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Summary P rior to the Medical Device Amendments (MDA) of 1976, medical de- vices generally had not undergone premarket review by the US Food and Drug Administration (FDA). The MDA created three classes of device types on the basis of the risks posed and the ability of postmarket controls to manage them (see Box S-1). Each device type includes a number of devices. As originally contemplated, the high-risk category (Class III) would require FDA review and approval, through the premarket approval (PMA) process, before a device could be marketed. The moderate-risk and low-risk categories (Class II and Class I, respectively) would not require as rigorous a review. Rather, device manufacturers would be required to notify the FDA at least 90 days before they marketed such a device. This premarket-notification requirement was contained in Section 510(k) of the Federal Food, Drug, and Cosmetic Act and is commonly referred to as 510(k) notification or 510(k) clearance. A device not on the market at the time of the enactment of the MDA (a “postamendment” device) would be required to demonstrate through a 510(k) notification that it was “substantially equivalent” to a “preamend- ment” device and, for Class II devices, complied with the applicable perfor- mance standard promulgated by the FDA. If the new device were substan- tially equivalent, it would be classified in the same class, and cleared for marketing subject to the same terms and conditions, as that preamendment device (for example, conformance to a performance standard). Postamend- ment devices that were not substantially equivalent to any preamendment device would be automatically placed in Class III and would require either PMA or reclassification by the FDA to Class I or Class II to enter the market. 1

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2 MEDICAL DEVICES AND THE PUBLIC’S HEALTH BOX S‑1 The Three Device Classes • C lass I devices are those for which the general regulatory controls should be sufficient to provide reasonable assurance of safety and effectiveness. Class I may also include any device on which there is insufficient information to judge the adequacy of the controls but that is not represented to be for use in supporting or sustaining hu- man life (or preventing impairment to health) and does not present an unreasonable risk of illness or injury. • C lass II devices are those that cannot be classified into Class I, because general controls are not sufficient by themselves to provide reasonable assurance of safety and effectiveness, but on which there is sufficient information to establish a special control to provide rea- sonable assurance. Originally, Class II called solely for performance standards. A performance standard might include provisions regard- ing the construction, components, ingredients, and properties of the device and its comparability with power systems; provisions for the testing of the device to ensure conformity to the standard; provisions for measurement of performance characteristics of the device; provi- sions making the device a “restricted device”; and special labeling requirements related to the installation, maintenance, operation, and use of the device. Since 1990, Class II devices have been sub- ject to special controls, which may include performance standards, guidelines for the submission of clinical data in premarket notification submissions in accordance with Section 510(k), and other controls, such as compliance with an FDA guidance document. • C lass III devices are those that are represented for use in support- ing or sustaining life (or preventing impairment of health) or create a potentially unreasonable risk of illness or injury, but which cannot be classified into Class I or Class II, because the general controls are inadequate to give reasonable assurance of safety and effectiveness and the available information is insufficient to establish a special control to provide the requisite assurance. The Safe Medical Devices Act (SMDA) of 1990 permitted substantial equivalence to be established to marketed postamendment, in addition to preamendment, “predicate” devices, except for devices approved by PMA. Congress’s interpretation of substantial equivalence, as stated in the SMDA, is shown in Box S-2. The SMDA also gave the FDA authority to impose

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3 SUMMARY BOX S‑2 Definition of Substantial Equivalence in the 1990 Safe Medical Devices Act A. For purposes of determinations of substantial equivalence . . . the term “substantially equivalent” or “substantial equivalence” means, with respect to a device being compared to a predicate device, that the device has the same intended use as the predicate device and that [FDA] by order has found that the device – ( i) has the same technological characteristics as the predicate de- vice, or ( ii) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including clinical data if deemed nec- essary by [FDA], that demonstrates that the device is as safe and effective as a legally marketed device and (II) does not raise different questions of safety and efficacy than the predicate device. B. For purposes of subparagraph (A), the term “different technologi- cal characteristics” means, with respect to a device being compared to a predicate device, that there is a significant change in the materials, design, energy source, or other features of the device from those of the predicate device. on Class II devices, one or more special controls (which include a range of regulatory options), in addition to performance standards.1 The Food and Drug Administration Modernization Act of 1997 elimi- nated the requirement for 510(k) clearance for most Class I and some Class II device types, narrowed the array of issues that the FDA may consider in a 510(k) review, and directed the FDA to limit, to the “least burdensome” level, the scientific evidence requested to determine substantial equivalence of devices that involved new technologies. Today, the 510(k) clearance process is the primary pathway to market for Class II devices. More than 80% of 510(k)-cleared devices are catego- rized as Class II device types. Some Class I and Class III device types also are cleared through the 510(k) process. In 2002, in an effort to address insufficient resources of the 510(k) and PMA programs, Congress passed legislation to create a 5-year user-fee program. The user-fee program was renewed in 2007 for another 5 years. 1Specialcontrols include performance standards, postmarket surveillance, patient registries, and guidelines for the submission of clinical data in premarket notification submissions in ac- cordance with Section 510(k).

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4 MEDICAL DEVICES AND THE PUBLIC’S HEALTH The 510(k) clearance process has become a major component of medical-device regulation in the United States. Thousands of devices are cleared via the 510(k) process each year—about one-third of devices en- tering the market. The remaining devices are exempt from any premarket review (67%) or enter the market by the PMA pathway (1%) or by other means such as the humanitarian-device exemption (1%). Because the FDA has not promulgated performance standards or special controls for the vast majority of types of Class II devices, and because when a special control applies it does not necessarily apply to all aspects or components of the de- vice, the basis for market entry for Class II devices has been (and remains) demonstration of substantial equivalence to a predicate device. In recent years, individuals and organizations have expressed concern that the 510(k) clearance process is neither making safe and effective de- vices available to patients nor promoting innovation in the medical-device industry. Several high-profile mass-media reports and consumer-protection groups have profiled recognized or potential problems with medical devices cleared through the 510(k) clearance process. The medical-device industry and some patients have asserted that the process has become too burden- some and is delaying or stalling the entry of important new medical devices to the market. THE COMMITTEE’S TASK The FDA asked the Institute of Medicine to review the 510(k) clearance process for medical devices and to answer two questions: 1. Does the current 510(k) clearance process optimally protect patients and promote innovation in support of public health? 2. If not, what legislative, regulatory, or administrative changes are recommended to optimally achieve the goals of the 510(k) clearance process? CONCLUSIONS In its approach to its task, the committee evaluated components of the 510(k) process and other relevant factors, including • he legislative history of the 510(k) program. T • he 510(k) regulatory framework that resulted from legislation. T • ow the 510(k) process fits into the larger medical-device regula- H tory framework. (The 510(k) clearance process is an integrated component of the larger medical-device regulatory framework. The

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5 SUMMARY committee evaluated the 510(k) program in the context of this larger framework.) • ow the 510(k) process is implemented by the FDA. H • vailable postmarket information on the safety and effectiveness of A 510(k)-cleared devices. • ther factors that affect medical-device regulation (for example, the O process of innovation and the environment in which medical devices are developed and commercialized). On the basis of its review and evaluation of legislative, regulatory, and administrative components of the 510(k) clearance process and other related components of medical-device regulation, the committee came to two major conclusions. Conclusion 7-1 The 510(k) clearance process is not intended to evaluate the safety and effectiveness of medical devices with some exceptions. The 510(k) process cannot be transformed into a pre- market evaluation of safety and effectiveness as long as the standard for clearance is substantial equivalence to any previously cleared device. The 510(k) process is technically a classification mechanism by which a new device can be assigned to Class II and thereby enter the market without undergoing either the PMA process or the time-consuming formal device reclassification process. By law, the standard for classification and clear- ance is substantial equivalence to any predicate device already in Class II. The assessment of substantial equivalence does not require an independent demonstration that the new device provides a “reasonable assurance of safety and effectiveness,” as the statute requires for PMAs for new Class III devices. Rather, substantial equivalence requires a comparison of a new device to a legally marketed predicate that is, with few exceptions, either a preamendment device placed in Class II by the FDA based on reviews by outside advisory panels, a postamendment device that was originally approved as safe and effective by PMA and subsequently was reclassified into Class II, a postamendment device that was placed in Class II by the de novo review process based on a showing of safety and effectiveness, or a postamendment device that has been cleared through the 510(k) process as substantially equivalent to a device in one of the foregoing categories. In practice, most predicates fall within the first and last groups. According to the FDA and the Supreme Court, when the FDA finds a device substantially equivalent to a predicate device, the agency has not determined that the device is actually safe and effective; it has done no more than find that the

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6 MEDICAL DEVICES AND THE PUBLIC’S HEALTH new device is as safe and effective as the predicate. Thus, a critical question is whether the predicate was found to be safe and effective. The classification of preamendment devices did not include any evalu- ation of the safety or effectiveness of individual medical devices. The FDA created advisory panels to assist in the device classification process. These panels reviewed information on the risks posed by types of devices, includ- ing the potential risks resulting from a failure of lack of effectiveness, and recommended into which class the device type should be placed, in order to provide a reasonable assurance of safety and effectiveness. Neither the panels nor the FDA itself undertook an assessment of the clinical safety or effectiveness of individual devices during the original classification process. Thus, it is common for devices to be cleared through the 510(k) program by being found substantially equivalent to devices that were never indi- vidually evaluated for safety and effectiveness, either through the original device classification program or through the 510(k) process. Because the predicate device to which equivalence was established was itself generally not reviewed for safety and effectiveness, the committee found that clear- ance of a 510(k) submission was not a determination that the cleared device was safe or effective. The 1990 SMDA permitted the FDA to require evidence of safety and effectiveness, including clinical studies, when necessary to determine whether a difference in technologic characteristics between a new device and its predicate renders the new device less safe or effective than the predicate or raises different questions of safety and effectiveness from the predicate. If, despite the change in technologic characteristics, the new device is as safe and effective as the predicate, it will be found substantially equivalent. Nearly all 510(k) submissions for devices that have new technologic char- acteristics receive a determination of substantial equivalence. The committee found that available information on postmarket perfor- mance of devices does not provide sufficient information about potential harm or lack of effectiveness to be a useful source of data on the safety and effectiveness of marketed devices. The committee does not believe, however, that there is a public-health crisis related to unsafe or ineffective medical devices. Although the safety and effectiveness of individual preamendment Class II devices have not been systematically reviewed, their continued use in clinical practice provides at least a level of confidence in their safety and effectiveness. Conclusion 7-2 Information that would allow an understanding of the extent to which the 510(k) clearance process either facilitates or inhibits innovation does not exist.

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7 SUMMARY The committee believes that innovation is not just a change but a fa- vorable change in the context of public health, and it defined innovation as improving the quality of, efficiency of, or access to health care. It is not necessary for a Class II device to be demonstrated to be innovative to be cleared for marketing. The FDA should not be the arbitrator of what con- stitutes innovation, nor should it seek to channel device development and premarket review toward agency-determined public-health priorities. The regulatory process can facilitate innovation that improves public health by making safe and effective Class II medical devices available to consumers in a timely manner. The FDA’s role in facilitating innovation in Class II medical devices through premarket review should be to create a regulatory framework that sets appropriate thresholds for bringing products to the market. Those thresholds should be stringent enough to satisfy the agency’s objective of ensuring that marketed medical devices will be safe and effective throughout their life cycles but realistic enough to permit timely entry of new devices that may offer improvements over already marketed devices. Rather than be charged with promoting innovation, the committee believes that the FDA should seek to facilitate it. To assess how innovation is affected by medical-device regulation, the committee studied the legislative history and implementation of the 510(k) process. It is unclear—and the committee argues that it is indeterminable, given current data—whether legislative, regulatory, and administrative changes over the past 35 years have had a positive or negative effect on innovation. Several assessments of the 510(k) program have concluded that the FDA’s implementation of the program—not the underlying process itself— has stifled innovation because of a lack of transparency and predictability, which has had an adverse effect on venture-capital investment in future medical-device development. Typical measures used in those assessments are the ease of premarket review and relative speed to market compared with the European Union premarket process. The committee, however, does not believe that such measures are surrogates for innovation. The FDA has procedures for developing, adopting, and implementing guidance and standards. The agency, however, is persistently hindered in fully developing those materials by a lack of or limitations on human, fis- cal, and technologic resources and capabilities. The lack of clear guidance affects the timeliness and consistency of 510(k) device submissions provided by industry and the ability of reviewers to evaluate them. RECOMMENDATIONS The committee does not believe that further investment in the 510(k) process is a wise use of the FDA’s scarce resources and is not recommending

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8 MEDICAL DEVICES AND THE PUBLIC’S HEALTH specific changes in the 510(k) clearance process itself. Instead, it believes that the FDA’s resources would be put to better use in obtaining information needed to develop a new regulatory framework for Class II medical devices and addressing problems with other components of the medical-device regulatory framework. The committee recognizes that scarce resources in the FDA could affect its ability to implement the recommendations and, therefore, has directed the recommendations toward activities that are use- ful in both the short term and the long term to conserve scarce resources. Designing a New Medical-Device Regulatory Framework Recommendation 7-1 The Food and Drug Administration should obtain adequate information to inform the design of a new medical- device regulatory framework for Class II devices so that the current 510(k) process, in which the standard for clearance is substantial equivalence to previously cleared devices, can be replaced with an integrated premarket and postmarket regulatory framework that effectively provides a reasonable assurance of safety and effective- ness throughout the device life cycle. Once adequate information is available to design an appropriate medical-device regulatory framework, Congress should enact legislation to do so. The committee believes that a move away from the 510(k) clear- ance process should occur as soon as reasonably possible but recognizes that it will take time to obtain the information needed to design the new framework. The new regulatory framework must be based on sound science and be developed in harmony with other components of the FDA’s medical-device regulatory system. The committee does not believe that available informa- tion is adequate to inform the design of an appropriate framework. The types of evidence necessary to demonstrate a reasonable assurance of safety and effectiveness according to the new framework should be care- fully considered. It is beyond the committee’s scope of work to detail those types of evidence. It may be possible, however, for the performance of com- parative devices to be a component of the evidentiary materials supporting a claim of safety and effectiveness of Class II devices. On the basis of its findings, the committee identified several topics to which the FDA should give particular consideration as it develops a new framework. A number of existing and emerging technologies (for example, combination products, software, nanotechnology, and medical robotics) merit detailed thought as part of the development of the new framework. The FDA should consider integrating some elements of the quality-system regulations, especially those related to design controls and product-release

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9 SUMMARY criteria, into the premarket review process of the new framework to dem- onstrate that devices will perform as represented by their manufacturers. The FDA should also consider, as part of the new framework, including a more extensive review of device labeling and a system of tracking of label- ing changes. A comprehensive review of the successes and problems of device regula- tion over the past 35 years would better inform the FDA and Congress how to change the overall regulatory structure for devices. Finally, medical-device regulatory systems in other countries and jurisdictions should be evaluated to determine whether components of those systems could inform the design of the new regulatory framework in the United States. The committee urges the FDA to create a regulatory framework that closely matches the ideal regulatory framework outlined by the committee. The attributes of the ideal framework are as follows (not presented in any priority order): • T he process should be based on sound science. • T he process should be clear, predictable, straightforward, and fair. • T he process should be self-sustaining and self-improving. • T he process should facilitate innovation that improves public health by making medical devices available in a timely manner and ensuring their safety and effectiveness throughout their life cycle. • he process should apply relevant and appropriate regulatory au- T thorities and standards throughout the life cycle of devices to ensure safety and effectiveness. • he process should be risk-based. T FDA staff at all levels, the medical-device industry, consumers, health- care providers, payers, and Congress must play a role in the development of the proposed regulatory framework. Postmarketing Surveillance Robust postmarketing surveillance is particularly important for medical devices because devices often are used by small numbers of patients, so large premarket safety and effectiveness studies are not feasible. As noted above, the 510(k) clearance process is not a stand-alone program but a component of the larger medical-device regulatory framework. As part of that frame- work, the 510(k) program depends on the effectiveness of other regulatory components. The committee found substantial weakness in postmarketing surveillance of medical devices. The inadequate postmarketing surveillance systems, both those in the FDA and those that are privately funded, and the resulting lack of useful, consistent, and reliable data make it impossible to

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10 MEDICAL DEVICES AND THE PUBLIC’S HEALTH draw confident conclusions about the performance of medical devices that are now on the market. Recommendation 7-2 The Food and Drug Administration should develop and implement a comprehensive strategy to collect, analyze, and act on medical-device postmarket performance information. The FDA should give priority to postmarketing surveillance as an in- valuable investment in short-term and long-term oversight of medical-device safety and assessment of device effectiveness. Congress should support the capacity of the FDA’s postmarketing surveillance programs by providing stable and adequate funding. The FDA should develop a postmarketing surveillance strategy to meet the following objectives: providing performance information for use in the premarket review process, informing the development and use of postmar- keting tools (that is, general and special controls2) to better manage the risk-benefit ratio throughout the life cycle of devices, and informing the design of a new regulatory framework. Postmarket Regulatory Authorities3 When the FDA discovers violations of the law or products that pose unacceptable risks to consumers, it has a wide variety of authorities (or tools) available to try to remedy the situation and to sanction the violators. The committee found that the agency uses those authorities sparingly. The FDA reports that there are “important limitations” on the use of postmarket authorities, but does not describe them. The committee identified the pro- cedural requirements that the FDA must fulfill to exercise the authorities, but the requirements do not in themselves appear to explain the agency’s perception that there are limitations on its use of postmarket tools. Recommendation 7-3 The Food and Drug Administration should review its postmarket regulatory authorities for medical devices to identify existing limitations on their use and to determine how the limitations can be addressed. The appropriate use of postmarket regulatory authorities is an essential component of a successful medical-device regulatory program. The FDA should analyze barriers to efficient and effective use of the authorities and 2General controls include manufacturer registration, device listing, and good manufacturing practices. Special controls are described above. 3In this report, the phrase regulatory authority refers to the power that the legislature gives the FDA to enforce statutes.

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11 SUMMARY identify means of mitigating them. If it is required, Congress should pass legislation to remove unnecessary barriers to the FDA’s use of postmarket regulatory authorities. A Modified De Novo Process The de novo process is a mechanism by which the FDA can down- classify, to Class I or Class II, devices that have no predicates but are deemed to be of low to moderate risk. The process avoids having novel, low- to moderate-risk devices go through the PMA process. In the de novo process, a 510(k) submission for the device is sent to the FDA, which is- sues a determination of “not substantially equivalent” and indicates to the applicant that the device may be eligible for the de novo process. Special controls generally need to be developed for the device. The general and special controls must be sufficient to provide reasonable assurance of safety and effectiveness. The de novo process offers a potential basis of a better regulatory model for premarket review of Class II devices. In its current state, however, the de novo process is time-consuming and difficult for both the FDA and manu- facturers to navigate. Recommendation 7-4 The Food and Drug Administration should investigate the viability of a modified de novo process as a mecha- nism for evaluating the safety and effectiveness of Class II devices. A pilot program of a modified de novo process would allow the FDA to determine its feasibility as a replacement for the 510(k) clearance pro- cess. As part of a modified de novo process, the FDA should explore ways to expedite development of special controls, develop guidance, and adopt standards for devices. The agency also should consider expanded use of external expertise and preinvestigational device-exemption meetings with submitters and use of conditional clearances (such as postmarketing sur- veillance or use of registries) for devices on which there is little premarket performance information. A Continuous Quality-Improvement Program It is the committee’s assessment that the FDA lacks a continuous quality- assurance process for regulation of medical devices. As a result, the FDA cannot effectively address new issues as they arise. Recommendation 7-5 The Food and Drug Administration should de- velop and implement a program of continuous quality-improvement

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12 MEDICAL DEVICES AND THE PUBLIC’S HEALTH to track regulatory decisions on medical devices, identify potential process improvements in the medical-device regulatory framework, and address emerging issues that affect decision-making. The committee found evidence that the inadequate information tech- nology and management infrastructure in the FDA affects not only the 510(k) program but also the agency’s other programs for regulating medical devices. For example, because data systems are inadequate, the FDA does not have the ability to trace the history of 510(k) decisions. Prior 510(k) clearances are legally binding on the FDA when making 510(k)-clearance decisions. Thus, any unsafe or ineffective devices are embedded in the system and as both a legal and a practical matter may be used as predicates for new devices until the predicates are removed from the market. It may be difficult for the FDA to remove devices from the market because it has no systematic way to identify them. By developing a business model grounded in continuous quality-improvement, the FDA will be better able to identify problems with devices and develop the information and capacity to address them in a data-driven, transparent manner. Facilitating Innovation in the Medical-Device Industry The FDA’s role in facilitating innovation with respect to Class II devices is to create and enforce a regulatory framework for which the threshold to market provides reasonable assurance that medical devices are safe and effective throughout their life cycle while permitting timely entry of new devices that may offer improvements over already marketed devices. The committee did not find assessments of how much and in what way (that is, facilitating or inhibiting) innovation is influenced by the 510(k) clearance process. Recommendation 7-6 The Food and Drug Administration should commission an assessment to determine the effect of its regulatory process for Class II devices on facilitating or inhibiting innovation in the medical-device industry. The recommended study should include various ways to measure in- novation beyond “time to market” or the number of devices of a particular type on the market and instead focus on a broader understanding of the relationship among regulation, innovation, and patient health and safety throughout device life cycle.

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13 SUMMARY Software Manufacturers are increasingly using software in devices, software as devices, and software as a tool in producing devices. That trend is expected to continue. The committee found that current guidance on software vali- dation is insufficient for preventing serious software-based device failures. Recommendation 7-7 The Food and Drug Administration should develop procedures that ensure the safety and effectiveness of soft- ware used in devices, software used as devices, and software used as a tool in producing devices. The FDA should develop a better understanding of the roles of software in medical devices, analyze its potential effects on the safety and effective- ness of the devices, and insist on evidence-based procedures that ensure de- vice safety and effectiveness. Given the increasing use of software in devices and as devices (for example, medical device data systems), the integration in devices of commercial software not intended for use in medical devices, the increasing uncertainty introduced by device complexity, and potentially unsafe interactions with other software systems, the committee believes that the FDA should review and update its guidance on software validation. Preamendment 510(k)-Eligible Class III Devices After 35 years, the FDA has not completed the task of calling for PMAs for or reclassifying preamendment Class III device types. Until the FDA completes that task, those devices are allowed to enter the market through the 510(k) clearance process. Congress in 1990 directed the FDA to com- plete this task in a timely manner. Twenty-five Class III device types remain eligible to enter the market through the 510(k) process. The FDA has begun a five-step process to require PMAs or to down-classify those device types. As of April 2011, the FDA had assessed the risks and benefits associated with 21 device types (step 2 of the process) and had received and reviewed public comments on five device types (step 4 of the process). The agency has issued a final rule for one of the 26 device types. The committee recognizes the resource constraints that have prolonged the process, but it nevertheless urges the FDA to give high priority to completing the task. Recommendation 7-8 The Food and Drug Administration should promptly call for PMA applications for or reclassify Class III de- vices that remain eligible for 510(k) clearance.

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