Benefits of US EFS: A Clinical Perspective Ron Waksman, MD, FACC,FSCAI Professor of Medicine, Georgetown University Director, Cardiovascular Research Advanced Education MedStar Heart Institute, Washington DC

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

Objectives Rational for new pathways within FDA for investigational new device evaluation for the US population FIM Trial Status EFS status What is still needed from FDA

Medical Device Innovation Meeting unmet clinical needs Improving diagnostic strategies and treatments Advantages for the device development process with US clinical studies (including FIH and early feasibility studies) of innovative devices Opportunity for close contact between developers and investigators Early access to promising novel technology Continuity of clinical investigations Safer More predictive More effective Less invasive More accurate Simpler to use

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 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

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 7

FDA response to the call for new pathways… Initiated a pilot Early Feasibility Study program on December 12 ,2011 Accepted 9 devices into this pilot program This pilot program will continue until May 8, 2013 for these 9 sponsors Success of this program, however, is to come http://www.gpo.gov/fdsys/pkg/FR-2012-03-06/html/2012-5311.htm

What is an EFS? Clinical investigation of a small number of subjects (generally fewer than 10 initial subjects) Device early in development, typically before the device design has been finalized, for a specific indication, e.g., Innovative device for a new or established intended use Marketed device for a novel clinical application Does not necessarily involve the first clinical use of a device Intended to provide proof of principle and initial clinical safety data

Purpose of Early Feasibility Studies To obtain initial insights into: the safety of the device-specific aspects of the procedure; whether the device can be successfully delivered, implanted or used; operator technique challenges with device use; human factors (e.g., difficulties in comprehending procedural steps); patient characteristics that may impact device performance (e.g., anatomical limitations); and therapeutic parameters (e.g., energy applied, sizing, dose released) associated with device use.

Key Principles of the EFS An EFS may be appropriate when: Nonclinical testing methods are not available or Adequate to provide the information needed to advance the developmental process; and Clinical experience is necessary. An EFS must be justified by an appropriate benefit/risk analysis and adequate human subject protection measures. FDA approval of an EFS IDE application may be based on less nonclinical data than would be expected for a traditional feasibility or a pivotal study.

Pros and Cons of EFS Pros Cons Enabling to start a clinical investigation early while the pre-clinical and bench data is on going Patient populations are very limited (~10) allows for iterations to progress during clinical testing Does not address: FIM trials in US Devices that have a lot of OUS clinical data Creating transparency, trust and open discussion with FDA Early assess to cutting edge device for the US patient population

MedStar Cardiovascular Research Network IST FIM Experience Therapeutic Device: Vascular Brachytherapy for renal denervation Evaluation Option 1: Outside the US Conduct safety animal study Submission protocol to local EC of collaborator Approval to start investigation within a short time period Advantage: Shorten time to study initiation Disadvantages: soliciting OUS investigators, foreign regulatory agency, language, etc Evaluation Option 2: US Submission IDE Approval to start investigation within 30 days (hopefully!!) Advantage: PI and patients from US Disadvantages: Time and costs of required application elements

What is still needed?

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 15

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 16

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 17

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 18

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 19

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 20