Update on WHO Prequalification of IVDs Geneva, 11 March 2016 Mercedes Perez Gonzalez Anita Sands Prequalification Team - Diagnostics World Health Organization
Outline Progress and Pipeline Ongoing concerns Addressing the challenges Update on post-qualification activities
WHO Prequalified IVDs Products prequalified in 2015 Total products prequalified to date 17, including 8 malaria RDTs 55 IVDs > Broadcast email sent when each product is prequalified > List of prequalified products and each of their PQ Public Reports is available at http://www.who.int/diagnostics_laborator y/evaluations/pq_list/en/
What s new? (1) > PQ scope expanded to include HPV assays HIV assays intended for self-testing G6PD assays (for administration of primaquine and tafenoquine for radical cure of P. vivax) > Alternative mechanism for WHO PQ performance evaluation Shift performance evaluations to current pre- phase Expanding network of evaluating sites Establish requirements and assess laboratories Provide opportunity to manufacturers to mandate evaluations to WHO assessed laboratories
What s new? (2) > Updated guidance on how to report changes Currently available for public comment > Development of the Emergency Use Assessment and Listing as an emergency quality assurance mechanism for the listing of products outside of PQ scope in the context of a PHEIC Ebola (6 products listed) Zika
HIV RDTs in the Pipeline Product name Product code(s) Manufacturer name Dossier review On-site inspection Laboratory evaluation Aware HIV-1/2 OMT First Response HIV 1-2-0 Card test REF-98164, REF-98166 and REF-98169 I05FRC30, I05FRC60, I05FRC05, I05FRC01 Calypte Biomedical Corporation u u u Premier Medical Corporation Ltd F u u BioTracer HIV 1/2 Rapid Card 11112 Bio Focus Co., Ltd. F R u Genie Fast HIV 1/2 72330, 72327 Bio-Rad R u u OraQuick HIV 1/2 Rapid Antibody Test 5x4-0010, 5x4-0012 OraSure Technologies, u Inc. u u u DPP HIV 1/2 Assay 65-9500-1 Chembio Diagnostic u Systems, Inc. u u u RightSign HIV 1.2.O rapid test cassette (Whole blood/serum/plasma) IHIV-C42W Alere HIV Combo MP Diagnostics MULTISURE HIV Rapid Test Diagnostic Kit for HIV(1+2) Antibody (Colloidal Gold) V2 7D2842, 7D2843 and 7D2343SET 43031-020 KH-R-02, R-401-50-C-2, and A-GOLD-01 Hangzhou Biotest Biotech Co,Ltd F u Alere Medical Co. Ltd. F u u MP Biomedicals Asia Pacific Pte. Ltd. Shanghai Kehua Bioengineering Co., Ltd. R 1 S 1
HIV EIAs and Supplemental Assays HIV EIAs Product name Product code(s) Manufacturer name Enzygnost HIV Integral 4 OPKR035, OPKR055, OPKR055Q, OUVP175 Siemens Healthcare Diagnostics Products GmbH Dossier review On-site inspection Laboratory evaluation u u HIV Supplemental Product name Product code(s) Manufacturer name MP Diagnostics HIV Blot 2.2 11030-018 and 11030-036 Geenius HIV 1/2 Confirmatory Assay with Geenius HIV1/2 Confirmatory Controls Dossier review On-site inspection MP Biomedicals Asia Pacific Pte. Ltd. u R Laboratory evaluation 72460 and 72329 Bio-Rad u u u
HIV Virological Technologies Product name Product code(s) Manufacturer name Dossier review On-site inspection Laboratory evaluation Xpert HIV-1 Quant with GeneXpert Instrument Systems (GeneXpert Dx) GeneXpert Dx Model GX-I Product Codes/catalogue numbers: GXI-1-L and GXI-1-D. GeneXpert Dx Model GX-II Product Codes/catalogue numbers: GXII-1-L, GXII-1-D, GXII-2-L, and GXII-2-D.Etc. Cepheid u 1 Alere q HIV-1/2 Detect 270110050, 270110010, 270300001 Aptima HIV-1 Quant Dx Assay PRD- 03000, PRD-03002, PRD-03001, 303014, PRD-03003, 303095 Alere Technologies GmbH u 1 1 Hologic, Inc. Generic HIV Charge Virale TR001-250IC and TR001-440IC Biocentric u 1 1 S SAMBA HIV-1 Semi-Q Test 4100-12, I19-0004, I19-0005, S01-001, S01-0002 Xpert HIV-1 Qual Assay Xpert with GeneXpert Dx, GeneXpert Infinity-48s, and GeneXpert Infinity-80 GXXVI-4-L, GXXVI-4-D, GXXVI-8-L, GXXVI-8-D, GXXVI- 12-L, GXXVI-12-D, GXXVI-16-L, GXXVI-16-D GeneXpert Infinity-48s: INFINITY48-16, INFINITY48-16- EUROPE, INFINITY48-24, INFINITY48-24-EUROPE, INFINITY48-32, INFINITY48-32-EUROPE, INFINITY48- Cepheid 40, INFINITY48-40-EUROPE, INFINITY48-48, INFINITY48-48-EUROPE etc. Diagnostics for the Real World Ltd R u 1
Product name Enzygnost Anti-HCV 4.0 Multisure HCV Antibody Assay 43130-020 HCV Assays Product code(s) OPFM035 and OPFM055 Manufacturer name Siemens Healthcare Diagnostics Products GmbH MP Biomedicals Asia Pacific Pte. Ltd. INNOTEST HCV Ab IV 80068, 80330 Fujirebio Europe NV Murex HCV Ag/Ab Combination (4J24) 4J24-01 and 4J24-02 HCV Antibody ELISA Kit PT-HCV-96 Monolisa HCV Ag-Ab ULTRA V2 72561, 72562 Bio-Rad MONOLISA Anti-HCV PLUS Version 3 72340, 72341 Bio-Rad DiaSorin South Africa (Pty) Ltd Pishtaz Teb Zaman Dossier review On-site inspection u Laboratory evaluation u 1 Diagnostics R S u u u u HCVSCAN 3-303-20, 3-003-100 EY Laboratories Ltd F 1 SD BIOLINE HCV RightSign HCV rapid test cassette (Serum/Plasma) 02FK10 IHCV-C31W Standard Diagnostics, Inc. F u 1 Hangzhou Biotest Biotech Co,Ltd Oraquick HCV RDT 1001-0274, 1001-0270 Orasure Technologies F 1 u 1 Xpert HCV Viral Load with GeneXpert Dx, GeneXpert Infinity-48s, and GeneXpert Infinity-80 Product Codes/catalog numbers: GXHCV-VL-CE-10. GeneXpert Dx: GXI- 1-L, GXI-1-D, GXII-1-L, GXII-1-D, GXII-2- Cepheid L, GXII-2-D, GXIV-1-L,, GXIV-1-D,, GXIV-2-L,, GXIV-2-D,, GXIV-3-L, etc. u
HBV and HPV Assays HBV Assays Product name Product code(s) Manufacturer name DS-EIA-HBsAg-0,01 B-1252, B-1254, B-1255, B-1256, B- 231 Dossier review On-site inspection Laboratory evaluation RPC "Diagnostic Systems" u u u Bioelisa HBsAg 3.0 3000-1158 and 300-1159 Biokit S.A. u u 1 Siemens Healthcare Diagnostics Enzygnost HBsAg 6.0 OPIH035 and OPIH055 Products GmbH u u SD BIOLINE HBsAg 01FK10W Standard Diagnostics 1 u 1 RightSign HBsAg rapid test cassette (Serum/Plasma) IHBSG-C31-W Hangzhou Biotest Biotech Co,Ltd F 1 HPV Assays Manufacturer On-site Product name Product code(s) Dossier review name inspection carehpv Test 614015 QIAGEN GmBH 1 R Laboratory evaluation
Ongoing concerns > Quality of product dossier submissions The quality of the data submitted in the product dossiers remains incomplete or low quality. Mainly an issue for HIV and malaria RDTs, and hepatitis submissions. However, quality has improved in subsequent submissions from the same manufacturer. > Quality management systems Site inspections continue to identify major and critical non-conformities > Access to appropriate specimens for certain laboratory evaluations (oral fluid, EID, certain levels of VL)
Addressing the Challenges > PQ Technical Guidance Series TGS 1 Standards applicable to the WHO Prequalification of in vitro diagnostics, final version published. TGS 2 Establishing stability of an in vitro diagnostic for WHO Prequalification, draft for public review. In development: o Guidance on Performance Studies that will encompass both Analytical Studies and Clinical Studies. o Guidance document on Instructions for Use. > Sample product dossiers for WHO PQ CD4 IVD for POC, final version published HIV RDT for HIV self-testing, draft for public review HIV POC EID and VL in development > Alternative performance evaluation mechanism (in development) and strategic partnerships
Update on post-qualification activities
Updated guidance on how to report changes > New classification of changes: Changes are defined either as reportable or non-reportable All substantial changes and certain administrative changes associated with a prequalified IVD are considered as reportable changes These must be reported via submission of the WHO document PQDx_119 Change Report Form for a WHO Prequalified In Vitro Diagnostic The document is currently out for public comment.
WHO post-market surveillance of IVDs Any class of IVD Proactive PMS Reactive PMS Lot verification testing Evaluation of EQA/QC data Pre-distribution Post-distribution Complaint Possible Field Safety Corrective Action Possible issuance of Field Safety Notice
Proactive PMS for IVDS: lot testing > Lot verification by suitably qualified laboratory using SOPs so that each lot testing event is consistent > Through physical inspection of packaging, labelling, IFU Looking for breaches of packaging that might affect stability > Testing of samples from each lot of the same IVD Against a well-characterized panel of specimens Same panel for both pre-distribution and post-distribution lot testing > Lot acceptance criteria (pass/fail) for inspection and testing
Proactive PMS for IVDs: evaluation of EQA/QC data > Review data from EQA schemes (proficiency testing) and end-user QC Greatest value when there are many users are of the same assay > Useful to report differences in performance such as this example of a shift (lot to lot)
Reactive post-market surveillance of IVDs > Reporting of administrative and technical complaints by end-users/procurers/ implementers As soon as you become aware Reactive PMS Complaint > Ensures that any necessary investigation is conducted Possible Field Safety Corrective Action Possible issuance of Field Safety Notice
Reactive PMS: Field Safety Corrective Action > A FSCA is triggered when there is an unacceptable increase in risk associated with use of the IVD > the manufacturer should reduce a risk of death or serious deterioration in the state of health associated with the use of an IVD > FSCAs may include: return of IVD to supplier (recall), IVD modification (including IFU), IVD exchange (swap-out), IVD destruction, retrofit by purchased of IVD according to manufacturer modification\design control (usually related to instruments)
Reactive PMS: Field Safety Notice > If a FSCA is undertaken E.g. change to reading time to improve specificity, shortening of expiry date for a particular lot, etc. > End-users will be informed using a Field Safety Notice sent by the manufacturer, via their in-country distributor > End-users should follow instructions of FSN and contact WHO when in doubt
WHO normative guidance on PMS > Roles/responsibilities of stakeholders > Forms IVD complaint form Manufacturer complaint investigation report Field Safety Corrective Action report Lot testing data collection & report > Notices Field Safety Notice
Complaints submitted to WHO > In total, 38 complaint notifications to WHO False negative x9 False positive x5 (+1 combined with FN) Invalid rate x8 Defective product x5 Mislabelling x3 Safety x2 Miscellaneous x2 > Mostly complaints resolved through agreed FSCA (modification of IFU, return of devices, revised design, etc.)
Where to find information > Contact us by email diagnostics@who.int > Sign up for our mailing list By emailing diagnostics@who.int > Check our website Post-market surveillance http://www.who.int/diagnostics_labora tory/postmarket/en/ > Complaints and product alerts http://www.who.int/diagnostics_labora tory/procurement/complaints/en/