1. Device regulations In Europe Dr Phil Warner

2. www.annejury.com Where to find directives www.newapproach.org (portal)www.newapproach.org leads to the EUROPA website (EC) Published in the L series of the Official Journal of the European Communities http://ec.europa.eu/consumers/sectors/medical-devices/documents/index_en.htmhttp://ec.europa.eu/consumers/sectors/medical-devices/documents/index_en.htm

3. At the End of This lecture You Should Understand EU law and how it was devised Understand why the law exists Understand what medical device means in terms of the regs. Understand the main EU regulations for devices Have some understanding of the regulatory process

4. And You Should Understand the terms used in the Medical Device Directive Then go on to read the main instrument the medical Devices Directive (MDD) so that you can increase your understanding

5. How are regulations Framed European Directives ( like treaties) adopted by member states of the EU and passes by each member state into law They harmonise the laws and hence create a “single market” They are driven by the industry (largely) working with and lobbying the regulator They are operated by national bodies

6. Overview – Medical Directives

7. Where to find directives www.newapproach.org (portal)www.newapproach.org leads to the EUROPA website (EC) Published in the L series of the Official Journal of the European Communities http://ec.europa.eu/consumers/sectors/medical-devices/documents/index_en.htmhttp://ec.europa.eu/consumers/sectors/medical-devices/documents/index_en.htm

8. Other New Approach directives www.annejury.com

9. The Medical Device Directive Two directives 93/42/EEC 2007/43/EC Published September 2007, applied March 2010

10. MDD Core Principles To be placed on the market, devices must|: Bear a CE ( Conformitee Europeen) mark unless for use in a clinical trial or custom made Meet the “Essential Requirements”

11. MDD Core Principles Manufacturers must: Follow a conformity assessment procedure Sign a declaration of conformity Hold a technical information justifying a CE Mark & Conformity Assessment

12. What Isn’t there Language requirements-National states can require that their language is used Penalties-basic penalties defined but national law can elaborate penalties set level of fines etc. Process and power of competent authorities

13. What is a Medical Device Any instrument, apparatus, appliance material or other article, whether used alone or in combination, including the software necessary for it proper application intended by the manufacturer to be used by human beings for the purpose of:

14. What is a Medical Device - Diagnosis, monitoring, prevention treatment or alleviation of disease - Diagnosis, monitoring, treatment, alleviation or compensation for an injury or handicap -Investigation, modification or replacement of the anatomy or of a physiological purpose - Control of conception

15. And……… And which does not achieve its principal action on or in the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means

16. The CE Mark European Conformity Marking Applied by the manufacturer Third parry certification required for some products ( not the regulator or manufacturer) Declaration of conformity required Not Product Approval There is no such thing as CE approval The CE mark is “received” from a regulator –it is essentially a quality standard

17. Definitions Manufacturer – means the natural or legal person with responsibility for design manufacture packaging and labelling of a device before it is placed on the market under his own name regardless of whether these operations are carried out by that person himself or on his behalf by a third party

18. Definitions Manufacturer’s obligations apply to natural or legal persons who assemble, process, package or fully refurbishes and/or labels ready made products and/or assigns them their intended process as a device with a view to them being placed on the market.

19. Intended Purpose The use for which the device is intended according to the data supplied by the manufacturer in the labelling the instructions for use and/or in prmotional materials

20. Definitions Placing on the Market placing on the market' means the first making available in return for payment or free of charge of a device other than a device intended for clinical investigation, with a view to distribution and/or use on the Community market, regardless of whether it is new or fully refurbished

21. Definitions Putting into service' means the stage at which a device is ready for use on the Community market for the first time for its intended purpose

22. How is the MDD Structured Recitals- help with language Article I – definitions and scope, combination devices Article 2 – Placing on the market and entry into service Take all necessary steps to ensure devices may only be placed on the market if they do not compromise safety and health Article 3 – Essential Requirements Devices must meet essential requirements taking into account their intended use (Annex 1)

23. Essential Requirements General -Risks must be acceptable versus the benefits - Achieve performance intended by the manufacturer packaged so that they are suitable for one or more of functions referred to in article I

24. Annex 1- Essential Requirements The device....... 1.Should not cause harm, but allowing risk where outweighed by clinical benefit 2.Must be protected by an effective risk management (quality) system 3.Must have demonstrable performance

25. Essential Requirements – the device… 4. Must continue to meet performance throughout the product’s lifetime 5. Must survive storage and shipment 6. Must have any side-effects it has outweighed by clinical benefit 6a. Must include a clinical evaluation

26. Essential Requirements – the device… 7. Must have safe chemical, physical and biological properties 8. Must have appropriate biological contamination control 9. Must have safe construction and environmental interaction 10.Must have safe measuring functions 11. Must protect against radiation exposure 12. Must be safe if equipped with, or connected to, an energy source 13. Must include appropriate information to allow safe use (many sub sections)

27. Article 4 Free movement, devices intended for special purposes Member States shall not create any obstacle to the placing on the market or the putting into service within their territory of devices, devices for clinical investigation or custom-made devices Devices not bearing the mark can be exhibited at trade fairs if not offered for sale Where the devices are subject to other Directives concerning other aspects and which also provide for the affixing of the CE marking, the latter shall indicate that the devices also fulfil the provisions of the other Directives

28. Article 5 Reference to standards Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices which are in conformity with the relevant national standards adopted pursuant to the harmonized standards the references of which have been publishes in the Official Journal of the European Communities; Member States shall publish the references of such national standards.

29. Why use Standards? Occasionally mandatory Accepted by authorities Developed in tandem with industry experts Saves re-inventing the wheel Often include useful guidance as Annexes And you can influence their development

30. What else can be used? MEDDEVs http://ec.europa.eu/consumers/sectors/medical- devices/files/meddev National, European Pharmacopeiae monographs FDA guidance documents Notified Body Recommendations ISO Technical Reports Global Harmonization Task Force documents ICH guidelines

31. Why use Harmonised Standards? Occasionally mandatory Accepted by authorities –Presumption of conformity if harmonised –Expected by Notified Bodies Developed in tandem with industry experts Saves re-inventing the wheel Often include useful guidance as Annexes You can influence their development

32. Example Harmonised Standards ISO 13485:2003 - QMS ISO 14971:2008 – Risk Management EN 980 – Graphic symbols ISO 14155-x (series) – Clinical Evaluation ISO 10993-x (series) - Biocompatibility ISO 60601-x (series) – Electrical safety EN 455 – Medical gloves single use EN 13726 – Test methods for primary wound dressings

33. Articles 6 and 7 Article 6. Committee on Standards and Technical Regulations Article 7 Committee on Medical Devices

34. Article 8 Safeguard clause Where a Member State ascertains that devices when correctly installed, maintained and used for their intended purpose, may compromise the health and/or safety of patients, users or, where applicable, other persons, it shall take all appropriate interim measures to withdraw such devices from the market or prohibit or restrict their being placed on the market or put into service. The Member State shall immediately inform the Commission of any such measures, indicating the reasons for its decision and, in particular, what non- compliance with this Directive is due to (a list follows)

35. Article 8 Safeguard clause The Commission shall enter into consultation with the parties concerned as soon as possible. Where, after such consultation, the Commission finds that: the measures are justified, it shall immediately so inform the Member State which took the initiative and the other Member States -the measures are unjustified, it shall immediately so inform the Member State which took the initiative and the manufacturer or his authorized representative established within the Community.

36. Article 8 Safeguard clause Where a non-complying device bears the CE marking, the competent Member State shall take appropriate action against whomsoever has affixed the mark and shall inform the Commission and the other Member States thereof. The Commission shall ensure that the Member States are kept informed of the progress and outcome of this procedure.

37. Article 9 Classification Devices shall be divided into Classes I, IIa, IIb and III There is a lot of information regarding this in Annex IX of the document and its complex; the higher the classification the more rigorous the testing before marketing Any dispute involving a notified body must be resolved by the competent authority

38. Classification Annex IX Definitions Transient (,60 min), short term (not >30 days), long term (>30 days) Invasive, surgically invasive, implantable, body orifice Reusable surgical equipment etc Active medical device Active device for diagnosis Central Nervous System (CNS) & Central Circulatory System (CCS) Implementing rules Classification rules 18 in total, risk based

39. Classification of devices MDD - Annex IX - Classification Criteria Class 1 - low risk Class 2a - low to medium risk Class 2b - medium to high risk Class 3 - high risk

40. Classification - risk class Iclass I*class IIaclass IIbclass III Potential risk Corrective glasses Sterile wound dressing Hypo- dermic- needle Syringe- pump Heart valve Picture courtesy of Aortech

41. Non-invasive devices Rule 1 –“all non invasive devices are in Class 1, unless one of the rules set out hereinafter applies. Rule 2 –Channelling or storing blood, liquids etc for eventual infusion.. Class IIa, Rule 3 –modifying composition of blood, other body liquids…IIb, unless defined instances….IIa Rule 4 –contact with injured skin…Class I …IIb ……IIa depending on intended use There are then a series of rules, abbreviated here

42. Invasive devices abbreviated Rule 5 Invasive but not surgically invasive –Class I transient use –Class IIa short term –Class IIb long term Rule 6 Surgically invasive, transient IIa unless –CCS – III –Reusable surgical instrument – I –Supply energy as Radiation – IIb –Biological effect or absorbed – IIb –Hazardous medicine administration - IIb

43. Invasive devices abbreviated Rule 7 surgically invasive, short term IIa unless –CCS - III –CNS – III –Radiation – IIb –Biological or absorbed – III –Chemical change or administer medicines – IIb Rule 8 Implant/long term surgically invasive, IIb unless –Teeth – IIa –CCS or CNS – III –Biological effect, absorbed, chemical change or administer medicine - III

44. Active devices abbreviated Rule 9 Active therapeutics.. –IIa unless in a potentially hazardous way … IIb Rule 10 Active diagnostic.. –IIa, unless … CNS IIb…… ionizing radiation IIb Rule 11 Active and administer/remove medicines/liquids… –IIa.. Potentially hazardous ….. IIb Rule 12 –All other active devices are Class I

45. Special Rules abbreviated Rule 13 If incorporate as an integral part Medicinal product, –defn Art 1 2001/83/EC Class III Rule 14 Contraceptives, prevention of STD’s.. –IIb, implantable/long term.. III Rule 15 Contact lens solution… –IIb, disinfecting.. IIa unless specifically for disinfecting invasive devices in which case IIb Rule 16 Recording diagnostic X ray images…. IIa Rule 17 Animal tissues….III except where coming nito contact with intact skin Rule 18 Derogation… blood bags… IIb

46. Article 10 Vigilance 1. Member States shall take the necessary steps to ensure that any information brought to their knowledge, in accordance with the provisions of this Directive, regarding the incidents mentioned below involving a Class I, IIa, IIb or III device is recorded and evaluated centrally:

47. Article 10 Vigilance (a) any malfunction or deterioration in the characteristics and/or performance of a device, as well as any inadequacy in the labelling or the instructions for use which might lead to or might have led to the death of a patient or user or to a serious deterioration in his state of health; (b) any technical or medical reason in relation to the characteristics or performance of a device for the reasons referred to in subparagraph (a), leading to systematic recall of devices of the same type by the manufacturer.

48. Article 10 Vigilance 2.Where a Member State requires medical practitioners or the medical institutions to inform the competent authorities of any incidents referred to in paragraph 1, it shall take the necessary steps to ensure that the manufacturer of the device concerned, or his authorized representative established in the Community, is also informed of the incident. 3. After carrying out an assessment, if possible together with the manufacturer, Member States shall immediately inform the Commission and the other Member States of the incidents referred to in paragraph 1 for which relevant measures have been taken or are completed

49. Vigilance Reporting Vigilance reporting applies to: –devices which carry the CE-mark and –devices which do not carry the CE-mark, where such incidents lead to corrective action relevant to CE-marked devices. (e.g. devices in other markets) –vigilance reporting required for products undergoing clinical evaluation

50. Vigilance Types of incident to report - –Those which led to a death –Serious deterioration in state of health can include: life-threatening illness or injury; permanent impairment of a body function or permanent damage to a body structure; a condition necessitating medical or surgical intervention to prevent permanent impairment of a body function or permanent damage to a body structure –in cases of doubt it is suggested that there is a predisposition to report rather than not report

51. Vigilance Types of incident to report - –‘Near incidents’ –an incident associated with a device happened, and –the incident was such that, if it occurred again, it might lead to death or serious deterioration in health OR –an examination of the device or Instructions For Use (IFU)indicated some factor which could lead to an incident involving death or serious deterioration in state of health to be reported, a possible link with the device or IFU should be clearly established

52. Post-marketing surveillance “Experience gained from devices in post-production phase” a “system” or “systematic procedure” is required Includes post market clinical follow up (PMCF)

53. PMS Guidance NB-MED Recommendation NB-MED/2.12/Rec1 (Feb 2000) “Post-Marketing Surveillance (PMS)” http://www.team-nb.org/documents.htm

54. Articles 11,12,13,14 Article 11 sets out conformity assessment procedures Article 12 sets out procedures for systems and procedure packs Article 13 allows for derogation regarding decisions regarding classification Article 14 deals with registration of persons placing devices on the market

55. Articles 15 and 16 Article 15 deals with devices intended for clinical investigation Article 16 – Notified Bodies - The Member States shall notify the Commission and other Member States of the bodies which they have designated for carrying out the tasks pertaining to the procedures referred to in Article 11 and the specific tasks for which the bodies have been designated. The Commission shall assign identification numbers to these bodies, hereinafter referred to as 'notified bodies'.

56. Clinical Investigation ARTICLE 15 –Notify Competent Authorities (CA) of MS in which investigations are to be carried out according to Annex VIII –60 days notification period at CA –Conduct investigations according to Annex X

57. Clinical Evaluation Annex X –confirmation of conformity with the requirements concerning the characteristics and performances referred to in Annex 1 and acceptability of benefit / risk ratio must be based on clinical data Can be either –Critical evaluation of literature OR –Critical evaluation of results of all clinical investigations made OR –Both

58. Clinical investigation ISO 14155: 2011 “Clinical investigation of medical devices for human subjects –Single document with new name – –“Clinical investigation of medical devices for human subjects – Good clinical practices” –Applies to pre and post marketing studies

59. Article 17 CE marking 1.Devices, other than devices which are custom-made or intended for clinical investigations, considered to meet the essential requirements referred to in Article 3 must bear the CE marking of conformity when they are placed on the market. 2. The CE marking of conformity, as shown in Annex XII, must appear in a visible, legible and indelible form on the device or its sterile pack, where practicable and appropriate, and on the instructions for use. Where applicable, the CE marking must also appear on the sales packaging. It shall be accompanied by the identification number of the notified body responsible for implementation of the procedures

60. Article 17 CE marking 3. It is prohibited to affix marks or inscriptions which are likely to mislead third parties with regard to the meaning or the graphics of the CE marking. Any other mark may be affixed to the device, to the packaging or to the instruction leaflet accompanying the device provided that the visibility and legibility of the CE marking is not thereby reduced. Article 18 refers to wrongly affixed CE marking

61. Article 19 Decision in respect of refusal or restriction 1. Any decision taken pursuant to this Directive: (a) to refuse or restrict the placing on the market or the putting into service of a device or the carrying out of clinical investigations or(b) to withdraw devices from the market, shall state the exact grounds on which it is based. Such decisions shall be notified without delay to the party concerned, who shall at the same time be informed of the remedies available to him under the national law in force in the Member State in question and of the time limits to which such remedies are subject.

62. Articles 21 and 22 Article 21 - Repeal and amendment of Directives Article 22 Implémentation, transitional provisions

63. Annexes More detials are then set out in a series of Annexes; I shall only point out a few highlights

64. TECHNICAL DOCUMENTATION Why compile technical documentation? –Demonstrates how manufacturer knows that they meet Essential Requirements –Keeps all product safety related information in one place –Similar to Device Master File for USA# –Quality system requirement (ISO 13485) –Product liability (illustrates due diligence) –Training –Purchasing –Sits on the shelf as a record

65. Who holds Technical Documentation? OEM Research & Development Manufacturing Quality Assurance Clinical Affairs Marketing Purchasing Subcontractors Archives

66. Combination Products - Drugs Article Where a device is intended to administer a medicinal product within the meaning of Article 1 of Directive 2001/83/EC, that device shall be governed by this Directive, without prejudice to the provisions of Directive 2001/83/EC with regard to the medicinal product. If, however, such a device is placed on the market in such a way that the device and the medicinal product form a single integral product which is intended exclusively for use in the given combination and which is not reusable, that single product shall be governed by Directive 2001/83/EC (Medicinal Products). The relevant essential requirements of Annex I to this Directive shall apply as far as safety and performance related device features are concerned.

67. Declaration of Conformity The declaration of conformity is the procedure whereby the manufacturer who fulfils the obligations imposed by Section 1 ensures and declares that the products concerned meet the provisions of this Directive which apply to them. Annex II.2

68. Declaration of conformity = CE Marking Annex VII Sterile or measuring ? Notified Body verifies those aspects of manufacture concerning sterility or metrology (using Annex II, IV, V or VI) Yes Class 1 device No Mftr responsibility Notified Body - QAS Notified Body - Product evaluation MDD

69. Annex VI Product Quality System Class 1 device Declaration of conformity = CE Marking Annex II Full Quality System Annex V Production Quality System Class 2a device Annex VII Declaration of Conformity Annex IV Batch Verification MDD or plus

70. Declaration of conformity = CE Marking Annex II Full Quality System Annex V Production Quality System Class 2b device Annex III Type Examination Annex VI Product Quality System Annex IV Batch Verification MDD or plus

71. Declaration of conformity = CE Marking Annex II Full Quality System Annex V Production Quality System Class 3 device Annex III Type Examination Annex IV Batch Verification Design Dossier examination by Notified Body MDD or plus

72. Class III with ancillary substance Combination product Notified Body required –Agree a Medicines Competent Authority or EMEA for verification of substance safety, quality and usefulness by analogy with pharmaceutical controls for medicinal ancillary – separate fees –Use EMEA for products with a human blood derivative ancillary Design dossier examination by Notified Body includes consideration of above consultation

73. Summary Manufacturer determines conformity assessment route as influenced by device classification Increasing oversight with higher class devices

75. Other Directives Other directives may apply to a device e.g. Biocides directive Amendment regarding blood products(2001/104/EC) RTTE ( telecoms) WEEE ( waste electrical electronic equipment ROHS (Hazardous substances) Medicinal products Weighing Equipment Tissue of animal origin Etc

76. You need to read the Directive To read more go to: http://eur- lex.europa.eu/LexUriServ/LexUriServ.do? uri=CELEX:31993L0042:EN:HTML www.newapproach.org (portal)www.newapproach.org leads to the EUROPA website (EC)

77. So do you still want to be a regulator?