1° CORSO DI AGGIORNAMENTO SUI DISPOSITIVI MEDICI: ASPETTI REGOLATORI E APPLICATIVI ROMA, 18-19 MAGGIO 2009

1. IL RUOLO DELL’ISTITUTO SUPERIORE DI SANITA’ COME ORGANO TECNICO: IL CONTRIBUTO DEL DIPARTIMENTO DI MALATTIE INFETTIVE, PARASSITARIE, ED IMMUNOMEDIATEDr. Maria RapicettaDirigente di ricerca – DIRETTORE DEL REPARTO EPATITI VIRALI DIP. MIPI 1° CORSO DI AGGIORNAMENTO SUI DISPOSITIVI MEDICI: ASPETTI REGOLATORI E APPLICATIVIROMA, 18-19 MAGGIO 2009

2. RIFERIMENTI NORMATIVI DPR 13/3/1986, n. 128– Regolamento di esecuzione delle norme di cui all’art.189 del testo unico delle leggi sanitarie, approvato con regio decreto 24/7/1934, n. 1265, e successive modificazioni, in materia di produzione e commercio dei presidi medico-chirurgici. G.U. Serie Gen. n. 98 del 29/4/1986. DM 3/3/1987, n. 133- Assoggettamento alla disciplina dei presidi medico-chirurgici dei Kit per la rilevazione di anticorpi anti HIV. G.U. Serie Gen. n. 80 del 6/4/1987. DM 12/12/1991- Assoggettamento dei reagenti per il rivelamento di HBsAg ed anti HCV alla disciplina dei presidi medico-chirurgici. G.U. Serie Gen. n. 41 del 19/2/1992. DPR 6/10/1998, n. 392- Regolamento recante norme per la semplificazione dei procedimenti di autorizzazione alla produzione ed all’immissione in commercio di presidi medico-chirurgici, a norma dell’art. 20, comma 8, della legge 15/3/1997 n. 59. G.U. Serie Gen. n. 266 del 13/11/1998. Provvedimento ministeriale 5/2/1999– Approvazione dei requisiti della domanda e relativa documentazione da presentare ai fini dell’autorizzazione all’immissione in commercio ed alla variazione di autorizzazioni già concesse per i presidi medico-chirurgici. G.U. Serie Gen. n. 34 del 11/2/1999. Circolare ministeriale 30/10/2000, n. 17– Adeguamento dei livelli di sicurezza trasfusionale in presenza di metodiche atte alle indagini sui costituenti virali per HCV. G.U. Serie Gen. n. 258 del 4/11/2000. Circolare ministeriale 19/12/2001, n. 14– Indicazioni integrative alla Circolare 30/10/2000 n. 17, recante: “Adeguamento dei livelli di sicurezza trasfusionale in presenza di metodiche atte alle indagini sui costituenti virali per HCV”. G.U. Serie Gen. n. 300 del 28/12/2001. DL 9/5/2003, n. 103- Disposizioni urgenti relative alla sindrome respiratoria acuta severa (SARS). G.U. Serie Gen. n. 108 del 12/5/2003. Direttiva 98/79/CE del Parlamento Europeo e del Consiglio del 27/10/1998relativa ai dispositivi medico-diagnostici in vitro. G.U. C.E. n. L.331 del 7/12/1998. DL 8/9/2000, n. 332– Attuazione della Dir. 98/79/CE relativa ai dispositivi medico-diagnostici in vitro. G.U. Serie Gen. n. 269 del 17/11/2000.

3. NATIONAL CONTROLS OF HIV AN HEPATITIS TEST KITS IN EC MEMBER STATES* * from CPMP Biotechnology working group

4. ATTIVITA’ DI CONTROLLO E CONSULENZA DEL DIPARTIMENTO MIPI DELL’ISS NEL SETTORE DEI KIT DIAGNOSTICI IN VITRO ● Controllo di kit di tipo immunometrico per determinazioni qualitative e quantitative di marcatori di infezioni● Controllo e validazione di kit per determinazione qualitativa e quantitativa di acidi nucleici (NAT) quali marcatori di infezioni● Controlli di kit diagnostici post-marketing su segnalazione ● Allestimento di pannelli sierici e Preparazioni Standard per controlli interni di qualità● Attuazione di programmi nazionali di valutazione esterna di qualità (VEQ) per laboratori del SSN● Partecipazione a commissioni EU ed a Comitati Tecnici associati alla Direttiva 98/79/CE● Organizzazione di convegni sulle specifiche tematiche rivolti a personale tecnico del SSN

5. Gruppo di lavoro CdG/DMDV - Direttiva 98/79/CE (7 dicembre 1998) SISTEMA DI GESTIONE DELL’AUTORIZZAZIONE (SGA) • Il sistema è articolato in modo da definire, per le varie fasi delle attività: • Politica e conduzione della certificazione; • Organizzazione tecnica, amministrativa e delle risorse umane; • Pianificazione delle attività interessate, ivi comprese l’assegnazione delle risorse e la documentazione; • Misura delle prestazioni conseguite con l’adozione del sistema, ivi incluse le verifiche ispettive (audit); • Verifica e riesame del sistema. • La struttura generale dell’ SGA risponde allo stato dell’arte in materia ed è schematizzabile nel seguente modello logico: Politica per la Certificazione di dispositivi medico-diagnostici in vitro Pianificazione delle attività Verifica delle soluzioni adottate Miglioramento continuo Controlli e azioni correttive Attuazione dell’ SGA

6. Gruppo di lavoro CdG/DMDV - Direttiva 98/79/CE (7 dicembre 1998) ARTICOLAZIONE DEL SISTEMA DI GESTIONE DELL’AUTORIZZAZIONE L’ SGA è articolato nelle seguenti Sezioni e Sottosezioni:

7. ORGANIGRAMMA NOMINATIVO DEI RESPONSABILI DEL COMITATO DI GESTIONE DEI DMDV (CdG/DMDV - Dipartimento Malattie Infettive, Parassitarie ed Immunomediate - MIPI) Direttiva 98/79/CE (7 dicembre 1998)

8. PROCEDURES FOR DIAGNOSTIC KITS CONTROL IN ITALY (Decrees: 3 March 1987 (anti-HIV), 12 December 1991 (HBsAg, Anti-HCV) • Licensing after the evaluations of technical documentation and of sample kit by the Istituto Superiore di Sanità and by the Ministry of Health* • Batch release procedure by the Istituto Superiore di Sanità • External quality control (NEQAS) by the Istituto Superiore di Sanità • * Any variation of components, expire date and production procedure must be authorised

9. REQUIREMENTS FOR TECHNICAL DOCUMENTATION • THE TECHNICAL DOCUMENTATION PROVIDED BY THE MANUFACTURERS MUST BE BASED, FOR LICENSING PROCEDURE ON: • biological principles of methodology • production methods & characterization of each reagent • type of reagents and their shelf life including their assessment • description of testing procedures • adapted procedures for result assessment • sensitivity, specificity and accuracy (with description of the assessment methods) • information sheet, also in Italian, as an integral part of the kit, reporting the elements listed above, handling precautions and limitation on the physical, biological and clinical aspects, and the list of necessary but not provided materials • FOR BATCH RELEASE PROCEDURE, ON: • series number of the batch and of the individuals components • expire date of the batch and the individual reagents (which must comply with the registration documentation) • the number of kits in the batch • quality control certificate and quality control assays performed by the manufacturer

10. ANTI-HIV TESTING KITS (VEQ 2004)

11. ANTI-HCV and HBsAg TESTING KITS (VEQ 2004)

12. HIV, HBV, HCV NAT TESTS

13. DISTRIBUZIONE CENTRI PARTECIPANTI NEL 1994 E NEL 2003

14. TIPOLOGIA DEI CAMPIONI POSITIVI INVIATI

15. DISTRIBUZIONE GEOGRAFICA E PERCENTUALE DI COPERTURA DEI CENTRI PARTECIPANTI

16. CHARACTERISTICS OF POSITIVE SAMPLES OF EACH SHIPMENT PANEL, BY YEAR

18. EU IVD DIRECTIVEDirective 98/79/EC of the European Parliament and of the Council on in vitro Diagnostic Medical Devices - adopted on 5 October 1998- published in Official Journal of EU Committees on 7 December 1998- published in Italian GU n. 269 on 17 November 2000 ■ has introduced at EU level common regulatory requirements for safety quality and performance of IVDs■ applies to:reagents and reagent products, calibrator materials or instruments including specimen receptacles intended by the manufacturer for the in vitro examination of human tissue, blood or fluid samples for the purpose of providing information about a patient’s state of health

19. Directive 98/79/CE (7 December 1998)ANNEX IESSENTIAL REQUIREMENTS The manufacturer has to demonstrate that the in vitro diagnostic medical devices:■ do not compromise the health and safety of patients and users■ are designed and manufactured to be suitable for the stated medical purpose, taking into account of the generally acknowledged state of the art■ are able to achieve the performance, where appropriate, in terms of: analytical sensitivity, diagnostic sensitivity, analytical specificity, diagnostic specificity, accuracy, repeatability, reproducibility, including control of known relevant interferences, and limits of detection.■ possess the elements of traceability, i.e.: a - The values assigned to calibrators and/or control materials, are assured through available reference measurement procedures and/or available reference materials of a higher order.b - are designed, manufactured and packed in such a way that their characteristics and performances during their intended use will not be adversely affected under storage and transport conditionsc - labeling information and instructions for use, both for devices intended for professional use and for self-tests are addressed to lay persons.■ Is characterized by risk analysis including the identification and demonstration of acceptability of risks related with their use.

20. Directive 98/79/CE (7 December 1998)CLASSIFICATION OF IVDS INTO CATEGORIES 1 - Devices listed in Annex II-List AReagents and reagent products for detection of infections by HIV 1 and 2, HTLV-I and II or by hepatitis B, C and D viruses. Reagents for determination of ABO system, Rhesus-C, c, D, E, e, anti-Kell.2 - Devices listed in Annex II-List BReagents and reagent products for determination of anti-Duffy, anti-Kidd, irregular anti-erythrocytic antibodies, tumor marker PSA, HLA tissue groups DR, A, B, detection of phenylketonuria, detection of the infectious diseases: rubella, toxoplasmosis, cytomegalovirus and chlamydia, detection of trisomy 21. Self-testing devices for the measurement of blood glucose.3 -Devices for self-testing4 - All other devices not listed in Annex II and not intended for self-testing

21. Document GHTF/SG1/N045: 2008PROPOSED GENERAL CLASSIFICATION SYSTEM FOR IVD MEDICAL DEVICES

22. Directive 98/79/CE (7 December 1998)CONFORMITY ASSESSMENT ROUTES FOR IN VITRO DIAGNOSTIC MEDICAL DEVICES LISTED IN ANNEX II-LIST-A

23. Directive 98/79/CE (7 December 1998)CONFORMITY ASSESSMENT ROUTES FOR IN VITRO DIAGNOSTIC MEDICAL DEVICES LISTED IN ANNEX II-LIST-B

24. Directive 98/79/CE (7 December 1998)CONFORMITY ASSESSMENT ROUTES FOR IN VITRO DIAGNOSTIC MEDICAL DEVICES TO BE USED FOR SELF-TESTING

25. Directive 98/79/CE (7 December 1998)CONFORMITY ASSESSMENT ROUTE FOR GENERAL IN VITRO DIAGNOSTIC MEDICAL DEVICES

26. Document GHTF/SG1/N045: 2008CONCEPTUAL ILLUSTRATION OF REGULATORY REQUIREMENTS INCREASING WITH DEVICE RISK CLASS

27. COMMON TECHNICAL SPECIFICATIONS (CTS) 2009/108/EC amending 2002/364/ECSCREENING ASSAYS: ANTI-HIV 1 AND 2, ANTI-HTLV I AND II, ANTI-HCV, HBSAG, ANTI-HBC

28. COMMON TECHNICAL SPECIFICATIONS (CTS) 2009/108/EC amending 2002/364/ECNAT ASSAYS FOR HIV 1, HCV, HBV, HTLV I/II(QUALITATIVE AND QUANTITATIVE; NOT MOLECULAR TYPING) 1

29. COMMON TECHNICAL SPECIFICATIONS (CTS) 2009/108/EC amending 2002/364/EC 2

30. 3 COMMON TECHNICAL SPECIFICATIONS (CTS) 2009/108/EC amending 2002/364/EC For quantitative NATs a study shall be performed on at least 100 positive specimens reflecting the routine conditions of users (e.g. no pre-selection of specimens). Comparative results with another NAT test system shall be generated in parallel. For qualitative NATs a study on diagnostic sensitivity shall be performed using at least 10 seroconversion panels. Comparative results with another NAT test system shall be generated in parallel.

31. COMMON TECHNICAL SPECIFICATIONS (CTS) 2009/108/EC amending 2002/364/ECRAPID TESTS: ANTI- HIV 1 AND 2, ANTI-HCV, HBSAG,ANTI-HBC, ANTI-HTLV I AND II

32. COMMON TECHNICAL SPECIFICATIONS (CTS) 2009/108/EC amending 2002/364/ECHIV 1 ANTIGEN SEROTYPING AND GENOTYPING ASSAY: HCV

33. DEFINITION OF THE “STATE OF ART” FOR HIV DETECTION DEVICES INCLUDING HIV AG/AB COMBINATION ASSAYS, ANTI-HIV-1/2 ASSAYS AND HIV RAPID TESTS Common Technical Specifications (CTS, 3 February 2009 amending Decision 2002/364/EC) “diagnostic tests sensitivity during the early infection phase (sero-conversion) has to represent the state of art”. Furthermore, two categories of samples are defined:Early sero-conversion HIV samples:- p24 antigen and/or HIV RNA positive and; - not recognised by all of the antibody screening tests and; - indeterminate or negative confirmatory assaysSero-conversion HIV:- p24 antigen and/or HIV RNA positive and; - recognised by all of the antibody screening tests and; - positive or indeterminate confirmatory assaysHIV tests shall identify all sero-conversion HIV samples as positive; and at least 40 early sero-conversion HIV samples shall be tested. Results should conform to the state of the art.

34. SERO-CONVERSION PANELS USED

35. DETECTION DELAY IN RECOGNITION OF HIV INFECTION RELATIVE TO NAT (DAYS)

36. DETECTION DELAY OF HCV INFECTION (DAYS)

37. DETECTION DELAY OF HBSAG INFECTION (DAYS)

38. SUMMARY RESULTS OF THE SERO-CONVERSION STUDYHIV 1/2, Ab TEST KIT Test kit

41. Directive 98/79/CE (7 December 1998)ANNEX III sect. 3TECHNICAL DOCUMENTATION Must include:1 - General description of the product2 - Documentation of the quality system3 - Design information including origin of material; drawings and diagrams and the operation of the product; description of the procedures used for sterile products; labels and instructions for use4 - Results of the risk analysis5 - Results of the design calculations and of the inspections carried out6 - The test reports7 - The results of stability studies

42. SUMMARY RESULTS OF THE SERO-CONVERSION STUDYHIV 1/2 Ag/Ab TEST KIT Test kit