Current EU and Global Activities in the Clinicals

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

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

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

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

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

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. . .

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

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

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

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

Clinical Investigation Table of correspondence of Directives Aspect Dir 93/42/EEC Dir 90/385/EEC Definition of device for CI; clinical data Art. 1. 2. (e) + (k) Art. 1. 2. (e)+(k) Free movement if Art. 15+Ann. VIII if Art. 10+Ann. 6 Administrative Procedures for CI Art. 15 Art. 10 Statement for CA + Documentation Ann. VIII Ann. 6 Clinical Evaluation Clinical Investigation Ann I. I. 6 a+Ann X. 1 Ann I. I. 5 a+ Ann 7. 1. Ann. X. 2 Ann. 7. 2.

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

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

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

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

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

MF/Sponsor Art. 10/15 Administrative Procedures for Clinical Investigations Dir. 90/385/EEC and 93/42/EEC 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

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

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

Documents • 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 •

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

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

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 ZA Relationship between this European standard and the Essential requirements of EU Directive 93/42/EEC i Bibliography Tables n. . . normative; i. . . informative

GHTF SG 5 Guidelines: SG 5/N 2 R 8: 2007 SG 5/N 1 R 8: 2007 SG 5 …. . SG 2/5 …. SG 1/5 …. Clinical Evaluation Clinical Evidence – Key Definitions and Concepts Post Market Clinical Follow Up Studies Clinical Investigations SAE-Reporting Clinical Evaluation of IVDs

HTA

FDA/CDRH - Guidance

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