Modern AAV trials embed antibody screening within layered risk architectures: conservative dosing, structured immunosuppression, complement monitoring, and predefined stopping rules. In this context, Clinical Laboratory Improvement Amendments (CLIA)-compliant laboratory-developed tests (LDTs) with rigorous analytical bridging offer a scientifically sound and proportionate alternative to categorical IDE requirements. Blanket escalation to SR device status, absent harmonized clinical thresholds linking titers to patient harm, is not a cautious regulatory posture. Oversight must be context-sensitive, evidence- driven, and proportionate to preserve innovation in rare disease while safeguarding patients.