Classification of Medical Devices – Clinical Evaluation and Conformity Assessment

1. Classification of Medical Devices – Clinical Evaluation and Conformity Assessment Committee for Advance Therapies (CAT) Presidency meeting Dr. Juliet M. Doran Pre-market Evaluation Assessor Human Products Authorisation & Registration 28th February 2013

2. Presentation Content • Definition of a Device • Scope of MD legislation • Medical device life-cycle • Classification • Clinical Evaluation • Conformity Assessment

3. Medical Device LegislationDefinition of a Medical Device (Article 1 93/42/EEC) “‘medical device’ any instrument, apparatus, appliance, software, material or other article… intended …for… — diagnosis, prevention, monitoring, treatmentor alleviation ofdisease…or handicap, — investigation, replacement or modification of the anatomy or of a physiological process, — control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means;”

4. Medical Device Legislation-Definition of an Active Implantable Device (Article 1 90/385/EEC) ‘‘active implantable medical device’ … any device …intended to be totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain after the procedure;”

5. Medical Device Legislation-Definition of an In-Vitro Diagnostic Device (Article 1 98/79/EC “‘in vitro diagnostic medical device’ …any medical device which is a reagent… instrument, or system… intended …to be used in vitro for the examination of specimens, …for the purpose of providing information: — concerning a physiological or pathological state, or — concerning a congenital abnormality, or to determine the safety and compatibility with potential recipients, or — to monitor therapeutic measures.”

6. Scope of MD legislation (Directive 93/42/EC) Does not apply to… • IVDs, active implantable medical device • MPs covered by 2001/83/EC • Cosmetic products • Human blood, blood products, plasma or blood cells of human origin • Transplants or tissues or cells of human origin • Viable transplants or tissues or cells of animal origin.

7. Scope of MD legislation Does apply to devices incorporating… • a medicinal product, with an ancillary action • a medicinal product derived from human blood or plasma, with an ancillary action • non-viable tissues of animal origin

8. Lifecycle of Medical Device XXXX Prototype 1. Classification Pre-market 2. Clinical Evaluation Class I & Custom-made devices Class IIa, Class IIb, Class III & Class I sterile or measuring 3. Registration with Competent Authority 3. Conformity Assessment by Notified Body 4. CE marking & certificate issued 4. CE-marking 5. Post Market Surveillance Post-market 5. Post-market Clinical Follow-up

9. 1. Classification • To qualify as a medical device- must have medical purpose & primary physical mode of action. • 4 device classes, based on risk: • Deviceclassdetermined by 18 rules: • Rules 1-4- Non invasive devices • Rules 5-8- Invasive devices • Rules 9-12- Active devices • Rules 13-18- Special rules • These consider: • Duration contact (e.g. 1second15years?) • Degree invasiveness (e.g. intact  surgery?) • Anatomy affected (e.g. oral cavity  CNS?) • Active(i.e. uses a power source) • Re-usable? • Device Class determines the route to CE marking.

10. 1. Classification Rule 13** Drug-Device Combinations (Class III) If MD contains MP: • Device aspect assessed under device legislation but general principles of other MP legislation must apply • Notified body must verify the ‘usefulness’ of the MP • ‘Drug consultation’ required with a Competent Authority/EMA must give opinion on the ‘quality, safety and benefit/risk profile’. **Rule 13 also covers human blood derivatives. • Primary mode of action physical=> Medical Device (MD) e.g. Drug-Eluting Stent → MD e.g. Bone cement containing antibiotic → MD • Primary mode of action pharmacological, immunological / metabolic => Medicinal Product (MP) e.g.Asthma inhaler → MP e.g. Patches for trans-dermal drug delivery → MP

11. 1. Classification Rule 17 Devices Containing Tissues of Animal Origin (Class III) If MD contains Tissue of animal origin (relevant): • (In addition to MDD) Manufacturer subject to Directive 2003/32/EC (Regulation 722/2012 from 28th August 2013). • If starting material has an EDQM CEP- considered by notified body in its overall assessment. • If starting material has no EDQM CEP, the notified body prepares a Summary Evaluation Report (SER) (conduct risk assessment, review alternative materials, evaluate source of tissue) • SER circulated to all CAs for comments, considered by notified body.

12. 1. Classification The exception to the 18 medical device classification rules is…. ‘Medical devices’ containing Advanced Therapy Medicinal Products (ATMPs)- combined ATMPs under ATMP Regulation No 1394/2007). • Doesn’t matter if primary mode of action is physical (i.e. by a medical device)

13. 2. Clinical Evaluation • Allmedical devices require clinical evaluation: Class I, IIa, IIb, III & AIMD • Must be based on clinical data- 3 different routes: • Clinical investigation Clinical investigations “shall be performed unless it is duly justified” to rely on existing clinical data for (high risk devices): • Implantable devices • Class III devices • Active implantable medical devices.

14. 3. Conformity Assessment (by a Notified Body) • Notified bodies assess medium and high risk devices for conformity: • Notified bodies are- • Designated by their national Designating Authority as competent for particular device types & • Notified to the European Commission as NANDO scope expressions. • Monitored routinely by Designating Authority. • Currently 77 notified bodies for medical devices in Europe (http://ec.europa.eu/enterprise/newapproach/nando/). 0050 0123 0086 0124

15. 3. Conformity Assessment (by a Notified Body) • The number of (the 77) notified bodies designated to assess selected device types/technologies: • (Ref. http://ec.europa.eu/enterprise/newapproach/nando)

16. 3. Conformity Assessment (by a Notified Body) • Class III devices (assessed by a notified body under e.g. Annex II) would require… • ANNEX I Essential Requirements review of device including… • General • Risk : benefit assessment (clinical & safety) and reduction (Risk EN ISO 14971) • State-of-the-art design & construction • Lifetime device performance • Transport& storage impact • Clinical evaluation(Clinical Investigation EN ISO 14155) • Side effects • Residual risk information • Chemical, physical & biological properties • Materials of construction: toxicity, flammability • Compatibility of materials of construction • Biocompatibility (EN ISO 10993) & Compatibility with other contact materials • Device <-> MP compatibility • Pre-clinical testing- animal, bench, computer • Drug & blood consultation • Residual material contamination, leaking & ingress

17. 3. Conformity Assessment (by a Notified Body) • Infection & microbial contamination • Animal tissues- SER/EDQM (TSE EN ISO 22442 ) • Sterility & packaging validation and stability(Sterilisation EN ISO 11135, 556) • Construction & environmental properties • Combination safety & performance testing • Device ergonomics, usability & interference(Usability EN ISO 62366) • Measurement • Accuracy & stability (Thermometers ISO EN 1060) • Radiation • Energy sources (Medical electrical equipment EN 60601) • Labelling/IFU(Labelling EN ISO 980, IFU EN ISO1041) • FullQuality System (ISO13485) plus… • Clinical data SOPs • Design Control & Verification SOPs • Post-market surveillance system • In-process and Final QC release tests & SOPs • Sterilisation, Purchasing, labelling SOPS

18. 3. Conformity Assessment (by a Notified Body) • Design dossier review of device • Product description & Intended use • Design Verification & Validation • Risk assessment • Standards applied • Sterilisation, Biocompatibility, Risk etc. • Solution to Essential Requirements • Pre-Clinical Testing • Bench Testing / simulation • Animal Model • Clinical Evaluation • Literature review • Clinical Investigation (Human Model) • First In Man • Acute In-Vivo Device Performance • Device labelling & IFU • Stability Testing • Significant changes • Performance / Complaint Analysis

19. 3. Conformity Assessment (by a Notified Body) • Declaration of Conformity by the manufacturer • CE certificate issued • Notified body assessment of all Substantial Changes • Annual surveillance, recertification- 3-5 years.