Post on 27-Mar-2015
WHO Prequalification of Diagnostics
WHO/UNICEF Technical Briefing Seminar on Essential Medicines Policies 29 Oct – 2 November, Geneva
Anita SandsDiagnostics & Laboratory Technology Team
Department of Essential Medicines & Health Products
2 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Regulation of diagnostics (IVDs)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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Who sets international standards?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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Role of WHO 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 | 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 Aim of WHO Prequalification of Diagnostics
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Prequalification of Diagnostics Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
7 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Application: requirements 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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prioritization of PQDx applicationsPrioritization of PQDx applications
Comment Current 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 community Rapid test format
Ensure known supply chain; no duplication of effort, best possible prices
Original product manufacturers
Focus on unmet market / procurement needs Few other prequalified products exist in the product category such as CD4, VL
9 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification of Diagnostics Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
10 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Dossier: requirements 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
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Dossier: submission 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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification of Diagnostics Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
13 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Inspection: requirementsInspection: 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 responsibilityincluding customer focus, quality policy
Resource managementincluding human resources, work environment
Product realizationincluding production and service provision, control of monitoring and measuring devices
Measurement, analysis and improvementincluding control of nonconforming product, improvement
14 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Inspection: requirementsInspection: 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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification of Diagnostics Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
16 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Laboratory evaluation: protocolLaboratory evaluation: protocol
Panel name No. of specimens
WHO HIV specimen reference panel
460 HIV positive 658 HIV negative
Lot-to-lot variation panel 16 member 2-fold dilution series of 10 specimens (n=160)
HIV seroconversion panels 8 panels (n=52)
HIV mixed titre panel 1 panel (n=25)
WHO reference preparation 2 panels (n=7)
If Ag/Ab assay
HIV p24 antigen panel 1 panel (n=25)
HIV culture supernatant 6 member 2-fold dilution series of 10 subtypes
Specimens are characterised by
– 3rd generation EIA (Ab) – 4th generation EIA (Ab/Ag)– HIV-1 24 antigen EIA (Ag) – HIV-1/2 line immunoassay
(Ab only)
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Laboratory evaluation: outcomeLaboratory 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) RDTs EIAs
Sensitivity ≥99% 100%
Specificity ≥98% ≥98%
Inter-reader variability
≥5% N/A
Invalid rate ≥5% ≥5%
18 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification of Diagnostics Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
19 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification: decisionPrequalification: 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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification of Diagnostics Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
21 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Post-market surveillancePost-market surveillance
WHO PQDx complaint form for end users to report issues– http://www.who.int/diagnostics_laboratory/procurement/
complaints/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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
PQDx assessment status for all productsPQDx 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 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Products eligible for procurementProducts eligible for procurement
http://www.who.int/diagnostics_laboratory/procurement/purchase/en/index.html
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Contact us Contact us
Contact us by email
diagnostics@who.int
WHO Prequalification of Diagnostics programme
website
http://www.who.int/diagnostics_laboratory/evaluations/en/