1. 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

2. 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.

3. 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

4. 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

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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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