Early Feasibility Studies for Device Evaluation ISCTR 2018 San Diego, CA September 21, 2018 Early Feasibility Studies for Device Evaluation 15 mins FRIDAY, SEPTEMBER 21, 2018, 9:20 AM San Diego Convention Center Room 30A-C, Upper Level Andrew Farb, MD Co-Leader of the Early Feasibility Studies Program Center for Devices and Radiological Health (CDRH) Food and Drug Administration andrew.farb@fda.hhs.gov

Disclosure Statement of Financial Interest I, Andrew Farb, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation

Purposes of Early Feasibility Studies safety whether the device performs its intended purpose therapeutic parameters device failure modes patient characteristics that may impact device performance 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) Early clinical experience Provides the basis for iteration & product improvement Integral to the device development process

Acknowledging Problems With Medical Device Innovation and Development in the US US was the 42nd nation to approve a TAVR device Migration of initial clinical testing of novel devices overseas Growing time lag in the access to beneficial medical devices for US patients Delay in physician experience with new products Concern that device innovation may follow overseas 1 to 2 decades problem Steep decline in the proportion of initial clinical studies of new devices being performed in the US. On 2004, 87% of clinical studies for medical technology products listed on ClinicalTrials.gov were conducted in the US, by 2009, that number dropped to 45% The US was 42nd country to approve the first TAVR device Many clinical trial ecosystem factors contributed to these trends including FDA’s requirements to initiate clinical studies of new devices in the US

We needed a guidance doc

EFS Guidance Scope Elements that define an EFS: Small number of subjects Device may be early in development and before the device design has been finalized Does not necessarily involve the first clinical use Needed when information to advance device development cannot be practically obtained with additional nonclinical assessments, or nonclinical tests are unavailable we needed an EFS definition Not all new devices or new uses, or first in human studies warrant an EFS One has gone as far as possible in the bench and in animal studies – further non-clinical testing will not add value

EFS Program Objectives Re-establish/increase US participation in the early clinical evaluation of innovative medical devices under the current IDE regulations Provide the earliest patient access to potentially beneficial medical devices in the US Enhance collaboration among device developers, industry, regulators, and investigators Protect study participants The program has defined objectives We sought to increase US EFS under current IDE regulations Change the ecosystem The IDE regulations provide enhanced Protection for study participants

EFS Guidance Key Guidance Principle – EFS IDE approval may be based on less nonclinical data than would be needed to support a larger clinical study of a more finalized device design Guidance Provisions – New ways for sponsors and regulators to justify and support transitioning from bench to bedside with an increased focus on: Clinical condition Availability, benefits, and risks of alternative treatments Risk mitigation strategies, enhanced monitoring, and a tailored consent process to enhance patient safety Foundational principle New ways of thinking

Just-In-Time Testing (JITT) Doing the Right Testing at the Right Time It may be acceptable to defer some nonclinical testing until the device design has been finalized for use in a pivotal study in a larger number of patients Comprehensive testing in early phases of device development may add cost without return Some tests have limited applicability if the device is modified Conducting non-informative testing delays device access to patients who may have limited alternatives Why can it be OK to accept less non-clinical testing?

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 tools to facilitate timely device and clinical protocol modifications: 5-day notices Contingent approval Interactive review Devices are not the same as drugs

Suggested EFS Pre-IDE Submission Timeline Goals Initial review team meeting Follow-up Review Team meeting Feedback to Sponsor Meeting with Sponsor Pre-Sub Supplements or IDE submission Within 2 weeks of receipt of Pre-Sub Pre-submission informational meetings can jumpstart interactions between sponsors and FDA reviews teams Within one month of receipt of Pre-Sub Within 45-55 days of receipt of Pre-Sub To re-establish US leadership in being a venue/destination for EFS, we need to be have nimble process and responsive regulatory timelines for pre-submission interactions with sponsors Within 60 days of receipt of Pre-Sub

Early Feasibility Study IDEs Finalized EFS Guidance document issued October 1, 2013 80% of EFS IDE submissions approved in 1 review cycle EFS IDEs Submitted Growing interest in US EFS from non-US sponsors EFS IDEs Approved US EFS used to support CE Mark Transition from US EFS to pivotal studies The number of EFS patients approved is 1628 for FY14 thru FY17. Through promotion of the EFS program (at mtgs like this), interest on the part of sponsors that see the value of performing studies in the US, and adoption of EFS principles by FDA staff, we’ve seen a progressive increase in the number of EFS IDEs submitted to CDRH over the past 4 fiscal years. And importantly, due to the involvement of the EFS rep and significant interactions that are held during the pre-subs, nearly 80% of EFS IDEs are approved or approved with conditions on the first round of FDA review. And those numbers increase after a second round of review. Transition to pivotal: Medtronic Harmony Transcatheter Pulmonary Valve System http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-newsArticle&ID=2345036 Intrepid Transcatheter Mitral Valve Replacement System http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irol-newsArticle&ID=2313389 Abbott Tendyne Mitral Valve System http://abbott.mediaroom.com/2018-07-26-Abbott-Begins-U-S-Pivotal-Trial-for-the-Tendyne-Mitral-Valve-Replacement-System-to-Treat-Patients-with-Heart-Valve-Disease

Complete Characteri-zation Value of Interactions and Application of Just-In-Time Testing (JITT) Principles Beyond EFS FDA Innovators & Investigators Sponsors First Generation EFS Traditional feasibility study (if needed) Finalized Design Pivotal IDE study Complete Characteri-zation PMA submission Familiarity with the technology and regulatory considerations throughout product development Consensus on data requirements to move forward from bench to clinical use Smoother transitions between types of clinical studies

Allows consideration of 510(k) products Highly interactive Established by the 21st Century Cures Act and supersedes the Expedited Access Pathway Accelerated pathway for devices that FDA finds could provide more effective treatments or diagnose life-threatening or irreversibly debilitating diseases or conditions, particularly those that address unmet needs Allows consideration of 510(k) products Highly interactive Sprint discussions to facilitate agreement between FDA and sponsors on product development topics within a set period of time Regular status update meetings The underlying benefits of the program remain essentially unchanged Expedited PMA program, even with the Cures Act reforms. The key elements are: Sponsors of devices with breakthrough designations will enjoy outsized collaboration with FDA reviewers and managers – starting from early-stage development and through marketing submission – including an emphasis on timely communication; FDA may accept more uncertainty about the benefit-risk profile for breakthrough devices, allowing approval with some data requirements shifted from the pre-market to post-market phase; An emphasis on flexible clinical study design, including surrogate endpoints and phased study designs; Priority-review designation once a marketing submission is made; and The potential for a PMA manufacturing facility inspection to be pushed until after product approval. With EAP, and now the Breakthrough Program, FDA stresses that the most important and potentially accelerating elements of the pathway are the early-stage collaborations between the agency and sponsor on the data development plan.

The EFS Program Within FDA Strategic Priorities Our Measure of Success: “By December 31, 2020, more than 50 percent of manufacturers of novel technologies for the U.S. market intend to bring their devices to the U.S. first or in parallel with other major markets.” https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHVisionandMission/UCM592693.pdf Mission: Patients in the U.S. have access to high-quality, safe, and effective medical devices of public health importance first in the world. CDRH Leadership Committed to the Success of the EFS Program

Building a Successful US EFS Ecosystem JACC 2016;68:1908-15 Gov’t: FDA and CMS Industry Sponsors Inventors/Innovators Investigators Clinical Sites Private Funders and Payers Study subjects IDE approval IRB approval Insurance coverage Contracting and indemnification Site start-up Patient enrolment Gratified with the progress of the program, but our outlook increasing extends beyond FDA

Addressing the Clinical Trial Ecosystem to Improve the Climate for US EFS Ongoing multi-stakeholder effort organized under the Medical Device Innovation Consortium (MDIC) Collaboratively develop and adopt best practices of study conduct Participants: Industry, FDA, CMS, clinical sites, investigators Working groups: Administrative and Clinical Practices Reimbursement Patient Advocacy Vision: A voluntary, open research network of clinical sites in a consortium that are committed to high quality, efficiently executed EFS

What’s Working Well FDA Approvals and Site IRB Reviews N=13 EFS MDIC Collected data from 13 EFS Company Sponsors on study and site performance. Data collected April-Sept 2017 from Studies performed in 2015/16/17 Slide courtesy of Chip Hance, TCT Conference 2017

Room for Improvement Site Contracting and Patient Enrollment Shift to the right MDIC Collected data from 13 EFS Company Sponsors on study and site performance. Data collected April-Sept 2017 from Studies performed in 2015/16/17 Slide courtesy of Chip Hance, TCT Conference 2017

Cardiovascular Devices EFS Pilot Pilot initiated, centrally administered by the MDIC (http://mdic.org/cts/efs/) >30 US clinical research sites interested in participating Agreement to test drive tools to increase efficiency of the EFS start-up process Master clinical trial agreement (MCTA) Informed consent document template Educational materials for IRBs, research staff, and study subjects Collection of de-identified EFS performance metrics for process improvement Public presentations of progress MCTA key topic areas IP protection Confidentiality Indemnification Insurance coverage 60/60 EFS goal: First 60 days for IRB and contract approval/Next 60 days to first patient enrolled

FDA’S Role in the US EFS Ecosystem The EFS Program is integral to FDA’s mission and has fostered a paradigm shift in performing early phase device studies in the US. FDA continues to facilitate interactions among stakeholders to address site start-up challenges. Improving the EFS ecosystem requires the commitment of industry, investigators, and clinical sites. FDA will be at the table to help facilitate interactions among stakeholders and find solutions to remaining challenges

Resources EFS Website: https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm572934.htm 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

CDRH Division EFS Contacts https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm572934.htm General inquiries: CDRH_EFS@fda.hhs.gov CDRH Review Group Email Address Division of Anesthesiology, General Hospital, Respiratory, Infection Control, and Dental Devices DAGRID_EFS@fda.hhs.gov Division of Cardiovascular Devices DCD_EFS@fda.hhs.gov Division of Ophthalmic and Ear, Nose, and Throat Devices DOED_EFS@fda.hhs.gov Division of Neurological and Physical Medicine Devices DNPMD_EFS@fda.hhs.gov Division of Orthopedic Devices DOD_EFS@fda.hhs.gov Division of Surgical Devices DSD_EFS@fda.hhs.gov Division of Reproductive, Gastro-Renal, and Urological Devices DRGUD_EFS@fda.hhs.gov Office of In Vitro Diagnostics and Radiological Health OIR_EFS@fda.hhs.gov