Faculty of Health Sciences, LiU Medical devices in clinical trials

1. Faculty of Health Sciences, LiU Medical devices in clinical trials Tuesday 20th November 2012 in Linköping

2. Peter Landvall, PhD Cellwell cellwell@medteq.se Tfn 0703 540 512

3. Instrument, apparatus and other aids

4. 0344 Communauté Européene

5. Cassis de Dijon (“mutual recognition”) - principle A product without legal restriction that can be sold in an EU country, should be freely marketed throughout all EU Member States European Court of Justice, 1979

6. European regulationNew Approach • Not an approval system(Compare with FDA in US och medicinal regulation in Europe = Old Approach) • Huge responsibility of manufacturer, (but also a huge confidence, Declaration of Conformity) • Third part assessment for high risk class products (Notified Body)

7. 500 000 medical device products…… in all medical specialities - Computer tomography - Dialysis equipment- Infusion pumps- Medical beds- Gas systems- Heart valves- Pacemakers- Defibrillators • - Joint replacement implants  - Pregnancy Tests / Blood Sugar Tests  - Dentures / Dental Filling material  - Glasses / Lenses / Frames  - Hearing Aids  - Wheelchairs / Crutches  - Incontinence   - Patches

8. EU Direktiv The basis for national laws

9. Sweden Act SFS 1993:584 and Ordinance SFS 1993:876 about Medical Devices. Covers ALL types of medical devices.

10. Swedish Act on Medical Devices, SFS 1993:584, 2§ / MDD, Article 1, Definition, § 2 (a) ‘medical device’ means any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:

11. “— diagnosis, prevention, monitoring, treatment or alleviation of disease, — diagnosis, monitoring, treatment, alleviation of or compensation for an injury 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;” SFS 1993:584, 2§ / MDD, Article 1, Definition, § 2 (a)

12. SFS 1993:584 / MDD A medical device shall be suitable for its use ... .... achieve the performances intended by the manufacturer

13. Swedish Act on Product Safety(SFS 1988:1604; 2004:451) • Only products that are suitable for their intended use shall be placing on the market and put into service • Suitable product = Product under normal use for the purpose intended by the manufacturer achieves specified performance and meets the high standards of safety for patients, users and other

14. Swedish Act on Habilitation & Health(SFS 1982:763) Good care: • Patient satisfaction • High levels of patient safety • Good quality • Cost benifit

15. Medical devices • Active implantable devices • General Medical devices • In vitro-diagnostic devices

16. ALL medical devices shall be CE-marked, with exception of - Products for clinical trials - Custom made products - Proprietary products

17. LVFS 2001:5 LVFS 2003:11LVFS 2001:7 +LVFS 2009:19 Active implant +LVFS 2009:18 General MD In vitro-diagnostic MD Guideline to useMEDDEV 2.12-1 rev 6for Handling of Accidents and Incidents and SOSFS 2008:1 (M), Proprietary medical devices

18. Paired directives to directive 93/42/EEC 2000/70/EC MDD containing human blood eller human plasma 2003/32/EC MDD using animal cells 2005/50/EC Reclassification of hip, knee and shoulder joint replacement LVFS 2003:11, Annex 1, pkt 7.4 LVFS 2003:11, Annex 11 LVFS 2007:3

19. Directive 93/42/EECshall not apply to: (a) in vitro diagnostic devices (b) active implantable devices, Directive 90/385/EEC; (c) medicinal products, Directive 2001/83/EC. (d) cosmetic products, Directive 76/768/EEC (e) human blood, blood products, plasma or blood cells of human origin, Directive 2004/23/EC (f) transplants or tissues or cells of human origin, Directive 2001/83/EC (g) transplants or tissues or cells of animal origin, Directive 2003/32 EEC

20. - Drug directive 2001/83/EG / SFS 2003:463 Medical device versus • Personal protecting equipment- • directive 89/686/EEG - Machinery - directive 98/37/EEG (2006/42/EG) • Radio and telecommunication equipment – • directive 1999/5/EG - Cosmetic - directive 76/768/EEG - Toy - directive 88/378/EEG

21. Products can be hard to classify – medical device or pharmaceutical? Mechanical vertebra joining coupled with growth hormone Contact lenses containing drugs for glaucoma Arterial blood vessels with drugs Tampons including microorganisms ”Mode of action” and ”Intended Use”

22. Classification base of medical devices Manufacturer states : - intended use - intended performance - product safety The law state : - essential requirements - stated safety and performance shall be verified

23. Classification of general medical device MDD 93/42/EEC, Annex IX LVFS 2003:11, Bilaga 9 Guide document: MEDDEV 2.4/1

24. Classification of general medical devices • Class I Class I, sterile Class I, measure • Class IIa • Class IIb • Class III

25. Duration • Transient: Continuous use < 60 min • Short term: Continuous use < 30 days • Long term: Continuous use > 30 days Invasive device • Invasive device device penetrates a body orifice or through surface • Surgically invasive device device penetrates the body surface through surgical operation • Implantable device device intended to remain in the body

26. Annexes in LVFS 2003:11 /MDD 93/42/EEC Essential requirements - Annex 1 Compliance Annexes Annex 2, 3, 4, 5, 6, 7, 8, 9,10, 11

27. Essential requirements – LVFS 2003:11, Bilaga 1 / MDD 93/42/EEC, Annex I I General requirements • I.1. Intended purpose • I.2. Safety • I.3. Specification, performance • I.4. Lifetime, stability • I.5. Prevent performance degradation • I.6. Prevent undesirable side effects • I.6a. Clinical evaluation

28. Essential requirements – LVFS 2003:11, Bilaga 1 / MDD 93/42/EEC, Annex I II Requirements regarding design and construction • Chemical, physical and biological properties • Infection and microbial contamination • Construction and environmental properties • Devices with measuring function • Protection against radiation • Requirements about connections with an energy sourse • Information supplied by the manufacturer

29. MDD Annexes, general medical devices Annex II Full quality assurance system Annex III EC Type examination Annex IV EC Verification Annex V Production quality assurance Annex IV Product quality assurance Annex VII EC Declaration of Conformity Annex VIII Statement concerning devices for special purposes Annex IX Classification criteria Annex X Clinical evaluation Annex XI Criteria to be met for the designation of Notified Body

30. Class I Class IIa Class IIb Class III Annex III Type examination Annex II Full Quality Assurance System Annex VII Declaration of Conformity Annex IV Verification Annex V ProductionQuality Assurance Annex VI Product Quality Assurance Annex I, Essential requirements Third part verification by Notified Body Class I, s & m

31. Class I Class IIa Class IIb Class III Annex III Type examination Annex VII Declaration of Conformity Annex II Full Quality Assurance System Annex IV Verification Annex V Production Quality Assurance Annex VI Product Quality Assurance CE

32. Class IIa Class I Class IIb Class III either or Annex III Type examination Annex II Full Quality Assurance System Point 4 in this annex does not concern class IIa and IIb Annex VII Declaration of Conformity with either or or Annex VI Product Quality Assurance Annex V Production Quality Assurance Annex IV Verification CE CE CE CE

33. Class I Class IIa Class III or either Annex III Type examination Annex VII Declaration of Conformity Annex II Full Quality Assurance System Point 4 in this annex does not concern class IIa and IIb with or either or Annex VI Product Quality Assurance Annex V Production Quality Assurance Annex IV Verification CE CE CE CE Class IIb

34. Class IIb Class I Class IIa or either Annex III Type examination Annex VII Declaration of Conformity Annex II Full Quality Assurance System Point 4 in this annex does not concern class IIa and IIb with either or Annex VI Product Quality Assurance Annex V Production Quality Assurance Annex IV Verification CE CE CE Class III

35. Specificerade produkter Generella IVD- produkter Lista A (Bilaga 2) Lista B (Bilaga 2) Produkter för självtestning Bilaga 1, Väsentliga krav Bilaga 5 EG-typkontroll Bilaga 3 Tillverkar- deklaration Bilaga 4 Fullständig kvalitetssäkring Bilaga 7 Kvalitetssäkring av produktion Bilaga 6 EG-verifikation Bilaga VIII, Performance evaluation Självtestning, Bilaga 3, pkt 6 Tredjepartsverifiering av anmält organ

36. Declaration of Conformity Regulatory requirements / Quality system • The following content should be available in • Declaration of Conformity • Responsible manufacturer • Product and variants • Referred regulation • Referred standards • If applicable, Notified Body • Intended market • Declaration of safety • SignatureSS-EN ISO/IEC 17 050-1:2005

37. Borderline pharmaceutical and medical device? - “Pharmaceutical or medical device” - “Pharmaceutical with medical device” - “Medical device with Pharmaceutical”

38. ”Medical device with pharmaceutical” - LVFS 2003:11 / MDD 93/42/EEC, Annex I, § 7.4 ”… medical device incorporating, as integral part, a substance … considered to be a medicinal product … act upon the body with action ancillary to that of device… the substance must be verified …with methods specified in Annex I to Directive 2001/83/EC” ”… medical devices incorporating, as integral part, a substance … considered to be a medicinal product … are in Class III.”

39. If in doubt about classification prevails according to Directive 2004/27/EC (amendment to 2001/83/EC) article 2, § 2 Medicinal Directive 2001/83/EC

40. Guidance to enable the fulfilment of the essential legal requirements MEDDEV documents Standards - Mandated - Harmonized • General, overall • Product specific

41. General, overall, standards • Quality management system SS-EN ISO 13485:2003 • Risk management SS-EN ISO 14971:2007 • Biological evaluation SS-EN ISO 10993:2004 • Clinical investigation SS-EN ISO 14155:2003 • Symbols SS-EN ISO 15 223:2012 • Performance evaluation SS-EN 13612:2002

42. Quality system versus Technical documentation Quality system, is a tool that shows howin a structured way produce technical documentation Technical documentation, is the document that will show that legal requirements are met.

43. Quality System versus Technical documentation Quality system, examined to determine that a quality assured system operates for company activity, not necessarily product dependent. Examined by the Authority and Notified Bodies. Technical documentation, examined from product point of view by Authority and the Notified Body.

44. Involved organisations • EU-Commission • Competent Authority (CA) for medical • device Regulatory Authority • Notified Body (NB)

45. Clinical trial Clinical trials are governed by the Helsinki Declaration

46. Swedish laws in clinical trials of medical devices • Hälso- och sjukvårdslagen SFS 1983:763 • Patientjournallagen SFS 1985:562 • Produktansvarslagen SFS1992:18 • Lag om CE märkning SFS 1992:1534 • Sekretesslagen SFS 1992:1474 • Lag om medicintekniska produkter SFS 1993:584 • Patientskadelagen SFS 1996:799 • Personuppgiftlagen (PuL) SFS 1998:204 • Yrkesverksamhet inom hälso- och sjukvården SFS 1998:531 • Biobankslagen SFS 2002:297

47. The regulation of medical devices states about evaluation • Active implantable device and general medical device one discuss clinical evaluation, to determine product performance and safety • In vitro diagnostic device one discuss only evaluation to determine product performance

48. What induce an evaluation of clinical data • and possibly clinical trial, • or evaluation of performance? • Essential requirements • Risk Management • Biological evaluation

49. Clinical data does not automatically means Clinical trial

50. Requirements EssentialRequirements- Clinical evaluation MDD 93/42/EEC, Annex I • 6 Any undesirable side-effect must constitute an acceptable risk when weighed against the performances intended. • 6a. Demonstration of conformity with the essential requirements must include a clinical evaluation in accordance with Annex X.