1. WHO Prequalification of Diagnostics WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies 29 Oct – 2 November, Geneva Anita Sands Diagnostics & Laboratory Technology Team Department of Essential Medicines & Health Products

2. 2 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Regulation of diagnostics (IVDs) Regulation specifically for diagnostics is often poorly understood and/or poorly enforced Different categories of IVDs regulated differently –HIV IVDs, particularly for blood screening, attract greatest stringency –Degree of stringency is usually risk-based –Risk perception is different in different settings Procurement policies drive supply of quality assured products –often acting as de facto regulatory control

3. 3 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Who sets international standards? Organization International Organization for Standardization (ISO) Certification of ISO compliance is made by an independent agency. Global Harmonization Task Force (GHTF) Comprised on national regulators & industry. Issues guidance on specific topics related to medical devices including IVDs. International Medical Device Regulators Forum (IMDRF) - replaced GHTF Comprised on national regulators. Maintains GHTF guidance documents. Clinical and Laboratory Standards Institute (CLSI) Issues guidance documents specific for testing processes.

4. 4 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Role of WHO To provide normative guidance to Member States on when and how to use IVDs to guide clinical decision-making –WHO ART guidelines To provide recommendations on quality and performance of IVDs through the WHO Prequalification of Diagnostics programme according to international standards To increase in-country capacity to effectively regulate & to monitor quality of diagnostics in their market

5. 5 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 To promote and facilitate access to safe & appropriate diagnostic technologies of good quality in an equitable manner –Through adoption of GHTF guidance and ISO requirements Customers –WHO Member States –UN agencies –Funding and procurement agencies Aim of WHO Prequalification of Diagnostics

6. 6 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

7. 7 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Application: requirements Manufacturer may submit application at any time to diagnostics@who.int –Must use the Prequalification of Diagnostics application form –Instructions for the completion of the application form contains information to help fill the form

8. 8 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prioritization of PQDx applications CommentCurrent prioritization criterion Ensure continuity of supply and quality of products procured Already listed on WHO/UN procurement scheme and procured by UN organizations in significant levels Focus on priority disease areas – highest historical procurement Assist diagnosis of infection with HIV-1/HIV-2, or malaria Bringing testing closer to the communityRapid test format Ensure known supply chain; no duplication of effort, best possible prices Original product manufacturers Focus on unmet market / procurement needsFew other prequalified products exist in the product category such as CD4, VL

9. 9 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

10. 10 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Dossier: requirements Dossier must demonstrate that the IVD conforms to the Essential Principles of Safety and Performance of Medical Devices (GHTF/SG1/N41R9:2005) Key Components Product description Design and manufacturing information Product performance specifications & associated validation and verification studies Labelling Commercial history Regulatory history Quality management system

11. 11 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Dossier: submission Clinical evidence to validate performance claims –One clinical evaluation* performed by Manufacturer –One clinical evaluation* performed independently Must clearly relate to the product undergoing prequalification (same name, same product code, same regulatory version) *The EC Common Technical Specifications (CTS) for IVDs 2009 are a useful guide http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:039:0034:0049:EN:PDF Performance characteristics Clinical (diagnostic sensitivity) including seroconversion sensitivity Clinical (diagnostic) specificity Positive and negative predictive values (high/low prevalence) Different clinical stages Geographical distribution (consider intended use setting) Genotypic differences

12. 12 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

13. 13 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Inspection: requirements The manufacturer must demonstrate that the IVD is produced under a functional quality management system e.g. conforms to ISO 13485:2003 Key Components Quality management system including documentation requirements Management responsibility including customer focus, quality policy Resource management including human resources, work environment Product realization including production and service provision, control of monitoring and measuring devices Measurement, analysis and improvement including control of nonconforming product, improvement

14. 14 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Inspection: requirements Dossier submission data – to confirm is true QC and lot release –QC panels should be challenging enough to detect failure or drift –Independence and adequately staffed QA/QC department –Deviation reporting procedures observed WHO related/end user issues -IFU -stability (transport, in-use, expiry dates) -training -complaints reporting mechanisms

15. 15 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

16. 16 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Laboratory evaluation: protocol Panel nameNo. of specimens WHO HIV specimen reference panel 460 HIV positive 658 HIV negative Lot-to-lot variation panel16 member 2-fold dilution series of 10 specimens (n=160) HIV seroconversion panels8 panels (n=52) HIV mixed titre panel1 panel (n=25) WHO reference preparation2 panels (n=7) If Ag/Ab assay HIV p24 antigen panel1 panel (n=25) HIV culture supernatant6 member 2-fold dilution series of 10 subtypes Specimens are characterised by –3 rd generation EIA (Ab) –4 th generation EIA (Ab/Ag) –HIV-1 24 antigen EIA (Ag) –HIV-1/2 line immunoassay (Ab only)

17. 17 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Laboratory evaluation: outcome If RDT, results are read by 3 independent readers Two production lots are submitted to assess lot-to- lot variation Results of the WHO laboratory evaluation must meet the acceptance criteria Parameter (HIV)RDTsEIAs Sensitivity99%100% Specificity98% Inter-reader variability 5%N/A Invalid rate5%

18. 18 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

19. 19 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification: decision Final prequalification outcome depends on: –Results of dossier assessment and acceptance of action plan –Results of inspection and acceptance of action plan no critical nonconformities outstanding –Meeting the acceptance criteria for the laboratory evaluation WHO PQDx Public Report is posted on WHO website and product is added to the list of WHO prequalified products Product is then eligible for WHO and UN procurement

20. 20 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

21. 21 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Post-market surveillance WHO PQDx complaint form for end users to report issues –http://www.who.int/diagnostics_laboratory/procurement/complain ts/en/index.html GHTF/SG2-N54R8:2006 –Medical Devices Post Market Surveillance: Global Guidance for Adverse Event Reporting for Medical Devices GHTF/SG2-N57R8:2006 –Medical Devices Post Market Surveillance: Content of Field Safety Notices

22. 22 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 PQDx assessment status for all products WHO website updates the status of each product undergoing PQDx assessment monthly http://www.who.int/diagnostics_laboratory/pq_status/en/index.html

23. 23 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Products eligible for procurement http://www.who.int/diagnostics_laboratory/procurement/pur chase/en/index.html

24. 24 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012 Contact us Contact us by email diagnostics@who.int WHO Prequalification of Diagnostics programme website http://www.who.int/diagnostics _laboratory/evaluations/en/