Adherence to the Labeling John Laschinger, M.D. Medical Officer FDA/CDRH/ODE/DCD/SHDB

I/we have no real or apparent conflicts of interest to report. John Laschinger, MD I/we have no real or apparent conflicts of interest to report.

Current On Label Indication for Use: SAPIEN THV SAPIEN is indicated for transfemoral delivery in patients with severe symptomatic calcified native aortic valve stenosis without severe aortic insufficiency and with ejection fraction > 20% who have been examined by a heart team including an experienced cardiac surgeon and a cardiologist and found to either be: in operable and in whom existing co-morbidities would not preclude the expected benefit from correction of the aortic stenosis; or be operative candidates for aortic valve replacement , but who have a Society of Thoracic Surgeons predicted operative risk score > 8% or are judged by the heart team to be at a 15% risk of mortality for surgical aortic valve replacement.

What is “On-label” Use FDA Device Clearance or Approval is limited to specific Indications for Use – 3 Components: Intended Use: What - What device is designed to do (e.g. Correction of aortic stenosis) Why – Clinical disease or condition (e.g. Critical AS) Conditions of Use Where, who, and how of insertion (e.g. Hybrid suite, heart team, transfemoral access, training, etc) Target Population Who – Target patient population (e.g., patient at high or extreme risk for surgery, symptomatic with no AI) Label Purpose: Provide information regarding results of evaluation Transmit applicable warnings and precautions for that indication Describe potential limitations of the evaluation (e.g., populations not included in studies) or potential performance problems under described circumstances or conditions

Why Off-label Use? FDA does not regulate the practice of Medicine Information provided in the labeling may or may not be applicable depending on how far “off-label” FDA recognizes other clinical needs/uses not covered by the label may exist Device has not been evaluated for the Indication New Intended use New or lower risk Target Population The focus of the pivotal trial was inadequate to support a specific marketing approval or clearance for all clinical situations New Conditions of Use within an approved target population Higher risk segment of an approved target population RCT Generally Needed Targets for Label Expansion

A Better Path: Label Expansion Encourages the collection of additional data needed for the expanded Indications RCT not always necessary Early interaction with FDA Common Goal: least burdensome path Sponsors – Ability to Market devices appropriately End-users - Provided with clinically relevant information Patient - Protection and Early Access

Current Initiatives in SHDB with Labeling Implications Clinical studies based on pre-operative risk stratification (e.g. PARTNER IIA, COAPT) Initiation of registries to capture real-world use - TVT Identify how devices are really used Capture “real world” performance information Acquire data necessary for expansion of label indications within approved populations Refine pre-clinical testing requirements to keep up with rapid evolution of devices and materials Encouraging pre-clinical testing outside of the proposed labeling to help understand potential issues with “off label” use (e.g. valve-in-valve)

Progress on Initiatives TVT Registry active at > 130 sites FDA has accepted the concept of using single arm study data to support label expansion for approved indications/populations FDA has approved ACCF/STS sponsored IDE study using data from real-world registries Alternate Access (non-femoral) in patients inoperable for surgical AVR TVT registry used for data collection Data from TVT registry used as comparator

John Laschinger, M.D. john.laschinge@fda.hhs.gov Thank You! John Laschinger, M.D. john.laschinge@fda.hhs.gov

On-label The pre-clinical evaluation was appropriate for the intended use Testing involved use of the device in accordance with the instructions for use (e.g., preconditioning, sizing) Clinical information included in the label reflects the intended use

Regulation and Off-label Use FDA regulates interstate commerce of medical devices, not the practice of medicine FDA encourages appropriate evaluation of devices to allow for modification of the labeling to protect and promote public health Manufacturers need to do what they can to limit known off-label usage Restrict distribution/promotion Modify labeling