ISO 15189 is a sufficient instrument to guarantee high-quality manufacture of laboratory developed tests for in-house-use conform requirements of the European In-Vitro-Diagnostics Regulation

Abstract

The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks.

Keywords: AB, accrediting body; BRCA1/2, breast cancer genes 1 and 2; CA, competent authority; CAPA, corrective and preventive actions; CDx, companion diagnostics; CGP, comprehensive genomic profile; CRGA, clinically relevant genomic alterations; EEA, European economic area; EFLM, European Federation of Clinical Chemistry and Laboratory Medicine; EMA, European Medicines Agency; EU, European Union; European Regulation 2017/746 on In-Vitro-Diagnostic Devices; FMEA, failure-mode effects analysis; GA, genomic alterations; GDPR, General Data Protection Regulation; HI, health institution; HRD, homologous recombination deficiency; HRR, homologous recombination repair; ISO 15189:2012; ISO, International Organization for Standardization; IVDD, In-Vitro Diagnostic Device Directive; IVDR, In-Vitro Diagnostic Device Regulation; LDT, laboratory-developed test; MDCG, Medical Device Coordination Group; MSI, micro satellite instability; MU, measurement uncertainty; NB, notified body; NGS, next generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; PARPi, poly (ADP-ribose) polymerase inhibitors; PRRC, person responsible for regulatory compliance; PT, proficiency testing; RUO, research use only; RiliBÄk, Richtlinie der Bundesärztekammer zur Qualitätssicherung Laboratoriums medizinischer Untersuchungen; SOP, standard operating procedure; TMB, tumor mutational burden; UDI, unique device identifier; VAF, variant allele frequency; iQC, internal quality control; laboratory-developed tests for in-house use; method validation.