WHO Prequalification of Diagnostics WHO Technical Briefing Seminar on Essential Medicines and Health Products WHO HQ, Geneva, 28 October - 1 November 2013 Mercedes Pérez González Department of Essential Medicines & Health Products

2 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Regulation of diagnostics (IVDs) Regulation specifically for diagnostics is often poorly understood and/or poorly enforced Production of many diagnostic products has been moved to countries with less strict regulatory framework. 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 Different regulatory versions of the same product

3 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

7 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Application: requirements Manufacturer may submit application at any time to –Must use the Prequalification of Diagnostics application form –Instructions for the completion of the application form contains information to help fill the form

8 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

10 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Dossier: requirements Based on best international practice (ISO, EN, GHTF, CLSI); follow the content of the GHTF STED Looks into critical aspects for WHO Member States often not dealt with/dealt with from a local prospective by SRAs (stability, IFU, RA, etc.). Dossier must demonstrate that the IVD conforms to the Essential Principles of Safety and Performance of Medical Devices (GHTF/SG1/N41R9:2005)

11 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Dossier: requirements Key Components Product description Design and manufacturing information Product performance specifications & associated validation and verification studies Labelling Commercial history Regulatory history Quality management system

12 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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 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

13 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

14 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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

15 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Inspection: requirements Dossier submission data – to confirm is true Production 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

16 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

17 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Evaluations performed WHO evaluation protocols followed, based on existing international standards and best practice and adapted to assay type Performance and operational characteristics WHO Collaborating Centres performs evaluation under supervision of WHO WHO Composite Reports of all products produced –Report 17 to be released

18 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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 EIA (Laboratory)RDT (Point of Care or Laboratory) HIV serology Sensitivity: 100% Specificity: ≥ 98% Sensitivity ≥ 99% Specificity ≥ 98% Inter-reader variability ≤5% Invalid rate ≤5% HCV serology Sensitivity: 100% Specificity: ≥ 98% Sensitivity ≥ 98% Specificity ≥ 97% Inter-reader variability ≤5% Invalid rate ≤5% HBsAg serology Sensitivity: 100% Specificity: ≥ 98% Sensitivity 100% Specificity ≥ 98% Inter-reader variability ≤5% Invalid rate ≤5%

19 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

20 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 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

21 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 PQDx fast track procedure The process relies on provision of relevant “evidence” of certification issued by a stringent regulatory authority (SRA) or their authorised representative(s) Submitted evidence will be considered for its suitability in satisfying WHO requirements. This applies to –the dossier assessment (product design and development), –and/or inspections of the site of manufacture and the quality system –And/or the laboratory evaluation

22 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 PQDx assessment status for all products WHO website updates the status of each product undergoing PQDx assessment monthly

23 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Products eligible for procurement chase/en/index.html

24 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Prequalification of Diagnostics Application by Manufacturer Meets Requirements Dossier Assessment Manufacturing Site Inspection Laboratory Evaluation Product Prequalified Post Market Surveillance

25 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Post-market surveillance Should be the onus of the manufacturer, but poorly executed WHO PQDx complaint form for end users to report issues – en/index.htmlhttp:// 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 Pilot project on PMS –Regulatory capacity building –Capacity building at the NRL level

26 | WHO Technical Briefing Seminar on Essential Medicines and Health Products, Geneva l 31 October 2013 Contact us Contact us by WHO Prequalification of Diagnostics programme website _laboratory/evaluations/en/