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
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
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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.
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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
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Aim of WHO Prequalification of Diagnostics
 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
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Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing
Site Inspection
Laboratory
Evaluation
Meets
Requirements
Product Prequalified
Post Market Surveillance
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Application: requirements
 Manufacturer may submit
application at any time to
[email protected]
– Must use the Prequalification of
Diagnostics application form
– Instructions for the completion
of the application form contains
information to help fill the form
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Prioritization of PQDx applications
Current prioritization criterion
Comment
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,
or malaria
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, VL
Focus on unmet market / procurement needs
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Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing
Site Inspection
Laboratory
Evaluation
Meets
Requirements
Product Prequalified
Post Market Surveillance
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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
 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)
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
*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
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Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing
Site Inspection
Laboratory
Evaluation
Meets
Requirements
Product Prequalified
Post Market Surveillance
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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
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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
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Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing
Site Inspection
Laboratory
Evaluation
Meets
Requirements
Product Prequalified
Post Market Surveillance
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Laboratory evaluation: protocol
 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)
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
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Laboratory evaluation: outcome
 If RDT, results are read by
3 independent readers
 Two production lots are
submitted to assess lot-tolot 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%
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Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing
Site Inspection
Laboratory
Evaluation
Meets
Requirements
Product Prequalified
Post Market Surveillance
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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
19 | Technical Briefing Seminar on Essential Medicines Policies, Geneva l 29 Oct – 2 Nov 2012
Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing
Site Inspection
Laboratory
Evaluation
Meets
Requirements
Product Prequalified
Post Market Surveillance
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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
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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
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Products eligible for procurement
 http://www.who.int/diagnostics_laboratory/procurement/pur
chase/en/index.html
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Contact us
 Contact us by email
[email protected]
WHO Prequalification of
Diagnostics programme
website
http://www.who.int/diagnostics
_laboratory/evaluations/en/
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