1. Overview of WHO Prequalification of In Vitro Diagnostics Programme
Mercedes Pérez González
Department of Essential Medicines & Health Products
WHO Prequalification Team – Diagnostics

2. WHO work with in vitro diagnostics (IVDs)
World Health Organization
15 April, 2017
WHO work with in vitro diagnostics (IVDs)
WHO has been assessing diagnostics performance and operational characteristics 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

3. World Health Organization
15 April, 2017
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

4. World Health Organization
15 April, 2017
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

5. Who sets international standards?
World Health Organization
15 April, 2017
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.

6. World Health Organization
15 April, 2017
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

7. Aim of WHO Prequalification of IVDs
World Health Organization
15 April, 2017
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
Sustainable systems cannot be developed without the commitment and support of national health authorities and the global community. WHO has the global health mandate and with this is the role of advocacy. National blood programmes, safe injection policies, implementation of appropriate diagnostic support systems all need to be addressed and improved.
WHO’s working together will need to be improved and synergies developed so that this department will provide the necessary and appropriate technology. The provision of relevant international biological reference preparations and provision of training for national regulatory authorities need to be further strengthened.
Global Collaboration for Blood and Injection Safety will need to be improved and partnerships develop - WHO’s Special Initiative on HIV/AIDS and access to essential drugs will be supported.

8. Prequalification of In Vitro Diagnostics Programme
World Health Organization
15 April, 2017
Prequalification of In Vitro Diagnostics Programme
Full prequalification assessment
Abbreviated prequalification assessment
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
Priority product
Decision on abbreviated PQ assessment

9. WHO prequalification assessment
World Health Organization
15 April, 2017
Pre-submission form
Dossier review
Site inspection
 Laboratory evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes No

10. PQDx pre-submission form: requirements
World Health Organization
15 April, 2017
Manufacturer may submit a form at any time to
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

11. 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

12. WHO prequalification assessment
World Health Organization
15 April, 2017
Pre-submission form
Dossier review
Site inspection
 Laboratory evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes No

13. Dossier: requirements
World Health Organization
15 April, 2017
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)
Such STED is derived from the technical documentation held by the manufacturer and allows the manufacturer to demonstrate that the medical device to which it applies conforms to the Essential Principles of Safety and Performance of Medical Devices.
SG1/N041:2005 Essential Principles of Safety & Performance of Medical Devices
Requirements for dossier compilation and assessment were agreed with experts from SRAs (FDA, EU, Health Canada, NRL).

14. Dossier: requirements
World Health Organization
15 April, 2017
Key Components
Product description
Design and manufacturing information
Product performance specifications & associated validation and verification studies
Labelling
Commercial history
Regulatory history
Quality management system
Product dossier = the selection of records and documents from the technical documentation that shows how the diagnostic product was developed, designed and manufactured
WHO reviews the dossier with the purpose of
- Assessing the product and how it performs
- Assessing the product manufacture
- Determining if the manufacturer's quality management system is of an adequate to ensure consistent quality

15. World Health Organization
15 April, 2017
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

16. WHO prequalification assessment
World Health Organization
15 April, 2017
Pre-submission form
Dossier review
Site inspection
 Laboratory evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes No

17. Inspection: requirements
World Health Organization
15 April, 2017
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

18. Inspection: requirements
World Health Organization
15 April, 2017
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

19. WHO prequalification assessment
World Health Organization
15 April, 2017
Pre-submission form
Dossier review
Site inspection
 Laboratory evaluation
Dossier incomplete
Prequalification decision
Dossier complete
Dossier screening
Priority product
Yes No

20. Laboratory evaluation: requirements
World Health Organization
15 April, 2017
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

21. Laboratory evaluation: outcome
World Health Organization
15 April, 2017
Laboratory evaluation: outcome
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 ≥ 98%
Specificity ≥ 97%
HBsAg serology
Sensitivity 100%
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

22. Prequalification of Diagnostics
World Health Organization
15 April, 2017
Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing Site Inspection
Laboratory Evaluation
Meets Requirements
Product Prequalified
Post Market Surveillance

23. Prequalification decision
World Health Organization
15 April, 2017
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

24. 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

25. PQDx assessment status for all products
World Health Organization
15 April, 2017
PQDx assessment status for all products
Status of active applications to the prequalification of IVDs available at:

26. Prequalification of Diagnostics
World Health Organization
15 April, 2017
Prequalification of Diagnostics
Application by Manufacturer
Dossier
Assessment
Manufacturing Site Inspection
Laboratory Evaluation
Meets Requirements
Product Prequalified
Post Market Surveillance

27. 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
Proactive PMS
Complaints
Lot verification testing
Field Safety Corrective Action
Field Safety Notice

28. Post-market surveillance
World Health Organization
15 April, 2017
Post-market surveillance
Should be an obligation of the manufacturer, but poorly executed
WHO PQDx complaint form for end users to report issues
Pilot project on PMS
Regulatory capacity building
Capacity building at the NRL level

29. World Health Organization
15 April, 2017
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