Author + information
- Received March 5, 2018
- Revision received May 3, 2018
- Accepted May 8, 2018
- Published online November 5, 2018.
- David R. Holmes Jr., MDa,∗ (, )
- Robert Hance, BS, MBAb,
- Tamara S. Syrek Jensen, JDc,
- Daniel A. Schwartz, BA, BSb,
- Aaron Kaplan, MDd,
- Andrew Farb, MDe,
- Bram Zuckerman, MDe,
- Martin Leon, MDf,
- Jamie Waklowiak, JDg,
- Michael J. Mack, MDg and
- Jeff Shuren, MDe
- aDepartment of Cardiology, Mayo Clinic, Rochester, Minnesota
- bMedical Device Innovation Consortium, Arlington, Virginia
- cCenters for Medicare & Medicaid Services, Baltimore, Maryland
- dLebanon Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
- eU.S. Food and Drug Administration, Silver Spring, Maryland
- fColumbia University Medical Center, New York, New York
- gBaylor Scott and White Health, Dallas, Texas
- ↵∗Address for correspondence:
Dr. David R. Holmes, Jr., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905.
Performance of early feasibility studies in the United States can advance the goal of evaluating the safety and effectiveness of new devices aimed at unmet clinical needs and facilitating earlier access for U.S. patients to new technology. Early feasibility studies are an important component of the 21st Century Cures Act, enacted by Congress in 2016. Although regulatory processes have improved since the introduction of the Early Feasibility Studies Program, impediments at the hospital and clinical site level remain. In this paper, the authors review these issues and outline the structure and function of a clinical site consortium designed to address the problems and improve the U.S. clinical trial ecosystem.
Enacted by Congress in 2016, the 21st Century Cures Act was designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently (1). The U.S. Food and Drug Administration (FDA) early feasibility study (EFS) guidance document is an important component of these efforts (2). FDA approval of an EFS investigational device exemption (IDE) allows early clinical device evaluation to provide proof of principle and initial clinical safety data as well as earlier access to potentially beneficial medical devices. The document streamlines the EFS approval process by identifying the information required by FDA support study initiation and allows reviewers to more broadly consider the underlying clinical condition, the current standards of care, and mitigation strategies to reduce patient risk. A key EFS principle is the application of “just-in-time testing,” which acknowledges that devices are often modified on the basis of the experience gained during initial clinical use, and it may be acceptable to defer some nonclinical testing until the device design has been finalized for use in a pivotal study. The enhanced interaction between the FDA and EFS sponsors facilitates the design of subsequent pivotal studies required for device approval.
Current Status of EFS
Since its implementation in 2013, the number of EFS IDEs received annually by FDA’s Center for Devices and Radiological Health increased from 33 during that first year to 47 in 2016, and the number approved annually by the Center for Devices and Radiological Health increased from 17 to 40 (Figure 1). From 2015 to 2017, cardiovascular devices accounted for 27.6% of EFS submissions, the majority of which were company sponsored (Figure 2).
To further assess the progress of the EFS Program, the Medical Device Innovation Consortium (3), a public-private partnership between the FDA and industry created to advance medical device regulatory science, obtained detailed administrative trial data from device sponsors for 13 EFS IDEs, representing 47 sites, from 2015 to 2017. These data represent 22.8% of all industry-sponsored IDEs submitted to the Center for Devices and Radiological Health during that time frame. Analysis of these submissions documents strengths as well as problems with the current EFS Program.
The time from IDE submission to FDA approval was ≤60 days for 9 of 13 submissions (69%), and the time from IDE approval to site Institutional Review Board (IRB) approval was ≤60 days at 26 of 47 sites (55%) (Figure 3). Although there was variability in timelines for some EFS submissions (with IDE and IRB approval requiring >120 days and 180 days in 2 submissions and at 4 sites, respectively), the times spent on FDA and IRB review and approval were favorable.
Although the EFS guidance document focused on streamlining the FDA regulatory process for initial approval of EFS IDEs, it did not address clinical site issues. Information from hospital sites documented major delays in study initiation (Figure 4). The mean time from receipt of the sponsor contract to site approval was 133 days. The time from site contract completion to first subject enrollment often required >180 days. Following both site IRB approval and contract signoff, the mean time to first subject enrollment at 35 of 50 sites was 202 days. These clinical site delays reduce the ability of the EFS Program to meet the objective of early patient access to medical devices and negatively affect the EFS process for all stakeholders (Table 1).
Major issues for EFS hospitals and sites (Table 2) include the contractual arrangements between the sponsor and trial site, including payment for services, resolution of intellectual property concerns, and legal indemnification for subject injury (4).
A crucial element is informed consent, relating to greater uncertainty regarding risks associated with novel devices. The FDA guidance document includes specific recommendations for informed consent to help communicate how an EFS differs from other types of investigations, that the risks and benefits of participating in an EFS may not be fully known, and the procedures included in the study to mitigate risks. Specific risk mitigation strategies include more frequent study monitoring and reporting to IRBs and the FDA than usually required for non-EFS trials and the ability to use the standard of care if the study device does not function as intended (2).
Additionally, EFS investigators themselves must be committed to the successful execution of the IDE, fully appreciate the unique aspects of the trial, and have access to the target patient population. Excellent hospital management and research staff support are required to execute these challenging trials and be responsible for complete, timely data acquisition.
Reimbursement for EFS
Centers for Medicare and Medicaid Services (CMS) beneficiaries often make up a substantial portion of patients enrolled in EFS, and CMS reimbursement is therefore extremely important (5,6). Generally, novel EFS devices are classified as experimental by CMS (category A); CMS may at their discretion, and consistent with their rules, cover reasonable and necessary costs associated with a category A device being studied in an EFS (but not the cost of the device itself). In contrast, for a category B device (nonexperimental or investigational), Medicare may cover the investigational device as well as the routine care and services. Importantly, as safety and effectiveness data are captured on the EFS device, the category can change from A to B (7,8).
The FDA, CMS, device companies, and hospital and site investigators are collaborating on an initiative to address the wider EFS ecosystem through the development of a pilot clinical site network consortium to develop and implement standardized processes by which site challenges such as delays in contract approval and patient enrollment could be addressed. Pilot clinical sites would commit to patient safety and high-quality clinical conduct and data capture and continual process improvement. The lessons learned could be expanded to a wider group of sites in an open environment.
Hospital Stakeholder Value
There may be considerable value to a clinical site from participation in an EFS consortium (Table 3). Identification as a facility conducting studies of novel devices has numerous advantages, including access to new devices, recognition as an institution participating in new therapies, and the prospect of increased patient referrals. Although the specific number of patients in any one EFS is typically small, a large number of patients may be referred as part of a “halo effect.” Although not all referrals will be candidates for a particular EFS, they may be amenable to clinical care and/or enrollment in other research studies being conducted at that institution. Other benefits include enhancement of staff profiles, leading to greater participation in professional organizations and increased academic productivity. A particularly important potential advantage is the development of more efficient internal processes of care associated with collaborative working relationships among legal departments for contractual issues, IRBs, and business units. A final hospital stakeholder value is a greater knowledge of regulatory requirements.
Industry Stakeholder Value
For sponsors, there will be a number of potential advantages associated with an EFS site consortium (Table 4). Because overseas migration of device testing requires resources for additional training in processes used outside of the United States, performing EFS in the United States would lower expenses and facilitate interactions between device engineers and investigators without the need for overseas travel. Implementation of more standardized processes would foster timely data gathering and event adjudication and enhance FDA interactions early in device development. Increased interaction with FDA and CMS could potentially facilitate the approval process of beneficial devices and allow more efficient use of data in subsequent studies to broaden indications for use. Identification of excellent efficient EFS centers would enhance industry efforts to select more optimal sites to evaluate specific devices.
It is necessary to demonstrate the potential advantages of the EFS pilot. Planned next steps include the following:
1. Identification of a small group of clinical sites (15 to 25) willing to work collaboratively to develop and implement best practices. This pilot EFS consortium will not be exclusionary but will require commitment to setting up standard operating procedures that additional institutions could adopt when perfected.
2. Development of a consortium steering committee, which will include representation from all the stakeholders in EFS.
3. Specific goals include the following:
a. Implementation of common IRB language, including a common consent form template that can be accepted and used by each hospital.
b. Agreement to consider using a common central IRB, which is a National Institutes of Health expectation for multisite studies.
c. Commitment that at the time of receipt of the initial sponsor contract, the EFS proposal would be submitted simultaneously to the legal department for contract execution and to the site IRB for review to reduce the total time to final study approval.
d. Development of a common patient advocacy template for education and communication with the patient and family about EFS concepts and benefit/risk considerations.
e. Development of an EFS-specific master services agreement to streamline sponsor-site clinical trial agreements negotiations by: i) prespecifying clinical trial agreement clauses that are known to be the most resource-intensive issues to negotiate, including indemnification, intellectual property, and subject injury; ii) allowing individual EFS trial negotiations to focus on the clinical and therapeutic indication through the use of abbreviated statements of work; and iii) identifying specific site attorneys and contracting personnel experienced and versed in EFS issues.
f. Interaction with CMS for discussions regarding coverage for category A versus B devices.
g. Agreement on goals for time lines from EFS IDE approval to patient enrollment.
The EFS initiative is an important component of the vision of the 21st Century Cures Act; it has already demonstrated success in several areas to help meet the goals of the initial evaluation of the safety and effectiveness of new devices aimed at unmet clinical needs and facilitating the access of U.S. patients to new technology. The EFS process continues to evolve as other hurdles to more widespread adoption are identified. The currently proposed EFS consortium pilot approach is aimed at addressing inefficiencies in the clinical trial ecosystem of trial sites and developing common strategies to optimize the approval process for potentially beneficial novel medical devices.
Drs. Shuren, Zuckerman, and Farb are employees of the U.S. Food and Drug Administration. Dr. Syrek Jensen is an employee of the Centers for Medicare and Medicaid Services. Mr. Schwartz and Mr. Hance are employees of the Medical Device Innovation Consortium. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- Centers for Medicare and Medicaid Services
- early feasibility study
- U.S. Food and Drug Administration
- investigational device exemption
- Institutional Review Board
- Received March 5, 2018.
- Revision received May 3, 2018.
- Accepted May 8, 2018.
- ↵U.S. Food and Drug Administration. 21st Century Cures Act. Available at: https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/21stCenturyCuresAct/default.htm. Accessed April 27, 2018.
- ↵U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. Investigational device exemptions (IDEs) for early feasibility medical device clinical studies, including certain first in human (FIH) studies: guidance for industry and Food and Drug Administration staff 2013. Available at: http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103.pdf. Accessed November 3, 2017.
- ↵Medical Device Innovation Consortium. Medical Device Innovation Consortium releases first-of-its-kind patient preference framework. May 13, 2015. Available at: http://www.meddeviceonline.com/doc/medical-device-innovation-consortium-releases-first-of-its-kind-patient-preference-framework-0001. Accessed November 3, 2017.
- Holmes D.R.,
- Califf R.,
- Farb A.,
- et al.
- ↵Centers for Medicare and Medicaid Services. Medicare coverage related to investigational device exemption (IDE) studies. Available at: https://www.cms.gov/Medicare/Coverage/IDE. Accessed November 3, 2017.
- ↵U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services. Medicare coverage of items and services in category A and B investigational device exemption (IDE) studies. MLN Matters: MM8921 2015. Available at: https://www.cms.gov/Medicare/Coverage/IDE/Downloads/MM8921.pdf. Accessed November 3, 2017.
- ↵U.S. Food and Drug Administration. Payer Communication Task Force. Available at: https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHInnovation/ucm456149.htm. Accessed November 3, 2017.
- ↵U.S. Department of Health and Human Services, Centers for Medicare and Medicaid Services, Food and Drug Administration. Program for parallel review of medical devices. Available at: https://www.federalregister.gov/documents/2016/10/24/2016-25659/program-for-parallel-review-of-medical-devices. Accessed November 3, 2017.