New Guidance & Technical Specifications. Dr Ute Ströher, Technical Officer, IVD Assessment

Transcription

1 New Guidance & Technical Specificatins Dr Ute Ströher, Technical Officer, IVD Assessment Cpenhagen, Denmark September

2 Guidance fr manufacturers Develped by the WHO Prequalificatin Team Diagnstic Assessment grup Guidance dcuments are intended t assist manufacturers f IVDs when seeking WHO prequalificatin assessment r when seeking eligibility fr prcurement by WHO and ther UN agencies. Cpenhagen, Denmark September

3 Guidance and training sectin n the WHO website Technical guidance series Sample prduct dssiers Technical specificatin series Cpenhagen, Denmark September

4 Guidance fr manufacturers WHO Guidance dcuments represent the WHO Prequalificatin Team s current thinking n a tpic, with a fcus n: IVDs eligible fr WHO Prequalificatin assessment: - HIV antibdies (EIA & RDT), NA (qual & quan) - Hepatitis C antibdies & antigen (EIA & RDT), NA - Hepatitis B antigen (EIA & RDT) - Malaria / Plasmdium spp antigen (RDT) - HPV NA - CD4 assays - Syphilis antibdies (RDT)* - G6PD enzyme (POC) - Vibri Chlerae txin (RDT) the intended use settings where the WHO prequalified IVDs are prcured; and the intended users f WHO prequalified IVDs. Cpenhagen, Denmark September

5 Trigger actin fr new TGS & TSS dcuments - needs assessment - Issues identified in current practices thrugh the prequalificatin assessment prcess and by technical experts; Absence r lack f existing published guidance (WHO, internatinal r natinal guidance r standards) n similar r related tpics; Prequalificatin eligibility criteria expanded t a new IVD; Cnsultatin with disease fcused prgrammes within WHO headquarters r reginal ffices; Anticipated new WHO recmmendatins which will impact WHO Prequalificatin Diagnstic Assessment activities; and/r Key stakehlders request fr new r additinal guidance dcuments. Cpenhagen, Denmark September

6 TGS & TSS dcuments In alignment with relevant internatinal and natinal standards, literature and best practise (e.g., CLSI, IMDRF, FDA, ISO..) as applicable Deviatins might be due t additinal requirements t demnstrate suitability f the IVD in resurce limited settings Lessns learned Scientific evidence/experience/disease prgramme Benchmark fr bth manufacturers and assessrs Cmmunicate t manufacturers what is required aiming t strike balance between needs, alignment and practicability avid inefficiency, time, resurces Assessing inadequate studies Repeating wrk Cpenhagen, Denmark September

7 Drafting External Experts Research Manufacturing Clinical Use Cnsultatin Technical experts Regulatrs R&D IVD standard assciatins Public Cmment IVD mx industry assciatin Manufacturers IVD standards rganizatin Regulatry bdies Technical experts Finalizatin Cnslidatin f cmments and review f final dcument Cpenhagen, Denmark September

8 Technical Guidance Series (TGS) The Technical Guidance Series is fr manufacturers interested in WHO prequalificatin f their IVD. The series is intended t help manufacturers in meeting prequalificatin requirements. Gal: t cntinue t create TGS in respnse t needs identified primarily in the dssier assessment phase f PQ Cpenhagen, Denmark September

9 Technical guidance series (TGS) nce_series/en/ TGS 1 Standards applicable t the WHO prequalificatin f IVD TGS 2: Establishing stability f an IVD fr WHO prequalificatin (TGS2 Annex: cmpnent stability) TGS 3: Principles f perfrmance studies f an IVD fr WHO prequalificatin TGS 4: Guidance n test methd validatin fr an IVD TGS 5: Designing instructins fr use fr IVD TGS 6: Panels fr QA and QC f IVD TGS 7: Risk management fr manufacturers f IVD (published Sep 2018) In develpment TGS 8: Use f bilgical reference materials in the develpment f IVDs TGS 9: Precisin and rbustness TGS 10: Accessries Cpenhagen, Denmark September

10 TGS 7 - Risk management fr manufacturers f IVD I This dcument was develped t aid manufacturers f IVDs t develp apprpriate risk management within their quality management system prir t cmpiling a prduct dssier fr submissin t WHO and in preparatin fr the site inspectin cmpnent f the WHO prequalificatin assessment. Key cncepts RM is nt generic but it is specific fr a prcess RM is a whle IVD life cycle activity and is nt retrspective RM is a cmpany-wide activity Cpenhagen, Denmark September

11 TGS 7 Risk management fr manufacturers f IVD II TGS 7 gives practical guidance t manufacturers n the implementatin f an effective risk management prcess Fcuses n the issues identified during PQ assessment Guidance dcuments and standards that shuld be used during the risk assessment Risk assessment and prblem-slving tls (e.g., failure mde and effects) analysis /FMEA) Risk evaluatin and classificatin (e.g. risk grid) Optins fr risk cntrl measures such as prtective measures r safety by design Cpenhagen, Denmark September

12 TGS 7 Risk management fr manufacturers f IVD III Key activities f risk management: QMS must be develped using risk management principles (ISO 13486:2016) Risk management is an integral part f design cntrl. A risk management prcess is assciated with each stage f the IVD life cycle (design, R&D, manufacture, ) Verificatin & Validatin (risk analysis) Analytical & clinical perfrmance studies (TGS 3) Change Cntrls (equipment change, change f supplier f a critical cmpnent, change f intended use) IFU & ther labelling (TGS 5) Manufacturing (suppliers & prcesses) Cpenhagen, - examples Denmark f 24 issues 27 September seen 2018 during PQ assessment & inspectin - 12

13 TGS 8 - The use f bilgical reference materials in the design, verificatin, validatin f IVDs I TGS 8 gives practical guidance t manufacturers n bth the awareness and use f different bilgical reference materials (BRMs) that are used thrughut the life cycle f an IVD Explres the differences between BRMs (in-huse r cmmercial) and discusses the key prperties f BRMs Primary, secndary tertiary and panels Material used t develp the BRM Characteristics f traceability, uncertainty f measurement and cmmutability Establishment f the BRM surces Cpenhagen, Denmark September

14 TGS 8 - The use f bilgical reference materials in the design, verificatin, validatin f IVDs II Discusses the different uses f apprpriate BRMs during life cycle f an IVD Stage 1: Assay design and develpment Stage 2: Manufacturing and lt release Stage 3: Onging mnitring and pst market surveillance Cnsideratins when surcing and prducing BRMs Specimen type and cmmutability Cncentratin, vlume Strage temperatures and stability Matrix, infectivity Cpenhagen, Denmark September

15 TGS 9 - Precisin and rbustness I - qualitative assays - Key cncept: a manufacturer must be able t demnstrate with bjective evidence that a test system will, if used accrding t the IFU, prvide cnsistent, precise results and fr its cmmercial life cycle fulfil all claims with a stated degree f cnfidence. TGS 9 prvides manufacturers f qualitative IVD with guidance n prcedures t use t achieve cmpliance with PQ requirements by develping cnsistent manufacturing prcesses and generating prf f that cnsistency Cpenhagen, Denmark September

16 TGS 9 - Precisin and rbustness II - qualitative assays - Part 1: Rbustness in manufacturing prcesses Part 2: Rbustness & Precisin f the IVD itself Part 3: Human factrs and usability/flex Prvides verview f precisin studies in each phase f the life-cycle f the IVD Hw t measure cnsistency in prcesses Hw t measure precisin and imprecisin Determinatin f rbustness parameters Cpenhagen, Denmark September

17 TGS 10 - Validatin f accessries I Key cncept: the manufacturer must specify and validate the auxiliary items s that the user will cnsistently btain the claimed functinality (and safety) f the IVD when used with thse items The purpse f TGS 10 is t prvide IVD manufacturers with guidance n pssible appraches t specificatin, surcing and validatin f auxiliary items (such as accessries, cmpnents r ancillary items) fr use with an IVD s as t ensure a cnsistent perfrmance f the IVD itself. Discusses principles f installatin, peratinal & perfrmance qualificatin (IQ, OQ, PQ) Supplier validatin and the rle f pst market surveillance Cpenhagen, Denmark September

18 TGS 10 - Validatin f accessries II Cpenhagen, Denmark September

19 Sample Prduct Dssiers Fictitius IVDs CD4 IVD Qualitative NAT fr the detectin f HIV1 & HIV2 RNA Quantitative NAT fr the detectin/measurement f HIV1 RNA IVD intended fr HIV self-testing (under review) Prvide examples f frmatting and reprting details required hw t cmplete an Essential Principles checklist risk assessment Cpenhagen, Denmark September

20 Technical Specificatins Series (TSS) Summarize minimum perfrmance requirements fr WHO prequalificatin, t establish: apprpriate perfrmance evaluatin and re-evaluatin criteria apprpriate reference methds and reference materials Specific requirements tailred t types f infectins, cnditins, etc. Requirements that address needs f Member States in LMIC Requirements that relate t general perfrmance characteristics Clarify requirements: Manufacturers Assessrs Cpenhagen, Denmark September

21 Technical specificatin series (TSS) - published - en/ TSS 1: HIV RDT fr prfessinal and/r self-testing TSS 2: IVDs t identify G6PD activity TSS 3: Malaria RDT TSS 4: IVD used fr the detectin f high-risk HPV types in cervical cancer screening TSS 5: RDT used fr surveillance and detectin f an utbreak f Chlera Cpenhagen, Denmark September

22 Technical specificatin series (TSS) - in develpment - TSS 6: Syphilis RDT (Cnsultancy meeting 2018 Q3) TSS 7: HCV RDTs (Cnsultancy meeting 2018 Q4) TSS 8: HIV Enzyme Immunassays TSS 9: HCV Enzyme Immunassays (Cnsultancy meeting 2018 Q4) TSS 10: NAT t detect HCV (quantitative) (Cnsultancy meeting 2019 Q1) TSS 11: NAT t detect HIV-1 (quantitative) (Cnsultancy meeting 2019 Q1) TSS 12: NAT t detect HIV-1 & HIV-2 (qualitative) (Cnsultancy meeting 2019 Q1) (lay ut accrding t the IMDRF In-Vitr Diagnstics Market Authrizatin Table f Cntents) Cpenhagen, Denmark September

23 Implicatins f new TSS dcuments Date f effect: 3 mnths after publicatin Prequalified IVD prducts: 3 years t ensure cmpliance (after ntificatin) New submissins (> 3mnths after TSS publicatin date): will be assessed against new requirements New submissins (< 3 mnths after publicatin date): will be assessed against ld requirements and if successful have 3 years t ensure cmpliance with new TSS requirements Cpenhagen, Denmark September

24 Part 1) Establishing analytical perfrmance characteristics I - nn clinical evidence - Specimen Stability Cllectin, prcessing, transprt, strage f all specimen type(s) claimed in the IFU Analytical Specificity Ptentially interfering substances (endgenus, exgenus) Crss-reactivity Validatin f Specimens Demnstratin f equivalence between specimen types (analytical & clinical) Demnstratin f equivalence between specimen cllectin methds Metrlgical traceability f calibratrs and cntrl material values Accuracy f Measurement Trueness Precisin (repeatability, reprducibility) Analytical Sensitivity Limit f detectin Limit f quantitatin High Dse Hk Effect Measuring Range f the Assay Validatin f Assay Cut-ff Validatin f Assay Prcedure - Implementatin f IMDRF Table f Cntents frmat - Cpenhagen, Denmark September

25 Part 1) Establishing analytical perfrmance characteristics II - nn clinical evidence - IVD Stability* Shelf life In-use stability Transprt/Shipping stability Carry ver cntaminatin Usability/human factrs Flex studies Cpenhagen, Denmark September

26 Part 2) Establishing clinical perfrmance characteristics - clinical evidence - Diagnstic Sensitivity Diagnstic Specificity Perfrmance Panels Sercnversin Panels Qualificatin f Usability fr POC IVDs Part 3) Self testing qualificatin f usability Label cmprehensin study Results interpretatin study Observed untrained user study Cpenhagen, Denmark September

27 Flex studies - usability/human factrs - IMDRF: Studies specifically assessing the instructins and/r IVD design in terms f impact f human behaviur, abilities, and ther characteristics. n the ability f the IVD t perfrm as intended Testing that takes int cnsideratin the brad range f peratinal and envirnmental cnditins cnsistent with intended use (risk assessment) IVDs suitable in lwer- and middle-incme cuntries Influence f any numerical factrs in the IFU methd specimen/reagent vlume, dilutin factr incubating, mixing, reading times deviatin f temperature (perating and exceeding temperature) humidity Cpenhagen, Denmark September

28 Validatin f Specimens Testing f relevant specimen types Data must be presented t shw the equivalence between specimen types used in perfrmance studies Analytical : cntrived specimens Impact f additives (e.g. anticagulants) Clinical : paired specimens Equivalent cncentratin f the measurand in claimed specimen types Plasmdium falciparum: CAP > VEN (micrscpy & qpcr) (1) Ebla virus: VEN > CAP (qrt-pcr) (2) Measles IgG: VEN S > CAP DBS (3) 1: Mischlinger et al. JID 2018; 218 (8), p : Strecker et al. CID 2015; 61 (5), p ) 3: Riddell et al. Bulletin WHO 2003; 81 (10), p Cpenhagen, Denmark September

29 Qualificatin f usability - Testing that reflects diversity f users skills, training and experience - Users f IVDs shuld be specified in IFU, e.g. labratry prfessinal, trained lay prviders Testing shuld be cnducted: at different gegraphical and epidemilgical settings representative f intended users by a variety f intended users Cpenhagen, Denmark September

30 Qualificatin f usability Optimize the presentatin f an IVD and the understanding f users in POC setting Assessment f prduct design, instructins fr use and usability f RDTs (fr self-testing) Label cmprehensin study Results interpretatin study Observed untrained user study www// Cpenhagen, Denmark September

31 Where t find infrmatin Sign up t ur mailing list t get updates f new TSS and TGS publicatins By ing diagnstics@wh.int Find publicatins n ur website guidance/en/ Tak Thank yu Merçi Cpenhagen, Denmark September