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POINT-of-IMPACT testing. A European perspective - Bert Niesters

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At SoGat meeting 2019 Bert Niesters - Professor in Molecular Diagnostic in Clinical Virology, Medical Molecular Microbiologist at University Medical Center Groningen, Department of Medical Microbiology, Division of Clinical Viroloy, The Netherlands - has talked about the developing trends in molecular diagnostics and the impact on the Laboratory.

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POINT-of-IMPACT testing. A European perspective - Bert Niesters

  1. 1. Bert Niesters SoGat meeting 2019 Department of Medical Microbiology Division of Clinical of Virology University of Groningen University Medical Center Groningen The Netherlands Chair, Executive Board QCMD Glasgow Scotland/United Kingdom POINT-of-IMPACT testing A European perspective
  2. 2. Disclosures • Chair, Executive Board of QCMD • Lead-Assessor and Technical Assessor for the Dutch Council of Accreditation • Editor-in-Chief of the Journal of Clinical Virology • Update on http://www.rug.nl/staff/h.g.m.niesters/ Images and references to organizations, companies, and products are for representative examples only and do not constitute complete representation or endorsement.
  3. 3. Multiplex testing Clinical laboratories Move to more commercial assays Quantitation & better standardisation Automation & Integration More appropriate EQA & QC Increasing accreditation pressure Clinical relevance Near patient testing (PoC) Developing trends in molecular diagnostics: the impact on the Laboratory Next Gen Seq (NGS)
  4. 4. The diagnostic market is changing Laboratories > Hospitals > Clinics > Home > On Scene Professional Non-Professional Very Complex > Moderate Complex > Easy Test Complexity POC/POI Diagnostic Market Movements 20252000
  5. 5. Large diversity of molecular assays (in house / commercial) in use can complicate the QA process
  6. 6. Random Access Medium/High Throughput Platforms
  7. 7. GeneXpert Infinity System Biocartis platform Examples of multiplex platforms (Point-of-Care or Point-of-Impact) FilmArray, BioFire GenMark DxLuminex AriesGenePOC QIA-stat Dx
  8. 8. True Molecular POC/POI Results in less then 30 minutes
  9. 9. The recent key points in molecular diagnostics  Asides the use of Laboratory Developed Tests (LDT), more commercial multiplex platforms and POC-systems are being introduced.  Laboratories have to be accredited according to –in most cases- ISO15189:2012. Discussion will also be on ISO22870:2016 where appropriate. Both are interlinked.
  10. 10.  Bedside testing, or near patient testing (emergency room, ambulance, remote areas).  Suited for several applications.  Where fast TAT is needed.  Where centralized laboratory services face limitations.  In rural areas and places hard to reach.  In resource limited countries with a high infectious disease burden and challenges in diagnostics.  During epidemics and pandemics. What is Point-of-Care testing
  11. 11. • In a different laboratory by personnel not employed by your laboratory. • In a primary care facility (like doctors office). • In an emergency room. • In an ambulance. • The central word is “decentralization with not your own personnel”. BUT under the responsibility of an accredited laboratory according ISO15189:2012 Where is Point-of-Care testing performed
  12. 12. Required Features for POC Devices WHO ASSURED Guidelines  Affordable – for those at risk of infection.  Sensitive – minimal false negatives.  Specific – minimal false positives.  User-friendly – minimal steps to carry out of the test.  Rapid & Robust - short TAT (< 30 min.) and no need for refrigated storage.  Equipment-free – no complex equipment.  Delivered – to end users; safe to use. Adapted from St. John A. and Price CP. 2014. Clin. Biochem. Rev. 35: 155-167.
  13. 13. MDx POC Market Drivers Patient Focused • Personalized medicine • Rapid actionable results impact clinical decisions • Enhance linkage to care • Earlier treatment • Not lost to follow-up • Immediate counseling and management • Improve clinical care and outcomes • Access to data • Patient satisfaction Economic • Healthcare reform • Reduce healthcare spending • Aging populations • New healthcare delivery models • Organizational impact • Decentralized healthcare • Epidemics, pandemics, emerging pathogens • Faster results R. Hodinka PASCV 2019
  14. 14. • We are at the initial introduction phase of new systems that enable rapid molecular testing. Rapid implies near bedside testing or while the patient is still waiting for the results (emergency room, out-of-office post). • The new rapid molecular assays are still “in development ” and quality indicators are not clearly defined (like what is an acceptable clinical detection limit). Most –if not all- of them are qualitative. • Important is clinical support related to the interpretation of the results. • POC testing also implies compliant with ISO22870:2016 in combination with ISO15189:2012. Excluded is self-testing in a home or community setting. The POI test don’t need to comply with the ISO22870:2016 guideline. • (Pitfall is CE/IVD and FDA approved). Why I call it Point-of-Impact (and not Point-of-Care, more specific for molecular testing)
  15. 15.  The laboratory director remains responsible for performing POC diagnostics, whether in a central laboratory or remotely in an ED.  ISO22870:2016 is linked to ISO15189:2012.  Training records and continued training is mandatory.  A hospital needs to have a POC-committee, who is responsible for the choice of equipment/technology, costs/benefit. Various stakeholders need to be involved (also from outside the laboratory).  Linked to the patient information system electronically.  Risk assessment! The ISO 22870:2016 Point-of-Care (what is needed)
  16. 16.  Laboratories need to be accredited according to ISO15189:2012, and for POC also ISO22870:2016.  Reimbursement issues in several countries hinder the introduction of molecular POC testing.  The new CE/IVD directive is stricter on clinical relevance of molecular tests.  In some countries, diagnostic laboratories are very close to the hospital; in other countries, there are more decentralized organized.  Discussion on costs/benefit of POC/POI. Challenges in Europe for POC/POI Molecular Testing
  17. 17. • Analytical validation – Does the assay perform reasonable accurately, with a sensitivity as shown to be present in different patient populations. • Clinical validation - Is what the test identifies clinically relevant or meaningful. Are peer-reviewed publications available. Evidence related to disease. Are relevant genotypes and/or strains detected. • Clinical utility – Is the test useful in the management of patients. • (Pitfall is CE/IVD and FDA approved). Information needed to be made available (the right test for the right patient at the right time)
  18. 18. Clinical relevance of laboratory testing: any information that contributes to patient management  Testing purpose: diagnosis, monitoring, screening  DNA load: threshold level for disease, relation to severity/outcome?  Type of patient: immunocompetent/-compromised; neonate vs adult  Duration of illness, treatment?  Type (and quality) of material: CSF, vesicle fluid, BAL, stool, swab Interpretation of MDx results requires clinical information and medical expertise
  19. 19. Quality Control and ISO15189:2012, ISO22870:2016  Define the parameters or targets you want clinically and whether assays are available to your need. You must verify them (CE/IVD – FDA approved), or validate these assays (mostly for LDTs).  RISK assessment is the magic word.  Define clinical relevance (major topic) for your patient population. Not related to CE/IVD or FDA approved. Interestingly, assays provide mostly only qualitative data.  Define how you want to use the assays and who should use them. Related to ISO22870:2016. The discussion about point-of- care testing (POC).  Define how you introduce proficiency testing into procedures. They have to be fit-for-purpose.
  20. 20. Responsibility • The laboratory director is responsible for the whole diagnostic process; from taking the right sample until the result given to the clinician/patient.
  21. 21. Important aspects of the new IVD Regulation NEW EUROPEAN REGULATION of in vitro diagnostic medical devices  New Regulation Global overview Context & Timelines
  22. 22. WHAT is changing ? – New Classification Devices revamped in the 4 classes : A, B, C & D “Others” Class D Class C Class B Class A Directive « Annex II list A & B devices » New regulation « Risk based rules » + R I S K - + R I S K - Annex II list B Annex II list A Risk to:  public health, and  patient
  23. 23. WHY? • Improve patient safety • More consistency across borders • Enforced control, increased transparency • A regulation replacing a directive – Regulation (EU) 2017/746 replacing Directive 98/79/EC
  24. 24. • Extended scope • New Classification • Clinical Evidence and Scientific Validity • Strengthened role of Notified Bodies • Qualified Person • Increase Transparency and Traceability • Post-Market requirements (eg surveillance) WHAT?
  25. 25. WHEN? Both regulatory systems coexist IVDs compliant with European Directive (CE) IVDs compliant with new European regulation (CE) Transition period 2017 2022 New European IVD regulation Exit the European IVD Directive 2003
  26. 26. WHAT is changing ? Demonstration of the Clinical Evidence
  27. 27. WHAT is changing ? New or reinforced concepts • Scientific Validity / Clinical Utility – Association of an analyte to a clinical condition/physiological state – Key for new or recent analytes / new or recent intended purpose • Concepts of established versus novel assay / standardized assay – Make providing clinical performance facultative or mandatory and more complex – Definitions may vary from one range to another • Clinical performance: Trial population – Increased vigilance in the performance evaluation study population – Representativity of the trial population as claimed in the product intended use – Patients characterization more documented
  28. 28. The challenges and unknowns • Information on performance of POI/POC testing related to LDT, more –semi- quantitative information. • Information on detection of strains, variants, species. Relevant not only for influenza and influenza typing, but also for e.g. enteroviruses. • Shared information on clinical relevance. Is related to patient populations and may be differently interpreted in various settings.
  29. 29. Important to relate the EQA programme to clinical situation Clinical picture and herpesvirus: DNA load in CSF Virus Clinical picture Virus load in CSF Range Mean HSV 1 Acute encephalitis or meningitis 2.3 x 102 – 1.8 x 106 6.9 x 104 HSV 2 Meningitis or encephalitis Perinatal infection 3.9 x 103 – 4.9 x 105 5.5 x 104 5.4 x 104 – 9.9 x 109 1.5 x 106 SW Aberle and E Puchhammer-Stockl, Journal of Clinical Virology 25 (2002) S79-S85
  30. 30. Data UMC Utrecht dr. AM van Loon Clinical relevance at low viral load levels: relation to clinical material: CSF vs vesicle fluid
  31. 31. Histograms based on LDT data
  32. 32. Clinical relevance and viral load  Viral load: relation between disease severity/ course and viral load often unknown, but general perception is: • the more virus, the more severe the disease • low viral loads have less significance: “sensitivity is an overestimated issue”  Problem: lack of international reference material
  33. 33.  Implementation  QC/QA similar to other diagnostic tests  Interference/Inhibition  Internal process controls  Contamination  Specimen cross-contamination  Amplicon contamination (fully integrated, self contained device)  Oversight by the laboratory director  Evaluation and trend analysis  Reimbursement Managing POC/POI testing
  34. 34. EQA Design has to be fit-for-purpose… • Meet regulatory requirements - ISO17043:2010 as an EQA / PT provider • Be practical and cost effective • Meet requirements of clinical laboratory (ISO15189:2012 or equivalent). • Both Educational and Regulatory driven. • ‘state of the art’ keep up with current clinical and technological developments (industry). • Clinically relevant – close to clinical sample (where possible)
  35. 35. I thought we agreed to measure everything in the same unitage? We did! What conversion factor did you use? Education on how to use them Need for reference material, standards
  36. 36. Reference Materials/Strains; NA Controls and References
  37. 37. Multiple pathogen / Syndromic molecular EQA schemes • Bacterial Gastroenteritis • Bacterial Sepsis • CNSII (Non-viral) • Immunocompromised • Parasitic Gastroenteritis • Bacterial Respiratory • Sexually Transmitted Infections • Neonatal / New-born infections • Meningitis-Encephalitis (ME) “Multiplex and / or Point of Impact based molecular diagnostic tests”
  38. 38. The Extended Diagnostic Triangle TAT Cost or €hr Quality Diagnostics Treatment Infection Control L I S
  39. 39. NOTE: There will be a special issue (peer reviewed) from the Journal of Clinical Virology, dealing with papers on “all” aspects on Point-of-Care (2020). Co-edited by Richard Hodinka (USA) and Gorm Lisby (EU).
  40. 40. Scientist A lot of questions. No answers. Diagnostics Only needs answers. No questions.

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