doi: 10.1161/01.CIR.0000159254.11881.72
(Circulation. 2005;111:e164-e165.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Articles by Kereiakes and Willerson, Mehran et al, and Kaplan et al, "Mini-Review: Expert Opinion"
Rush University, Chicago, Ill, Member, Circulatory Device Panel
University of New Mexico, Albuquerque, NM, Chairman, Circulatory Device Panel
University of Arizona and Southern Arizona Veterans Affairs, Healthcare System, Tucson, Ariz, Member, Circulatory Device Panel
Director, Interventional Cardiology and Associate Professor of Medicine, Columbia University, New York, NY, Member, Circulatory Device Panel
The articles by Kereiakes and Willerson,1 Mehran et al,2 and Kaplan et al3 were most informative as to the device development process; however, the undercurrent theme that a "device lag" exists between Europe and the United States and that this can be adjusted by modifying the US system has significant flaws. Specifically, "The concept of effective post-market surveillance to facilitate pre-market approval, while intuitively attractive, needs very careful evaluation. The example of the CYPHER drug-eluting stent cited in the reviews speaks against altering the approval process. The regulatory demands for a randomized controlled efficacy trial resulted in the demonstration of a substantial benefit for the CYPHER stent. When reports of adversity appeared, it was the knowledge of proven efficacy that was balanced against a small number of adverse reports, which supported its continued use. Without careful trials evaluating efficacy, no legitimate judgment on the appropriate use of a class III device can be made.
Certainly better registries are needed for postmarket follow-up for devices; however, a better registry must not be a substitute for initial well-controlled, adequately powered clinical trials. The problem of early availability of devices in Europe stems not from excessive US regulation but from inadequate criteria for approval in Europe. A device must do more than function as it should to be approved; it must be effective by being beneficial. Moreover, there are many examples of devices being approved for use in Europe that have failed in US Food and Drug Administration preclinical or clinical testing. Recent examples include some of the drug-eluting stents and abdominal aortic aneurysm grafts.
One may question whether the present US standard is actually rigorous enough. Consider recent examples such as Trans Myocardial Revascularization and Pericutaneous Myocardial Revascularization. Drilling holes successfully in the heart is not informative, a study needs to demonstrate a benefit over control. Harmonization between the US and European device approval systems needs to evolve along the lines that have occurred with pharmaceuticals (ie, raising standards that improve therapeutics). The substantial limitations of the European device regulation system are well recognized by individuals who interact with European-notified bodies. Unfortunately, these limitations have not been explored in the Circulation articles. We urge a careful examination of the current European process for device approval before reaching conclusions that may have a negative impact on health care in the United States.
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References |
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- Kereiakes DJ, Willerson JT. Medical technology development and approval: the future is now. Circulation. 2004; 109: 3078–3080.
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- Mehran R, Leon MB, Feigal DA, Jefferys D, Simons M, Chronos N, Fogarty TJ, Kuntz RE, Baim DS, Kaplan AV. Post-market approval surveillance: a call for a more integrated and comprehensive approach. Circulation. 2004; 109: 3073–3077.
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- Kaplan AV, Baim DS, Smith JJ, Feigal DA, Simons M, Jefferys D, Fogarty TJ, Kuntz RE, Leon MB. Medical device development: from prototype to regulatory approval. Circulation. 2004; 109: 3068–3072.
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Response
The Lindner Center/Ohio Heart Health Center/The Christ Hospital, Cincinnati, Ohio
Dartmouth Medical School/Dartmouth Hitchcock Medical Center, Lebanon, NH
Columbia University Medical Center/Cardiovascular Research Foundation, New York, NY
We appreciate the interest of Somberg et al in the 3 articles1–3 on medical device approval and release. We are concerned that they have misinterpreted the premise of our work. Important differences between the regulatory process in the United States and Europe exist. The purpose of our articles was to highlight these differences and to provide a better understanding of the US regulatory process in the hope of identifying ways to streamline the US approval process while maintaining high standards of safety and efficacy. Several points require comment.
First, an appreciable time lag exists between European CE-mark and US Food and Drug Administration (FDA) approval, and this time lag has progressively widened during the past 5 years. In 2002, David W. Feigal, MD, MPh, then director of the Center for Devices and Radiological Health of the FDA, projected that a 2.5-year time delay would occur by 2004.4 Indeed, we are unaware of a significant first-in-class disposable interventional cardiology device being available in the US before it was available in Europe.
Second, a more comprehensive postmarket surveillance program is needed and should be complementary, not exclusive, to the "well controlled, adequately powered clinical trials" suggested by Somberg et al. The case of the CYPHER stent illustrates shortfalls in our current postmarket surveillance program. Soon after market release of this stent, the FDA received reports of subacute thrombosis via the medical device reporting process, which is the principal means for monitoring safety and effectiveness of a device after approval. This system has many inherent flaws that limit its utility.5 For example, it has been estimated that <3% of adverse device-related outcomes are reported through the medical device reporting system.6 Although Somberg states, "When reports of adversity appeared it was the knowledge of proven efficacy that was balanced against a small number of adverse reports, which supported its continued use," the true numerator of adverse events from which the FDA could evaluate safety was ill-defined. Despite the appreciable morbidity and mortality associated with stent thrombosis, it took almost 1 year after the initial advisory7 for the FDA to issue this conclusive statement: "The Cypher stent remains a safe and effective device when used according to the labeling, particularly with regard to patient selection and appropriate periprocedural medications."8 In the context of nearly 3000 CYPHER stents being deployed daily worldwide, a more accurate postmarket reporting process could have been invaluable. As Somberg and colleagues should appreciate, the pivotal randomized controlled trial supporting CYPHER approval was powered to show a difference in the more frequently occurring end point of target vessel failure (device efficacy), not stent thrombosis. To the extent that confidence can be established in a postmarket surveillance program, such a program may facilitate the premarket device-approval process.
Finding the correct balance in the regulatory process is difficult and requires that we continuously reexamine the new device-approval process. As Somberg et al imply, there is harm when a device that fails reasonable standards of safety and effectiveness is introduced into clinical practice. Similarly, delays in approving safe and effective devices may also cause "harm" by restricting access to potentially lifesaving technologies. Finally, as clinicians, inventors, investigators, and regulators (FDA), we have an obligation to the American public both to ensure patient safety and provide timely access to leading-edge technologies.
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References |
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TopReferencesReferences |
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- Kereiakes DJ, Willerson JT. Medical technology development and approval: the future is now. Circulation. 2004; 109: 3078–3080.
[Free Full Text]
- Mehran R, Leon MB, Feigal DA, Jefferys D, Simons M, Chronos N, Fogarty TJ, Kuntz RE, Baim DS, Kaplan AV. Post-market approval surveillance: a call for a more integrated and comprehensive approach. Circulation. 2004; 109: 3073–3077.
[Free Full Text]
- Kaplan AV, Baim DS, Smith JJ, Feigal DA, Simons M, Jefferys D, Fogarty TJ, Kuntz RE, Leon MB. Medical device development: from prototype to regulatory approval. Circulation. 2004; 109: 3068–3072.
[Free Full Text]
- Feigal DW. CDRH: looking ahead. Available at: http://www.fda.gov/cdrh/present/fdliapril01.pdf. Accessed November 1, 2004.
- Feigal DW, Garner SN, McClellan M. Ensuring safe and effective medical devices. N Engl J Med. 2003; 348: 191–192.
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- US General Accounting Office. Medical Devices: Early Warning of Problems Is Hampered by Severe Underreporting. Washington, DC: US Government Printing Office; 1987. GAO/PEMD 87-1.
- US Food and Drug Administration. FDA public health web notification: information for physicians on sub-acute thrombosis (SAT) and hypersensitivity reactions with the use of the Cordis CYPHER coronary stent. Available at: http://www.fda.gov/cdrh/safety/cypher.html. Accessed April 2, 2004.
- US Food and Drug Administration. FDA public health web notification: final update of information for physicians on sub-acute thromboses (SAT) and hypersensitivity reactions with use of the Cordis CYPHER sirolimus-eluting coronary stent. Available at: http://www.fda.gov/cdrh/safety/cypher3.html. Accessed October 20, 2004.
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Issue Highlights
Circulation 2005 111: 1455.[Full Text]
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