Prequalification of in vitro diagnostics - Technical Update 24 November 2015

Transcription

1 Prequalification of in vitro diagnostics - Technical Update 24 November 2015 Copenhagen, Denmark November

2 Product Dossier Copenhagen, Denmark November

3 PQDx Data Quality Expectations Copenhagen, Denmark November

4 Data Integrity Maintaining and assuring the accuracy and consistency of data over its entire life-cycle Data Quality Analysing the relevance of the data in the dossier Copenhagen, Denmark November

5 Data integrity Data may be generated by > Paper based record of an observation (manual) > Equipment or computerised Risk to data integrity depends on the system used and the possibility it can be potentially manipulated Data integrity requirements apply equally to manual (paper) and electronic data There must be appropriate data integrity controls Copenhagen, Denmark November

6 Data integrity Systems of low complexity (eg recording of results of tests generated from an RDT) may produce results that are easier to manipulate without detection > Eg repeat testing WHO assessors will look for evidence of compliance with data integrity principles Copenhagen, Denmark November

7 Data integrity Aspects that will ensure traceability Comprehensive protocols Evidence of control e.g. > User access rights, other evidence of data governance > Controlled blank paper templates for results recording > Control of intended and unintended changes > Evidence of verification that documentation a true record eg senior management sign off Other evidence of good recording practice Copenhagen, Denmark November

8 Good recording practice Data for a study must be > Attributable to the person generating the data > Legible and permanent > Contemporaneous > Original record > Accurate Copenhagen, Denmark November

9 Data Integrity WHO Guidance on Good Data and Record Management Practices (Draft September 2015) Copenhagen, Denmark November

10 Data Quality Analysing the relevance of the data in the dossier Reports should be complete and transparent WHO assessment of a study report will assess it for bias and for generalisability of the results For accuracy studies (eg diagnostic sensitivity and specificity), recommend the use of STARD list Standards for Reporting Diagnostic accuracy studies Study authors can use the list to write informative study reports Copenhagen, Denmark November

11 Data Quality Copenhagen, Denmark November

12 Data Quality WHO TGS will provide manufacturers with comprehensive guidance on issues considered of critical importance to PQ TGS 1 Standards > Provides background on why standards should be used > Describes solutions for when appropriate standards do not exist > Provides a list of relevant standards, guidance and reference material for manufacturers > Will be routinely updated Copenhagen, Denmark November

13 Data Quality Not just relying on good reporting, but also relevant data TGS 2 Stability > Provides background on why standards should be used > Describes solutions for when appropriate standards do not exist > Provides a list of relevant standards, guidance and reference material for manufacturers > Will be routinely updated Copenhagen, Denmark November

14 Data Quality Not just relying on good reporting, but also relevant data TGS 3 Test Method Validation > Appropriate test methods need to be developed to define whether predetermined specifications are being met. > Validation of the testing process provides documented evidence that the product conforms to defined user needs and intended use. > PQ experience indicates many manufacturers do not understand the basic concepts and as a result, dossiers contain suboptimal evidence of test performance Copenhagen, Denmark November

15 Performance evaluations Copenhagen, Denmark November

16 Performance evaluation Performance evaluation of HIV Ab/Ag, HIV/Syphilis, HIV oral fluid, HBsAg, HCV, CD4 technologies Progress in 2015 > Completed evaluation 14 > Ongoing evaluations 8 > Scheduled 7 Issues to note > Challenge to obtain sufficient OF samples > Wide variation on seroconversion sensitivity > Ability to detect HIV subtypes e.g. Subtype O > Cross reactivity between HIV-2 and HIV-2 > HBsAg limit of detection of 0.13 IU/ml for RDTs Copenhagen, Denmark November

17 Performance evaluation Performance evaluation of HIV NAT-based qualitative technologies for diagnosis > Two evaluations ongoing > Whole venous blood and DBS > In collaboration with NHLS South Africa and CDC Atlanta Performance evaluation of HIV NAT-based quantitative technologies > One evaluation ongoing > Plasma > In collaboration with NHLS South Africa and CDC Atlanta Copenhagen, Denmark November

18 Current Malaria Product Testing Comparative evaluation of commercially-available antigen-detecting malaria rapid diagnostic tests RDTs. Open call EOI Evidence of quality manufacturing RDTs to specimen bank & payment $8000USD/product Performance versus panel Stability Ease-of-Use assessment Longer-term stability test by manufacturer Review of results by technical group Results released to manufacturers Final publication 5 years 18

19 Product Testing (at US CDC) Performance panel detection score, false-positive and invalid rates Phase 1 20 cultured P.falciparum samples; 2 lots; 1 ; 2 200p/µl + 20 clean negative samples Phase 2 P.falciparum (100), P.vivax (35), 2 lots; 1 ; 2 200p/µl negative samples (100; mixed clean and other disease conditions) Antigen concentrations (HRP2,pLDH, aldolase) not statistically different in panel samples between Rounds 1-6 Heat stability (4 C, 35 C, 45 C; 75% humidity x 60 days) Ease of use assessment blood safety, instructions quality, no. timed steps, RDT anomalies Adherence to international standards and best practice for IVD labelling and instructions for use (Round 7) 19

20 Results Panel detection score: Pf 200 and 2000p/µL

21 Rounds 1-7 Published Rounds 1-5 > 206 RDTs evaluated (147 unique products) Round 6 > 41 RDTs (30 combo; 11Pf only; 22 manufacturers) Round 7 > Report in production - November 2015 > Expression of interest 85 products > Limit to 2 products per manufacturer (plus compulsory resubmissions) > 45 shipped for evaluation to begin December

22 Inspections * Based on ISO (new version pending) * Customer & Product Focus; Dossier Confirmation and * Harmonization with Medical Device Single Audit Program (MDSAP) * Rationalization of timelines Copenhagen, Denmark November

23 Changes and Improvements Changes implemented Adopted the format of the IMDRF - MDSAP (International Medical Device Regulators Forum; Medical Device Single Audit Program) Advantages Internationally harmonised, transparent, documents in public domain, adopted by IMDRF members (e.g. FDA, ANVISA, TGA, HC) Establish readiness for inspection (desktop document review, i.e. Stage 1) Clear timelines for follow up actions (schedule inspection, CAP response) Defer to technical assistance for deficient systems Inspection planned if manufacturer s QMS has been fully implemented (and dossier acceptable) Transparent process, clear expectations that reduce time to PQ decision Plan follow-up / re-submission when the QMS has been fully implemented Copenhagen, Denmark November

24 Copenhagen, Denmark November

25 Inspection process (Seek techn. assistance) Stage 1 Dossier Screening Terminate N Ready for Inspection Plan Y List of questions Dossier Review N N Stage 2 Inspection Compliant? (<3 level 4 NC) 2 rounds CAP Y Recommendation for PQ Y Y Compliant? N 2 rounds CAP N Terminate Information for manufacturers on prequalification inspection procedures for the sites of manufacture of diagnostics (WHO PQDx_014) Copenhagen, Denmark November

26 Onsite Inspections Inspection Cycle: > Dossier review: QMS documentation section > Stage 1: Evaluation of readiness for inspection > Desktop of additional documentation (Certificates, recent audit reports, procedures, summary of product on the market...) > And/or Stage 1 inspection (1 inspector day to inspect state of QMS implementation, facility, competence of staff, critical suppliers incl. outsourced activities, internal audit and management review / commitment) > Stage 2: > Initial Inspection > Possible follow up inspection: confirm implementation of CAP if required for multiple nonconformities (within 6 months of initial inspection). > Calculation of (abbreviated) inspection time > MDSAP MDSAP_AU_P0008_Audit_Time_Calculation_Procedure > MDSAP_AU_F0008.1_Audit_Time_Calculation_Spreadsheet > Re-Inspection (risk based, after 3-5 years) Copenhagen, Denmark November

27 Abbreviated Inspection Procedure Information pack requested: based on Stage 1 inspection documentation (Reference: WHO PQDx-173). > QMS Documentation e.g. change control procedure, risk management > Evidence of Certification e.g. audit reports of most recent regulatory inspections / audits > Product labelling (IFU, component labels and box labels, photographs of kit box including kit components, accessories) > Manufacturing - floor plan, manufacturing flowchart including in-process control points, list of significant suppliers (incl. type of supply), outsourced processes Copenhagen, Denmark November

28 Grading Nonconformities - GHTF Model GHTF/SG3/N19:2012 Quality management system Medical devices Nonconformity Grading System for Regulatory Purposes and Information Exchange. Grading nonconformities - Levels 1 to 5. Copenhagen, Denmark November

29 How the grading system works Grading is a two-step process: Step 1: Grading matrix The clauses of the ISO standard are divided into two categories 1. Indirect QMS impact: ISO 13485:2003 clauses : 1. enablers for the QMS processes to operate 2. considered to have indirect influence on medical device safety and performance. Starts at Level Direct QMS impact: ISO 13485:2003 clauses : 1. direct influence on design and manufacturing controls 2. have direct influence on medical device safety and performance. Starts at level 3. Copenhagen, Denmark November

30 How the grading system works Step 2: Escalation Rules raises NC up one level subsequent inspection - same finding absence of documented process nonconforming product on the market e.g. a Level 3 nonconformity left uncorrected will automatically be escalated to a Level 4 nonconformity at a subsequent inspection. Note: Fabrication of information / data is graded as Level 5 and the inspection can be terminated. Outcome If no level 5 NCs and <3 Level 4 NCs then can proceed to CAP request. Copenhagen, Denmark November

31 Impact of ISO13485:20xx (in Draft) on Manufacturers Medical devices Quality management systems Requirements for regulatory purposes Risk-based approach greatly up-emphasized at all stages of product life cycle (Ref ISO 14971: Medical devices -- Application of risk management to medical devices) Contains more detailed explanation in particular Communication with regulatory authorities Validation / verification (for design, re-validation) Design and Development transfer new Control of Design and Development changes Records (especially design and development new) Annex B provides a detailed comparison (2003 vs 20xx) Three year introductory period Easier for manufacturers; clearer guidance for inspectors. Copenhagen, Denmark November

32 Inspection activity: IVDs (and MDs (October 2014-September 2015) 24 - Sites or manufacture inspected 15 - Inspections completed 9 - Outcome pending: > 5 - Verification of effective Corrective Action Plan (multiple complex issues for Mx to address) > 3 - Corrective Action Plan review underway > 1 - Site noncompliant (closed) (systemic QMS failure or fabrication of information) Copenhagen, Denmark November

33 Implications for Manufacturers Reduced time and timelines defined: Abbreviated PQ for approved products / QM-systems (includes brief dossier review and on site only) CAP response to onsite NC list; 2 rounds of responses only Improved transparency and efficiency: Harmonised IMDRF reporting; GHTF for nonconformity grading Pre-inspection - Stage 1 review report to Mx, inspection plan On site issues communicated, list of nonconformities left onsite Post-inspection - harmonised report format, corrective action plan & review (30day TAT; 2 WHO responses only), follow up inspection (or technical assistance) if needed. Revised ISO13485:20xx: Implementation (over 3 years) Copenhagen, Denmark November