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

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

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

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

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.

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

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.

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

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

PQDx pre-submission form: requirements World Health Organization 15 April, 2017 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 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

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

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

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).

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

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 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2009:039:0034:0049:EN:PDF 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

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

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

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

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

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

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

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

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

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

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: http://www.who.int/diagnostics_laboratory/pq_status/en/index.html

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

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

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 http://www.who.int/diagnostics_laboratory/procurement/complaints/en/index.html Pilot project on PMS Regulatory capacity building Capacity building at the NRL level

World Health Organization 15 April, 2017 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/