1. Regulatory Basics: Europe and the CE Mark
CRT 2011
Washington DC February 27th - March 1st,
Regulatory Basics:
Europe and the CE Mark
Eberhard Grube, MD, FACC, FSCAI
University Hospital, Dept. Medicine II, Bonn, Germany
Hospital Alemaõ Oswaldo Cruz, Saõ Paulo, Brazil
Stanford University, School of Medicine, Palo Alto, CA

2. Disclosure Statement of Financial Interest
Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below.
Physician Name Company/Relationship
Eberhard Grube, MD Medtronic, CoreValve: C, SB, AB, OF
Sadra Medical: E, C, SB, AB
Direct Flow: C, SB, AB
Mitralign: AB, SB, E
Boston Scientific: C, SB, AB
Biosensors: E, SB, C, AB
Cordis: AB
Abbott Vascular: AB
Capella: SB, C, AB
Embrella, SB
Claret, SB
Key
G – Grant and or Research Support E – Equity Interests S – Salary, AB – Advisory Board
C – Consulting fees, Honoraria R – Royalty Income I – Intellectual Property Rights
SB – Speaker’s Bureau O – Ownership OF – Other Financial Benefits‘ 2

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. Once a CE Mark is Received
The company is free to market the device in the EU
Reimbursement in the EU is a separate issue
Certain countries outside of EU also recognize the CE Mark
The CE Mark in and of itself 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 9

10. 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 10

11. New Medical Device Directive
A New Medical Device Directive in the EU took effect last 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 11

12. The CE Mark Creates Strategic Options
Begin to sell product in the EU to support development efforts and generate market 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 12

13. 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 13

14. Back-Up Slides 14

15. Strategic Options
Begin to sell product in the EU to support development efforts:
- CoreValve example (had reimbursement)
Built a Pan-European distributor network
Built sales rapidly
Revenue line built value for the company
Company was then able to support further progress on the device
Value was recognized by the market w/o USA piece
This model has become increasingly important, given delays in US approval (companies need to stay alive) 15

16. 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 16

17. 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 17