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WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Overview of WHO Prequalification of In Vitro Diagnostics Programme
Mercedes Pérez González
Department of Essential Medicines & Health Products
WHO Prequalification Team – Diagnostics
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
WHO work with in vitro diagnostics (IVDs)
HIV assays since 1988
HIV assays since 1988
Hepatitis B assays since 2000
Hepatitis C assays since 2000
Syphilis assays since 2001
Chagas assays since 2002
Malaria assays since 2002
CD4 technologies ad-hoc in 1996 & 2003
WHO has been assessing diagnostics performance and operational characteristics since 1988
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
PQDx Launch – 2008
Shift from test kit evaluations to Prequalification of IVDs:
• More stringent approach• Alignment with global standards for assuring
quality of IVDs
Identify diagnostics that meet the quality standards through a rigorous process
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Regulation of IVDs
•Regulation specifically for IVDs is often poorly understood and/or poorly enforced•Production of many IVD products has been moved to countries with less strict regulatory framework•Different regulatory versions of the same product•Different categories of IVDs regulated differently
– Degree of stringency is usually risk-based– Risk perception is different in different settings– HIV IVDs, particularly for blood screening, attract
greatest stringency
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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.
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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 (supplement March 2014)– WHO HCV treatment guidelines (April 2014)
•To provide recommendations on quality and performance of IVDs through the WHO Prequalification of In Vitro Diagnostics Programme according to international standards•To increase in-country capacity to effectively regulate & monitor quality of diagnostics in their market
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Aim of WHO Prequalification of IVDs
•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
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Prequalification of In Vitro Diagnostics Programme
Pre-submission form
Dossier review Site inspection Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
No
Pre-submission form
Abbreviated site inspection
Laboratory evaluation
Prequalification decision
Yes
Full PQ assessment
No
Yes
Priority product
No
Decision on abbreviated PQ
assessment
Full prequalification assessment Abbreviated prequalification assessment
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
WHO prequalification assessment
Pre-submission form
Dossier review Site inspection Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
No
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
PQDx pre-submission form: requirements
•Manufacturer may submit a form at any time to [email protected]
– Must use the Prequalification of IVDs pre-submission form
– Instructions for the completion of the form available
– Instructions for use must be submitted
•The new form asks for more detailed information on regulatory versions of the product submitted to determine if eligible for abbreviated PQ procedure
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Prioritization criteriaCurrent prioritization criteria Rationale
Already listed on WHO/UN procurement scheme and procured by UN organizations in significant levels
Ensure continuity of supply and quality of products procured
Assist diagnosis of infection with HIV-1/HIV-2, malaria and hepatitis C
Focus on priority disease areas – highest historical procurement
Rapid test format Bringing testing closer to the community
Original product manufacturers Ensure known supply chain; no duplication of effort, best possible prices
Few other prequalified products exist in the product category such as CD4, viral load
Focus on unmet market / procurement needs
Adult male circumcision devices Focus on the needs of WHO disease programmes
Prioritization criteria
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
WHO prequalification assessment
Pre-submission form
Dossier review Site inspection Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
No
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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)
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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 characteristicsClinical (diagnostic) sensitivity including seroconversion sensitivity Clinical (diagnostic) specificityPositive and negative predictive values (high/low prevalence)Different clinical stagesGeographical distribution (consider intended use setting)Genotypic differences
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
WHO prequalification assessment
Pre-submission form
Dossier review Site inspection Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
No
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Inspection: requirementsThe manufacturer must demonstrate that the IVD is produced under a functional quality management system e.g. conforms to ISO 13485:2003
Key ComponentsQuality management system including documentation requirements Management responsibilityincluding customer focus, quality policyResource managementincluding human resources, work environmentProduct realizationincluding production and service provision, control of monitoring and measuring devices Measurement, analysis and improvementincluding control of nonconforming product, improvement
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Inspection: requirements
Dossier submission data – to confirm its veracityProduction 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
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
WHO prequalification assessment
Pre-submission form
Dossier review Site inspection Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
No
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Laboratory evaluation: requirements
•WHO evaluation protocols followed, based on existing international standards and best practice and adapted to assay type
– To evaluate performance and operational characteristics
•WHO Collaborating Centres performs evaluation under supervision of WHO•WHO Composite Reports of all products produced
– Report 17 published, Report 18 to come
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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 serologySensitivity: 100% Specificity: ≥ 98%
Sensitivity ≥ 99% Specificity ≥ 98%Inter-reader variability ≤5%Invalid rate ≤5%
HCV serologySensitivity: 100% Specificity: ≥ 98%
Sensitivity ≥ 98% Specificity ≥ 97%Inter-reader variability ≤5%Invalid rate ≤5%
HBsAg serologySensitivity: 100% Specificity: ≥ 98%
Sensitivity 100% Specificity ≥ 98%Inter-reader variability ≤5%Invalid rate ≤5%
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
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 level 5 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
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
PQDx Abbreviated Procedure (previously known as Fast-track)
Categories of products submitted to PQ:•Version submitted for PQ has been stringently assessed
– CE: List A, Annex 2; FDA: PMA or BLA; Health Canada: Class IV; TGA: Class 4; Japan: Minister's approval
•Version submitted for PQ has not been stringently assessed but a regulatory version exists that has been
•Where stringent assessment has been conducted by founding member of GHTF
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
PQDx assessment status for all products
Status of active applications to the prequalification of IVDs available at:http://www.who.int/diagnostics_laboratory/pq_status/en/index.html
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
DossierAssessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market Surveillance
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
WHO post-market surveillance for IVDs
WHO is developing guidance for reactive and proactive post-market activities
Post-market surveillance continually monitors the safety, quality and performance of an IVD once it is placed on the market
WHO prequalified product
Reactive PMS
Field Safety Notice
Complaints Lot verification testing
Proactive PMS
Field Safety Corrective Action
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Post-market surveillance
•Should be an obligation of the manufacturer, but poorly executed
WHO PQDx complaint form for end users to report issueshttp://www.who.int/diagnostics_laboratory/procurement/complaints/en/index.html
•Pilot project on PMS
Regulatory capacity building
Capacity building at the NRL level
WHO PREQUALIFICATION TEAM: DIAGNOSTICS WHO TECHNICAL BRIEFING SEMINAR
Contact us
Contact us by email
WHO Prequalification of In Vitro Diagnostics Programme
website
http://www.who.int/diagnostics_laboratory/evaluations/en/