In gene therapy, your in-vitro diagnostic (IVD) doesn’t sit on the sidelines—it drives clinical decisions. If a result screens a participant in/out, times dosing, or informs safety management, you’re in IVDR performance study territory with ISO 20916 as the operational backbone. Treat the IVD like a product under evaluation, not a lab tool, and design a study that proves it’s fit for the exact decision your trial needs.
What actually triggers a performance study in gene therapy?
Use the simplest rule of thumb: does the assay influence patient management? If yes, plan for an IVDR Article 58 performance study in parallel with your clinical trial authorization. Typical triggers:
- Eligibility/stratification: AAV neutralizing antibody (NAb) or total-antibody (ELISA) results that gate inclusion/exclusion or set a dosing window.
- Patient monitoring: Assays that guide timing or continuation (e.g., changes in humoral markers relevant to vector readiness).
- CDx trajectory: When the test is essential for safe and effective use, your evidence should be built to scale toward CDx—even if you’re not filing as CDx yet.
Treat these as combined trials (IMP + IVD). Align the performance study application with the drug CTA so approvals move together.
Build the right “assay stack” for AAV programs
Design your assay plan around the decisions your trial must make. In combined trials (IMP + IVD), that usually means separating screening, decision-making, and context/supporting activities—and documenting exactly which assay output drives which action in the CPSP and APR.
1) Screening assays
- Purpose: Identify participants who may be eligible for dosing or further evaluation.
- Typical methods: Total antibody (ELISA) and/or neutralizing antibody (NAb) assays.
- Predefine: intended purpose, the output used for screening, cut-off, QC/controls, and invalid/repeat handling.
- Regulatory note: If screening impacts enrollment/timing, it’s within IVDR performance study scope—reflect this in the protocol and dossier.
2) Decision-making assays
- Purpose: Provide the result that directly guides patient management (e.g., eligibility for AAV dosing or readiness after a waiting/intervention period).
- Typical method: Cell-based NAb assay when the decision depends on functional inhibition of transduction.
- Predefine: a validated cut-off and how it’s applied at the decision point; acceptance criteria (controls/repeats), handling of invalid/borderline results, and any repeat-testing logic.
3) Context/supporting assays
- Purpose: Provide supporting information (e.g., PCR/NGS for inclusion criteria or other exploratory markers) without driving patient management unless explicitly pre-specified.
- Governance: These may be exploratory assays; do not let them influence decisions unless pre-declared.
Designing the CPSP: endpoints that matter (and survive small-N)
Tie endpoints to the decision you must defend. In rare diseases, power is constrained—precision and transparency carry weight.
Primary, decision-linked endpoints (illustrative):
- Proportion below cut-off at the dosing/decision point.
- Time-to-negativity (post-intervention or natural decline).
- Duration of sustained negativity.
- Change from baseline in NAb titers.
Key secondaries (analytical + feasibility + safety):
- Analytical performance in operations: run-level QC pass rate, invalid/repeat rate, assay deficiencies/deviations.
- Feasibility: turnaround time from collection to result, pre-analytical robustness (freeze–thaw, transport windows, matrix effects), stability.
- Safety: AEs from sample collection/device use as per IVDR performance study reporting.
Correlative (pre-specified, descriptive):
Relate NAb kinetics to other humoral markers (e.g., total IgG, capsid-specific antibodies) where it clarifies the biology without over-claiming.
When your IVD sample size is constrained by the gene therapy protocol, say so. Set precision targets for agreement or proportions and specify how you’ll treat indeterminates/missing—regulators prefer realistic clarity over decorative p-values.
From LDT to IVDR: documentation that actually wins
Many gene therapy assays start as lab-developed tests or adapted RUO methods. Under IVDR you need an Analytical Performance Report (APR), not just a conventional validation report. The APR:
- Maps analytics to intended purpose and clinical decision.
- Uses a structured narrative per characteristic: Purpose → Study design → Statistics → Acceptance criteria → Results → Conclusion.
- References applicable frameworks (IVDR, ISO, MDCG) and integrates ICH Q2(R2)/Q14 principles within the IVDR lens.
- Justifies non-applicable GSPR requirements explicitly instead of hiding them.
What reviewers expect to “see on the page”
- Analytical sensitivity: LoD/LoQ with methods, not just point estimates.
- Analytical specificity: cross-reactivity, interference, matrix effects—demonstrated, not assumed.
- Accuracy (trueness/bias): vs. reference materials/known concentrations across the measuring range.
- Precision: repeatability, reproducibility and intermediate precision (operators, days, instruments).
- Measuring interval/reportable range: tied to clinical decisions.
- Robustness & stability: small-parameter changes; specimen/reagent stability across the actual logistics.
- Traceability: metrological traceability to reference materials or SI units wherever feasible.
Bridging without back-tracking
If you migrate platforms or laboratories, pre-declare equivalence boundaries, commutable panels, and the statistical approach before you switch. Link the APR to the Design History File and ultimately to the Performance Evaluation Report to keep evidence audit-ready.
Operational blueprint: lab-centric, ISO 20916–aligned execution
Programs that run smoothly accept a basic truth: lab operations are clinical operations when an assay drives decisions.
- Risk-based monitoring (ISO 20916): Prioritize calibration records, control runs, instrument logs, sample accountability, LIMS audit trails, and lab-critical SDV.
- Clear RACI across stakeholders: pharma sponsor, diagnostic partner, central lab, CRO(s). Assign a single “owner of truth” for eligibility calls and a documented adjudication path for gray-zone results.
- Sample governance: pre-analytical controls (shipping, temperature, freeze–thaw limits), redraw/retest SLAs, and chain-of-custody that survives inspection.
- Safety integration: define device-side AE/device-deficiency flows and their handshakes with the IMP SAE process—who reports what, where, when—and hold joint drills before FPI.
Common pitfalls (and the fix)
Copy-pasting a validation report into IVDR—without showing how analytics support the clinical decision.
- Fix: Rewrite into an APR aligned to the intended purpose; connect every analytic claim to the use case.
Pretending power exists in tiny cohorts.
- Fix: Pre-specify precision not power; make QC-forward primary endpoints; keep clinical associations descriptive.
Letting exploratory assays creep into decision-making ad hoc.
- Fix: Lock the assay stack and decision logic in the CPSP; label everything else exploratory.
Underplaying pre-analytical risk.
- Fix: Measure it (transport windows, freeze–thaw), set acceptance criteria, and track at run-level.
Ambiguity in roles and safety.
- Fix: Publish a RACI and an integrated safety matrix early; rehearse escalations.
Sponsor checklist
- Decide early if the assay changes patient management → if yes, plan an IVDR performance study.
- Lock claims, cut-offs, and gray zones; write the CPSP to those decisions.
- Choose your study model (prospective/retrospective/bridging) to match real sample access and clinical trial needs.
- Produce an APR with complete traceability and justified non-applicable requirements.
- Stand up lab-centric monitoring (ISO 20916), eTMF rigor, and LIMS auditability.
- Align device and drug safety reporting—on paper and in practice.
- Embrace small-N: set precision goals, prioritize QC endpoints, and keep associations descriptive.
- Think CDx-ready: structure today’s evidence so tomorrow’s filing doesn’t start from zero.
How MDx CRO accelerates combined gene therapy studies
We run the device side of your combined trial end-to-end: strategy, CPSP/APR/PER authorship, submissions, ISO 20916-aligned operations, lab-centric monitoring and SDV, data/biostats, and inspection-ready traceability. We design performance studies that mirror real clinical decisions, so approvals and operations move in lockstep.
