Overview of the Current Global Regulatory and Clinical landscape

1. John Kilmartin IMDA Regulatory Steering Committee ChairSenior Regulatory Affairs Director Medtronic Ireland Overview of the Current Global Regulatory and Clinical landscape

2. Today (An Industry Perspective) • MedTech sector at a glance • Clinical trial infrastructure • Are we on the right path ? • Current environment for clinical studies • Global trends in clinical studies • What are other countries doing ? • Conclusions/thoughts

3. Med Tech Industry in Ireland

4. Are We on the Right Path ? • MedTech cluster (indigenous and multinationals) • Its happening on the commercial and R&D fronts • Small country, ability to network • Can do attitude, make it happen • The pieces of the jigsaw seem to be here

5. Clinical Trial Infrastructure • Competent Authority ICRIN Ethics Academic institutions Patients Industry CRF’s IMDA Clinicians ??? • Can we put all the pieces together ?

6. Thoughts • 10 years of good intentions/reports! • Past 2-3 years have shown real progress/willingness • KEY: Need each stakeholder to look at themselves • A few small wins will make a big difference • Needs impetus and examples that we can share • How do we promote a culture of clinical research ?

7. Lets look at the Current Environmentfor Clinical Studies Increasingly stringent safety requirements (increased patientnumbers, more trials, longer follow-up etc.) High level of scrutiny to ensurereturn of investment Challenge for regulators to keep pace with rapidly developing technologies

8. Lets look at Global Trends in Clinical Trials Conduct Observation (Cause?) • 1980’s – Increased regulation in US (FDA) • FDA Acceptance of European clinical data (2008) • Development of regulations & clinical trial infrastructure in Europe (+ others) Observation(Effect?) • Migration of clinical trials to Europe • Migration of Clinical trials to CEE, Lat Am, India, China & Australia/New Zealand etc.

9. Data from Clinicaltrials.gov • Global – 12,373 Medical device clinical trials • US – 5,338 • Europe– 3,756 • Ireland – 44 Germany - 1076 France - 790 UK - 570 Italy – 500 80% !!

10. US FDA: Reversing the trend ? • April 9, 2012, launch of "Innovation Pathway 2.0" - tool for FDA to evaluate FIH clinical trials • Evolving system with the goal of making the regulatory process more efficient and timely • Improving collaboration between FDA and innovators early in the process, prior to pre-market submission • Currently 9 device companies selected into the early feasabilitypilot program

11. European Medical Device Clinical Trials

12. So what is happening in the rest of the world? • What are other countries or regions doing that we need to be aware of?

13. Slide taken from a US presentation (focusing on Regulatory burden) • Where to conduct a clinical trial? Western Europe: Moderate Regulatory Burden North America: High Regulatory Burden Greater Asia: Growing Area of Interest Japan: High Regulatory Burden Africa: Challenging Politically and Varied Regulations South America: Complicated & Varied Regulations Australia / New Zealand: Low Regulatory Burden

14. Australia • Language:English ispeaking, little/no communication problems and little (if any) translation needs • Health Care: 1st world health care system, clinical outcomes are easily translatable to European and US populations • Population: Australia is a big country but its major cities are densely populated which provide a good patient population • Well established CRO network • Favorable place to conduct research, Fast activation time • HREC’s – pivotal role in reviewing scientific and ethical aspect of trial proposals • Reasonable regulatory environment: • CTN – HREC and hospital review & approval, TGA notification only • CTX – TGA review & approval, HREC and hospital approval

15. Central and Eastern Europe 29 countries , total population over 400 million people (including Russia) Benefits: • Attractive destinations for clinical trials - low cost & cultural barriers • Deliver high quality data and more efficient regulatory processes when compared to other emerging markets • Working to bring their regulations in line with EU requirements- clearer rules & greater stability in fee requirements Challenges: • Timelines • Document requirements by regulatory bodies • Costs of process • Language barrier • Lack of understanding of international regulations ?

16. Latin America • Becoming a preferred destination for clinical trials • 2005 to 2008: 30% increase in participation in clinical trials   Benefits: • Large subject pool concentrated in urban areas - Lower costs • Well-qualified medical professionals • Reliable, quality data - high compliance and completion rates • Less competition due to less clinical trials • US: growth rate 7% / * trial density - 120 • Brazil: growth rates 16% / trial densities - 4 Challenges: • Inconsistent legal environment • Cultural and national differences • Different regulatory environments • Intellectual property concerns • Post study requirements *(number of recruiting sites divided by country population in millions)

17. Fast growinghealthcare economy(annual rate of 15%), huge population, and large pool of well-educated, English-speaking medical professionals Benefits Well-qualified investigators and well-run sites Low cost (40-60% cheaper than US) and rapid implementation of trials Make-up of the patient population (genetic diversity) The regulatory environment Proven data quality India

18. Conclusion • Many countries are available/open for business • Trends in certain countries can vary (e.g. FDA – early feasibility programme) • Within Europe, lots of opportunities STILL exist • Ireland punches below its weight ? • What do we need to do to promote future investment in ClinicalTrials in Ireland? • Acknowledge FIM vs. pre-market vs. post-market • PATIENT ACCESS TO NEW TECHNOLOGIES • Serious of small steps – today is another step in the right direction

19. Thank You Enjoy today Questions ? Acknowledge – Tanja Lennon and Taragh Keily

20. Appendix

21. Europe - what is changing ? CURRENT SITUATION • Medical Devices Directive • Amendments via 2007/47/EC • Today: Proposed Revisions to the existing Directives WHAT MIGHT CHANGE ? • Introduces concept of ‘sponsor’ ? • New role of Member States in ensuring ethical reviews ? • Single application via the database for multi country investigations ? • Lead/ Co-ordinating CA appointed ? • Notification of Post Market Studies (if additional patient burden, interventional)?

22. EU clinical data requirements To support CE marking requirements, device must be • Safe • Perform as intended • Positive risk/benefit ratio • lower risk devices • relevant scientific literature to support the ER’s • combination of data - clinical investigations and relevant scientific literature. • higher risk devices • expectation is that CI is conducted unless it is duly justified to rely on existing clinical data

23. US clinical data requirements 2 phases – pilot/feasibility and pivotal studies Pilot/feasibility: • Establish safety • Assist in design of the pivotal trial • Generally less than 100 patients, small number of sites Pivotal: • Demonstrate that device is safe and effective • Prospective, randomized controlled study, high patient numbers / multiple sites For class III devices • Demonstrate reasonable safety and effectiveness • Premarket approval required to support device claims For class II devices • Increased demand for clinical data For both classes, if device is not exempt, IDE application is required