1. Current EU and Global Activities in the „Clinicals“ Dr. Wolfgang Ecker Federal Ministry of Health, Austria Chairman of EU WG CIE 3rd National Conference for Medical Devices, 13/14 April 2010, Rome

2. EU Working Group on Clinical Investigation and Evaluation CIE GHTF SG 5 EU WG on Clinical Investigation and Evaluation (incl. PMCF) Clinical Safety and Performance COM + Member States + NB + Industry ISO/CEN/CLC

3. ! Upgrade of Clinical Evaluation in the Revision of the Medical Device Directives 2007/47/EC ! HTA/EBM use by health care financers Request for high quality clinical trials will raise!

4. Acceptance in Health Care/Remuneration HTA Health Technology Assessment Medico-(Economical) Analysis Conformity Assessment/CE Premarket Approval Medical Devices/IVD‘s Medical Evaluation Clinical Evaluation/Performance Evaluation Technical/Preclinical/Analytical Evaluation Market Pre-Market PMCF Market

5. Important documents for medical devices EU – Legal System New Approach Global Approach Medical Device Directives Decrees, Ordinancies Nat. Medical Device Act Harmonised Standards MEDDEV‘s + other Interpretative doc‘s GHTF-Guidelines COM-legislation

6. EU Medical Device - Directives Directive 90/385/EEC Active Implantable Medical Devices Directive 93/42/EEC Medical Devices Directive 98/79/EC In-vitro-Diagnostic- Medical Devices Pacemakers; ICD‘s Implantable Infusion pumps Artificial hearts... + software and accessories NMR, US, X-ray, Hip-implants, ECG, EEG, Intravascular catheters, Stents, syringes, IOL, RR, med. lasers, med. software HIV-tests, Hepatitis-tests, Pregnancy-tests, Lab-Automats, Reagents, Calibrators, Control materials Prim. specimen receptacles...

7. Clinical Evaluation: What do Directives 93/42/EEC and 90/385/EEC say (after Revision 2007/47/EC)?

8. 1. Layer Clinical Data/Evaluation Flow Model 2.Layer Documentation 3.Layer Conformity Assessment Revision of 93/42/EEC and 90/385/EEC CLINICAL EVALUATION = Core Element of 2007/47/EC!!

9. (+) Clin Invest Route Literature Route Combin Route Clinical Data Clinical Evaluation Demonstration of conformity with clinical ER Conformity with ER Documentation of Clinical Evaluation Process + Preclinical Evaluation + Risk management Techn Doc/STED/Design dossier incl. clinical data and Clin. Evaluation Report + preclinical data + Risk management output QM Modules Design Modules 1.Layer Clinical Model 2.Layer Documentation 3.Layer Conformity assessment 3 layer model of clinical evaluation in EU medical device regulation Updates of clin eval; ev. PMCF Manuf. Claims; risk mgt output State of the art EN's, Techn+other Eval Clin Exper. Route

10. Clinical Investigation: What do Directives 93/42/EEC and 90/385/EEC say (after Revision 2007/47/EC)?

11. Clinical Investigation Table of correspondence of Directives Art. 10 Art. 15 Administrative Procedures for CI Ann. 6Ann. VIII Statement for CA + Documentation Ann I.I.5a+ Ann 7.1. Ann I.I.6a+Ann X.1 Clinical Evaluation Ann. 7.2.Ann. X.2 Clinical Investigation if Art. 10+Ann. 6 if Art. 15+Ann. VIII Free movement Art. 1.2. (e)+(k) Definition of device for CI; clinical data Dir 90/385/EECDir 93/42/EECAspect

12. Clinical Investigation (Art. 15/10; Ann VIII/6, X/7) Manufacturer/Sponsor: Notification of SAE to all MS concerned Notification of finalisation to MS concerned; in case of early termination with justification! If for safety reasons > all MS + COM! Declaration/Documentation accompanying notification of a Clin. Investigation (Ann. VIII/Ann. 6) Draw EUDAMED-Code for Clinical Investigation (from May 2011; optional from 2010) Revision Directive 2007/47/EC

13. Draft

15. MS: (refusal, halt, sign. modification, temp. interruption of CI) MS Info-Exchange (refusal, halt, sign. modification, temp. interruption of CI) Inclusion of CI-module in EUDAMED Ethics Committee has to evaluate Clinical Investigation Plan Revision Directive 2007/47/EC

16. Preparation of EUDAMED Clinical Investigation Module Preparation of EUDAMED Clinical Investigation Module Stage 1: administrative data > identifier Stage 1: administrative data > identifier 1a: general administrative data > identifier 1a: general administrative data > identifier 1b: Art.15-6/7 procedures (refusal, halt, sign. modification, temp. interruption of CI; early termination on safety reasons) 1b: Art.15-6/7 procedures (refusal, halt, sign. modification, temp. interruption of CI; early termination on safety reasons) Stage 2: SAE-Reporting Stage 2: SAE-Reporting  Stage 3: (full dossiers)? CIE Clinical Investigation and Evaluation

17. EN ISO 14155-1 General Safety/Ethical and Procedural Aspects Clinical Investigation Plan Informed Consent Documents EN ISO 14155-2 Final Report Investigator‘s Brochure Literature Review CRF Roles Monitor Sponsor Clinical Investigator

18. Clinical Investigation of Medical Devices Essential Requirements Safety Performance Preclinical and Clinical Experiences Risk Analysis Training Investigator‘s Brochure EN ISO 14155 Harmonized Standards Science Clinical Investigation Plan CRF‘s Literature Review EN ISO 14155 Directives Ethics Organisation Finances Informed Consent; Insurance; Special Target Groups; Roles; Documentation; Decl. of Helsinki EN ISO 14155 Model of Financiation of MDAdministrativeProcedures Ethics Committee Notification to CA 60-Day Procedure CE marked MD DIRECTIVES (Inspections) Final Report EN ISO 14155 Administrative Procedures Ethics Committee Notification to CA 60-Day Procedure CE marked MD Communication Decisions EUDAMED DIRECTIVES (Inspections; Fees) SAE/Changes/(early) Termination Directive MEDDEV EN ISO 14155

19. Art. 10/15 Administrative Procedures for Clinical Investigations Dir. 90/385/EEC and 93/42/EEC MF/Sponsor Ethics Committee(s) Notification Art. 10/15 Statement Ann. 6/VIII.2.2 (Documentation) Ann. 6/VIII.3.2 Competent Authority AIMD; MD: Class III, Class IIa+IIb- Implantable or long-term invasive (TACIT) APPROVAL (<) 60 d Start of Clinical Investigation

20. Statement accompanying notification of a clinical investigation (Ann. 6 of 90/385/EEC and Ann. VIII of 93/42/EEC) (Notification form) Clinical Investigation Plan (CIP) incl. CRFs Investigator‘s Brochure Votum of Ethics Committee(s) Material for informed consent Confirmation of insurance of subjects Declaration to Essential Requirements Statement/Declaration concerning components of human/animal origin

21. Directive 93/42/EEC Directive 90/385/EEC Clinical Investigations: Where can you find helpful documents?

22. Directives National Legislation/Administration and Guidance Declaration of Helsinki Harmonized Standards –EN ISO 14155-1 and 2; forthcoming: FDIS (GCP for Medical Devices) –14971; 10993; 60601; 14630; 10555; … Horizontal Guidance (MEDDEVs: Clinical Evaluation; PMCF; …) Vertical Guidelines (Coronary stents; …) FDA: –IDE/PMA-Guidelines –summaries of safety and effectiveness HTA-Reports, Cochrane-Reports Clinical/Scientific Societies Documents

23. New/updated Guidance New/updated Guidance  Guidance on SAE-Reporting/Forms  Guidance on Clinical Investigations (> GHTF)  Update of PMCF-Guidance (> GHTF) Strategic Development Strategic Development  Recast Clinicals  Build up Cooperation with Clinical Societies Clinical Societies (Implant) Registries (Implant) Registries EUnetHTA (Joint Action HTA of DG SANCO) EUnetHTA (Joint Action HTA of DG SANCO)  Rapid Clinical Task Force(s)/Device Panels?  Regulator‘s Forum for (specific) multinational CI‘s CIE Clinical Investigation and Evaluation

27. EN DIS ISO 14155 Clinical investigation of medical devices for human subjects — Good clinical practices 1.Scope 2.Normative References 3.Terms and Definitions 4.Ethical Considerations 5.Clinical Investigation Planning 6.Clinical Investigation Conduct 7.Suspension, Termination and Close-out 8.Responsibilities of the Sponsor 9.Responsibilities of the Principal Investigator

28. EN DIS ISO 14155 Clinical investigation of medical devices for human subjects — Good clinical practices Annexes a.Clinical Investigation Plan (CIP) n b.Investigators Brochure (IB) n c.Case Report Forms (CRF) i d.Clinical Investigation Report i e.Essential clinical investigation documents i f.Adverse event classification decision tree i ZARelationship between this European standard and the Essential requirements of EU Directive 93/42/EEC i Bibliography Tables n... normative; i... informative

29. SG5/N2R8:2007 Clinical Evaluation SG5/N1R8:2007 Clinical Evidence – Key Definitions and Concepts SG5 …..Post Market Clinical Follow Up Studies SG5 …..Clinical Investigations SG2/5 ….SAE-Reporting SG1/5 ….Clinical Evaluation of IVDs GHTF SG5 Guidelines:

31. HTA

32. FDA/CDRH - Guidance

34. Thank You! 3rd National Conference for Medical Devices, 13/14 April 2010, Rome