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Ann Thorac Surg 2006;82:773-775
© 2006 The Society of Thoracic Surgeons

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Editorial

FDA Perspective on Clinical Trial Design for Cardiovascular Devices

Food and Drug Administration, Center for Devices and Radiological Health, Office of Device Evaluation, Rockville, Maryland

^_* Address correspondence to Mr Chen, Food and Drug Administration Center for Devices and Radiological Health, Office of Device Evaluation, 9200 Corporate Blvd, HFX-450, Rockville, MD 20850 (Email: eric.chen{at}fda.hhs.gov).

	Introduction

Top Introduction Regulatory Issues Regulatory Approaches to Trial... Conclusion Footnotes References

 
The papers by Parides and colleagues [1] and Grunkemeier and colleagues [2] in this issue of The Annals address the challenge of designing clinical trials for heart valves and mechanical circulatory support devices (MCSD). As discussed in these two papers, study designs range from randomized controlled trials to single-arm studies measured against Objective Performance Criteria (OPC). This editorial describes aspects of clinical trial design that the Food and Drug Administration (FDA) believes necessary to provide the scientifically valid data for regulation of heart valve prostheses and MCSDs.

	Regulatory Issues

Top Introduction Regulatory Issues Regulatory Approaches to Trial... Conclusion Footnotes References

 
The 1976 Medical Devices Amendment of the Food, Drug, and Cosmetic Act mandated that the FDA regulate market approval of new medical devices based on scientific evidence that there is reasonable assurance that the device is both safe and effective. This data must specify indications for use and the intended patient population as determined by the risk/benefit ratio [3]. It should be noted that the FDA is limited to regulating manufacturers and devices and prevented from any such regulation of practioners or practice of medicine by the FDA Modernization Act of 1997 [4].

The FDA provides three paths whereby medical devices can achieve market access: Demonstration of Substantial Equivalence to a "Pre-Amendment Device" product [510(k)], by Pre-Market Approval, and Humanitarian Device Exemption. For devices that present the highest level of risk to the patient in event of failure, the stringent requirements of a Pre-Market Approval process are generally necessary. A Humanitarian Device Exemption reduces the level of benefit that must be demonstrated to permit use in a clearly defined plausible patient subset of no more than 4,000 patients annually. These regulatory processes differ from those for European Union device regulation where, except in the highest risk device category, self-certification by the manufacturer that devices meet specified standards permits labeling with the Conformite Europenne mark to allow distribution throughout the Union. For high-risk devices, the data supporting an application for a Conformite Europenne mark must first be reviewed by an independent notifying body [5].

Considerable advantage might accrue to the conduct of clinical trials for medical devices from a more uniform regulatory environment that crosses national borders to permit pooling of data. To this end, introduction of global harmonization to regulatory requirements for devices is a matter of ongoing discussion between the FDA and foreign peer organizations.

The FDA is committed to monitoring the total product life cycle of medical devices (Fig 1) including early preclinical development, clinical study, marketing approval, post-approval evaluation, and the development of subsequent device generations. The post-market monitoring of medical devices characterizes real world performance outside of the highly selective protocol of an Investigational Device Exemption (IDE). The FDA may require such studies to be conducted as a condition of Pre-Market Approval where such studies can provide data that cannot be derived pre-approval. Similarly, post-market registry participation may also be requested by the Center for Medicare and Medicaid Services (CMS) and can be a reimbursement criterion required by CMS in certain cases.

View larger version (36K): [in this window] [in a new window]   Fig 1. Total product life cycle.

	Regulatory Approaches to Trial Design

Top Introduction Regulatory Issues Regulatory Approaches to Trial... Conclusion Footnotes References

 
The statutory stipulation that the FDA assure safety and effectiveness of devices before approval for marketing was supplemented in the Medical Device Modernization Act of 1997 [7] to require the FDA employ a "least burdensome" approach, one that generates the required safety and effectiveness data in the most efficient, unbiased manner. In conformance with this mandate, the FDA addressed the difficulties with ventricular assist device trials outlined by Parides and colleagues [1] with approval of IDE protocols that are tailored to the specific intended use of the device. The FDA has also addressed the differences in devices designed for similar indications. Thus, IDE trials for MCSDs to treat patients with terminal stage cardiac failure awaiting transplantation and who are already on maximal alternative therapy, "bridging to transplant," have been approved employing observational studies controlled to concurrent and/or historical data. By contrast, use of the same devices as "destination" therapy for treatment of patients in end-stage cardiac failure has required demonstration of benefit compared to the standard maximum medical management with the most robust of clinical trial design, a randomized controlled trial. The FDA recommended this design to clearly, and in an unbiased fashion, determine that ventricular assist devices provided benefit for these end-stage heart failure patients without alternative options. Such a trial, the REMATCH, did indicate that necessary safety and effectiveness data existed to support approval of the MCSD as an alternative therapy for patients in end-stage cardiac failure despite maximum therapy who are not candidates for transplant [8].

Grunkemeier and colleagues [2] have described the use of OPC as originally introduced for study of cardiac valve prostheses. The authors point out that standards can be generated for the clinical performance of an established device therapy when the device technology is mature and well-documented historical data are available. In contrast to valve prostheses, MCSDs lack this level of maturity. Such standards can be extrapolated to criteria against which any similar new device for the same indication can be evaluated. Such control values, OPC, were constructed from the vast clinical experience with cardiac valve prostheses. The uses of OPC have expedited the review of devices in single-arm studies. Since their introduction in 1994, the FDA has approved 15 cardiac valve prostheses with data derived from single-arm studies.

The papers of Parides and colleagues [1] and Grunkemeier and colleagues [2] have underscored some of the trade-offs necessary when performing new cardiac device trials and the constraints that clinical reality imposes on their design. Emphasis on demonstrating statistical validity to clinical outcomes can raise concerns regarding equipoise in the choice of study control and the endpoints for determining an acceptable safety and effectiveness ratio that provides evidence of utility. These are important elements that factor into the practicality of completing the study and achieving study objectives. Parides and colleagues [1] have suggested several trial designs for the standard frequentist superiority model that may circumvent these problems. The FDA is willing to accept alternative designs and controls, such as OPC, when based on sound arguments that they will provide sufficiently robust data.

Demonstrating superiority of a device treatment can require a large sample size when small treatment benefits are anticipated. As illustrated by Parides and colleagues [1], composite endpoints can permit a reduction in sample size and have been employed in many IDE study designs despite important limitations that may occur in subanalysis of individual components. Sample size can also be reduced where a study seeks to establish equivalence or noninferiority to a control treatment rather than superiority, and the choice of the delta for equivalence is of moderate size. However, the use of this approach may confound the ability to determine true equivalence between control and experimental device.

Several newer concepts in trial design have been approved for IDE trials of other cardiovascular devices that permitted more timely study completion and expedited availability of innovative devices. Prospective adaptive trial designs allow modifications to some aspects of the trial such as sample size during the conduct of the trial without penalty to statistical analysis. Bayesian design can provide an advantage over the Frequentist model if certain conditions exist and have been the topic of a recent FDA guidance publication [9]. This design could prove helpful for evaluating new MCSDs and for the development of percutaneous implanted heart valves. With existence of satisfactory prior information for clinical use of a similar device, the Bayesian approach may facilitate analysis of a study of smaller size and/or shorter duration. Such prior information is often available for a medical device, and this approach has been satisfactorily employed for approval of cardiac valve prostheses. For nonrandomized controlled trials, the use of Propensity Score analysis may allow a more appropriate comparison of control to treatment data.

	Conclusion

Top Introduction Regulatory Issues Regulatory Approaches to Trial... Conclusion Footnotes References

 
Clinical trials are complex. Their designs involve multiple trade-offs. One study design does not fit all. This is particularly exemplified with developing technology in the heart valve arena. Grunkemeier and colleagues [2] have described a study design with OPC that has served well for open surgical cardiac valve replacement with established technology. In contrast, the developing field of percutaneous heart valve replacement demands far different paradigms with innovative trial designs to address difficult new concerns. These concerns include defining target populations; establishing the correct risk/benefit ratio based on a new balance between safety and effectiveness perceived for the reduction in surgical risk; and choice of appropriate endpoints for assessment.

Although innovative trial design may be necessary in certain cases of new technology, the most appropriate study design remains a randomized controlled trial as the gold standard. When other options are to be considered for new technology, early interaction of sponsors and investigators with the FDA is seminal to navigating the challenges presented by these complex clinical trial designs.

	Footnotes

Top Introduction Regulatory Issues Regulatory Approaches to Trial... Conclusion Footnotes References

 
The views and opinions are those of the authors and do not necessarily reflect those of the US FDA, the US Department of Health and Human Services, or the Public Health Service.

	References

Top Introduction Regulatory Issues Regulatory Approaches to Trial... Conclusion Footnotes References

 

1. Parides MK, Moskowitz AJ, Ascheim DD, Rose EA, Gelijns AC. Progress versus precisionchallenges in clinical trial design for left ventricular assist devices. Ann Thorac Surg 2006;82:1140-1146.[Abstract/Free Full Text]
2. Grunkemeier GL, Jin R, Starr A. Prosthetic heart valvesobjective performance criteria versus randomized clinical trial. Ann Thorac Surg 2006;82:776-780.[Abstract/Free Full Text]
3. Federal Register. 43FR 32988. Washington, DC: Government Printing Office..
4. Food Drug and Cosmetic Act Amendment Federal Register (21U.S.C.396, Section 906) 1998;63(225):64617.
5. European Commission Directives. Available at: http://www.europa.eu.int (accessed July 31, 2006)..
6. InterAgency Registry for Mechanically Assisted Circulatory Support. Available at: www.intermacs.org (accessed July 31, 2006)..
7. Least Burdensome Provisions of the FDA modernization Act of 1997. Available at: http://www.fda.gov/cdrh/ode/guidance/1332.pdf (accessed July 31, 2006)..
8. Rose EA, Gellins AC, Moskowitz AJ, et al. Long term use of a left ventricular assist device for end-stage heart failure New Engl J Med 2001;345:1435.[Abstract/Free Full Text]
9. FDA Bayesian Draft Guidance. Available at http://www.fda.gov/cdrh/osb/guidance/1601.pdf (accessed July 31, 2006)..

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