WHO Prequalification of Diagnostics

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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
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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
Product Prequalified
Meets Requirements
Post Market Surveillance
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Application requirements

• Manufacturer may submit application at any time
  to diagnostics_at_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

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Prioritization 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
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Prequalification of Diagnostics
Application by Manufacturer
Dossier Assessment
Product Prequalified
Meets Requirements
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/N41R9200
  5)

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)
• The EC Common Technical Specifications (CTS) for
  IVDs 2009 are a useful guide
• http//eur-lex.europa.eu/LexUriServ/LexUriServ.do?
  uriOJL200903900340049ENPDF

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
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Prequalification of Diagnostics
Application by Manufacturer
Dossier Assessment
Product Prequalified
Meets Requirements
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 134852003

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
Product Prequalified
Meets Requirements
Post Market Surveillance
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Laboratory 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 (n160)
HIV seroconversion panels 8 panels (n52)
HIV mixed titre panel 1 panel (n25)
WHO reference preparation 2 panels (n7)
If Ag/Ab assay If Ag/Ab assay
HIV p24 antigen panel 1 panel (n25)
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 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
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Prequalification of Diagnostics
Application by Manufacturer
Dossier Assessment
Product Prequalified
Meets Requirements
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

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Prequalification of Diagnostics
Application by Manufacturer
Dossier Assessment
Product Prequalified
Meets Requirements
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/procurem
  ent/complaints/en/index.html
• GHTF/SG2-N54R82006
• Medical Devices Post Market Surveillance Global
  Guidance for Adverse Event Reporting for Medical
  Devices
• GHTF/SG2-N57R82006
• 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_statu
  s/en/index.html

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Products eligible for procurement

• http//www.who.int/diagnostics_laboratory/procurem
  ent/purchase/en/index.html

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Contact us

• Contact us by email
• diagnostics_at_who.int

• WHO Prequalification of Diagnostics programme
• website
• http//www.who.int/diagnostics_laboratory/evaluati
  ons/en/