OUS Data: What does the CE Mark Really Mean? CRT 2010 Washington DC, January 21, 2010 OUS Data: What does the CE Mark Really Mean? Eberhard Grube, MD, FACC, FSCAI St.Elisabeth Hospital, Essen, Germany, Heart Center Rhein Ruhr Instituto Cardiologico Dante Pazzanese, São Paulo, Brazil

Eberhard Grube, MD DISCLOSURES Consulting Fees Honoraria Abbott Vascular, Boston Scientific Corporation, Cordis, a Johnson & Johnson Company, Medtronic CardioVascular, Inc. Honoraria Biosensors International , Boston Scientific Corporation, Medtronic CardioVascular, Inc Ownership Interest (Stocks, Stock Options or Other Ownership Interest) Biosensors International , Medtronic CardioVascular, Inc. I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation. I intend to reference off-label use of stents and valve prosthesis.

What does the CE Mark Mean? The CE Mark means a medical device is in compliance with Essential Requirements of European Directives 93/42/EEC and 90/385/EEC Compliance with these requirements ensures a high degree of: Health protection Performance Safety ……for patients and users. 3

What does the CE Mark Mean? In the EU, the CE Mark is focused more on Safety Reimbursement of the device in specific countries is focused more on effectiveness Therefore, patients have potential access to a device once it is deemed safe, but the government will not pay for it until it is deemed clinically effective and in many cases cost-effective as well. 4

CE Mark: Who are the Players? Manufacturer Notified Bodies Competent Authorities 5

CE Marking Responsibilities Manufacturer: Placing a product on the market Fulfilling relevant legal requirements Tracking the product on the market Notifying Competent Authorities in Member States when incidents occur 6

CE Marking Responsibilities Notified Bodies: Independent auditing of manufacturer Certification of the quality system at the manufacturer Certification of specific products There are notified bodies in all member states 7

CE Marking Responsibilities Competent Authorities: Ensure requirements of the Medical Device Directive are carried out in the Member State (country) Oversee the notified body Ensure adverse incidents are reported appropriately Manufacturers must register with the competent authority in their country and specify the devices they market 8

EU Class III Requirements For Class III: Medical devices in heart or central nervous system, Combo Products, etc. Clinical Investigation approved by Competent Authority of Member State Certification for Full Quality System of manufacturer by Notified Body (NB) Type test of medical device for Essential Requirements by NB Review Design Dossier, pre-market inspection by NB, then Approval of CE marking 9

Once a CE Mark is Received The company is free to market the device in the EU Certain countries outside of EU also recognize the CE Mark The CE Mark in and of itself does may not help with approval in the US/Japan, but a positive track record in the EU may have a positive influence, and a negative track record can hurt you Provides additional strategic options to support a US submission 10

The CE Mark Creates Strategic Options Begin to sell product in the EU to support development efforts and generate track record (may need reimbursement in key countries) CoreValve example Edwards example Use the CE Mark to start a pilot trial in the EU, to support an IDE submission for pivotal in the US EU clinical sites can be leveraged to support enrollment in a US pivotal trial 11

Strategic Options Begin to sell product in the EU to support the development efforts: - CoreValve example (had reimbursement) Built a Pan-European distributor network Built sales from 0 to ________ in ____ months Revenue line built value for the company Company was then able to support progress on the device Value was recognized by the market w/o USA piece 12

Strategic Options Begin to sell product in the EU to support development efforts: Edwards example (had reimbursement) Built a network of distributors and direct sales Built strong sales in Europe that built a positive clinical track record Sales and positive clinical track record helped support significant investment in US pivotal trial Company was also then able to support significant progress on device development 13

EU Clinical Data- for US Requirements: EU Clinical investigations to be performed in accordance with EN ISO 14155 Clinical Investigations of Medical Devices for Human Subject Clinical Investigations to be performed in accordance with ICH Good Clinical Practice (GCP) Guidelines ICH GCP compliant clinical investigations are also required by FDA under IDE Essentially, the clinical data requirements are the same in the US and EU 14

OUS Clinical Data- For U.S. KEY to Success: Obtain early clinical and regulatory feedback from FDA in a Pre-IDE meeting including: Bench testing, preclinical testing and clinical testing requirements for IDE European and U.S. Clinical Development Plan- FIM, Safety and Benefit, Safety and Efficacy (Pivotal) Clinical site list – have they supported a US trial before? Identification of threshold for cases performed outside the US…. 30% ? 40% ? 50%? 15

OUS Clinical Data- For U.S. KEY to Success: Obtain early clinical and regulatory feedback from FDA in a Pre-IDE meeting including: Specific Clinical Protocols (OUS, US, Global) Clinical Trial Design: RCT versus Registry Endpoints: Safety and Efficacy Testing and Follow-up requirements Statistical plan Data/Safety Monitoring & CEC adjudication 16

What the Future Holds A New Medical Device Directive in the EU takes effect on March 21 A more unified approach among notified bodies CE Mark for certain devices could become more difficult More clinical trials will be required prior to CE Mark This will have to be taken into account when thinking of the CE Mark as leverage for US submissions 17

Summary The CE Mark provides assurance that a device complies with regulations, holds a certain level of quality and is SAFE. The CE Mark can allow the initiation of sales in the EU, that when coupled with reimbursement can support further development efforts The CE Mark can allow the initiation of trials in the EU to generate clinical data to support a US submission Clinical data collection standards are similar in the US and EU Any effort to use EU data for a US submission should be discussed with the FDA 18