In Vitro Diagnostics Programme Mercedes Pérez González Department of Essential Medicines amp Health Products WHO Prequalification Team Diagnostics WHO work with in vitro diagnostics IVDs ID: 413500
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Slide1
Overview of WHO Prequalification of In Vitro Diagnostics Programme
Mercedes Pérez González
Department of Essential Medicines & Health Products
WHO Prequalification Team – DiagnosticsSlide2
WHO work with in vitro diagnostics (IVDs)
HIV assays since
1988
HIV assays since 1988Hepatitis B assays since 2000Hepatitis C assays since 2000Syphilis assays since 2001Chagas assays since 2002Malaria assays since 2002CD4 technologies ad-hoc in 1996 & 2003
WHO has been assessing diagnostics performance and operational characteristics since 1988Slide3
PQDx Launch – 2008 Slide4
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 frameworkDifferent regulatory versions of the same product
Different categories of IVDs regulated differently
Degree of stringency is usually risk-basedRisk perception is different in different settingsHIV IVDs, particularly for blood screening, attract greatest
stringencySlide5
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.Slide6
Role of WHO
To
provide
normative guidance to Member States on when and how to use IVDs to guide clinical
decision-makingWHO 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 marketSlide7
Aim of WHO Prequalification of IVDs
To
promote and facilitate access to safe & appropriate diagnostic technologies of good quality in an equitable
mannerThrough adoption of GHTF guidance and ISO requirements
Customers
WHO Member States UN agencies Funding and procurement agencies Slide8
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 assessmentSlide9
WHO prequalification assessment
Pre-submission form
Dossier review
Site inspection
Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
NoSlide10
PQDx pre-submission form: requirements
Manufacturer may submit a form at any time to diagnostics@who.int
Must use the Prequalification of IVDs pre-submission form
Instructions for the completion of the form availableInstructions for use must be submittedThe new form asks for more detailed information on regulatory versions of the product submitted to determine if eligible for abbreviated PQ procedureSlide11
Prioritization criteria
Current 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 criteriaSlide12
WHO prequalification assessment
Pre-submission form
Dossier review
Site inspection
Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
NoSlide13
Dossier: requirements
Based on best international practice (ISO, EN, GHTF,
CLSI);
follow the content of the GHTF STEDLooks 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)Slide14
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 systemSlide15
Dossier: submission
Clinical
evidence
to validate performance claimsOne clinical evaluation* performed by ManufacturerOne clinical evaluation* performed independentlyMust 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) specificity
Positive and negative predictive values (high/low prevalence)
Different clinical
stages
Geographical
distribution (consider intended use setting)
Genotypic differencesSlide16
WHO prequalification assessment
Pre-submission form
Dossier review
Site inspection
Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
NoSlide17
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 policyResource managementincluding 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, improvementSlide18
Inspection: requirements
Dossier submission data – to confirm its veracity
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
Slide19
WHO prequalification assessment
Pre-submission form
Dossier review
Site inspection
Laboratory
evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes
NoSlide20
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 WHOWHO Composite Reports of
all products producedReport 17 published, Report 18 to comeSlide21
Laboratory evaluation: outcome
If
RDT,
results are read by 3 independent readersTwo production lots are submitted to assess lot-to-lot variationResults 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%Slide22
Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
Dossier
Assessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market SurveillanceSlide23
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 evaluationWHO PQDx Public Report is posted on WHO website and product is added to the list of WHO prequalified
productsProduct is then eligible for WHO and UN procurementSlide24
PQDx Abbreviated Procedure (previously known as Fast-track)
Categories of products submitted to
PQ:
Version submitted for PQ has been stringently assessedCE: List A, Annex 2; FDA: PMA or
BLA; Health Canada: Class IV; TGA:
Class 4; Japan: Minister's approvalVersion
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 GHTFSlide25
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.htmlSlide26
Prequalification of Diagnostics
Application by Manufacturer
Meets Requirements
Dossier
Assessment
Manufacturing Site Inspection
Laboratory Evaluation
Product Prequalified
Post Market SurveillanceSlide27
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 ActionSlide28
Post-market surveillance
Should be
an obligation
of the manufacturer, but poorly executedWHO PQDx complaint form for end users to report issues
http://www.who.int/diagnostics_laboratory/procurement/complaints/en/index.html
Pilot project on PMSRegulatory capacity buildingCapacity building at the NRL levelSlide29
Contact us Contact us by email
diagnostics@who.int
WHO
Prequalification of
In Vitro Diagnostics
Programme website
http://www.who.int/diagnostics_laboratory/evaluations/en/