Global Regulatory Affairs US vs. EU

1. Global Regulatory AffairsUS vs. EU Nariko Koto, MBA Global Regulatory/Business Consultants, LLC January 13, 2014 For French Chamber of Commerce

2. Nariko Koto Bio • 15 years experience in the medical device, biologics and pharmaceutical industries • Worked at Medtronic, Johnson & Johnson, 3M and AGA Medical (now part of St. Jude Medical) • Formed Global Regulatory/Business Consultants LLC • Responsibilities: Global Regulatory, Quality, Clinical and Business Development including CRO and clinical site management to perform quality of clinical studies and distributor/supplier management to receive approvals/clearances and deliver quality products throughout the world • Developing global QA, RA and clinical strategies and dealing directly with global government authorities including US FDA, EU, Middle East, Africa (EMEA), Health Canada, Japanese PMDA, China, India, Korea, Singapore, Thailand and other international locations in numerous devices, biologics and combination devices for various therapeutic areas • Ensuring regulatory/clinical/quality compliance with FDA, Health Canada, MDD, 93/42/EEC, MEDDEV, JPAL, ISO 9001, ISO 13485/EN 46001, ISO14155, ISO14971 Risk Management, and applicable standards to determine filing or notification requirements • Provided presentations at RAPS, Infection Control, NASPE, etc. • Living and working in the US, the Netherlands, the UK and Japan. Traveled to over 40 countries. Speaks several languages including English, Japanese, French, some German, Chinese and Russian.

3. Why do you need FDA approvals to market products? • “TheFood and Drug Administration (FDA or USFDA) is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments. The FDA is responsible for protecting and promoting public health through the regulationand supervision of food safety, tobacco products, dietary supplements, prescription and over-the counter pharmaceutical drugs (medications), vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation, cosmetics, emitting devices (ERED), and veterinary products.” • http://en.wikipedia.org/wiki/Food_and_Drug_Administration

4. FDA Medical DeviceSubmission and Approval System Medical Device Classifications • CLASS I • Simple design, low risk • Most exempt from premarket submission exempt from premarket submission • CLASS II • More complex, higher risk • Premarket Notification [510(k)] - Substantial Equivalence (SE) to a predicate device (currently on U.S. market) • CLASS III • Most complex, highest risk • Premarket Application [PMA] - Device is reasonably safe and effective for its intended use; Contain valid scientific evidence and provide reasonable assurance • HDE - Additional Classification • Devices for orphan diseases intended to benefit patients in diagnosis and/or treatment of disease or condition affecting or manifested in fewer than 4,000 patients per year in the United States . (Approval based on safety & probable benefit)

5. FDA – Clinical Study PhasesDevice/Biologics Device and Biologics • First in human (FIH) study Aspecific indication is evaluated for the first time in human subjects • Early feasibility study Initial clinical safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) • Traditional feasibility study To capture preliminary safety and effectiveness information • Pivotal study Aclinical investigation designed to collect definitive evidence of the safety and effectiveness of a device for a specified intended use, typically in a statistically justified number of subjects

6. FDA – Clinical Study PhasesDrugs • Phase I: Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. (15 – 30 volunteers) • Phase II: The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety. (Fewer than 100 volunteers) • Phase III: The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. (100s – 1000s of volunteers) • Phase IV: Studies are done after the drug or treatment has been marketed to gather information on the drug's effect in various populations and any side effects associated with long-term use. (After approval)

7. EU Submission and Approval System • CE Mark for devices vs. Medicines Agency for drugs (Biologics must be decided based on the historic background) • CE Mark – classifications • Class I - This group covers low-risk devices and the conformity assessment procedures are carried out by the manufacturer. Examples of this type of classification include devices that do not penetrate the body such as bandages, hospital beds, sterilization packaging and dental mirrors. There is no need for a Notified Body for class I devices. • Class IIa- In most cases, the intervention of a Notified Body is compulsory at the production stage for class IIadevices. Examples include anesthetic gas masks, acupuncture needles, oxygen masks and spirometer peak flow meters. • Class IIb- In this class, inspection by a Notified Body is required with regard to the design and manufacture of the device. Examples of this type of classification include anesthesia gas machines, hyperbaric chambers and respiratory monitors. • Class III - This group covers the most critical devices for which explicit authorization with regard to conformity is required before commercialization. Examples include artificial hearts, pacemaker batteries and bone grafts.

8. US Study vs. European Study 21 CFR 812, 50, 54, 56 ISO 14155:2011

9. Common Clinical/Regulatory Practices for High Risk Devices and Biologics US EU CE Mark Literature approach with minimum indication Bring 10 pts feasibility study results to various global conferences Share annual report and interim publications, as well as the completed study results • Feasibility Study – 10 pts • Minimum indication • Preparation for Pivotal Study • Identify Endpoints • Pivotal study • US submission (Modular) Submit clinical section upon the Pivotal study completion

10. New FDA Guidance • New feasibility IDE guidance and FDA Teleconferences • FDA emphasizes early product development and willingness to work with sponsors in the US • May recommend small feasibility study if the assumption (it is a device) is correct

11. New EU Medical Device Reform Measures Background: A series of high-profile scandals and device failures, including deficient breast implants and faulty metal-on-metal hip implants. Oct 22,2013: The European Parliament approved compromise legislation for medical devices and in-vitro diagnostics: • "The proposed legislation seeks to improve transparency of information for patients and medical staff and to strengthen traceability rules, without creating additional burdens for innovative small manufacturers,“ • To "reinforce" public access to clinical trials data • The creation of an "implant card" system to allow patients to know which products are inside them • New CE marking requirements to permit only qualified experts to mark devices, new safety rules for IVDs that will require the approval of an ethics board, and new liabilities for device reprocessors. Next step: Parliament to negotiate a package with Europe’s other legislative body, the Council, but some are questioning whether more progress can be made before 2014 elections. Resources: Medical Device Today; and Regulatory Focus

12. Challenges, Opportunities andFuture with France • Challenges • Language barriers • Differences in systems and practices • Cultural • Opportunities and Future • to fill the current gap between the US and the EU • Adopt the new EU Medical Device Reform Measures faster than other EU nations

13. Merci!