(New) Challenges in Clinical Evaluation and Clinical Trials

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1 (New) Challenges in Clinical Evaluation and Clinical Trials Dr. Elisa Hoenig Prosystem AG Beim Strohhause Hamburg Telefon: Fax: Web:

2 Regulatory Requirements on Medical Devices Interview with AOK boss J. Graalmann in Die Welt (Feb. 2013). Die Welt: Was fordern Sie von der Politik? Graalmann: Medizinprodukte werden heute in Europa noch zugelassen wie Spielzeug. Theoretisch könnten Sie auch bei Toys'r'Us eine neue Hüfte kaufen. Das CE-Zertifikat klebt auf dem Spielzeug und auf der Hüftprothese, es sagt aber nichts darüber aus, wie gut das Produkt für den Menschen ist. [ ]. Which regulatory requirements need to be fulfilled, focusing on clinical perspective? Do they ensure patient safety and benefit? abgerufen info@prosystem-ag.com 2

3 Regulatory Requirements on Medical Devices / Research 1964 Declaration of Helsinki A negative example with regard to compliance: At the Willowbrook State School, students with learning disabilities were infected with Hepatitis virus (1963 and 1966) Parents were informed. Children, however, were only admitted to school, if parents agreed to study. 3

4 Regulatory Requirements on Medical Devices / Research 1964 Declaration of Helsinki 1977 Good Clinical Practice in the USA 1990 Good Clinical Practice in Europe 1993 Code of Medical Ethics in Germany 1995 Medical Devices Act in Germany 1996 Standard ISO Clinical investigation of medical devices Harmonised Tripartite Guideline for Good Clinical Practice th amendment of law of Medical Devices Act 2011 Complete revision of standard ISO EU Regulation on Medical Devices 4

5 Regulatory Requirements on Medical Devices Medical Device Directive 93/42/EEC Guidelines e.g. MEDDEV Clinical Evaluation Medical Devices Act MPBetreibV MPKPV (Clinical Trial) MPSV (Incidents) Code of medical ethics - European/international standards - Notified bodies recommendations (NB-MED) - ZLG recommendations (EK-Med) -. Reg. requirements - legally enforced Reg. requirements - not legally enforced, but expected 5

6 Regulatory Requirements on Medical Devices Placing medical devices on the market ( 6 MPG) Medical Device Intended Use Essential Requirements Clinical Evaluation Risk Management Harm. Standards Classification Conformity Assessment Procedure CE-Labelling 6

7 What is a Clinical Evaluation? Medical Device Directive 93/42/EEC, Annex X, Clinical Evaluation Purpose of the Clinical Evaluation is to assess the safety and performance of a medical device under its normal conditions of use based on clinical data, comprising the acceptability of the benefit/risk ratio the evaluation of side-effects. The Clinical Evaluation has to be presented for each medical device, irrespectively of the risk class and be kept up to date. 7

8 How is a Clinical Evaluation conducted? Medical Device Directive 93/42/EEC, Annex X, Clinical Evaluation The Clinical Evaluation must follow a defined and methodologically sound procedure based on the critical evaluation of: either scientific literature currently available, whereby a demonstration of equivalency between the device under evaluation and the device presented in literature needs to be provided. or the results of a clinical investigation or combined clinical data. Guideline MEDDEV

9 Clinical Evaluation during Product Development Design Development Idea Project Planning Verification Validation Input Launch Pre clinical Evaluation Literature, Clin. Inv.? Identification, Appraisal and Analysis of Clinical Data CER Pre clinical Evaluation - Definition of intended use - Possible market risks? - Initial risk/benefit analysis - Sufficient clinical evidence? - Clin. investigation necessary? Clinical Evaluation according to MEDDEV Compilation of all clinical data - Proof of safety and performance - Reference to design documentation - Part of technical documentation - Interface to risk management 9

10 Sufficient Clinical Evidence? LITERATURE EXPERIENCE DATA CLINICAL INVESTIGATION Need for CLINICAL EVIDENCE COMPILATION of clinical data CLINICAL DATA APPRAISAL & ANALYSIS of clinical data Generate additional clinical data CLINICAL EVIDENCE in technical documentation NO CLINICAL EVIDENCE? YES Clinical Evaluation Report 10

11 Clinical Evaluation including a Clinical Investigation Idea Project Planning Development Prototype [ ] Development Final Device Launch Pre clinical Evaluation Clinical Investigation Clinical Evaluation CER MPG 20-23a MPKPV ISO 14155:2011 Planning Clinical Investigation Conducting Clin. Investigation Analyzing Clinical Data Additional time, resources, costs 11

12 Regulatory Framework of Clinical Data / Clinical Evidence Project start Release Reimbursement Phasing out Product development Sales & Marketing (Pre) Clinical Evaluation Update of Clinical Evaluation Analysis of Postmarket Surveillance Data Clinical Investigation Postmarket Clinical Follow Up Studies info@prosystem-ag.com 12

13 MDD Recast Proposal by European Commission Chapter VI: Clinical evaluation and clinical investigations Article 49: Clinical evaluation Article 52: Registration of clinical investigations Article 53: Electronic system on clinical investigations Article 55: Substantial modifications to a clinical investigation Annex XIII and XIV required clinical data should be able to clearly demonstrate that devices perform well and are safe for patients when used by a physician as intended by their manufacturer The Commission has built on Directive 2007/47/EC by adding: More detail for clinical requirements (Art. 50); Centralized system for notifications and reporting of severe adverse events (Art.53); Increased protection of subjects undergoing clinical investigations (Art. 50, 52, 59); Extended post-market clinical follow-up by manufacturers (MDR, Annex XIII) 13

14 MDD Recast Impact on the Clinical Evaluation (Article 49 and Annex XIII Part A) In principle, clinical evaluation may still be based on already existing clinical data. It is still required to keep the Clinical Evaluation up to date during the entire product life cycle. For all class III devices und implants, the clinical data are to generated in a clinical investigation (demonstration of equivalence is not sufficient). Exception for active implantable medical devices (clinical evaluation without clinical data) is cancelled. High risk devices: Results of the clinical evaluation are to be made publically available. 14

15 Example: Implant Development in a Joint Project Lewis, S. (2013): "An implantable measurement system for control of advanced arm prostheses: Electrode development, signal analysis, control algorithms and sensory feedback." Measurement of muscle activity via implanted electrode Amplification, digitalization and first level of data processing on the implant Wireless data transfer and inductive energy transfer through skin External prosthesis control 15

16 Example: Implant Development in a Joint Project Research Foundation Electrodes Enclosure of the implant Technical University Integrated Circuits Software Commercial Company External components Projekt management energy inductive data RF link Research Institute Animal experiment Private Hospital Clinical investigation Lewis, S. et al. (2013): "Fully Implantable Multi-Channel Measurement System for Acquisition of Muscle Activity." IEEE Transactions on Instrumentation and Measurement, Jg. 619, Nr. 1, S

17 Example: Implant Development in a Joint Project Research Foundation Biocompatibility (ISO ) RM / QM Technical University Software life cycle (IEC 62304) RM / QM Commercial Company QM (ISO 13485) RM (ISO 14971) energy inductive data RF link Research Institute Tierschutzversuchstier- Verordnung Private Hospital Clinical investigation (ISO 14155) Lewis, S. et al. (2013): "Fully Implantable Multi-Channel Measurement System for Acquisition of Muscle Activity." IEEE Transactions on Instrumentation and Measurement, Jg. 619, Nr. 1, S

18 Thank you for your attention. 18