Up-Date IVD-R in Europe Dr. Jörg-M. Hollidt 15. November 2017
Table of Content • in.vent`s Mission and Capabilities • New Regulations in Europe (IVD-R) Principles and Pitfalls of sample Procurement Clinical studies •
in.vent is a member of the DiagnostikNet Berlin-Brandenburg
The Mission targeted procurement of human biomaterials We are human
in . vent • 40+ highly qualified Employees • 1200 m 2 office & lab, 1000 m 2 storage + cold storage • Active since 2001 in the field of diagnostics • Partner of all diagnostic Stakeholders for the procurement of biologic material of human origin (e.g. standardization, innovations, research, development, production, controls, clinical studies, ...) • Excellent national and international reputation • in.vent clinical services (ICS)
in . vent • Own study site in Hennigsdorf premises • Extensive co-operations • Sampling and shipping worldwide • Own protein-biochemistry laboratories • Extensive experience in processing, storage and logistics of human biomaterial • range: clinically defined samples 20 t prepared material • Disease state material in small volumes and bulks/units
certified according to: DIN EN ISO 9001:2015 DIN EN ISO 13485:2012
environment Regulatory affairs
Relevance of the Diagnostic Industry in the EU Quelle:
Changing regulatory environment in the EU
regulatory environment • current: IVD-directive (IVD-D 98/79/EC) translated in national laws and regulations • new: IVD-regulation (IVD-R 2012 / 0267) European law: valid for all memberstates increased requirements clinical studies performance studies IVD-R valid in Europe since 25.05.2017
Old IVD Directive (IVD-D) recitals: 35 on 5 pages definitions: 10 on 2 pages paragraphs: 24 on 17 pages annexe: 10 on 24 pages total: 47 pages New IVD Regulation (IVD-R) recitals: 101 on 37 pages definitions: 74 on 14 pages paragraphs: 113 on 229 pages annexe: 15 on 208 pages total: 476 pages
time line IVD-R effective in Europe since 25.05.2017 Transition period of 5 years (2022) plus: ‚ warehouse clause ‘ exemption of 3 years (final date 2025)
time line IVD Regulation current situation IVD-R valid in Europe since 25.05.2017 Folien für die interne Verwendung bereitgestellt von der Autorin
old directive IVD directive 98/79/EC annex II, list A Notified Body, QMS Audits, release of each lot individually by NB, DD HIV, Hepatitis, Bloodgrouptesting annex II, list B NB involved, technical documentation (TD) approved by NB, QMS Audit Rubella, PSA, Glucose (selftest) Products for self testing / home testing NB involved, approval of labelling, IFU pregnancy tests, hormone tests All other IVD No NB involved Clinical chemistry, cancer, CDx, genetic testing
Classification Class D Class C Class B Class A high risk for the public moderate risk for the public no risk for the public no risk for the public high individual risk high individual risk moderate individual risk no individual risk • • • • HIV ½ Syphilis Thyroid function Wash buffer • • • • Hepatitis C, B virus Newborn screening Analysers Fertility testing • • • • HTLV I/II Prenatal screening Clinical chemistry Sample vials • • • • Blood grouping ABO, Cancer-Marker Autoimmune diseases Culture media • Rhesus, Kell, Kidd and CDx • Duffy Bloodglucosesystems • • Chagas Home care products • Syphilis (screening of blood donations) intended use is of the essence
Up-coming Regulation Notified Body mandatory: 10-20% Notified Body mandatory : 80-90% Notified Body NOT involved: 80-90% Notified Body NOT involved: 10-20% IVD directive IVD regulation 98 / 79 / EC 2012 / 0267
Key challenges as manufacturer • New system of classification ( § 39) • New conformity compliance procedure ( § 40) • CDx • Verification of TD for class C and D • Clinical evidence ( § 47) • Surveilance, vigilance in the market (chapter VII, § 58-64) • UDI System ( § 22) • ‚ qualified person ‘ in place
Requirements as per Annex II • Product Verification and Validation Including: - Information on analytical performance characteristics - Information on clinical performance and clinical evidence • performance evaluation report: • reports on the scientific validity • the analytical performance • the clinical performance • Documents shall be included and/or fully referenced • Stability • Software verification and validation • Additional information in specific cases, e.g.: – Specific requirements for sterile devices (conditions for manufacturing, bioburden testing, pyrogen testing etc. – devices placed on the market with a measuring function (accuracy)
Diagnostic Development • Analytical validation: Consistency of the test in being able to measure the specific biomarker • Clinical validation: Consistency and accuracy of the test in predicting the clinical target or outcome claimed • Clinical utility: Test should improve the benefit or risk of an associated drug in the selected and non-selected groups Health Claim Drucker E, Krapfenbauer K, Pitfalls and limitations in translation from biomarker discovery to clinical utility in predictive and personalised medicine. EPMA J. 2013 Feb 25;4(1):7.
Lay-out of a transition-plan • Portfolio analysis • Classification • Clustering • Prioritize / view on rentability • Establishing / adopting of QMS Early contact with NB • Gap analysis of TD • Performance studies • Riskmanagement • Usability • Software / life-cycle / documentation • Analysis of the supply chain / Q-Agreements • Planing of Market-surveillance
Compliance Check TD Chapter 5 • Risk management Plan • Interdisciplinary team in place • R&D • Clinical • Production • QM/QA/QC • Product management • RM defined throughout the life span of the product • RM anaylsis and infrastucture • Definition of a risk acceptance matrix • Commitment to risk reducing activities • Reduce risk by Design
Performace evaluation and studies Mandatory! Exceptions only in well funded situations with sufficient clinical data • § 57 IVD-R / Annex XII part A • Left-overs / studies w/o risk for the donor • No authorization needed • Consent necessary • Ethical aspects according to national regulations • Data protection • § 58-64 IVD-R / Annex XIII part A & Annex XIV • potential risk for the patient (e.g. interventional clinical studies, CDx, complex sampling) • Design similar to Rx studies • Scientific and ethical approval • written informed consent • Ethical commitee / IRB mandatory • Aproval necessary
samples principles and pitfalls
Value chain of In-vitro-Diagnostics Clinical Analytical Definition Volume Quantity Definition Identification Evaluation Validation Development Production Standardization (technical)
Diversity of Material Plasma , Sera , Tissue, Organs , Swabs/Smears Sputum, Faeces , CSF , Lavage, Synovia, Sweat, Urine
Diversity of usage Biomarker identification , Standardisation , proficiency testing, internal QC , perfomance testing, pre-analytics , controls , market surveillance, clinical studies
Pitfalls in analytical methods I • Small number of samples • Lack of history information of the samples • Case and control specimens which are not matched with age / sex • Slow progression of a disease: requiring high numbers of well-stratified patients • Urgent need for novel therapeutics that have a positive impact on morbidity and mortality Issaq HJ, Waybright TJ, Veenstra TD. Cancer biomarker discovery: opportunities and pitfalls in analytical methods. Electrophoresis. 2011;32(9):967 – 975.
Pitfalls in analytical methods II • Samples with a complex matrix such as serum, plasma, urine or tissue from patients / controls • Limited metabolomic / proteomic coverage • Lack of sensitive / specific prognostic biomarkers for disease progression / regression screening • Need to follow clear SOPs for sample selection, collection, storage, handling, analysis and data interpretation Issaq HJ, Waybright TJ, Veenstra TD. Cancer biomarker discovery: opportunities and pitfalls in analytical methods. Electrophoresis. 2011;32(9):967 – 975.
Example Plasma Catecholamines • Increase of plasma catecholamine concentration by 50 to 100% due to stress reactions before venipuncture. Butterfly cannula, sampling 30 min after venipuncture 31
Patient ´ s preparation donor position horizontal to upright haemo concentration increase in concentration of all blood components not under going ultrafiltration increase around 5-15 % ( plus circadian) Upright to horizontal haemo dilution decrease in concentration of all blood components not under going ultrafiltration decrease around 5-15 % ( plus circadian) „ recovery “ of the patient under hospitalisation
The Quality is remembered long after the price is forgotten Sir Henry Royce Co-Founder of Rolls-Royce Motor Cars
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