First-in-Man, First In The USA: What’s The Difference? Ron Waksman, MD, FACC, FSCAI Professor of Medicine, Georgetown University, Associate Chief of Cardiology, Washington Hospital Center, Washington DC

Ron Waksman, MD Consulting Fee Abbott Laboratories Biotronik, Inc. Boston Scientific Corporation Medtronic, Inc. Merck and Company, Inc.

Honoraria Abbott Laboratories Boston Scientific Corporation Medtronic, Inc. Consulting Fee Merck and Company, Inc.

What is First-In-Man Study? FIM is the culmination of the pre-clinical device development “ecosystem” A FIM trial tests the new device in humans for the first time Generally, these trials are small in size and in very select patient populations (eg: stable patients with de novo lesions, etc.) Bench Testing Animal Safety Testing Pre-clinical Animal Studies First-in-Man Clinical Trial

Status of FIM Trials in the US Although device innovation continues to emerge from the US the initiation of the device development has moved to non-US sites Why? FDA’s requirements can be an impediment to early clinical testing of new devices FIM trials need the same rigorous IDE application as a pivotal trial (average time to IDE approval is 14 months) The cost associated with obtaining an IDE are very high Implications! These new devices will either not become available to the US public or emerge into the US market much later than the rest of the global market FDA Impact on U.S. Medical Technology Innovation: A Survey of Over 200 Medical Technology Companies • November 2010 http://www.advamed.org/NR/rdonlyres/040E6C33-380B-4F6B-AB58-9AB1C0A7A3CF/0/makowerreportfinal.pdf 5

Status of FIM Trials in the US Average Time By Stage For PMA Product Average per month Expenditure By Stage For PMA Product FDA Impact on U.S. Medical Technology Innovation: A Survey of Over 200 Medical Technology Companies • November 2010 http://www.advamed.org/NR/rdonlyres/040E6C33-380B-4F6B-AB58-9AB1C0A7A3CF/0/makowerreportfinal.pdf 6

First-in-the-US Investigation What is it? A proposed track for devices already tested outside the US (with or without OUS approval) that established relatively safe profiles Investigations would be limited to up to 100 patients at no more than 5 experienced US centers 7

First-in-the-US Investigation Intended Users? This proposed track would be available only to sponsors that intend to complete an IDE submission for a pivotal trial or pursue an PMA 8

First-in-the-US Investigation Brief Requirements: Required to have prior human experience (minimum 100 patients) with at least 6 months follow up Minimum requirements to initiate this Investigation will be less than a traditional IDE Completion of current IDE requirements may be submitted throughout First-in-the-US Investigation 9

First-in-the-US Investigation Implication on Patients: US patients will have an opportunity to be a part of early novel device evaluation Patients will be fully informed of the potential additional risk involved in being a part of such early device investigations 10

First-in-the-US Investigation Implication on Sponsors: Motivate sponsors to return to the US for early clinical investigations Streamline the US human subject investigation into the pivotal trial Allow for streamlining US track milestones to be reached (eg first patient in US, entering US market) Allows for data combination from both this track and pivotal trials for the PMA application 11

First-in-the-US Investigation Implication on Agency: The agency would gain earlier insight into the feasibility and safety of devices in the US population Utilized these data to help better design the pivotal trials 12

What’s Available Now from FDA

What’s Available Now from FDA Early feasibility study (NEW!) limited clinical investigation of a device early in development may be used to evaluate the device design concept with respect to basic safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) when this information cannot be readily provided through additional nonclinical assessments or appropriate nonclinical tests are unavailable. Information obtained from an early feasibility study may guide device modifications. An early feasibility study does not necessarily involve the first clinical use of a device. First in human (FIH) study study in which a device for a specific indication is evaluated for the first time in human subjects. This document only discusses FIH studies that meet the definition of an early feasibility study. Traditional feasibility study clinical investigation that captures preliminary safety and effectiveness information on a near-final or final device design to adequately plan an appropriate pivotal study. Pivotal study clinical investigation designed to collect definitive evidence of the safety and effectiveness of a device for a specified intended use. It may or may not be preceded by an early and/or a traditional feasibility study. 14