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3 Components of US Medical-Device Regulation F rom the inception of device regulation under the 1976 Medical Device Amendments, it was understood that devices would be subject to vari- ous degrees of premarket review, depending on their risk classification (see Chapter 2). In addition, all devices, once they entered the marketplace (by whatever review mechanism) would be subject to a wide array of regu- latory requirements. Premarket review and regulatory control after market entry were intended to operate together to provide a structure that would protect the public’s health while not inhibiting innovation. The committee notes several times throughout this report that the 510(k) process does not operate in isolation. It is part of a larger framework of regulatory tools. This chapter provides an overview of the components of medical-device regulation that come into play after a product is marketed and then an introduction to the available paths for premarket review of devices, including the 510(k) clearance process. TOOLS AND AUTHORITIES FOR REGULATING MARKETED DEVICES In general, medical-device regulation is described by following the typi- cal life cycle of a device, starting with research and development, progressing to premarket review by the Food and Drug Administration (FDA), follow- ing with regulatory requirements while the device is marketed, continuing with evolution of the device into several (often many) iterations and newer variants, and ending with product obsolescence (IOM, 2010; Kahan, 2009). To focus attention on the incremental aspects of premarket review, however, 41

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42 MEDICAL DEVICES AND THE PUBLIC’S HEALTH this chapter will begin with the FDA’s “general controls”—the regulatory system applicable to devices once they enter the marketplace. Once the “postmarket” system is understood, the supplemental controls provided by premarket review can be better appreciated. In its “Preliminary Report and Recommendations,” the FDA Center for Devices and Radiological Health (CDRH) 510(k) Working Group states (FDA, 2010a) that the aim of the 510(k) program is two-fold: (1) to assure, through a quality review process, that marketed devices, subject to general and applicable special controls, provide a reasonable assurance of safety and effective- ness; and (2) to foster innovation. Robust premarket review is an essential component of CDRH’s medical device oversight. CDRH’s postmarket tools, while valuable, have important limitations and are not sufficient to serve as a substitute for high-quality premarket review [emphasis added]. This chapter explores those potential or perceived limitations and the procedures by which the controls are imposed and enforced. Controls Affecting Marketed Devices The statute establishes a combination of prohibitions and mandates with which a device and its manufacturer must comply. Some of the man- dates are imposed on specific devices by order of the FDA at its discretion; others are adopted through regulations issued by notice-and-comment rule- making. This discussion covers only the legal authority of the FDA, not how that authority may have been used through individual enforcement actions or the exercise of discretion not to act. Many of the controls apply to all devices, regardless of risk presented or classification; others apply to a subset of devices based on risk but not classification; and a few apply only to devices classified in Class II or Class III. Compliance with the controls is monitored and enforced by the FDA through its own resources and with the assistance of the US Department of Justice (DOJ) and federal courts. The following text will review prohibitions and mandates related to all devices, prohibitions and mandates related to higher-risk devices, FDA monitoring systems, FDA enforcement powers, and procedural require- ments that may affect the FDA’s ability to use the powers granted by law.

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43 COMPONENTS OF US MEDICAL-DEVICE REGULATION Controls Applicable to All Devices Prohibitions Contamination A device may not consist in whole or in part of any filthy, putrid, or decomposed substance1 or contain an unsafe color additive.2 Container Contamination The container of a device may not be composed in whole or in part of any poisonous or deleterious substances that may render its contents injuri- ous to health.3 False Claims of Compliance The marketer of a device may not claim that it complies with a perfor- mance standard established by or recognized by the FDA, unless the device conforms in all respects to the standard.4 False or Misleading Labeling The labeling of a device may not be false or misleading in any par- ticular.5 It may not fail to make all required disclosures conspicuous and accessible to potential users under customary conditions of sale.6 Whether labeling is misleading is determined both by what is said and by what mate- rial information is omitted in light of what is said.7 Unsafe When Used in Accordance with Instructions A device may not be dangerous to health when used as suggested in its labeling.8 Mandates Registration of Manufacturers A US-located manufacturer, processor, packager (or reprocessor and repackager9) of a medical device must register with the FDA the business’s 1Federal Food, Drug, and Cosmetic Act [hereinafter FFDCA] § 501(a)(1); 21 USC § 351(a) (1) (2006). 2FFDCA § 501(a)(4), 21 USC § 351(a)(4)(B) (2006). 3FFDCA § 501(a)(3), 21 USC § 351(a)(3) (2006). 4FFDCA § 501(e), 21 USC § 351(a)(1) (2006). 5FFDCA § 502(a), 21 USC § 352(a) (2006). 6FFDCA § 502(c), 21 USC § 352(c) (2006). 7FFDCA § 201(n), 21 USC § 321(n) (2006). 8FFDCA § 502(j), 21 USC § 352(j) (2006). 9Reprocessors and repackagers may sterilize, refurbish, or repackage previously used devices. There are special requirements for those who reprocess single-use medical devices. Section 502(v); 21 USC 352(v) (2006).

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44 MEDICAL DEVICES AND THE PUBLIC’S HEALTH name and all places of business.10 Any additional place of business must be registered immediately.11 Registration is also required for establishments outside the United States where devices are made for importation into the United States.12 Registration is to be electronic.13 Listing of Products Each registered person must file with the FDA a list identifying each device made or processed for commercial distribution in the United States.14 The label and labeling15 for each listed device and a representative sample of other labeling must be provided.16 The FDA may request a registrant to provide a statement as to why it believes that any product listed is not sub- ject to a performance standard or a premarket approval (PMA) application requirement.17 If a device previously listed is no longer made, the registrant must provide a notice of discontinuance regarding the product.18 Listings are to be electronic.19 Label Information The label is affixed to the device or its immediate container.20 The label of a device must prominently disclose the company name, trade name, or trade symbol of the original manufacturer.21 It must also disclose the name and place of business of the manufacturer, packager, or distributor and the quantity of contents in the package.22 The device must be identified by its established or common nonproprietary name (if any).23 Labeling with Adequate Instructions for Use The labeling of a device must provide adequate directions for use and adequate warnings against unsafe use.24 The FDA has historically required 10FFDCA § 510(c), 21 USC § 360(c) (2006). 11FFDCA § 510(d), 21 USC § 360(d) (2006). 12FFDCA § 510(i), 21 USC § 360(i) (2006 & Supp. II 2008). 13FFDCA § 510(p), 21 USC § 360(p) (2006). 14FFDCA § 510(j)(1), 21 USC § 360(j)(1) (2006). 15A label is written matter affixed to a device or its immediate packaging. Labeling includes labels and other written materials accompanying the device (for example, an operator’s manual or detailed product information). The FDA also includes some promotional materials in the scope of labeling. For this chapter, promotional labeling is treated with advertising, below. 16FFDCA §§ 510(j)(1)(A)–(B), 21 USC § 360(j)(1)(A)–(B) (2006). 17FFDCA § 510(j)(1)(D), 21 USC §§ 360(j)(1)(D) (2006). 18FFDCA § 510(j)(2)(B), 21 USC § 360(j)(2)(B) (2006). 19FFDCA § 510(p), 21 USC § 360(p) (2006). 20FFDCA §§ 201(k)–(l), 21 USC §§ 321(k)–(l) (2006). 21FFDCA § 502(u), 21 USC § 352(u) (2006). 22FFDCA § 502(b), 21 USC § 352(b) (2006). 23FFDCA §§ 502(e)(2), (4), 21 USC §§ 352(e)(2), (4) (2006). 24FFDCA § 502(f), 21 USC § 352(f) (2006).

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45 COMPONENTS OF US MEDICAL-DEVICE REGULATION that directions be adequate for a layperson, both as to the conditions for which the device is to be used and as to the safe and effective way to use the device.25 The statute permits the FDA to exempt devices from these re- quirements, which the agency has done by declaring them (or allowing their manufacturers to declare them) to be prescription devices,26 for which the labeling need only be written for healthcare professionals, not laypersons.27 To take advantage of that exemption, however, the labeling must also pro- vide information that permits a healthcare practitioner to use the product safely and for the purpose for which it is intended.28 If a device is intended for use in healthcare facilities or by healthcare professionals, labeling required for a prescription device may be made avail- able solely by electronic means and need not be included physically with the device package.29 Design and Manufacture of Products Every device must be designed, manufactured, packed, stored, and in- stalled in conformity with current good manufacturing practice regulations established by the FDA.30 The regulations mandate use of design validation, investigation of complaints, a corrective and preventive action plan to iden- tify root causes of product nonconformance with standards and specifica- tions and to implement effective actions to prevent recurrence, and a quality system to oversee and ensure compliance with the FDA requirements and internal company procedures.31 Reports of Removals and Corrections A manufacturer or importer must report to the FDA any device correc- tion (for example, a software upgrade, change in operating instructions, or field modification) or removal (for example, recall, field recovery, or replace- ment) if the correction or removal was undertaken to reduce a risk to health posed by the device or to remedy a violation of the FFDCA caused by the device that may have presented a risk to health.32 The FDA has promulgated regulations to implement this provision.33 2521CFR § 801.5 (2009). 26Prescriptiondevices are not the same as restricted devices, although an individual device may be both. See below regarding restricted devices. 27FFDCA § 502(f), 21 USC § 352(f) (2010); 21 CFR § 801.109 (2009). 2821 CFR § 801.109 (2009). 29FFDCA § 502(f), 21 USC § 352(f) (2006). 30FFDCA §§ 501(h), 520(f)(1), 21 USC §§ 351(h), 360j(f)(1) (2006). 3121 CFR pt. 820 (2009). 32FFDCA § 519(g), 21 USC § 360i(g) (2006). 3321 CFR pt. 806 (2009).

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46 MEDICAL DEVICES AND THE PUBLIC’S HEALTH Reporting of Adverse Medical Events by Manufacturers and Importers In general, each manufacturer or importer of a medical device legally marketed in the United States must keep records and make reports to the FDA regarding deaths or serious injuries that the device may have caused or to which it may have contributed.34 Malfunctions that did not cause or contribute to deaths or serious injuries must also be reported if a death or serious injury would be likely to result should the malfunction recur.35 The agency has implemented this authority through regulations.36 Reporting of Adverse Medical Events by Device-User Facilities (Not Manufacturers) Hospitals, ambulatory surgical facilities, nursing homes, and outpatient diagnostic and treatment facilities (other than physician offices) are required to report to the FDA information that reasonably suggests that a device has or may have caused or contributed to the death or serious illness of or seri- ous injury to a patient of the facility.37 There is no comparable user-facility reporting requirement for drugs. This requirement has been implemented through regulations issued by the FDA.38 (Adverse-event reporting is dis- cussed in detail in Chapter 5.) Controls Applicable Only to Higher-Risk Devices Restricted Devices If the FDA determines that a device’s potential for harm or collateral measures necessary for its use are such that there cannot be reasonable as- surance of its safety and effectiveness without the restriction, the agency is authorized to require that the device be restricted to sale, distribution, or use, only on the written or oral authorization of a healthcare practitioner or “upon such other conditions as [the FDA] may prescribe.”39 The statute goes on to suggest both the types of other conditions that the FDA might consider and limitations of these conditions if used: No condition . . . may restrict the use of a device to persons with specific training or experience in its use or to persons for use in certain facilities unless [the FDA] determines that such a restriction is required for the safe and effective use of the device. No such condition may exclude a person 34FFDCA § 519(a), 21 USC § 360i(a) (2006). See 21 CFR pt. 803 (2009) (implementing regulations). 35FFDCA § 519(a)(8), 21 USC § 360i(a)(8) (2006). 3621 CFR pt. 803, subpts. D–E (2009). 37FFDCA § 519(b), 21 USC § 360i(b) (2006). 3821 CFR pt. 803, subpt. C (2006). 39FFDCA § 520(e), 21 USC § 360j(e) (2006).

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47 COMPONENTS OF US MEDICAL-DEVICE REGULATION from using a device solely because the person does not have the training or experience to make him eligible for certification by a certifying board recognized by the American Board of Medical Specialties or has not been certified by such a Board.40 That authority is exercised at the FDA’s discretion and may by imposed in any of three ways: by regulation issued through a notice-and-comment rule-making (usable for devices in any class),41 as part of a performance standard established by notice-and-comment rule-making (usable only for Class II devices),42 or as a condition for the approval of a PMA application (usable only for Class III devices).43 Although the language is quite similar to that used by the FDA to de- termine whether a device should be a prescription device,44 the designations as “restricted device” and “prescription device” are technically distinct. Numerous devices are recognized as “prescription devices” by their manu- facturers and the FDA through labeling and fall under exemptions from the “adequate directions for use” requirements.45 Those devices, however, are not “restricted devices” unless separately designated by the FDA. The FDA has generally used the restricted-device authority via the PMA application process and rarely by regulation (Hutt et al., 2007). Only a very few Class II devices are formally “restricted.”46 As early as 1983, however, the FDA was being criticized in Congress for failing to use its power to impose other conditions on use: The legislative history [of the 1976 amendments] explains that Congress sought to supersede and add to the existing authority used by the FDA to limit sale or use of certain devices except by prescription. Authority beyond prescription was necessary because many . . . believed that major problems arose from misuse of devices by practitioners, and not just from manu- facturing or design defects. Establishing conditions under which devices could be used, or limiting or describing the facilities where they could be used, or the training or qualification of those who use them in treatment, was envisioned as a way to address user-related problems. Controls such as these were not contemplated by the lone previously existing authority to limit devices to a practitioner’s prescription.47 40Id. 41Id. 42FFDCA § 514(a)(1), (b), 21 USC § 360d(a)(1), (b) (2006). 43FFDCA § 515(d)(1)(B)(ii), 21 USC § 360e(d)(1)(B)(ii) (2006). 4421 CFR § 801.109(a) (2009). 45See above regarding “Labeling with Adequate Instructions for Use.” 4621 CFR § 801.420, 21 CFR § 809.30, 21 CFR § 864.4020(d). 47Subcomm. on Oversight and Investigations of the H. Comm. on Energy and Commerce, 98th Cong., Medical Device Regulation: The FDA’s Neglected Child (Comm. Print 98-F).

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48 MEDICAL DEVICES AND THE PUBLIC’S HEALTH Once a device is designated as a restricted device, two additional im- portant legal consequences—apart from limiting access to the device to or through physicians—result: • dvertising and Promotional Materials. The promotion of medical A products is generally regulated by the Federal Trade Commission (FTC), with no official role for the FDA with two exceptions. The FDA has jurisdiction to regulate the advertising of prescription drugs. With regard to prescription devices, however, the agency is given jurisdiction only to regulate advertising for prescription devices that are also restricted devices. The marketer is prohibited from advertis- ing a restricted device with materials that are “false or misleading in any particular.”48 In addition, all advertisements for a restricted device must provide the device’s established or common name (if any) and a brief statement of the product’s intended uses, side effects, and contraindications.49 Because the FDA has declined to restrict almost all Class II devices, responsibility for preventing false or misleading advertising for these devices has remained exclusively with FTC. • nspections. During inspections of manufacturing plants, the FDA is I authorized by one provision of the statute to see the production and distribution records related to restricted devices but not to devices that are not restricted.50 A separate provision, however, empowers the FDA to inspect any records that are required by law to be kept.51 The agency has directed that specific production and distribution records on all devices be kept as part of good manufacturing practice requirements.52 Thus, the failure to designate devices as restricted has not adversely affected the FDA’s ability to examine manufacturing records. Controls Related Only to Class II or Class III Device Tracking The FDA may require a manufacturer to adopt a method for tracking a Class II or Class III device whose failure might be reasonably likely to have serious adverse health consequences, that is intended to be implanted for more than 1 year, or that is a life-sustaining or a life-supporting device 48FFDCA § 502(q)(1), 21 USC § 352(q)(1) (2006). 49FFDCA § 502(r), 21 USC § 352(r) (2006). 50FFDCA § 704(a), 21 USC § 374(a) (2006). 51FFDCA § 301(e), 21 USC § 331(e) (2006). 52FFDCA §§ 501(h), 520(f)(1), 21 USC §§ 351(h), 360j(f)(1); 21 CFR pt. 320, subpt. M.

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49 COMPONENTS OF US MEDICAL-DEVICE REGULATION used outside a device-user facility.53 In 2002, the FDA set forth three new nonbinding criteria in addition to those in the statute to determine whether device tracking might be required: the likelihood of sudden, catastrophic failure; the likelihood of serious adverse clinical outcomes; and the need for prompt professional intervention.54 Tracking requires that the manufacturer keep records of the name and address of each patient who received the device, the physician who prescribed the device, and (if different) the physician who is following the patient. The agency has issued regulations creating the general requirements for complying with this provision.55 The authority to impose tracking re- quirements is discretionary with the FDA and is exercised by an “order” to individual manufacturers covering each affected device.56 Postmarket Surveillance The FDA may require a manufacturer to conduct surveillance of a Class II or Class III device that meets any of the criteria for device tracking (above) or is expected to have substantial use in pediatric populations.57 “Postmarket surveillance” is a specific activity defined by the statute and is not to be confused with “postmarketing surveillance,” which encompasses a wide array of programs, including adverse-event reporting by manufac- turers and user facilities, third-party safety monitoring, and FDA–academic collaborations. Surveillance generally cannot last more than 36 months and must be designed to provide useful data that could reveal unforeseen adverse events or other information necessary to protect public health.58 The FDA has issued general regulations governing requirements when surveillance is ordered.59 Imposing a requirement for surveillance is discretionary with the FDA60 and is done by an “order” to the manufacturer of the affected device or, in the case of pediatric devices, as a condition for clearance of a Class II device or approval of a Class III device.61 53FFDCA § 519(e), 21 USC § 360i(e) (2006). 54Medical Devices; Device Tracking, 67 Fed. Reg. 5,943, 5,944 (Feb. 6, 2002) (codified at 21 CFR pt. 821). 5521 CFR pt. 821 (2009). 5621 CFR § 821.20 (2009). 57FFDCA § 522(a), 21 USC § 360l(a) (2006). 58FFDCA § 522(b), 21 USC § 360l(b) (2006). 5921 CFR pt. 822 (2009). 60FFDCA § 522(a)(1), 21 USC § 360l(a)(1) (2006). 61FFDCA §§ 522(a)(1)(A)–(B), 21 USC §§ 360l(a)(1)(A)–(B) (2006).

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50 MEDICAL DEVICES AND THE PUBLIC’S HEALTH Special Controls Class II devices may be subject to one or more “special controls” to supplement the general controls to provide reasonable assurance of safety and effectiveness.62 The definition of a Class II device specifies that it is a device which cannot be classified as a Class I device because the general controls by themselves are insufficient to provide reasonable assurance of the safety and effectiveness of the device, and for which there is sufficient information to establish special controls to provide such assurance, includ- ing the promulgation of performance standards, postmarket surveillance, patient registries, development and dissemination of guidelines . . ., recom- mendations, and other appropriate actions as [the FDA] deems necessary to provide such assurance63 [emphasis added]. In parallel, the definition of Class III covers devices that cannot be clas- sified as Class I because general controls are insufficient to ensure safety and effectiveness and that cannot be classified as Class II because “insufficient information exists to determine that the special controls . . . would provide reasonable assurance of its safety and effectiveness.”64 The statute does not require, however, that every Class II device be subject to special controls. Although the definitional sentences just quoted state that “general controls . . . are insufficient,” the definition of Class II goes on to provide that for a device that is purported or represented to be for a use in supporting or sustaining human life, [the FDA] shall examine and identify the special controls, if any, that are necessary to provide adequate assurance of safety and effectiveness and describe how such controls provide such assurance65 [emphasis added]. By implication, for a Class II device that is not so represented, the FDA is not even obliged to consider special controls. In addition, the various types of special controls identified in the statute (discussed below) are all written to be discretionary with the agency. As a practical matter, the FDA has always treated special controls as a discretionary matter. Today, roughly 15% of all device types classified in Class II are subject to special controls (Desjardins, 2010). The statutorily authorized “special controls” can include one or more of the following: 62FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006). 63Id. 64FFDCA § 513(a)(1)(C), 21 USC § 360c(a)(1)(C) (2006). 65FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).

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51 COMPONENTS OF US MEDICAL-DEVICE REGULATION • evice tracking (patient registries) and postmarket surveillance, as D discussed above. Each authority is exercised in individual cases by order of the agency. • Performance standards” that are promulgated either by the FDA “ (through an elaborate notice-and-comment rule-making)66 or by a third party and recognized by the FDA (through a simple published notice).67 Performance standards may cover the construction, com- ponents, ingredients, and properties of a device and its compatibility with power systems and connections with these systems; testing requirements; provisions for measurement of performance; and requirements for submission of test results to demonstrate confor- mity. A performance standard may also specify that the device is a restricted device in the same manner in which the FDA might restrict the device under separate authority (see above).68 • DA guidelines, including guidelines on the submission of clinical F data with a 510(k) notification.69 The FDA has adopted a form of notice-and-comment procedure for the adoption of guidelines (which the FDA now calls guidances).70 • DA recommendations. The statute refers only to “recommenda- F tions” without specifying what they might address or how a rec- ommendation would become an enforceable control.71 The agency may, in issuing recommendations, use the same procedures as for guidances.72 • ny “other appropriate actions.” The FDA is authorized to adopt A any other special control that it deems necessary to provide a reason- able assurance of safety and effectiveness.73 For a number of reasons, however, special controls have not trans- formed and cannot transform the 510(k) process into one based on safety and effectiveness rather than one based on substantial equivalence to a predicate device. First, as noted above, only about 15% of all Class II device types are subject to special controls. Second, some premarket special con- trols are focused on a particular aspect of the device, such as medical devices that include an antimicrobial agent, or on generic procedures for conducting research for a class of devices, such as animal studies for cardiovascular 66FFDCA § 514(b), 21 USC § 360d(b) (2006). 67FFDCA § 514(c), 21 USC § 360d(c) (2006). 68FFDCA § 514(a)(2), 21 USC § 360d(a)(2) (2010). 69FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006). 7021 CFR § 10.115 (2009). 71FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006). 7221 CFR § 10.90(c) (2009). 73FFDCA § 513(a)(1)(B), 21 USC § 360c(a)(1)(B) (2006).

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74 MEDICAL DEVICES AND THE PUBLIC’S HEALTH FIGURE 3-1 Federal government, Department of Health and Human Services, and FDA funding, FY 2008. Figure 3-1.eps SOURCE: GAO, 2009a. bitmap ary spending (GAO, 2009b). CDRH’s funding is augmented by user fees. However, as described in Chapter 2, there are limitations to how those funds can be used. The funding for CDRH has grown from $159 million in 1999 to $275.3 million in 2008—a 73% increase (GAO, 2009a). Despite the increase in funding, agency officials reported that the limitations placed on the use of the user-fee funds seriously undermine their ability to meet their responsi- bilities in programs not supported by user fees (GAO, 2002, 2009a). About two-thirds of all the funding for medical-products program centers (both user-fee funding and discretionary funding) supports user-fee–related ac- tivities (for example, submission review). Funding for the program centers increased three times as fast as funding for the FDA’s field operations, which are responsible for inspecting manufacturing facilities (GAO, 2009b). Staffing The FDA is concerned about its ability to attract and retain key staff who have essential expertise, such as biologists, chemists, computer pro- grammers, and epidemiologists (GAO, 2009b). For all the FDA centers— CDRH, the Center for Biologics Evaluation and Research (CBER), and the Center for Drug Evaluation and Research (CDER)—full-time equivalents (FTEs) funded by user fees increased by 113% from 1999 (856 FTEs) to 2008 (1,825 FTEs), whereas FTEs funded through appropriations declined

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75 COMPONENTS OF US MEDICAL-DEVICE REGULATION by 7% from 1999 (4,069 FTEs) to 2008 (3,802 FTEs).139 In an effort to re- duce staffing levels in programs funded through appropriations, the agency offered buyouts to some employees in FY 2004–2006 (GAO, 2009b). CDRH and the Office of Regulatory Affairs (ORA) estimated that they increased their use of contractors to fulfill their responsibilities during that period but were unable to provide the Government Accountability Office (GAO) documentation of total number of contractor hours. The decrease in FTEs resulted in a backlog in work (GAO, 2009b). CDRH staff are required to respond within 90 days of receipt of a 510(k) notification. In 2009, the FDA’s goal was to review 90% of 510(k) submissions within 90 days and 98% within 150 days (GAO, 2009b).140 Given the variability in the 510(k) submissions, FDA staff report that re- view times did not allow sufficient review of complex issues (FDA, 2011a). Over a 7-year period, the number of FTEs dedicated to processing 510(k) submissions has risen dramatically, from 166 in 2003 to 249 in 2009. The number of FTEs dedicated to processing PMA applications has grown from 133 to 152 in the same period (Desjardins, 2011). The FDA reported that it takes about 2 years to train new staff to review applications (GAO, 2009b). This long training period makes average annual turnover of 11–13% in the centers (CDER, CBER, and CDRH) an important issue for the FDA (GAO, 2009b). In 1989, GAO recommended that the FDA collect basic management information, such as staffing (including contractors), to estimate its future needs better (GAO, 1989). The FDA disagreed with that recommendation, indicating that the resources needed to collect the information would detract from the agency’s oversight responsibilities. In a 2009 report, GAO reiter- ated its recommendation with the assertion that the collection of this infor- mation is essential for the agency to be able to fulfill its mission adequately. Without the information, it is also impossible for external groups to verify whether the FDA is fulfilling its oversight requirements and optimizing its performance (GAO, 2009b). Third-Party Review In August 1996, the FDA initiated a voluntary third-party review pilot program for selected devices. The pilot’s purpose was to provide manufac- turers of eligible devices an alternative review process that might yield more rapid marketing clearances and enable the FDA to use its scientific review resources for higher-risk devices. All Class I and 30 select Class II device types were eligible for third-party review. The eligible Class II devices were 139These numbers do not include contractors. 140Compared with PMA reviews, for which the goals are 60% of original PMA submissions within 180 days and 90% within 295 days (GAO-09190).

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76 MEDICAL DEVICES AND THE PUBLIC’S HEALTH subject to a device-specific guidance or a recognized consensus standard. Well-recognized road maps for establishing device performance were con- sidered important in choosing products to be reviewed in the pilot because such documents would, it was believed, standardize the review process among third-party organizations. The FDA developed an accreditation and training process to ensure that third-party reviewers had the capacity to perform credible reviews and to avoid conflict of interest. The 1997 FDAMA formally recognized and extended the program. The FDAMA directed the FDA to accredit third parties to review devices of low to moderate risk and to set limits on the number of Class II devices that would be ineligible for third-party review. In September 1998, the FDA published an expanded list of Class II device types eligible for third-party review for which there were no device-specific guidances or standards. For a third party to review a device not subject to a guidance or standard, it must (FDA, 2009) • ave completed three successful 510(k) reviews in the program. H • gree to contact the appropriate CDRH branch chief or designee to A discuss issues and review criteria. • repare a summary of the discussion and submit it to the Office of P Device Evaluation with its 510(k) review. The third party charges a fee to submitters for review. Once a review has been completed, it must be submitted with a cover letter, a letter from the submitter authorizing submission, a summary of the presubmission dis- cussion described above, the complete 510(k) submission, and a completed review. In addition, there must be a certification that the reported informa- tion accurately reflects the data reviewed. The FDA supervisory official is expected to review the third-party submission and make a decision on the submission within 30 days of receipt. GAO found that often the third-party review could be faster than FDA review for traditional 510(k) submissions but that, as FDA review has be- come more efficient, the number of third-party reviews is likely to decrease (GAO, 2009c). As of February 2011, 670 Class I and Class II device types were eligible for third-party review. No Class II devices that are intended to be perma- nently implanted, that are intended to be life-sustaining or life-supporting, or whose 510(k) submission requires clinical data are eligible for third-party review (GAO, 2009c). Since 2004, about 250 510(k) submissions have par- ticipated in the third-party process per year (see Figure 3-2). Quality assessments were completed on 75% of third-party reviews received during the last 9 months of FY 2005. Overall, major problems were observed by supervisors who reviewed submissions in 31% of reviews;

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77 COMPONENTS OF US MEDICAL-DEVICE REGULATION Percentage of Total 510(k) Received Percentage of Total 510(k)s Received Number of Third-Party 510(k)s Received FIGURE 3-2 Third-party 510(k) submissions as percentage of total 510(k) submissions Figure 3-2.eps received, FY 1999–2009. bitmap SOURCE: FDA, 2010a. the most common problems were lack of rationale for conclusions and rec- ommendations, failure to provide an adequate comparison with a legally marketed device, and failure to resolve deficiencies in the 510(k) submis- sion or to address FDA requests (see Table 3-4) (von Eschenbach, 2007). A review of recall data from 2003–2009 found that 510(k) devices cleared via third-party review were more common among recalled devices than among nonrecalled devices (9.9% vs 7.3%) (IOM, 2011). Given the rate of review deficiencies and the higher recall rate, it is not certain that the program has met its goal of assisting the FDA in reducing its work burden. Information-Sharing and Technology Inadequacies in information-sharing and technology in the FDA are felt at all levels and centers in the agency. In 2007, the FDA produced a strategic action plan that focused on four strategic goals: strengthening the FDA, improving the safety of patients and consumers, increasing access to new medical and food products, and improving the safety and quality of manufactured products and the supply chain (FDA, 2007a). Improvement of the medical-product review process to increase the predictability and transparency of decisions was identified as a priority. The initiatives included in the plan were the integration of premarket-decision information into a

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78 MEDICAL DEVICES AND THE PUBLIC’S HEALTH TABLE 3-4 Frequency of Problems with Third-Party Reviews of 510(k) Submissions % Rated as % Rated as Review Element Minor Issue Major Issue Presubmission consultation with the FDA 15 4 Rationale for conclusions and recommendations 11 6 Comparison with legally marketed devices— 11 5 identification and analysis of key similarities and differences Summary of device characteristics, intended use, 10 4 performance, and reason for 510(k) Organization and format of review documentation 13 1 Use of guidance and standards 10 2 Scope of reviewer expertise 8 3 Resolution of 510(k) deficiencies and FDA requests 3 5 Determination of device eligibility for third-party 3 4 review Determination of 510(k) administrative completeness 6 1 NOTE: Data based on quality assessments completed by FDA supervisors when making final determinations on 510(k)s with third-party review. The FDA initiated the quality assessments in January 2005. SOURCE: Adapted from von Eschenbach, 2007. single comprehensive tracking warehouse accessible to all staff and the pilot testing and evaluation of a Web-based tracking system for premarket review of medical devices (GAO, 2009d). In a 2009 report, GAO found that although the FDA has an information- technology (IT) modernization project underway, it has failed to develop a comprehensive IT strategic plan to inform the modernization process. A plan would include a well-defined set of goals, strategies, milestones, and performance measures and would allow the agency to consider the human, infrastructure, and funding resources needed. Without a clear plan, GAO asserts, the FDA lacks a roadmap needed to develop an effective system (GAO, 2009d). In addition, CDRH has acknowledged that it is difficult for staff to share knowledge throughout the center (FDA, 2011a). The inability to communicate with other staff, seek essential expertise, and share relevant information can be attributed to problems of individual workload, the lack

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79 COMPONENTS OF US MEDICAL-DEVICE REGULATION of a system to institutionalize cross-center communication, the rigidity of review-turnaround expectations, and the presence of multiple information systems (FDA, 2010b). In an effort to address its information-systems issues, the FDA has implemented a number of pilot programs that have met with various de- grees of success. A program called eConsults is intended to facilitate the exchange of scientific information and staff expertise throughout CDRH. The program, in place for 5 years, fosters communication within CDRH by managing expert-consultation requests and allowing staff to access in- formation and analysis as needed (Desjardins, 2011). It prompts discussion among CDRH offices to access different types of expertise in premarket device submissions, postapproval studies, and compliance and enforcement actions (FDA, 2011b). CDRH included several items related to the improvement of IT systems in its 2010 strategic priorities. For example, the iReview program, a pilot application begun in 2008, automated the premarket certification of medi- cal devices. The iReview system is a workflow-management tool intended to automate the end-to-end 510(k) review process and to ensure that work is not duplicated in multiple systems, that technical risk is reduced, that future changes in the 510(k) process can be incorporated easily without af- fecting other applications, and that reviewers, supervisors, and consultants can use one system as a single repository for all 510(k) review status and work products (FDA, 2011c). However, during user-acceptance testing in May 2010, reviewers determined that iReview did not meet the center’s most pressing needs, namely, internal searches, reporting, and electronic document routing. As a result, iReview implementation was canceled, and CDRH will work to improve existing tracking systems to perform key func- tions (Desjardins, 2011). A nother pilot that proved unsuitable was the Appian business- management program introduced in the 2010 strategic priorities. In No- vember 2010, the FDA announced that it would sign a 5-year contract to use this platform in all its centers. The program was intended to improve and align processes between groups and departments and to improve man- agement of several core business processes. Because most of CDRH’s core functions involve knowledge creation, the business-management program did not survive the evaluation process and was determined to be the wrong tool for CDRH’s work (Desjardins, 2011). One successful pilot program is the @work toolset, internally known as Traction. Traction is a collaborative tool that combines the attributes of a wiki and a blog with networking capability to forge connections between people throughout the organization. Traction was piloted by CDRH and is now used throughout the FDA (Desjardins, 2011).

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80 MEDICAL DEVICES AND THE PUBLIC’S HEALTH Finding 3-4 The Center for Devices and Radiological Health faces persistent challenges because of a lack of or limitations on human, fiscal, and technologic resources and capabilities. Quality Assurance The preliminary report of the CDRH 510(k) Working Group finds that “CDRH does not currently have an adequate mechanism to regularly assess the quality, consistency, and effectiveness of the 510(k) program” (FDA, 2010a). That finding is amply supported by the results of the reviewer survey in Appendix D to the preliminary report. The survey asked CDRH personnel who review 510(k) submissions and their managers about their understanding of and opinions on a variety of issues related to making 510(k) substantial-equivalence decisions. In a number of cases, reviewers selected the correct answer only 50–60% of the time, and managers did not do much better (FDA, 2010a). Problems surrounding quality assurance in the 510(k) process are not new. The first public guidance to aid reviewers and industry in the 510(k) decision-making process was not issued until the program had been oper- ating for a decade (FDA, 1986).141 In 1988, GAO found a lack of a clear officewide policy and a lack of coordination among review divisions, and it recommended steps to improve consistency in 510(k) decision-making and documentation (GAO, 1988). The Department of Health and Human Ser- vices inspector general (IG) in 1990 determined that CDRH lacked a com- prehensive quality-control program to evaluate and critique the adequacy of the 510(k) review process independently.142 Three years later, the inspector general issued a follow-up report that concluded that CDRH had focused its quality efforts primarily on the administrative aspects of the 510(k) process, not on the scientific validity of the review decisions.143 CDRH has long required device manufacturers to operate a qual - ity system.144 In an oversimplified description, the regulations prescribe a continuous-improvement process in which specifications and operating procedures are established, persons who have appropriate backgrounds 141Memorandum Re: Medical Device Hearing, May 4, 1987, Medical Devices and Drug Issues: Hearing Before the Subcomm. on Health and the Env’t of the H. Comm. on Energy and Commerce, 100th Cong. 336-47 (1987) (referred to in the statement of Rep. Henry A. Waxman, Chairman, H. Subcomm. on Health and the Env’t). 142Memorandum Re: Internal Control Weaknesses in the Food and Drug Administration’s Medical Device 510(k) Review Process, from the HHS inspector general to the HHS assistant secretary for health (July 5, 1990), 2. 143Memorandum from the principal deputy inspector general to the acting assistant secretary for health, Re: Follow-Up Review on Internal Control Weaknesses in the Food and Drug Administration’s Medical Device 510(k) Review Process (Feb. 26. 1993), 19. 14421 CFR pt. 820.

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81 COMPONENTS OF US MEDICAL-DEVICE REGULATION are trained in the procedures, execution of the procedures is properly documented, and the resulting output is monitored for conformity to the specifications. When a deviation occurs, the manufacturer is to undertake a root-cause analysis and then implement a corrective-action and preventive- action plan to address the root problem and prevent its recurrence (for example, by revising operating procedures, retraining employees, or revis- ing specifications). The continuous-improvement process is overseen by a quality manager or group and executive management of the company. Those basic principles are as applicable to the making of 510(k) clearance decisions—and any other regulatory decisions (such as PMA application approvals and the use of postmarketing tools to address emerging safety concerns)—as to the production of medical devices. The absence of a quality system for the 510(k) process since its inception has important consequences for the future of the process. Prior 510(k) clear- ance decisions are by law binding on the FDA unless a predicate product is removed from the market by the FDA or declared adulterated or misbranded by a federal court.145 The agency is concerned that its authority to rescind prior decisions may be subject to challenge (Shuren, 2011). About 120,000 510(k) submissions have been cleared over the past 35 years (Tillman, 2010). As described in Chapter 2, those actions have by and large built on a chain of devices that link a new postamendment device to earlier postamendment devices that ultimately could be traced back to a preamendment device from 1976. CDRH has never had an effective quality- assurance system in the 510(k) process. In addition, at least in the early years of implementation, the FDA may have biased the review process in favor of finding substantial equivalence to avoid the administrative consequences of placing too many devices in Class III (OTA, 1984). Today, CDRH cannot reconstruct the “piggy-backing” of devices without a manual review of per- haps thousands of files. Even if a computerized database allowed easy access to the history, the agency would have to review every decision manually to identify questionable ones. The cost of the exercise would be staggering; the benefit would be, it is hoped, small in terms of identifying devices that should not have gotten to the market by a 510(k) clearance. However, it cannot be assumed that the number is zero. Finding 3-5 The committee agrees with the CDRH 510(k) Working Group that the Center for Devices and Radiological Health does not have “an adequate mechanism to regularly assess the quality, consistency, and effectiveness of the 510(k) program.” 145FFDCA § 513(i)(2), 21 USC § 360c(i)(2) (2006).

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82 MEDICAL DEVICES AND THE PUBLIC’S HEALTH SUMMARY OF FINDINGS • inding 3-1 The Food and Drug Administration has a wide array F of tools to address safety risks that are discovered to be posed by marketed devices. • inding 3-2 The Food and Drug Administration has not used the F tools at its disposal extensively. The Center for Devices and Radio- logical Health has suggested that there are important limitations in their use. The committee identified some procedural burdens on the exercise of these tools, but these burdens do not in themselves explain the historical and continuing sparse use of the tools. • inding 3-3 The 510(k) clearance pathway is generally more eco- F nomical, faster, and less burdensome to industry and the Food and Drug Administration than the premarket approval application route and has substantially fewer postmarketing controls. • inding 3-4 The Center for Devices and Radiological Health faces F persistent challenges because of a lack of or limitations on human, fiscal, and technologic resources and capabilities. • inding 3-5 The committee agrees with the CDRH 510(k) Working F Group that the Center for Devices and Radiological Health does not have “an adequate mechanism to regularly assess the quality, consistency, and effectiveness of the 510(k) program.” REFERENCES Desjardins, P. R. 2010. FDA response to information inquiry from the committee on the pub- lic health effectiveness of the 510(k) clearance process. Silver Spring, MD, 09/17/2010. ———. 2011. FDA response to information inquiry from the committee on the public health effectiveness of the 510(k) clearance process. Silver Spring, MD, 01/07/2011. Evans, B. 2009. Seven pillars of a new evidentiary paradigm: The Food, Drug, and Cosmetic Act enters the genomic era. Notre Dame Law Review 85(2):419-524. FDA (Food and Drug Administration). 1986. Guidance on the CDRH Premarket Notification Review Program (K86-3) (June 30, 1986). http://www.fda.gov/MedicalDevices/Device RegulationandGuidance/GuidanceDocuments/ucm081383.htm (accessed 02/16/2011). ———. 2005. Guidance for industry and FDA staff—format for traditional and abbreviated 510(k)s. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm084396.pdf (accessed 03/14/2011). ———. 2007a. FDA strategic action plan. http://www.fda.gov/AboutFDA/ReportsManuals- Forms/Reports/StrategicActionPlan/default.htm (accessed 12/3/2010). ———. 2007b. Premarket notification [510(k)] submissions for medical devices that in- clude antimicrobial agents. http://www.fda.gov/MedicalDevices/DeviceRegulationand Guidance/GuidanceDocuments/ucm071380.htm (accessed 05/31/2011). ———. 2009. Third party review. http://www.fda.gov/medicaldevices/deviceregulationand guidance/howtomarketyourdevice/premarketsubmissions/thirdparyreview/default.htm (accessed 02/16/2011). ———. 2010a. CDRH preliminary internal evaluations—Volume I: 510(k) working group pre- liminary report and recommendations. Silver Spring, MD: Food and Drug Administration.

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83 COMPONENTS OF US MEDICAL-DEVICE REGULATION ———. 2010b. CDRH preliminary internal evaluations—Volume II: Task force on the utiliza- tion of science in regulatory decision making: preliminary report and recommendations. Silver Spring, MD: Food and Drug Administration. ———. 2010c. Class II special controls guidance document: Tissue adhesive with adjunct wound closure device intended for the topical approximation of skin. http://www.fda. gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm233027. htm (accessed 05/24/2011). ———. 2010d. General considerations for animal studies for cardiovascular devices. http:// www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ ucm220760.htm (accessed 05/24/2011). ———. 2010e. Postmarket drug safety information for patients and providers. http://www. fda.gov/cder/drugSafety.htm (accessed 12/6/2009). ———. 2011a. 510(k) and science report recommendations: Summary and overview of com- ments and next steps. Silver Spring, MD: Food and Drug Administration. ———. 2011b. FDA-track CDRH office of surveillance and biometrics (OSB) dashboard. http:// www.fda.gov/AboutFDA/Transparency/track/ucm203271.htm (accessed 02/03/2011). ———. 2011c. FDA-track CDRH premarket dashboard. http://www.fda.gov/AboutFDA/ Transparency/track/ucm201070.htm (accessed 02/15/2011). ———. 2011d. Important information on the medical device user fee rates for FY2011. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/Medical DeviceUserFeeandModernizationActMDUFMA/ucm109179.htm (accessed 01/12/2011). GAO (Government Accountability Office). 1988. Medical devices: FDA’s 510(k) operations could be improved. Report to the chairman, Subcommittee on Health and the Environ- ment, Committee on Energy and Commerce, House of Representatives (PEMD-88-14). Washington, DC: General Accounting Office. ———. 1989. FDA resources: Comprehensive assessment of staffing, facilities, and equipment needed (HRD-89-142). Washington, DC: General Accounting Office. ———. 2002. Food and drug administration: Effect of user fees on drug approval times, withdrawals, and other agency activities (GAO-02-958). Washington, DC: General Ac- counting Office. ———. 2009a. FDA’s medical product resources (GAO-09-581). Washington, DC: Govern- ment Accountability Office. ———. 2009b. FDA faces challenges meeting its growing medical product responsibilities and should develop complete estimates of its resource needs (GAO-09-581). Washington, DC: Government Accountability Office. ———. 2009c. FDA should take steps to ensure that high-risk device types are approved through the most stringent premarket review process (GAO-09-190). Washington, DC: Government Accountability Office. ———. 2009d. Information technology: FDA needs to establish key plans and processes for guiding systems modernization efforts (GAO-09-523). Washington, DC: Government Accountability Office. ———. 2011. Testimony before the Special Committee on Aging, U.S. Senate. Medical devices: FDA’s premarket review and postmarket safety efforts (GAO-11-556T). 04/13/2011. Hutt, P. B., R. A. Merrill, and L. A. Grossman. 2007. Food and drug law: Cases and materials. Third edition. New York: Foundation Press. IOM (Institute of Medicine). 2007. The future of drug safety: Promoting and protecting the health of the public. Washington, DC: The National Academies Press. ———. 2010. Public health effectiveness of the FDA 510(k) clearance process: Balancing patient safety and innovation. Washington, DC: The National Academies Press.

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84 MEDICAL DEVICES AND THE PUBLIC’S HEALTH ———. 2011. Public health effectiveness of the FDA 510(k) clearance process: Measuring postmarket performance and other select topics. Washington. DC: The National Acad- emies Press. Kahan, J. S. 2009. Medical device development: Regulation and law, Needham, MA: Parexel International. OTA (Office of Technology Assessment). 1984. Federal policies and the medical devices indus- try. Washington, DC: Congress of the United States, Office of Technology Assessment. Shuren, J. 2011. CDRH summary of public comments; issues for committee to consider. Silver Spring, MD, 01/21/2011. Tillman, D. B. 2010. Understanding the premarket notification (510(k)) process. Presentation given at Public Health Effectiveness of the FDA 510(k) Clearance Process Committee, Meeting 1, March 1, 2010, Washington, DC. von Eschenbach, A. C. 2007. Third party review of medical device premarket notifications. Report to the Committee on Energy and Commerce, U.S. House of Representatives, and the Committee on Health, Education, Labor, and Pensions, U.S. Senate. Washington, DC.