Editor’s Note: The following is a perspective on the U.S. Food and Drug Administration (FDA) assessment of new cardiovascular devices through the Expert Panel perspective provided by Dr. Warren Laskey, a panel member for many years. When the FDA is considering a new device or a significant reassessment of an existing device that has sparked significant public interest, the FDA may convene a "Panel of Experts" to advise the FDA in the decision process. The panel has access to all of the data, published and non-published, available to the FDA, and answers questions posed by the FDA, including potential approval of the device or change in use, in a public forum. The panels include medical experts as well as industry and lay representatives. It is import to note that the FDA is not bound by the recommendations of a Panel. While we think only in terms of "thumbs up or thumbs down" for a specific device, panels sometimes involve advising the FDA on how to manage the evaluation of a new class of devices in evaluation, such as patent foramen ovale (PFO) closure devices or cardiac defibrillators being sold without a physician prescription. It is a dynamic process with clear input from all stakeholders.

Nowhere is the essential inter-relatedness of physicians, scientists, industry, government, and consumers better epitomized than in the workings of the U.S. Food and Drug Administration (FDA). Because the FDA is charged by law with the mandate to "oversee the public health," this daunting responsibility has led to a sequence of expectations,^1,2 disappointments,³ and vigorous criticisms^4,5 that have colored balanced discussions of this topic. Add to these discussions the frequent, often invidious, comparisons between U.S. and the European Union systems for medical device regulation, and the stage is set for much uninformed rhetoric and little prospect for process improvement when this stage should be an opportunity for a pragmatic dialog regarding innovation and regulation.^6,7

Fortunately, substantial effort, change, and improvement over the last decade at the FDA in general and at the Center for Devices and Radiologic Health (CDRH) in particular are having a real and positive impact on the medical device regulatory system. But first, this article will provide a bit of historical perspective and some important reminders.

Effort

The Safe Medical Device Act of 1990, the Medical Device Amendments of 1992, and the modernization act of 1997 (FDAMA) articulated the requirements for "reasonable assurance" and "scientific evidence" for "safe and effective" devices and proposed the "least burdensome" concept. However, available resources and infrastructure within FDA/CDRH were inadequate to match the exponential increase in productivity in the U.S. economy over this time. The unrelenting demand for enhanced efficiency and the capability of the process of pre-market approval ("better, faster, cheaper") led to the Medical Device User Fee and Modernization Act (MDUFMA) of 2002 and its subsequent iterations over recent years. Specifically, the Medical Device User Fee Amendments of 2007, part of a larger piece of legislation (FDA Amendment Acts of 2007) represented potential improvements in the streamlining of the pre-market approval (PMA) process. The FDA Safety and Innovation Act (FDASIA), which incorporated the Medical Device User Fee Amendments of 2012 (MDUFA III), specified performance goals as well as user fees when device manufacturers submit their PMA. Other provisions change the way FDA approves clinical trials, provides for a new de novo pathway for risk-based classification of devices, expands the FDA's post-market surveillance capacities, and changes the process for reclassification of devices. The impact of these changes on the regulatory approval process for cardiovascular devices cannot be underestimated and aligns with other within-CDRH efforts to "streamline" the approval process. Among these in-house efforts are a broad, multi-disciplinary emphasis on Regulatory Science.^8,9 It is this latter effort that has important and direct implications for the Advisory Committee, viz. the strengthening of the clinical trials enterprise, reaching an appropriate balance between pre- and post-market data collection, and the provision of "excellent customer service."

Change and Process Improvement

The primary charge of the agency over the past 100 years has remained the oversight and protection of the public's health, notwithstanding the aforementioned demands on process, structure, and function. In the case of medical devices, assessment and assurance of a specific device's safety and effectiveness is not simply a regulatory matter but a complex process whereby scientific evidence is brought forward in support of a specific hypothesis and the principles of statistical inference are conjoined with clinical judgment and experience in order to arrive at "reasonable assurance." The fundamental issue remains one of maintaining balance between the many urgencies associated with device development and marketing ("least burdensome") and the certainty with which safety and efficacy can be reasonably assured. It is this dialectic on which all discussion regarding regulatory science must be focused.

Regulatory science, as it has been articulated, represents a significant departure from a uni-dimensional, linear model of process and offers the promise of further maturation of the current "product life cycle" concept^8,9 in its integration of the spirit of translational medicine, pre- and post-approval device evaluation, risk assessment, risk management, risk communication and health policy development. Given these many levels of interaction, an ecological model of this process may be more appropriate and relevant from a public-health standpoint. Such a model would not only include the extant product life cycle but could account for the many other levels of influence on decision-making, e.g., legislative, health policy, societal forces. Consistent with the goals of regulatory science, the ecological perspective highlights interactions between and within these levels of influence.¹⁰

From the Advisory Committee perspective, improved "alignment" of the pre- and post-marketing aspects of device regulation results from, and benefits by, the enhanced transparency implicit in regulatory science,¹¹ requires an appreciation for the distinct statistical and epidemiologic methods for assessing and understanding device safety and efficacy in each domain,¹² and mandates efficient and effective communication among levels. New methodologies, however, must not abandon first principles of scientific experimentation and clinical trial design. Alignment of traditional pre- and post-market phases of device regulation is inherent in the workings of the present Office of Surveillance and Biometrics (OSB).¹³ This office is now fully integrated into the PMA process. The biostatistical and epidemiologic expertise housed within OSB will provide a solid "evidence base" in order to develop and evaluate appropriate post-approval device performance metrics. The transition to an active surveillance program began with the creation of the MedSun system in 2002,¹⁴ progressed further with the Sentinal Initiative (a product of the FDAAA) launched in 2008,¹⁵ and culminates in the present era with the passage of the Unique Device Identification System,^16,17 a mandatory national medical device registry linking each device (via a unique identifier) to the electronic health record for that individual.

These expanded capabilities bode well for monitoring device performance and safety in the post-approval setting. However, as noted previously in the cautions regarding the "streamlining" of the PMA process scientific integrity, first principles of statistical and epidemiologic inference and fundamental differences between prospective and retrospective observational data must be appreciated. The fascination with mega- and meta-numbers must also be tempered by the fact that missing data may significantly bias statistical inferences, that more data is not tantamount to accurate and reliable data, and that data mining is still an abstruse and technology-intensive science. The attractiveness of registries as aids to assessment of device performance and safety in the real world must be weighed against the unvalidated nature of the entered data in many instances and the many problems with missing data. Among the latter are unreliable survival inferences and the problem of the missing denominator. Registries and prospectively-designed cohort studies in the post-approval setting share common limitations in the absence of randomization, the absence of masking, and reliance on epidemiologic inferential methodology to draw conclusions regarding causality. The temptation to conduct comparative effectiveness research in this setting is great.¹⁸ However, the same transparency demanded of the acquisition of the data at the PMA level must be demanded at the post-approval study level. Similar concerns surround the use of statistical adjustment techniques to mitigate the problems of bias and confounding in observational data analysis. The increasing use of propensity scores is one such adjustment method but one which cannot overcome the problems of missing data elements or data elements that do not lend themselves to scaling or coding (e.g., a clinician's reasoning regarding treatment options).

A number of other administrative changes have been made to the advisory process.¹⁹ In order to streamline this part of the device regulation process, committee members will be asked to focus their thinking on the fundamental scientific issues (i.e., safety and efficacy) and less on traditional approvability, the latter falling under FDA jurisdiction. Enhanced transparency of this publicly deliberative process is further increased by a change in the voting process to an electronic ballot, thereby mitigating group-think or other less obvious structural confounders of the voting process.²⁰

In summary, medical device regulation at the FDA is alive, well, and in-step with the tectonic shifts in social, political, secular, informational, and clinical forces in the 21st century. The Advisory Committee will continue to play an important, if not expanded, role in the device approval process (Figures 1 and 2). Appreciation of the many changes in the device approval process will necessitate enhanced competency of individual members in regulatory science. However, it is in the interest of the public's health that the advisory process embrace FDA's efforts to "strengthen the clinical trials enterprise," achieve the "right balance between pre- and post-market data collection," and "provide excellent customer service."

Figure 1 Figure 2

References

1. U.S. Department of Health and Human Services. FDA's Critical Path Initiative (FDA website). 2012. Available at: http://www.fda.gov/ScienceResearch/Special Topics/CriticalPathInitiative/ucm076689.htm. Accesed 4/26/15.
2. Hamburg MA, Sharfstein JM. The FDA as a public health agency. New Engl J Med 2009;360:2493-5.
3. Smith SW. Sidelining safety--the FDA's inadequate response to the IOM. New Engl J Med 2007;357:960-3.
4. Garber AM. Modernizing device regulation. New Engl J Med 2010;362:1161-3.
5. Institute of Medicine. Medical devices and the public's health: the FDA 510(k) clearance process at 35 years. Washington, DC: National Academies Press. 2011. Available at: http://www.iom.edu/~/media/Files/Report%20Files/2011/Medical-Devices-and-the-Publics-Health-The-FDA-510k-Clearance-Process-at-35-Years/510k%20Clearance%20Process%202011%20Report%20Brief.pdf. Accessed 4/26/15.
6. Fraser AG, Daubert J-C, Van de Werf F, et al. Clinical evaluation of cardiovascular devices: principles, problems and proposals for European regulatory reform. Eur Heart J 2011;32:1673-86
7. U.S. Department of Health and Human Services. International Conference on Harmonisation (ICH) Guidance Documents (FDA website). 2014. Available at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm122049.htm. Accessed 4/26/15.
8. U.S. Department of Health and Human Services. Total Product Life Cycle (TPLC) (FDA website). Available at: http://www.fda.gov/aboutfda/centersoffices/ officeofmedicalproductsandtobacco/cdrh/cdrhtransparency/ucm199906.htm. Accessed 4/26/15.
9. U.S. Department of Health and Human Services. Regulatory Science in FDA's Center for Device and Radiologic Health (FDA website). 2015. Available at: http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHReports/default.htm. Accessed 4/26/15.
10. Brian D. Smedley and S. Leonard Syme, Editors; Committee on Capitalizing on Social Science and Behavioral Research to Improve the Public's Health, Division of Health Promotion and Disease Prevention. Promoting Health: Strategies from Social and Behavioral Research. Washington, DC, National Academies Press, 2000.
11. U.S. Department of Health and Human Services. CDRH Transparency (FDA website). 2015. Available at: http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHTransparency/default.htm. Accessed 4/26/15.
12. Campbell G. Statistics in the world of medical devices: the contrast with pharmaceuticals. J Biopharm Stat 2008;18:4-19.
13. U.S. Department of Health and Human Services. Office of Surveillance and Biometrics (FDA website). 2014. Available at: http://www.fda.gov/aboutfda/centersoffices /officeofmedicalproductsandtobacco/cdrh/ucm116002.htm. Accessed 4/26/15.
14. U.S. Department of Health and Human Services. MedSun: Medical Product Safety Network (FDA website). 2014. Available at: http://www.fda.gov/medicaldevices/safety/medsunmedicalproductsafetynetwork/default.htm. Accessed 4/26/15.
15. U.S. Department of Health and Human Services. FDA's Sentinel Initiative-Background (FDA website). 2010. Available at: http://www.fda.gov/Safety/FDAsSentinelInitiative/ucm149340.htm. Accessed 4/26/15.
16. Department of Health and Human Service. Food and Drug Administration. 21 CFR Parts 16, 801, 803, 806, 810, 814, 820, 821, 822 and 830. Unique Device Identification System; final rule. Fed Register 2013;78:58786-828.
17. U.S. Department of Health and Human Services. A Device Clinical Trials Data Bank - Public Health Need and Impact on Industry. A Report to Congress by the Secretary of Health and Human Services (FDA website). 1999. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulation andGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE//ucm139611.htm. Accessed 4/26/15.
18. Stafford RS, Wagner TH, Lavori PW. New, but not improved? Incorporating comparative-effectiveness information into FDA labeling. N Engl J Med 2009;361:1230-33.
19. U.S. Department of Health and Human Services. Summary of Changes to CDRH's Advisory Process (FDA website). 2014. Available at: http://www.fda.gov/AdvisoryCommittees/Committees MeetingMaterials/MedicalDevices/ucm208485.htm. Accessed 4/26/15.
20. Broniatowski D, Magee CL. Does seating location impact voting behavior on Food and Drug Administration advisory committees? Am J Ther 2013;20:502-6.

Keywords: Advisory Committees, Angiography, Clinical Coding, Committee Membership, Comparative Effectiveness Research, Device Approval, Electronic Health Records, Equipment Safety, Goals, Health Policy, Judgment, Linear Models, Marketing, Policy Making, Politics, Propensity Score, Prospective Studies, Public Health, Radiologic Health, Random Allocation, Registries, Retrospective Studies, Risk, Risk Assessment, Social Change, Translational Medical Research

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