The Regulation and Authorisation of Medical Devices, IVDs and ATP

1. The Regulation and Authorisation of Medical Devices, IVDs and ATP Tortworth Thursday, 6th June, 2013 Dr David Jefferys Eisai Europe Ltd

2. Pharmaceuticals and Medical DevicesThe Borderline, Combination Products and Advanced Therapy Products

3. Definitions • Background to Medical Device Regulations • IVDs • Borderline issues • Handling combination products • Vigilance and pharmacovigilance • Tissue engineering products • Future issues

4. Definitions Medical Device (93/42/EEC/2007/47) Any instrument, apparatus, material or other article, whether used alone or in combination, including the software necessary for proper application intended by the manufacturer to be used on human beings for the purpose of • Diagnosis, prevention, monitoring, treatment or alleviation of disease • Diagnosis, monitoring, treatment alleviation or compensation for an injury or handicap • Investigation, replacement or modification of the anatomy or physiological process • Control of conception

5. Directive 2004/27 EC (amends 2001/83) • a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or b) Any substance or combination of substances, which may be used in, or administered to, human beings either with a view to restraining, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis

6. Article 2.2 (New) “In cases of doubt where, taking account of all its characteristics, a product may fall within the definition of ‘a medical product’ and within the definition of a product covered by other Community Legislation, the provisions of this Directive shall apply”.

7. The Regulation of Medical Devices • New Approach Directives • 90/35 AIMD • 93/42 MDD • 98/79 IVD • 2000/70 stable derivatives of human blood and plasma derivatives • Directive 2007/47EC, technical revisions “updating directive” - Implemented March 2010 • 5 implementing Commission Directives (including TSE , breast implants, joint replacements) • Advanced Therapies Regulation 1394/2007

8. Key Features of Device Regulation • New approach - light touch directives • Different dynamics for the Devices Industry • Process of conformity assessment • Essential requirements • MEDDEV guidelines

9. Key Features of Device Regulation • Risk classification of products • Class I self regulation • Class IIA (measuring devices, sterile products) • IIB Quality systems review • III Design dossier review • Competent Authority Role • Safeguard Clause

10. Competent Authority Role • Designation and supervision of Notified Bodies • Clinical trial controls (CTN) • Compliance & enforcement role • Vigilance and User Reporting Adverse Incident Schemes

11. Comparison of Legislation Devices • New Framework • Both single markets • Different control points • Separation of Competent Authority and Notified Body (CAB) findings • Different entry points • Pharmaceuticals pre-authorisation control for all products • Emphasis on post authorisation safety assessment • Pre-authorisation conformity assessment • Less harmonised, detailed guidance

12. Comparison of the Industries • More diverse • Devices industry is larger than pharma • More smaller companies • Single product companies • Different markets • Lower profile • Greater diversity of products and technology • Different development cycles • Different product cycles

13. The Borderline • Medical Devices • Pharmaceuticals • Advanced Therapy Products • Cosmetics • Biocides • Foods (nutriceuticals) • Personal Protective Equipment

14. The Borderline PPE Cosmetics Medical Devices Pharmaceuticals Foods Advanced Therapy Products Biocides

15. In order to decide which regime applies the following criteria should be examined Step 1The intended purpose of the product taking into account the way the product is presented (this is likely to establish if either the MDD or the MPD apply, rather than distinguish between the two regimes), Step 2 The method by which the principal intended action is achieved

16. The principal intended action of a product may be deduced from: • The manufacturers labelling and claims • The scientific data regarding mechanism of action Although the manufacturer’s claim are important, it is not possible to place the product in one or other category in contradiction with current scientific data. Manufacturers may be required to justify scientifically their rationale for classification of borderline products

17. Seeking Clarification • Role of the Notified Body • C A and the MDEG Medical Device Expert Group (e-mail consultations system) • MEDDEV Guideline 2010, reproduced by MHRA (on MHRA website)

18. Combination Products • Drug/device • Device/drug • Diagnostic/drug combinations – companion diagnostics • Concept of “Primary intended purpose”

19. Medical Devices administering a Medicinal Product • The MDD applies if used separately (infusion pens, syringes) • If the device and the medicinal product form a single integral product which is intended for use exclusively in the given combination (and is not reusable) the product is regarded as a medicine (pre-filled syringes/injectors) • The relevant medicines agency has to contact a Notified Body or a Device CA

20. Medical devices incorporating a medical substance with an ancillary action • These products are medical devices • Examples (coated catheters, drug eluting coronary stents, steroid coated pacing wires, TACE products ) • Safety, quality and usefulness of the medical substance has to be verified by reference to the Directive 75/318/EEC as amended by a • Medicines CA • Involvement of the EMEA • Position for new active substances

21. Directive 2000/70 Combination with a stable blood product: Mandatory consultations with the EMEA/ CHMP

22. Drug/Device Combination Product Example: • Gliadel – drug delivery intra-cerebral wafer (carmusline) to treat MGBM) • Intra-cerebral ferro-nanoparticles Difficult Products TACE products (trans arterial chemo-embolisation) embolisation beads impregnated with a slow release cytotoxic • Drug eluting coronary stents

23. Adverse Incident Reporting • Mandatory - manufacturer vigilance scheme • User adverse incident reporting scheme • Direct electronic reporting • Patient reporting • Root cause analysis • National Patient Safety Agency Role

24. Vigilance (Device) Reporting • MDD Directive 93/42 EC ( modified by 2007/47 ) • IVD Directive 98/79 EC • Combines defect and designs reporting • Definitions • Eudamed database • User reporting schemes (separation) • No PSURs

25. The Investigation of Adverse Incidents • MHRA Investigations • Manufacturer Investigations • Causes of adverse incidents: • Device faults • Before delivery • After delivery • User error • No established link to the device

26. The Investigation of Adverse Incidents, contd ….. Specific approaches • Need to follow device procedures (quarantine the evidence) involve the Notified Body • UK Liaison officers in the NHS

27. In Vitro Diagnostics (IVDs) • Directive 98/79 EEC • Annex 1 products • Annex 2 products (defined list – includes all OTC direct to patient tests) • Most biomarkers and genetic tests are annex 1 (self- certification) • Commission Communication has proposed a move to a ‘risk based’ classification system • “Home brew” test kits – no ‘gold standard’ for IVDs

28. Advanced Therapy Products: “Tissue Engineering” • Background • History of Human Tissue Regulation in Europe • Current Situation

29. Advanced Therapy Products • Regulation 1394/2007EC • Covers • Viable human tissue products • Cell therapy products • Gene therapy products • Implementation date –December 2008 • New committee CAT committee on advanced therapies , reports to CHMP • Legislation covers allogeneic and autologous products

31. Revision of the MDD/IVD Directives New Proposed Regulations • The debate • Where are we? • Where are we going? • PIP debate

32. Key Features of the Draft Medical Device and IVD Regulations • Retain ‘new approach’ • Strengthens evaluation procedures for high risk products (Class III) • MDCG expert scrutiny • Consolidation of expertise, MDCG (Scrutiny Committee) Reference Laboratory Network • Increased co-ordination of vigilance and market surveillance across EU

33. New Legislation, contd • Extension of the scope to cover non viable human tissues e.g. human collagen implants • Enhanced approach to handling combination products • Risk based evaluation of IVDs (4 classes) • Companion diagnostics • Extension to cover genetic testing

34. New Legislation, contd • New clinical trial approval system (identical to the CTR) • Common database • Regulatory Qualified Person (Article 13) • Transparency –summary approval document to be generated and published

35. EU Legislative Process Estimated Timelines for Ordinary Legislative Procedure by European Parliament and Council of the EU European Parliament Elections June 2014 1st reading Possible 2nd reading Elections likely to have an impact on the process

36. Concluding Remarks Input page title in 1 line.- Input 24pt subtitle. - 〜