Author + information
- Received September 6, 2016
- Accepted September 11, 2016
- Published online December 1, 2016.
- Matthew Hillebrenner, MSEa,∗ (, )
- Bram Zuckerman, MDa,
- Mona Fiuzat, PharmDb,
- Norman Stockbridge, MD, PhDc and
- Robert Califf, MDb
- aCenter for Devices and Radiological Health, U.S. Food and Drug Administration, Silver Spring, Maryland
- bOffice of the Commissioner, U.S. Food and Drug Administration, Silver, Spring, Maryland
- cCenter for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver, Spring, Maryland
- ↵∗Reprint requests and correspondence:
Matthew Hillebrenner, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, White Oak 66, Silver Spring, Maryland 20933.
Regulatory decisions to approve or deny marketing applications for new drugs and devices for heart failure (HF) care often garner significant publicity and highlight the impact of the U.S. Food and Drug Administration (FDA) on HF care. However, there are a number of other activities and discussions occurring throughout the year that are also critical to the health of patients with HF. These activities involve scientific interchange about new product development and post-marketing assessment of risks and benefits. The influence of the FDA’s scientific expertise in the device ecosystem may raise awareness or affect disease burden and the future of patient health in this disease area. We aim to summarize recent regulatory activities that we deem important in this field. This commentary, which is focused on initiatives that have an impact on the regulation of HF devices, will be the first of a series of papers highlighting a specific area of FDA activity.
A major focus for the FDA in the recent era has been to provide more timely access to safe and effective devices, as reflected in the vision statement of the Center for Devices and Radiological Health (CDRH): “Patients in the United States have access to high-quality, safe, and effective medical devices of public health importance first in the world.” Over the past several years, CDRH issued strategic priorities specifically targeted at developing ways to achieve this vision, many of which are outlined in this summary.
Strengthen the Clinical Trials Enterprise
CDRH is committed to improving U.S. patient access to new devices by strengthening and streamlining the clinical trial enterprise so that medical device clinical trials are conducted in the United States in an efficient and cost-effective manner, while maintaining appropriate protections for patients who participate in clinical trials. In support of this effort, we established the pre-market Clinical Trials Program responsible for the oversight and performance of the Investigational Device Exemption (IDE) Program and the development and implementation of policies that contribute to the timely initiation and successful execution of medical device clinical trials. CDRH has also been an active participant in public-private partnerships, such as the Medical Device Innovation Consortium and Clinical Trials Transformation Initiative. Such partnerships have the potential to improve the efficiency of the clinical study process, leading to earlier access to beneficial innovative technologies for U.S. patients and more rapid and definitive determination of risks.
Achieving this goal has been a challenge, as we need to focus on maintaining an appropriate balance between timely IDE approvals while also ensuring adequate protection for patients who will be enrolled in the trials. CDRH staff have worked closely with IDE sponsors to improve the efficiency of the program through effective utilization of the pre-submission process, increased use of interactive review, and enhancing the quality of the IDE submissions themselves. It is worth noting that we have already seen a substantial impact due to these efforts:
• by June 30, 2015, CDRH reduced the number of IDEs requiring more than 2 cycles to reach an appropriate full approval decision by 53% compared with performance in fiscal year 2013; and
• by June 30, 2015, CDRH reduced the overall median time to full appropriate IDE approval to 30 days, compared with 174 days in fiscal year 2013.
Despite this success, there are still situations in which a disapproval decision is appropriate. In those cases, CDRH has committed to meeting with the IDE sponsor within 10 days to clarify the reasons for disapproval and establish an open line of communication to resolve concerns.
Another critical component of this initiative is the Early Feasibility Study (EFS) Program (1), which allows for early clinical evaluation of devices to provide proof of principle and initial clinical safety data. These studies may be appropriate early in device development when clinical experience is necessary because nonclinical testing methods are not available or adequate. As with all clinical studies, the initiation of an EFS must be justified by an appropriate benefit-risk analysis and adequate human subject protection.
The response of the ecosystem to the EFS approach has succeeded in increasing the number of early-feasibility IDE studies submitted to the FDA and conducted in the United States since the program’s inception, an achievement that has had a direct impact on HF patients. Between October 2014 and June 2016, there have been 11 EFS approved for devices to treat HF patients with varying etiologies of disease, including functional mitral regurgitation, acute decompensated HF, and chronic congestive HF requiring circulatory support, thereby providing a pathway for device innovation for a patient population with limited treatment options.
Strike the Right Balance Between Pre-Market and Post-Market Data Collection
A second key determinant of early U.S. patient access to high-quality, safe, and effective devices is how much pre-market data must be provided to the FDA. One step CDRH took to clarify this question was to conduct a retrospective review of certain device types requiring pre-market approval (PMA) to determine whether or not to shift some pre-market data requirements to the post-market setting or down-classify device types in light of our current understanding of the technology. Between June 2014 and December 2015, we completed more than 275 of these assessments, resulting in a shifting of data requirements and/or a recommendation to down-classify a device type for about 30% of the products.
It is equally important to consider increasing data requirements when appropriate, as exemplified by the Agency's regulation of automatic external defibrillators (AEDs) (2,3). Historically, manufacturers of AEDs were able to bring new devices to market in the United States through the pre-market notification, or 510(k), pathway. AEDs can be highly effective in saving lives when used in the first few minutes following collapse from cardiac arrest. However, the FDA received approximately 72,000 medical device reports associated with the failure of these devices between January 2005 and September 2014. In addition, manufacturers conducted 111 recalls from 2005 to 2015, affecting more than 2 million AEDs. The problems associated with many of these recalls and reports included design and manufacturing issues, such as inadequate control of components purchased from other suppliers. As a result, the FDA is now requiring manufacturers to obtain pre-market approval for future and currently marketed AEDs and AED accessories (e.g., pad electrodes, batteries, adapters, and hardware keys for pediatric use). In contrast to the 510(k) pathway, the PMA process allows the FDA to review quality systems and manufacturing information; conduct pre-approval inspections; review changes in manufacturing facilities; review design and manufacturing changes that affect safety and effectiveness; and review annual reports on device performance. The FDA believes these actions will help address problems that have been of concern for AEDs and aid in achieving the appropriate balance in pre-market and post-market data requirements for this device type.
We also established the Expedited Access Pathway (4) for certain medical devices that demonstrate the potential to address unmet needs for life-threatening or irreversibly debilitating diseases or conditions (“breakthrough devices”) and are subject to PMA or are eligible for de novo requests. In some cases, patients may be willing to assume greater risk for earlier access to a medical device. This may be particularly true for patients with conditions for which no treatments exist or who face serious or life-threatening conditions. The FDA must ensure that if access to medical devices is expedited, the Agency is reasonably assured the device is safe and effective. Reducing pre-market data requirements while increasing post-market requirements for devices subject to a PMA, when appropriate, can assist the FDA in making medical devices available to patients sooner than the traditional pre-market review pathway.
One important facet of the Expedited Access Pathway program that may be directly applicable to HF trials is the role that intermediate or reasonably likely surrogate endpoints can play in terms of trial design and establishing a viable regulatory pathway for new devices (5,6). The FDA may, as a basis for PMA approval, rely on assessments of a device’s effect on an intermediate or surrogate endpoint that is reasonably likely to predict clinical benefit—on the condition that remaining uncertainty about the predictive relationship between a surrogate and clinical benefit is minimized through confirmatory post-approval studies or that clinical benefit is verified through such studies. For example, initial regulatory approval could be based on the demonstration of benefit in intermediate endpoints such as a patient’s health status, ability to function, or quality of life, as well as other relevant biomarkers, which may allow for smaller trials or shorter follow-up, and thus permit earlier access to patients in need of new treatment options. This expedited approval would then need to be balanced by additional post-market data demonstrating an effect on clinical outcomes such as morbidity or mortality.
Although the Expedited Access Pathway is relatively new, we have seen several early successes. From May 2015 to May 2016, CDRH accepted 17 devices into the program (7), including a number of HF devices with the hope that this will facilitate innovation in such an important area for patients and public health.
Establish a National Evaluation System for Health Technology
A national evaluation system for health technology that leverages real-world evidence can help us more efficiently strike the right balance between pre-market and post-market data collection to facilitate patient device access and more quickly identify safety signals by ensuring timely and robust data collection (8). The necessary infrastructure for such a system would need to be put in place and would require collaboration among the various stakeholder communities in the medical device ecosystem. We have established a goal of gaining access to 100 million electronic patient records with device identification by December 31, 2017, and to increase by 100% the number of pre-market and post-market regulatory decisions that leverage real-world evidence in the same time frame.
Whereas a national evaluation system remains a work in progress, CDRH staff have continued to participate in a number of important projects that will lead to an increase in leveraging real-world evidence in regulatory decisions. In the cardiovascular space, we have been intimately involved in the development and maintenance of the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) and TVT (Transcatheter Valve Therapy) registries, as well as programs such as the MDEpiNet (Medical Device Epidemiology Network) Initiative. Within MDEpiNet, there are a number of ongoing projects, including the RAPID (Registry Assessment of Peripheral Interventional Devices), SAFE-STEMI for Seniors (Study of Access site For Enhancement of ST-Elevation MI for Seniors), and optimal integration of procedural and Medicare claims data for regulatory and reimbursement decision making involving innovative transcatheter mitral valve implantation (9).
Partner With Patients
We believe that if CDRH is to successfully achieve a mission and vision in the service of patients, we must interact with patients as partners and work together to advance the development and evaluation of innovative devices and monitor the performance of marketed devices (10). We have goals to establish new mechanisms for CDRH employees to obtain patient input on key pre-market and post-market issues facing CDRH and foster patient group participation in these mechanisms (11); increase employee interaction with patients as part of their duties; and increase the use and transparency of patient input as evidence in our decision making. CDRH staff are already embracing this new mandate, taking advantage of the opportunity to interact with patients through organizations such as WomenHeart and Heart Valve Voice, as well as visiting heart failure clinics—all of which will allow us to better understand patients’ experiences, needs, and priorities when it comes to their medical care.
As summarized herein, CDRH has developed a number of strategic initiatives to help achieve its vision. In addition, CDRH has recognized the paramount importance of providing excellent customer service to our stakeholders. Recognizing our need to rely on a multifactorial ecosystem to be successful, CDRH has expended considerable effort fostering relationships with stakeholders, including patients, investigators, providers, industry, payers, and others. This commitment to customer service has undoubtedly played a key role in positively affecting public health through changes in regulatory policy and decision making over the last several years, and the same could be said for any future accomplishments in this regard. Looking forward, CDRH remains committed to finding innovative ways to accomplish our mission of promoting and protecting the public health, which will continue to require close collaboration with our many stakeholders.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received September 6, 2016.
- Accepted September 11, 2016.
- American College of Cardiology Foundation
- ↵U.S. Food and Drug Administration. 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. October 1, 2013. Available at: http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103.pdf. Accessed September 1, 2016.
- ↵U.S. Food and Drug Administration. Automated External Defibrillators (AEDs). February 4, 2015. Available at: http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/CardiovascularDevices/ucm344669.htm. Accessed September 1, 2016.
- U.S. Food and Drug Administration. FDA takes steps to improve reliability of automated external defibrillators [press release]. January 28, 2015 (updated February 3, 2015). Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm431907.htm. Accessed September 1, 2016.
- ↵U.S. Food and Drug Administration. Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions: Guidance for Industry and Food and Drug Administration Staff. April 13, 2015. Available at: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM393978.pdf. Accessed September 1, 2016.
- ↵FDA-NIH Biomarker Working Group. BEsT (Biomarkers, Endpoints, and Other Tools) Resource. Available at: http://www.ncbi.nlm.nih.gov/books/NBK326791/. Accessed September 1, 2016.
- ↵Cutts E, Faris O, Shuren J. Celebrating a Year of the Expedited Access Pathway Program for Medical Devices. FDA Voice. May 31, 2016. Available at: http://blogs.fda.gov/fdavoice/index.php/2016/05/celebrating-a-year-of-the-expedited-access-pathway-program-for-medical-devices/. Accessed September 1, 2016.
- Shuren J.,
- Califf R.M.
- ↵Medical Device Epidemiology Network (MDEpiNet). Projects. Available at: http://www.mdepinet.org/projects/. Accessed September 1, 2016.
- ↵U.S. Food and Drug Administration. Patient Engagement Advisory Committee. September 18, 2015. Available at: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PatientEngagementAdvisoryCommittee/default.htm. Accessed September 1, 2016.