Europe

1. Europe

2. Overview of Actors and Roles Manufacturer Competent Authority Notified Body European Commission and Member States Certification and Audits (Inspections) Registrations Surveillance Enforcement Designation Surveillance Enforcement

3. The Revision is nearly with us and today we aim to gather insights into what is coming, why and what it means to key stakeholders. The Recast/Revision of the Medical Devices Directives – problems and solutions? Trevor Lewis, Principal Consultant Medical Device Consultancy

4. Proviso! My presentation is dependent upon an unofficial draft of the changes and related discussions with well informed individuals. Other speakers are likely to be better informed of the actual content of the Revision than me but I can say things that they just cannot possibly comment on! Alan Kent has explained how we got here and what the big global trends are. My aim is to encourage you to think about what matters as regulatory hurdles keep rising.

5. What characteristics should a good regulation have? • In the UK (and similarly beyond) they should follow the Hampton Principles: • Regulators should recognise that a key element of their activity will be to allow, or even encourage, economic progress and only to intervene when there is a clear case for protection. • Regulators, and the regulatory system as a whole, should use comprehensive risk assessment to concentrate resources in the areas that need them most. • Regulators should provide authoritive, accessible advice easily and cheaply.

6. What characteristics should a good regulation have? • In the UK (and similarly beyond) they should follow the Hampton Principles: • No inspection should take place without a reason. • Businesses should not have to give unnecessary information or give the same piece of information twice. • The few businesses that persistently break regulations should be identified quickly and face proportionate and meaningful sanctions. • Regulators should be accountable for the efficiency and effectiveness of their activities, while remaining independent in the decisions they take.

7. Does the Medical Device Regulation today achieve the Hampton Principles? • In the UK and most of Europe the answer is: Yes but we can always do better. • Medical Device regulators need to be seen as effective, until recently Trading Standards and especially the Advertising Standards Agency (ASA) were seen as having much more effective teeth. • IVD Directive (IVDD) classification of diagnostics was not risk based and means the regulations are not really applied in a risk based, proportionate manner. The change to a risk based GHTF like system is then clearly warranted and universally accepted as appropriate.

8. Further characteristics of good regulations... • Good regulations are fair: risk based, appropriate, proportionate, and do pay due consideration to economic considerations. • Good regulations are enforced and seen as effective by all stakeholders. Persistent transgressors must know they will be punished not just warned... • Good regulations need to be seen as beneficial to those subject to them, i.e. the medtech industry. • Good regulations evolve with time and radical changes are only made if absolutely required. • Are the likely changes represented by the Revision good regulations?

9. After more than 100 years of healthcare industry regulation FDA is still working on its ever evolving system, including most recently ‘Strengthening Our National System For Medical Device Postmarket Surveillance’ published September 2012.

10. FDA improved PMS system proposal September 2012 We can expect The Revision to have similar elements in it...

11. As we have heard from Alan Kent, global convergence is alive and well with the IMDRF, including exchange of information between regulators. I note that FDA have been very critical of the European approach and the cozy relationship between manufacturers and Notified Bodies (NBs).

12. The Regulatory Environment is Dynamic and Important…European UnionThe Medical Device Directivesincluding the In Vitro Diagnostics Directive (IVDD) is under review. The Revision Regulation is expected next week. United States of AmericaFood and Drug Administration (FDA) that has lots of useful guidance. The 510(k) premarket submission is under reform right now.

13. Its not just The Revision its about changing compliance too… EN 60601-1:2006 Medical electrical equipment. Part 1: General requirements for basic safety and essential performance became obsolete on the 1st June 2012 and is replaced by the 3rd Edition. The 3rd Edition is risk based and demands the use of: EN ISO 14971: 2009 Medical devices - Application of risk management to medical devices. The 3rd Edition sets the state of the art for electrical safety, EMC and software safety in medical devices and by association for in vitro diagnostics too. These European Standards do not necessarily cover the requirements introduced by Directive 2007/47/EC.

14. These European Standards are important and currently harmonised to the IVDD. EN 61010-2-101:2002 Safety requirements for electrical equipment for measurement, control, and laboratory use - Part 2-101: Particular requirements for in vitro diagnostic (IVD) medical equipment EN 61326-2-6:2006 Electrical equipment for measurement, control and laboratory use - EMC requirements - Part 2-6: Particular requirements - In vitro diagnostic (IVD) medical equipment EN 62304:2006 Medical device software - Software life-cycle processes. EN 62366:2008 Medical devices - Application of usability engineering to medical devices.

15. A recent unofficial draft of the proposed new Medical Devices Directives does provide insights into the likely changes and more importantly the direction of travel... ... as it has been discussed by the Medical Devices Expert Group (MDEG) but scope excludes IVDs. The changes are less dramatic than originally feared and have resulted in the process being termed (under EU comitology procedures) a Revision and not a Recast. It is almost certain that the Revised IVDD will have different classification risk as expected using the GHTF system (rules based classes A-D). It is considered likely (especially in the UK) but not certain that the use of in-house (home brew) tests for companion diagnostics / stratified medicine – will retain exemption except for the highest risk categories.

16. Rule 3: Class C • devices intended to be used as companion diagnostics, for disease staging and in screening for – or in the diagnosis of – cancer, as well as for screening for congenital disorders in the foetus; • genetic tests; • tests for detecting an infectious agent, an infective disease or immune status where there is a risk that a wrong result would cause death or severe disability, or lead to a patient management decision resulting in an imminent life-threatening situation, to the individual or foetus tested, or to the individual’s offspring

17. Rule 10: where standalone software falls within the scope of the definition of an "IVD medical device", and drives a separate IVD medical device or influences the use of the device, the software falls automatically in the same class as the device; where it is not incorporated in an IVD medical device, it is classified in its own right in accordance with the above-mentioned classification rules.

18. It is very likely the Revised IVDD will demand more clinical evidence for all but the lowest-risk, Class A products. This is expected and typically global IVD manufacturers have looked to meet the more stringent FDA requirements. CE was seen, until recently as a sub-set of required FDA documentation. The Revised IVDD is likely to be implemented across the EU during 2015 or 2016 and is likely to be a Regulation (as proposed for devices) and so will become effective soon after it is published. All manufacturers will need / would be well advised to have a post-market clinical follow-up plan consisting of documented methods and procedures to pro-actively collect clinical evidence data from actual use of the device. This data is then expected to be used in the development of risk management, design and clinical performance documentation. This requires a database that works transnationally!

19. There will be more work and added costs for IVD manufacturers… The risk based classification system for IVDs will result in many more IVD companies requiring the use of a Notified Body (NB) before products can be CE marked and placed on the market. Overall these most likely of changes are most likely to be accepted by most stakeholders as ‘good regulations’. Yes there will be some additional costs to industry but this is fully warranted, especially for molecular and companion diagnostics. I will leave further comments to Doris-Ann Williams of BIVDA.

20. EU “BLUE GUIDE” or “BLUE BOOK” Guide to the implementation of directives based on the New Approach and the Global Approach. Out of Date …but then virtually nobody reads it!

21. Review of the New Approach The New Legislative Framework The New Approach has recently been reviewed but changes relatively little for medical device manufacturers. For more please see: http://ec.europa.eu/enterprise/newapproach/review_en.htm Changes are applicable from 1 January 2010. Economic operators defined to include manufacturer, authorised representative, the importer and distributor. Economic operators should take appropriate measures to ensure they only make available products in regulatory compliance. This change needs to be in The Revision.

22. MDEG Concerns Prior to 2007 Revision • Notified Body examination of design for conformity assessment. • The sufficiency and adequacy of clinical data for all classes of device. • Coordination of post market surveillance. • Competence of Notified Bodies. • General public awareness of device approval. • These concerns still remain from my perspective, but there are emerging improvements in all of the above. • The Revision is expected to continue this theme.

23. What did the 2007 Revision Try to Do? • Resolve issues arising from technical progress, multiple interpretations and misunderstandings. • Attempted to force industry to take clinical evaluation more seriously. • However it inevitably created further issues to keep everyone engaged in dialogue for the foreseeable future. • The 2012 Revision is likely to reinforce this current situation and a more fundamental Recast has been rejected.

24. What are the Regulatory Hurdles? • Validation of Product Design, especially EMC (Electromagnetic Compatibility) & Software. • Risk Management for product, processes, Quality Management System (QMS) and Clinical Evaluation. • Pre-Clinical Testing. • Validation of Clinical Evidence, i.e. Clinical Literature Review and Clinical Investigation for devices. For IVDs analytical laboratory testing, Performance Evaluation and Clinical Validation. • Human Factors Engineering – more than usability. • Post Market Surveillance (PMS). • Competence of Notified Bodies. • Reimbursement and Health Technology Assessment (HTA).

25. Key Points Likely in The Revision of Medical Device Directives • Definition of ‘making available on the market’ replaces ‘putting into service’ and removes some confusion. • ‘Importer’ ‘Distributor’ and ‘Economic Operator’ defined to align with the Recast of the New Legislative Framework. • Those listed above must ensure products are compliant! • Definitions for ‘recall’; ‘withdrawal’; and ‘harmonised standard’ may be added so as to be clearer about some post-market surveillance requirements. • The poorly understood ‘device subcategory’ and ‘generic device group’ may be modified or clarified.

26. Key Points Likely in The Revision of Medical Device Directives • Further new definitions for ‘single use device’; ‘conformity assessment body’; ‘nanomaterial’; ‘health institution’; ‘field safety corrective action’; ‘field safety notice’; ‘clinical investigation’ and more expected. • Any product using ‘nanomaterials’ will be Class III, unless bound/encapsulated with no release to patient possible. • The definition of ‘qualified person’ may be added too. • All of these definitions will require careful study by both manufacturers and legal counsel.

27. Key Points Likely in The Revision of Medical Device Directives • Labelling to move closer towards the GHTF guidance on labelling, to enable manufacturers to have more ‘international’ labelling – hopefully reducing costs. • Own Brand Labelling requirements will probably be clarified and the name for agreements with brand owners explicitly stated. • The need to inform users of residual risks might be extended to include/encourage training of users [...where deemed appropriate, proportionate to the risk and cost effective to do so?]

28. Key Points Likely in The Revision of Medical Device Directives • Implantable or other invasive products, intended for human beings are likely to be classified as medical devices irrespective of the claims made by the manufacturer. This change might also be extended to non-corrective contact lenses; facial or other skin fillers; equipment for liposuction; and surgical laser equipment.

29. Key Points Likely in The Revision of Medical Device Directives • More regulation of single use devices, especially those that are reprocessed, is highly likely and many have lobbied hard and long for such changes. For many observers this is long overdue. • ‘Making available on the market’ will most likely bring in the concept of properly installing and maintaining a device. For many observers this is long overdue. • All medical devices made available, except custom devices or intended for clinical investigation, must include a clinical evaluation to demonstrate conformity with the Essential Requirements.

30. Key Points Likely in The Revision of Medical Device Directives • The General Essential Requirements (1 to 6) will remain but could be worded to better align with the GHTF Essential Principles.

31. Key Points Likely in The Revision of Medical Device Directives • In Vitro Fertilization (IVF) or assisted reproduction technologies (ART) likely to be regulated as Class IIb devices. • Some ingested devices for transient use will probably be regulated as Class IIb devices and short- to long-term devices as Class III devices. • Class III devices will probably require a full quality system and design dossier examination prior to placing on the market. Type testing should still be possible.

32. Key Points Likely in The Revision of Medical Device Directives • Notified Bodies (NBs) ‘involvement’ in the conformity assessment process will be more clearly spelt out • NBs and manufacturers will need to set and agree time limits to the implementation of corrective actions. • The expected ‘degree of rigour’ for NBs assessments is now likely to explicitly stated. This sadly is required. • It is good to know positive words and phrases are likely to be used, such as: • ‘In so doing, NBs shall act in a proportionate manner, avoiding unnecessary burdens for economic operators.’

33. Key Points Likely in The Revision of Medical Device Directives • Whilst it is understood to have been rejected, early drafts of The Revision do consider, upon duly justified request of MDEG, review of conformity assessment of high risk devices by MDEG or the Commission. • These would be probably be a rare process and reserved for those highest risk products, extremely novel devices, products with a significant impact on public health, or has some evidence of discrepancies from different NBs. • Note that change of NB will require a structured handover with appropriate checks been documented.

34. Key Points Likely in The Revision of Medical Device Directives • Certificates of free sale should be more readily available following The Revision and this is clearly welcomed. • The need for a product to have a Unique Device Identification (UDI) is possible (to eventually most probable) and should again be helpful – provided only one system is used globally... • There could be encouragement, via the Directives, to ask medical practitioners and/or medical institutions to report adverse incidents electronically where this is possible.

35. Key Points Likely in The Revision of Medical Device Directives • Post-market clinical follow-up will most probably have its own section and reinforce the need for continuous process to collect and evaluate clinical data systematically in the post-market phase. A plan will be expected! • The use of ‘Expert Panels’; ‘EU Reference Laboratories’ and ‘Scientific Advice’ have definitions and remits that mirror many of the activities of similarly named bodies well established by the Food and Drug Administration (FDA)...

36. The EU Data Protection Directive (Directive 95/46/EC) is under revision and a new version is expected to be published during 2014. Future fines for non-compliance could be as high as 2% of a company’s world-wide revenues! Plus various bans on processing data. It is an important area to monitor as the draft develops and it is important to realise it will most likely affect patient records and clinical decision support systems implementation. Taking legal advice once the changes are clear is considered vital.

37. Remember the RoHS Recast will apply to medical devices from the 22nd July 2014 and for IVDs from the 22nd July 2016. REACH is with us now!

38. Regulatory compliance, just like quality, is not a destination but a journey. Everything is legitimately subject to continuous review. The STATE-OF-THE-ART is enshrined into all the medical device directives and features in strict liability and consumer protection law all around the world. A key aspect of assessing what is expected is the reasonable expectations of the consumer – as determined in a Court of Law. Even with no Directives and no Code of Federal Regulations it would still be necessary to undertake due diligence in all things, act with a duty of care and be responsible taking into account all possible factors that make a product safe and do what it is supposed to do without undue harm. The implementation of compensation due to neglect or deliberate act dates back to English Common Law during the 13th Century, possibly earlier. The compensation culture is nothing new and is not an American invention, although it is clearly taken to extremes in the USA. The Regulatory Journey

39. Understand the clinical need and all relevant stakeholder’s perspectives. Never under estimate the importance of Human Factors Engineering (HFE). Create concepts, test them and use Ready – Fire – Aim where you can. Do market research, study users and patients, look at the Total Product Life Cycle (TPLC) of competitors, substitute technology and possible alternative clinical pathways – you will gain profound insights. Do write requirements specifications so you can generate Design Inputs and Design Outputs, i.e. know what you are going to produce and how to prove it when you do. Do work within a QMS to ISO 13485 so you can prove to YOURSELF and any inspector/auditor that you are in Demonstrable Control at all times and in all places. Make Evidence Based Scientific Decisions and ensure these are robust and where possible or demanded are subject to appropriate Peer Review. The Important Things

40. Never under estimate the importance of Ethical Review and do get truly independent advice before embarking on anything that uses significant resources. Always validate the clinical need has been met and review the entire design following initial use by real users/patients, in real life situations and refine your aim towards the best possible product you can create cost effectively. Always ensure all types of validation wherever and whenever possible are undertaken as independently as possible. Do not fool yourself or your colleagues – delusions always come back with a bite that hurts. Keep close to your TEAM – R&D / D&D, the supply chains, your distribution chain, manufacturing, regulators and most importantly close to your customers and patients. DO plan for several rapid iterations of design and validation that will improve your Ready – Fire – Aim route to success. Keeping checking and monitoring the market research, users / patients, competitors, substitute technologies and possible alternative clinical pathways – do not get surprised at launch! Do keep up-to-date with all regulatory requirements, relevant standards and guidance documents. Remember in Europe there are always at least two Directives that apply to every product, often it is many more and six is fairly common for electrical/electronic products. Do consider the environmental Directives and regulations from the start as an equally important to anything else. The Important Things

41. Do not rely on Regulators / Notified Bodies, Consultants, Lawyers, the Public, Doctors, Patients or anyone else to ensure you comply – as the legal manufacturer you are responsible for everything. You need to ensure you have the time to keep up-to-date and understand the ever changing state-of-the-art of medical device regulation. You need to read, to learn, to lead, to motivate, review and do all the routine things well, that we all do everyday, to make progress in our regulatory lives. Nearly all medical device businesses require teams of specialists and partners to make things happen and ensure compliance. So we all need to be, especially Top Management, good listeners and be open to learn from our teams and others. The Important Things

42. The key takeaways? Appropriate, proportionate and cost effective regulation of medical devices, including IVDs and various combination devices really matters to public health and wealth. Getting it wrong can cost lives and be expensive to fix. Note a diagnostic test can help keep a drug on the market, or indeed be vital in getting a drug to market! Co-development of IVDs, biologics and drugs is going to increase. The importance of clinical evidence is increasing, can you substantiate your product claims when subject to truly independent peer review? The regulations are hardly required for those who develop and/or sell innovations with scientific rigour and due consideration to the ethics of use. Regulations are vital to guide or control those who resent controls or are prepared to cut corners for whatever reason. Cost always matters and economic considerations have to be part of the equation.

43. Enforcement? We are not talking about... ...but perhaps we should!

44. Q&A – please wait for the panel session.

45. New EDMA tag line (28Nov11): “Diagnostics for Health” http://www.edma-ivd.eu/about-in-vitro-diagnostics

46. Diagnostics Development: Fragmented Landscape, Lack of Advocacy and Investment R&D: 2-10 years; $ 10-100 million Regulatory Approval: 2-5 years Diagnostic Targets Proof of Principle Product Prototype Lab & field evaluations Policy and guidelines for use Test adoption Target Product Profile Technology platform Policy & Uptake 5-7 years Courtesy of Prof. Peeling, Diagnostic Research London School of Hygiene & Tropical Medicine

47. Typically in the past: USA 40% to 50% typical Europe ~ 30% Japan 15% to 20% ROW balance but: Canada, Australia & New Zealand 3% to 5% Brazil, Russia, India, China & Turkey (BRICT) are becoming ever more significant. Question: Do you wish to access 90%+ of the world’s market for medical devices / IVDs?

48. FDA Proposals (expectations) for companion diagnostics: • Draft guidance completed 15th January 2012 and a final version is in progress, originally expected by 30th June 2012. • Provides definitions and indicates general policies. • Trials must be conducted under full IDE Regulations, i.e. a submission and review by FDA is required. A ‘pre-IDE’ consultative process is highly recommended. • Please download from: www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM262327.pdf • Please remember the European Medicines Agency (EMA) Qualification of novel methodologies for drug development: guide to applicants that discusses the regulation of biomarkers for companion diagnostics. • This does cover “....biomarkers, imaging methods or other drug development tools”.

49. 510(k) Reform key points: • The use of split predicates to end. • The use of reference devices allowed but ideally the single predicate should be ‘substantially equivalent’ in regard to both ‘intend use’ / ‘indications for use’ and technology used. • Otherwise a ‘hybrid’ 510(k) with prospective clinical performance data or PMA may be invoked.

50. Recently and periodically over many years this question has been raised or arguments have arisen about which regulatory approach is best: FDA or CE? All regulatory systems need to continually and progressively evolve and improve over time. Being a regulator is not a destination but a journey. The regulations in the US and EU represent only the minimum and provide guidance as to what is expected from manufacturers - who should always be striving to first ‘do no harm’ and only provide fully compliant products whose benefits outweigh the associated risks. All regulation should ideally be reasonable, appropriate, proportionate and pay due regard to economic considerations. FDA Vs CE – which is best?