1. 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

2. 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

3. 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

4. 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

5. We needed a guidance doc

6. 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

7. 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

8. 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

9. 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?

10. 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

11. 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 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

12. 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
Intrepid Transcatheter Mitral Valve Replacement System
Abbott Tendyne Mitral Valve System

13. 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

14. 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.

15. 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.”
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

16. Building a Successful US EFS Ecosystem
JACC 2016;68:
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

17. 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

18. 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

19. 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

20. Cardiovascular Devices EFS Pilot
Pilot initiated, centrally administered by the MDIC (
>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

21. 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

22. Resources
EFS Website:
EFS Guidance document:
Pre-Submission Guidance:
EFS CDRH Learn modules:
FDA Categorization of Investigational IDE Devices Draft Guidance document:

23. CDRH Division EFS Contacts
General inquiries:
CDRH Review Group
Address
Division of Anesthesiology, General Hospital, Respiratory, Infection Control, and Dental Devices
Division of Cardiovascular Devices
Division of Ophthalmic and Ear, Nose, and Throat Devices
Division of Neurological and Physical Medicine Devices
Division of Orthopedic Devices
Division of Surgical Devices
Division of Reproductive, Gastro-Renal, and Urological Devices
Office of In Vitro Diagnostics and Radiological Health