The State of Early Feasibility Studies in the US FDA Town Hall CRT 2017 Washington, DC February 21, 2017 The State of Early Feasibility Studies in the US Tuesday, February 21 Palladian Ballroom 8:30 AM - 8:37 AM 7 mins Andrew Farb, MD Clinical Consultant to the Early Feasibility Studies Program Center for Devices and Radiological Health (CDRH) Food and Drug Administration andrew.farb@fda.hhs.gov

Conflict of Interest No conflicts of interest to report

Early Feasibility Study (EFS) Program Intent - To facilitate US EFS under the IDE regulations Scope - Elements that define an EFS: Small number of subjects Device that may be early in development, typically before the device design has been finalized Does not necessarily involve the first clinical use of a device Needed when information to advance device development cannot be practically obtained with additional nonclinical assessments, or if nonclinical tests are unavailable Not all new devices or new uses, or first in human studies warrant an EFS! A US EFS may be done concurrently or in conjunction with non-US clinical studies

Purpose of Early Feasibility Studies safety whether the device performs its intended purpose therapeutic parameters device failure modes patient characteristics that may impact device performance other human factors operator technique challenges OBTAIN INSIGHTS There are many potential objectives in conducting an early feasibility study. For example, an early feasibility study can provide important initial insights into device safety parameters, mechanisms of device failure, patient characteristics that may impact device performance, and whether the device performs as intended (that is, proof of concept)

EFS Program Objectives Provide the earliest patient access to potentially beneficial medical devices in the US Maintain or regain US leadership in medical device innovation Encourage close collaboration between developers and users Provide clinical study continuity throughout: Early clinical use Pivotal studies US approval Post-approval

EFS Guidance Key Guidance Principle - IDE approval of an EFS may be based on less nonclinical data than would be needed to support the initiation of a larger clinical study of a more finalized device design Guidance Provisions - A toolkit that enables sponsors and regulators to think in new ways about device development Emphasizing Clinical condition Availability, benefits , and risks of alternative treatments Incorporating risk mitigation strategies, enhanced monitoring, and tailored consent process to enhance patient safety Justifying the appropriate evidence needed to move from bench to clinical study Document issued on Oct 1, 2013

Just-In-Time Testing (JITT) Doing the Right Testing at the Right Time Comprehensive testing in early phases of device development may add cost without return Testing could have limited future applicability if the device is modified Time-consuming, non-informative testing delays device access to patients who may have limited alternatives It may be acceptable to defer some nonclinical testing until the device design has been finalized for use in a pivotal study Key principle

Device Iteration During an EFS Experience and knowledge gained from initial study subjects can guide device or protocol changes Rounds of regulatory submissions and review can delay the implementation of changes and impede study progress Clinical success or failure Device or clinical protocol change Nonclinical testing The EFS Guidance includes new approaches to facilitate timely device and clinical protocol modifications during an early feasibility study 5-day notices Contingent approval Interactive review

Suggested CDRH Pre-Submission Timeline Initial team meeting Within 2 weeks Team review meeting Within one month Feedback to Sponsor Meeting with Sponsor Within 45 days of receipt of Pre-Sub Appreciate the importance of time. Here the overview of the time-line, and you can see that it is aggressive, and should be competitive with regulatory review outside the US

Suggested CDRH Pre-Submission Timeline Initial team meeting Within 2 weeks Team review meeting Within one month Feedback to Sponsor Meeting with Sponsor Within 45 days of receipt of Pre-Sub Here the overview of the tine-line, and you can see that it is aggressive, and should be competitive with regulatory review outside the US Within 60 days of receipt of Pre-Sub

Progress CDRH Office of Device Evaluation 2-fold increase Notable EFS IDE approvals in Structural Heart and Peripheral Devices Branches

Ongoing EFS Program Efforts Within FDA Publication of additional EFS CDRH Learn Modules Working group recommendations on EFS cross-cutting non-clinical basic safety testing to facilitate IDE approval Animal testing Biocompatibility Sterility Collaboration with CEDR on combination products Interaction with CMS regarding coverage for EFS

Category A vs. Category B Devices Device categories to assist CMS in coverage decisions has been an area of some uncertainty, and we are hopeful that this guidance along with continued interactions between FDA & CMS with improve coverage predictability Issued on June 1, 2016

Addressing the Clinical Trial Ecosystem to Improve the Climate for US EFS Multi-stakeholder effort organized under the Medical Device Innovation Consortium (MDIC) Industry, FDA, CMS, clinical sites, investigators Steering committee: David Holmes, Michael Mack, Marty Leon, Bram Zuckerman, and Jeff Shuren 3 working groups Administrative and Clinical Practices Reimbursement Patient Advocacy

Administrative and Clinical Practices Working Group Vision: Identify EFS administrative and clinical metrics and best practices to facilitate EFS initiation and execution in the U.S. Vision: Identify EFS administrative and clinical metrics and best practices to facilitate EFS initiation and execution in the U.S.

Working Group Goals and Objectives EFS Sponsor/Site survey: Administrative and clinical performance metrics Catalogue EFS performance metrics (2015-2016) Establish EFS best practices: Administrative, contracting, and clinical Enable identification of individual or networked sites specializing in EFS Publish EFS best practice tools and processes Develop an annual reporting process for publicly communicating EFS performance metric updates

Performance Metrics & Learnings: Anonymization to Disclosure Confidential EFS Metric Discussions* (CDA/NDA, if required) Public-Facing Outputs and Reporting‡ EFS Performance Metric Collection EFS site or sponsor completes Performance Metric Intake form Return Intake form to MDIC Performance Metric Anonymization De-identify EFS performance metrics Aggregate into Performance Metric Catalogue Bucket metrics by CDRH division Performance Metric Dissemination Inform WG of Metric Catalogue updates WG review of performance trends Identify & distribute EFS Performance Metric goals EFS Learnings Discussions MDIC collects EFS narratives (phone) Review Clinical and Administrative successes Identify improvement opportunities EFS Learnings Anonymization De-identify site or sponsor narratives Generalize to highlight EFS wins and improvement opportunities EFS Learnings Dissemination Ascertain clinical & administrative best practices Develop EFS Regulatory Science tool & process *2 – 6 hours per site or sponsor estimated ‡1 – 2 hours per monthly EFS WG Meeting Slide courtesy of Dan Schwartz

Administrative and Clinical Practices Working Group Leadership Co-Chair (MDIC Board Champion): Chip Hance, MBA Co-Chair (FDA): Andrew Farb, MD Co-Chair (Dartmouth): Aaron Kaplan, MD Project Manager (Dartmouth): Shawn Ahmad, MD Project Manager (MDIC): Dan Schwartz, MS WG Steering Committee (FDA): Owen Faris , PhD

Toward the Next Horizon Propelling the US EFS Forward Beyond FDA Addressing Barriers in the Clinical Trials Ecosystem

Back-up slides

Coverage Categorization of IDE Devices 42 CFR 405.201(b) FDA assigns the category based on whether initial questions of safety and effectiveness have been resolved Category A (Experimental) device A device for which “absolute risk” of the device type has not been established, that is: Initial questions of safety and effectiveness have not been resolved; or FDA is unsure whether the device type can be safe and effective. Category B (Nonexperimental/investigational) device A device for which the “incremental risk” is the primary risk in question and: Initial questions of safety and effectiveness of that device type have been resolved; or It is known that the device type can be safe and effective (e.g., that device type has obtained FDA premarket approval or clearance)

IDE Device Categorization Category A: Generally for feasibility studies of novel technology Category B: Generally for less novel technology or pivotal studies (i.e., feasibility has been established) Previously, could not transition from Category A to Category B New policy (draft): Transition from A to B possible as safety and effectiveness data are collected, for example: From Category A EFS to Category B pivotal trial During staged approval

Practical Implications for EFS Coverage Limitations Category A CMS may cover reasonable and necessary study-related costs but not the cost of the device itself Category B CMS may cover all or none of the study-related costs (including the device) depending on whether the study meets CMS’ criteria for coverage Practical Implications for EFS An EFS for a Category A device that CMS covers will likely proceed if the device cost can be borne by the sponsor If an EFS device is Category B, it may be difficult to obtain coverage due to the small study size, but it may be possible to negotiate a plan with CMS to pool data from other studies to meet CMS’ criteria Paying for the device can be challenging for some sponsor-investigators

Resources EFS Guidance document: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM279103.pdf2 Pre-Submission Guidance: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM311176.pdf EFS CDRH Learn modules: http://www.fda.gov/Training/CDRHLearn/ FDA Categorization of Investigational IDE Devices Draft Guidance document: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm504091.pdf