Update on WHO Prequalification of In Vitro Diagnostics Robyn Meurant and Mercedes Perez Gonzalez Prequalification Team Diagnostics Assessment Essential Medicines and Health Products World Health Organization Joint UNICEF, UNFPA and WHO meeting with manufacturers and suppliers of in vitro diagnostics, vaccines, finished pharmaceutical products, active pharmaceutical ingredients, contraceptive devices and vector control products Copenhagen, Denmark 18 to 21 September 2017 Copenhagen, Denmark 18-21 September 2017 1
2015 Update Improved aspect Impact Outstanding challenges Solutions for challenges Progress Streamlined process Focus on active applications, minimize effort into immature applications, assess more products, expanded programme scope High priority products with immature applications / impact on overall timelines Guidance, sample dossiers, technical assistance and training, TCs, WebEx Expanded network for performance evaluations Less burden for WHO CCs, wider utilisation of PQ outcomes through USAID Timelines for specific technologies still challenging Future laboratory evaluation pathway Adoption of IMDRF principles Alignment with best international practice and reliance MDSAP still in pilot, industry concerns over ToC/RPS Further collaboration with IMDRF and other harmonization WPs Implemented changes assessment and PMS reporting Better insight in post-pq phase Underreporting on vigilance, variable compliance for changes notifications Updated changes assessment procedure, PMS WebEx, PMS training 2
2017 Progress Report Improved aspect Impact Outstanding challenges Solutions for challenges Progress Streamlined process Focus on active applications, minimize effort into immature applications, assess more products, expanded programme scope High priority products with immature applications / impact on overall timelines Guidance, sample dossiers, technical assistance and training, TCs, WebEx Expanded network for performance evaluations Less burden for WHO CCs, wider utilisation of PQ outcomes through USAID Timelines for specific technologies still challenging Future laboratory evaluation pathway Adoption of IMDRF principles Alignment with best international practice and reliance MDSAP still in pilot, industry concerns over ToC/RPS Further collaboration with IMDRF and other harmonization WPs Implemented changes assessment and PMS reporting Better insight in post-pq phase Underreporting on vigilance, variable compliance for changes notifications Updated changes assessment procedure, PMS WebEx, PMS training 3
Streamlined process Improved aspect Impact Outstanding challenges Solutions for challenges Progress Streamlined process Focus on active applications, minimize effort into immature applications, assess more products, expanded programme scope High priority products with immature applications / impact on overall timelines Guidance, sample dossiers, technical assistance and training, TCs, WebEx
Streamlined process Pre-submission form Eligible product Yes No Dossier screening Laboratory evaluation Dossier incomplete Dossier complete Dossier review Site inspection PREQUALIFICATION DECISION Maintenance of PQ Status
Abridged Procedure Pre-submission form Eligible product Yes No Site inspection Laboratory evaluation PREQUALIFICATION DECISION Maintenance of PQ Status
Abridged Procedure Pre-submission form Dossier Aspects Eligible product Yes No Site inspection Laboratory evaluation PREQUALIFICATION DECISION Maintenance of PQ Status
Updates Increase in the number of malaria manufacturers applying for WHO PQ Increase in the number of abridged PQ assessments Assessment of dossier aspects as part of the site inspection Innovative products and new manufacturers continue to apply to PQ Addition of new diseases requiring full PQ assessment
WHO Prequalified IVDs Products currently prequalified HIV RDTs 16 HIV NAT Quantitative and qualitative 15 Overall Prequalified products: 67 IVDs HIV Confirmatory Assays 3 HIV EIAs 13 HCV RDT 2 HCV NAT 1 HCV EIAs 3 HBsAg EIA 4 HIV/syphilis 1 CD4 Technologies 5 Malaria 12
Highlights Prequalification: Prequalification of two HIV EID technologies: Performance evaluation conducted as a collaboration between WHO, NHLS and CDC under USAID/PEPFAR-WHO common quality assurance mechanism. Prequalification of the first two HCV rapid diagnostic tests Prequalification of a HCV viral load assay Prequalification of the first HIV Self Test
Highlights PQ scope expanded to include In 2016: HIV assays intended for self-testing G6PD assays (for administration of primaquine and tafenoquine for radical cure of P. vivax) In 2017 (applications to be accepted 1 January 2018): Cholera RDTs
Highlights New set of PQ documents Overview of the WHO PQ of IVDs Assessment PQ Assessment and Change Assessment Target Deadlines PQ Assessment and Changes Assessment Fees Eligibility Criteria for WHO PQ of IVDs Presubmission form IVDs
Purpose of the dossier unique characteristics Demonstrate that the manufacturer has considered the quality, safety and performance of in the countries where WHO PQ IVDs are procured Programmatic suitability: specific emphasis on issues of particular relevance to resource-limited settings, such as: Stability of products (heat conditions) Adapted specimen type Labelling of products Ease of use (in terms of training and material) Performance evaluated in the global population Life cycle management of products 13
Update on dossier assessment WHO perspective PQ working to increase transparency for manufacturers: through publication of WHO requirements, revision of WHO documents and alignment with other organizations, for example: Technical Specification Series Technical Guidance series Consultation with international experts on requirements for new eligible IVDs Influence on the development of new International Standards and reference panels Plans to update current Instructions for compilation of a product dossier 14
Highlights cont d Technical Guidance Series: Standards applicable to the WHO Prequalification of IVDs Establishing stability of an IVD for the WHO Prequalification Principles of performance studies Test method validation of IVDs DRAFT Designing Instructions for use for IVDs DRAFT Panels for quality assurance and quality control of IVDs Sample dossiers: Sample Product Dossier for a CD4 IVD Sample Product Dossier for an IVD intended for HIV self-testing Sample Product Dossier for a Qualitative NAT to detect HIV-1 and HIV-2 Sample Product Dossier for a Quantitative NAT to detect HIV-1 RNA Technical Specifications Series: HIV rapid diagnostic tests for professional use and/or self-testing Glucose-6-phosphate dehydrogenase (G6PD) activity Malaria rapid diagnostic tests DRAFT Detection of high-risk HPV genotypes in cervical cancer screening
Highlights cont d Dossier Assessors Training: Training sessions provided to WHO PQ assessors to ensure consistency and equity in the review process. Provided by WHO and by partner laboratories with experience in PQ activities Dossier assessors trained in assessing data quality and data integrity Aim is not to fail a good product! Commitments to PQ: Developing a rating system based on the severity of the dossier requirement If non severe, results in a commitment to PQ Generally compliance reviewed at inspection
2017 Progress Report Improved aspect Impact Outstanding challenges Solutions for challenges Progress Expanded network for performance evaluations Less burden for WHO CCs, wider utilisation of PQ outcomes through USAID Timelines for specific technologies still challenging Future laboratory evaluation pathway 17
Alternative mechanism for WHO PQ performance evaluation Pre-submission form Change in evaluations scheduling: Priority product Shift from assessment to pre-assessment phase to streamline assessment activities and avoid sequential steps Option 2: Performance evaluation scheduled by Mx and conducted by a Prequalification Evaluating Laboratory. Dossier incomplete Dossier screening Option 1: Performance evaluation scheduled by WHO and conducted by a Prequalification Evaluating Laboratory. Dossier complete Dossier review Site inspection Prequalification decision Copenhagen, Denmark 18-21 September 2017 18
Alternative mechanism for WHO PQ performance evaluation Manufacturers free to choose one of two performance evaluations pathways: Option 1: Performance evaluation coordinated by WHO Option 2: Performance evaluation commissioned by the manufacturer and carried out at a Prequalification Evaluating Laboratory listed by WHO Key principles All evaluations carried out following WHO protocol All sites audited and listed by WHO Manufacturers free to choose the pathway Copenhagen, Denmark 18-21 September 2017 19
Alternative mechanism for WHO PQ performance evaluation cont d WHO is auditing laboratories against predefined requirements based on ISO 15189 and ISO 17025 13 applications received 9 laboratories audited 6 laboratories already listed 2 lists of laboratories: List 1 - laboratories work directly with WHO and participate in Option 1 List 2 laboratories that work directly with manufacturers and participate in Option 2 Copenhagen, Denmark 18-21 September 2017 20
Update on PQ performance evaluations of NATbased technologies Progress in 2017 Completed evaluation: 9 Ongoing evaluations: 1 Scheduled: 2 Issues to note Challenge to obtain certain types of specimens: Viral load ranges Infant specimens Certain genotypes Evaluations involve instruments adding complexity: training required, possible breakdowns, space Copenhagen, Denmark 18-21 September 2017 21
Performance evaluation of HIV Ab/Ag, HIV/Syphilis, HIV oral fluid, HBsAg, HCV, CD4 technologies Progress in 2017 Completed evaluations: 64 Ongoing evaluations: 4 (2 HIV serology, 1 CD4 and 1 HBsAg) Scheduled: 4 (1 self-testing, 2 CD4) Issues to note HBsAg limit of detection of 0.13 IU/ml for RDTs Obtaining ethical clearance in prospective studies (CD4, self-testing (capillary whole blood) Use of similar clinical samples when evaluation will be conducted in new labs listed in ALE Copenhagen, Denmark 18-21 September 2017 22
2017 Progress Report Improved aspect Impact Outstanding challenges Solutions for challenges Progress Adoption of IMDRF principles Alignment with best international practice and reliance MDSAP still in pilot, industry concerns over ToC/RPS Further collaboration with IMDRF and other harmonization WPs 23
Harmonisation and PQ adoption activities Adoption of the IMDRF Table of Contents Input into the IMRDF Good regulatory review practice Input into the IMDRF Adverse event terminology Input into the IMDRF Common data elements Participation in the IVD working group of the Asian Harmonisation Working Party 24
2017 Progress Report Improved aspect Impact Outstanding challenges Solutions for challenges Progress Implemented changes assessment and PMS reporting Better insight in post-pq phase Underreporting on vigilance, variable compliance for changes notifications Updated changes assessment procedure PMS WebEx, PMS training 25
Post-qualification activities Revised guidance: Reportable changes to a prequalified IVD medical device changes to the prequalified product or its manufacture; changes to the Quality Management System (QMS) that the product was designed and manufactured under; and/or other reportable administrative changes. Changes identified as reportable or non reportable c.f. first version (minor or substantial). Provides greater clarity on what to report List of generic examples. Increased compliance, however, some manufacturers still implement changes prior to notification
Status of WHO complaint monitoring activities 59 complaints submitted to WHO since Nov 2014 16 complaints were for NAT technologies Signals came from both high and low resource settings Typically, the FSCAs were revised labelling and recall/destruction of certain lots A number of complaints have led to change notifications (revised manufacturing process, etc.) False negative Total complaints reported to WHO, by type False negative and false positive False positive Falsification Invalid rate Mislabelled Unreturnable result Defective reagent Weak reactivity Software Defective reagent Importantly, 4 complaints for falsified products reported
Handling complaints for NAT Complaints for NAT technologies High rate of invalid results Misclassification (downwards bias) for dried blood spot specimens Typical corrective actions Change to manufacturing and/or QC process Change of key supplier Enhanced detail of IFU, e.g. for specimen collection, warnings, etc. The expiry date was changed from 2015-09 to 2017-09 28
Global Diagnostics Working Group Global Diagnostics Working Group will establish a subgroup on post-market surveillance to: Exchange of information on complaints Enable coordinated action by GDWG and their partners 29
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