4

The 510(k) Clearance Process

Chapters 2 and 3 outlined the history of medical-device regulation in the United States and the components of the Food and Drug Administration (FDA) medical-device regulatory infrastructure, including the 510(k) clearance process. This chapter discusses the 510(k) process in more detail. It explains how the FDA has implemented its regulatory authorities1 and discusses the challenges faced by the FDA and others affected by the program.

The 510(k) submission is the most common premarket regulatory submission received by the Center for Devices and Radiological Health (CDRH) within the FDA. It applies to device types that are generally considered to pose moderate risk and that are not exempt from premarket review but not to high-risk device types that are subject to premarket approval (PMA). The Government Accountability Office (GAO) estimated that in 2003–2007, 31% (15,472) of all devices entered the market through the 510(k) pathway, 1% through PMA, and 1% through programs such as the humanitarian device exemption. The remaining 67% of device types were exempt from premarket review (Class I devices made up 95% and Class II devices 5% of these) (GAO, 2009c).2 A study of 510(k) submissions from 1996 to 2009 found that more than 80% of 510(k)-cleared devices were classified as Class II, about 10% Class I, and less than 2% Class III devices (IOM,

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1In this report, the phrase regulatory authority refers to the power that the legislature gives the FDA to enforce statutes.

2Data are for the 50,189 devices listed with the FDA by device manufacturers during the period October 1, 2002, through September 30, 2007 (GAO, 2009c).



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4 The 510(k) Clearance Process C hapters 2 and 3 outlined the history of medical-device regulation in the United States and the components of the Food and Drug Adminis- tration (FDA) medical-device regulatory infrastructure, including the 510(k) clearance process. This chapter discusses the 510(k) process in more detail. It explains how the FDA has implemented its regulatory authorities1 and discusses the challenges faced by the FDA and others affected by the program. The 510(k) submission is the most common premarket regulatory sub- mission received by the Center for Devices and Radiological Health (CDRH) within the FDA. It applies to device types that are generally considered to pose moderate risk and that are not exempt from premarket review but not to high-risk device types that are subject to premarket approval (PMA). The Government Accountability Office (GAO) estimated that in 2003–2007, 31% (15,472) of all devices entered the market through the 510(k) pathway, 1% through PMA, and 1% through programs such as the humanitarian device exemption. The remaining 67% of device types were exempt from premarket review (Class I devices made up 95% and Class II devices 5% of these) (GAO, 2009c).2 A study of 510(k) submissions from 1996 to 2009 found that more than 80% of 510(k)-cleared devices were classified as Class II, about 10% Class I, and less than 2% Class III devices (IOM, 1In this report, the phrase regulatory authority refers to the power that the legislature gives the FDA to enforce statutes. 2Data are for the 50,189 devices listed with the FDA by device manufacturers during the period October 1, 2002, through September 30, 2007 (GAO, 2009c). 85

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86 MEDICAL DEVICES AND THE PUBLIC’S HEALTH 2011). About 90% of 510(k) submissions for Class I and Class II devices are cleared by the FDA to enter the market (GAO, 2009c). A number of situations require a manufacturer to submit a 510(k) submission. By regulation, a new 510(k) notification must be submitted if the device is one that the person currently has in commercial distribution or is reintroducing into commercial distribution, but that is about to be signifi- cantly changed or modified in design, components, method of manufacture, or intended use. The following constitute significant changes or modifica- tions that require a premarket notification: (i) A change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemi- cal composition, energy source, or manufacturing process; (ii) A major change or modification in the intended use of the device3 [see Figure 4-1]. Although they are not specified in the 510(k) regulation, there are gener- ally four categories of parties who must submit a 510(k) submission to the FDA (FDA, 2010f): 1. Domestic manufacturers introducing a device into the US market. 2. Specification developers introducing a device into the US market. 3. Repackagers or relabelers who have made labeling changes or whose operations substantially affect the device. 4. Foreign manufacturers or exporters or US representatives of foreign manufacturers or exporters introducing a device into the US market. The 510(k) clearance mechanism rests on the notion of “substantial equivalence.” A device must be found to be substantially equivalent to a predicate device if it is to be cleared through the 510(k) process for com- mercial distribution. To be considered substantially equivalent, devices must meet criteria that are detailed in Figure 4-1. Congress has mandated that the FDA give priority review to PMA appli- cations that have innovative or breakthrough technology.4 There is no legal framework for the FDA to request or consider whether a 510(k)-eligible device is innovative with the review process. IMPLEMENTATION OF THE 510(K) PROCESS The Medical Device Amendments of 1976 provided that all posta- mendment devices were automatically to be classified into Class III—that is, as high risk—with specific exceptions.5 The primary exception involved 321CFR § 807.81 (a)(3). 4FFDCA § 515(d)(5); 21 USC § 360e(d)(5) (2006). 5FFDCA § 513(f)(1), 21 USC § 360c(f)(1) (2006).

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87 THE 510(k) CLEARANCE PROCESS a postamendment device that was “substantially equivalent” to a “type of device” that either was a preamendment device that had not been classified or was not a preamendment device but had already been classified into Class I or Class II.6 Another exception provided that a postamendment device would not be in Class III if the FDA, in response to a petition, classified it into Class I or Class II.7 The ultimate intention was that even postamend- ment devices would be classified, on the basis of risk, into the appropriate category. Until then, any new product proposed for marketing after 1976 would be subject to PMA requirements unless it were substantially equiva- lent to a preamendment device already in Class I or Class II (or not yet clas- sified) or reclassified by the FDA down from Class III. This structure would place enormous resource demands on the agency as technology evolved and newer devices were developed. The agency would either have to process in- creasing numbers of PMAs or have to go through a reclassification process that was procedurally cumbersome, labor-intensive, and time-consuming. Instead, the FDA permitted the manufacturer of a postamendment de- vice to demonstrate “substantial equivalence” to a preamendment device in Class I or II as part of the 510(k) submission. Substantial Equivalence As detailed in Appendix A, the FDA adopted a broad reading of the term substantial equivalence and used the 510(k) pathway to avoid re- quiring PMAs for (or down-classifying) many new and novel devices that would have been placed in Class III (Hutt et al., 2007, supra note 11, 986).8,9,10,11,12 Congress had not defined substantial equivalence in the 1976 law. The FDA’s liberal interpretation permitted the agency to clear 6FFDCA § 513(f)(1)(A), 21 USC § 360c(f)(1)(A) (2006). 7FFDCA § 513(f)(1)(B), 21 USC § 360c(f)(1)(B) (2006). 8Memorandum 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. 345 (1987) (referred to in the statement of Rep. Henry A. Waxman, Chairman, H. Subcomm. on Health and the Env’t). 9Food and Drug Administration Oversight: Hearing Before the Subcomm. on Health and the Env’t of the H. Comm. on Energy and Commerce, 102d Cong., pt. 2, at 1 (1992). 10Memorandum 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. 337 (1987) (referred to in the statement of Rep. Henry A. Waxman, Chairman, H. Subcomm. on Health and the Env’t). 11Medical Devices and Drug Issues: Hearing Before the Subcomm. on Health and the Env’t of the H. Comm. on Energy and Commerce, 100th Cong., 384 (1987) (statement of James S. Benson, Deputy Director, Center for Devices and Radiological Health, Food and Drug Administration, Department of Health and Human Services). 12Guidance on the CDRH Premarket Notification Review Program (K86-3) (June 30, 1986) available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm081383.htm.

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88 MEDICAL DEVICES AND THE PUBLIC’S HEALTH most postamendment devices as substantially equivalent to preamendment devices or even to a postamendment device previously cleared through the 510(k) process (a process known as piggybacking one device onto a series of precedents). By 1989, the agency was concerned that an adverse court ruling on this approach would cripple the 510(k) clearance process and force many new devices into the PMA system. The FDA sought13 and in 1990 obtained congressional ratification of its interpretation when the following language was added to the statute: 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 [the FDA] by order has found that the device – (i) has the same technological characteristics as the predicate device, or (ii)(I) has different technological characteristics and the information sub- mitted that the device is substantially equivalent to the predicate device contains information, including clinical data if deemed necessary by [the 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 technological characteristics” means, with respect to a device being compared to a predi- cate 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.14 Congress did not define predicate device but prohibited the use as a predicate of any device removed from the market by the FDA or found by a court to have been adulterated or misbranded.15 As mentioned in Chapter 3, the FDA has not used these authorities widely. The change provided legal support for the FDA’s policy of piggyback- ing various 510(k) submissions in a string of decisions, so a new product could rely on any lawfully marketed device as a predicate and substantial equivalence to a preamendment device did not have to be established. Also, by being permitted to show that its product was “as safe and effective as” a predicate (instead of merely having substantially equivalent safety and ef- fectiveness), a 510(k) submitter could improve the safety and effectiveness of its device without triggering the risk of being found not substantially 13Medical Device Safety: Hearings Before the Subcomm. on Health and the Env’t of the H. Comm. on Energy and Commerce, 101st Cong. 172 (1989–1990) (statement of James S. Benson, Acting Commissioner, Food and Drug Administration). 14FFDCA § 513(i)(1), 21 USC § 360c(i)(1) (added by SMDA § 12, 104 Stat. at 4523). 15FFDCA § 513(i)(2), 21 USC § 360c(i)(2) (added by SMDA § 12, 104 Stat. at 4523).

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89 THE 510(k) CLEARANCE PROCESS equivalent and having to undergo a PMA review. Thus, a new device might be superior to its predicate and still be substantially equivalent to it. “In this way, the standard for safety and effectiveness in a determination of substantial equivalence will evolve slowly as the prevailing level on the market changes, rather than being tied solely to comparison with a pre- 1976 device.”16 In contrast, the change did not require reliance on the best predicate device, so a product that was truly inferior to the current state of the art could still enter the market if the manufacturer could identify any predicate that had not been removed from the market and to which it was substantially equivalent. Once a device is cleared through the 510(k) process and becomes eligible as a predicate, it cannot be removed from the pool of available predicates unless it has been banned or declared adulterated or misbranded and pulled from the market. The FDA estimates that 29% of the devices that have been cleared either were never marketed or were marketed but are no longer available (FDA, 2010b). Whether that reflects deficiencies in product safety or effectiveness, cost, utility, or competitiveness is not known. Nevertheless, the discontinued (or never launched) products may all serve as predicates for future devices. The FDA is unable to dictate which predicates can be selected for 510(k) decision-making. In some cases, the FDA has published guidance documents advising manufacturers on how to demonstrate the predicate relationship. These guidance documents are nonbinding on the manufacturer or the agency. Devices are constantly updated with minor changes throughout their life cycle for a variety of reasons. The FDA has issued guidance on device modifications and on when a new 510(k) submission is required (FDA, 1997).17 This guidance does not require manufacturers to report all minor changes or series of minor changes to the agency. The decision of when there has been a significant enough change or series of changes to trigger a new 510(k) submission is largely at the discretion of the manufacturer. Incremental design changes are difficult to define and if poorly controlled can lead to device “creep,” in which there is the potential for a marketed device to differ significantly from a device cleared through the 510(k) review. Predicates Identifying an appropriate predicate is a central component of the 510(k) process. The FDA maintains databases that are used to identify predicate devices from a catalog of previously cleared devices. Classifica- tions can be found by searching the Product Code Classification Database. Products are cataloged by using both classification symbols and product- 16H.R.Rep. No. 101-808, at 25. 17Updated guidance was issued by the FDA on July 27, 2011, after the committee had completed its work.

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90 MEDICAL DEVICES AND THE PUBLIC’S HEALTH code symbols, known as procodes. Procodes are unique three-letter product identifiers assigned by the FDA to all products (whether classified or not). The databases can be searched by product name, manufacturer, whether the device is a preamendment or postamendment device, or procode (FDA, 2009c). The critical process of identifying predicates is hampered by problems with data systems and information-sharing within CDRH. The Product Code Classification Database is subject to nuances in spelling, formatting, and errors in entries and is unwieldy and difficult to use.18 In addition, the application of procodes by the FDA has been inconsistent, and there is no user-friendly glossary of this information. Those technical issues often make it difficult to track cleared products (FDA, 2010c). More detailed information on predicate devices can be obtained through a 510(k) summary or a 510(k) statement. A 510(k) summary or 510(k) statement is required for all 510(k) submissions (FDA, 2010e). The 510(k) summary must provide sufficient detail to understand the basis for a de- termination of substantial equivalence (FDA, 2010e). In lieu of a 510(k) summary, the manufacturer can opt for a 510(k) statement. The 510(k) statement is a certification that the manufacturer will provide information supporting the FDA finding of substantial equivalence to any person within 30 days of a written request (FDA, 2010e). The Office of In Vitro Diag- nostics posts a decision summary on line for devices that it clears through the 510(k) program. The Office of Device Evaluation (ODE) does not post decision summaries on line (FDA, 2010h). The FDA has acknowledged that information provided to manufactur- ers for the purpose of identifying predicates is often limited, that 510(k) summaries often lack critical details that might be of value to companies, and that the procode process used in the databases is not transparent (FDA, 2010b). Medical-device manufacturers, in general, agreed with that assess- ment and suggested that the agency eliminate the 510(k) statement and require a standardized summary and a better method of categorizing prod- ucts to allow identification of predicate devices (FDA, 2010d).19 The FDA has proposed posting on line a verified 510(k) summary, photographs and schematics of the device to the extent that they do not contain proprietary information, and information showing how cleared 510(k) devices are re- 18For example, Letter from the Medical Imaging and Technology Alliance to FDA, Docket Number FDA-2010-N-0054-0055 (March 19, 2010); Letter from AdvaMed to FDA Docket Number FDA-2010-N-0054-0058.1 (March 19, 2010); Comments from James W. Lewis, Salus Ventures, LLC to FDA, Docket Number FDA-2010-N-0054-0015.1 (March 8, 2010). 19For example, Presentation by R. Glenn Neuman, New World Regulatory Solutions, Docket Number FDA-2010-N-0054-0010.1 (February 18, 2010); Comments by Charmaine Sutton, The Tamarack Group, Docket Number FDA-2010-N-0054-0014.1 (March 6, 2010); Comments by Beth Johnson, Medline Industries Inc., Docket Number FDA-2010-N-0054-0016.1 (no date given).

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91 THE 510(k) CLEARANCE PROCESS lated to each other and identifying the premarket submission that provided the original data on or validation of a particular product type. This proposal has raised concerns in industry about the protection of proprietary informa- tion (FDA, 2010b, 2010c, 2011a). Once an appropriate predicate has been identified, the objective of the 510(k) submission is to demonstrate that the new device under review is substantially equivalent to the predicate(s). If it is determined that the device under review has different technologic characteristics from the predicate(s), the FDA may request additional information to evaluate whether the new device is as safe and as effective as the predicate. As mentioned in Chapter 2, about 15% of Class II and Class III 510(k) submissions in FY 2005–2007 had new technologic characteristics (GAO, 2009b). The FDA, in an internal review of its 510(k) program, noted the dif- ficulty of making comparisons when new issues of safety and effectiveness have been identified; industry representatives, in public comments, noted a lack of predictability in whether the agency would consider a design or material change important enough to constitute a technologic change that would affect the substantial-equivalence justification. The FDA and industry both noted a lack of consistency in the core evidence being requested by the agency for equivalence decisions; industry suggested that this was a process problem (FDA, 2010b, 2010d). Over the history of the program, systems for tracking and linking 510(k) decisions and predicates have been insufficient (see Chapter 3). As a result, it would be difficult for anyone to trace back the chain of predicates leading to the preamendment device in connection with a device currently on the market. Given that circumstance, the committee finds it important to note that a fundamental difference exists between the 510(k) and PMA pathways. In reviewing a PMA, the FDA must ask, Is this device reasonably safe and effective for its intended use? The 510(k) review asks, Is this device substantially equivalent to some other device whose safety and effectiveness may never have been assessed? Finding 4-1 The 510(k) process determines only the substantial equivalence of a new device to a previously cleared device, not the new device’s safety and effectiveness or whether it is innovative. Substantial equivalence, in the case of a new device with techno- logic changes, means that the new device is as safe and effective as its predicate. Finding 4-2 Current 510(k) decisions have been built on a chain of predicates dating back to devices on the market in 1976. Because data systems in the FDA are inadequate, the agency does not have the ability to trace the supporting decisions.

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92 MEDICAL DEVICES AND THE PUBLIC’S HEALTH Pushing the Limits of Predicates As technology moves forward and more sophisticated devices are de- veloped, the threshold of how predicates can be used in the 510(k) review is expanded and broadened. For the most part, manufacturers prefer to use the 510(k) process rather than the PMA process even for more complex devices because of the burden presented by the PMA process. The incentives for manufacturers to seek entry into the market through the 510(k) process rather than the PMA process are discussed in Chapter 3. The FDA has cited the practice of multiple and “split” predicates as important challenges in the 510(k) review process (FDA, 2010b). 510(k) submissions that use split predicates combine two or more predicates: one or more predicates for claiming intended use and one or more for claiming technologic characteristics. Split predicates have been used for a variety of devices, including devices with incremental changes. 510(k) submissions that use multiple predicates combine functions of more than one predicate device. The FDA’s concern about multiple and split predicates in device submissions stems from an internal analysis that showed a greater mean rate of adverse-event reports related to devices whose 510(k) submissions cited more than five predicates (FDA, 2010b). CDRH’s internal working group recommended further analysis of mul- tiple predicates and issuance of clarifying guidance on the use of multiple and split predicates in an effort to improve transparency and reproducibility of the review process. The center has not proposed stopping the use of mul- tiple predicates (FDA, 2011a). CDRH proposed elimination of or restriction in the use of split predicates. However, industry groups voiced concerns that eliminating or limiting the use of split predicates may have a chilling effect on innovation (FDA, 2011a).20 Key Regulatory Terms The determinations of “intended use” and “indications for use” are critical elements in the 510(k) process because they directly affect the deter- mination of substantial equivalence (see Figure 4-1). To continue through the 510(k) process, a new device must have the same intended use as its predicate. However, a device is not required to have the same indications for use as the predicate (FDA, 2010b). A 510(k) submission may include new or different indications for use as long as they do not affect the safety and effectiveness of the device by having different intended therapeutic, diagnostic, prosthetic, or surgical uses from the predicate. It is important 20In January 2011, CDRH announced that it no longer intends to use the term split predicate. It plans to issue guidance to clarify the circumstances under which it is appropriate to use multiple predicates to demonstrate substantial equivalence (FDA, 2011a).

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93 THE 510(k) CLEARANCE PROCESS 2 FIGURE 4-1 The FDA substantial-equivalence decision tree. Figure 4-1.eps SOURCE: FDA, 2009a. bitmap to note that terms intended use and indications for use were developed for other regulatory purposes but have been adapted by CDRH to be used as part of the substantial-equivalence decision-making process of the 510(k) review (FDA, 1997). As stated above, intended use is one of the legal standards that the FDA is required to adhere to in making a determination about substantial equivalence. The definition of a device in the statute twice uses the standard of something that is “intended for use” in disease or in affecting body struc-

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94 MEDICAL DEVICES AND THE PUBLIC’S HEALTH ture or function.21 The safety and effectiveness of a device are judged with respect to persons for whose use the device is intended and with respect to the conditions of use suggested in the labeling.22 The FDA’s regulations state that the intended uses of a device are “objectively” determined based on the persons legally responsible for the labeling of the device by written or verbal statements of those persons (for example, in product labels and labeling, marketing materials, or in reports to investors) or the circumstances surrounding the distribution of the de- vice.23 The uses that a seller intends for its product thus govern whether the agency has jurisdiction over the product and whether the product is a device, drug, or biologic. The phrase indication for use is not found in the statute. It is adapted from the regulations for the PMA process,24 which are in turn patterned on the prescription-drug approval process.25 The phrase is a key part of the essential directions to a healthcare practitioner on using the product safely and effectively. For prescription-drug approvals, the FDA created a standard format for labeling, which includes an “indications for use” section that describes the purpose of the drug in relation to a disease or condition (such as to diagnose, prevent, or treat for a named disease or a manifestation of the disease).26 The full prescribing information in the labeling must also contain sufficient details to provide for the safe and effective use of the drug, including such information as dosage forms, dose ranges, routes of admin- istration, duration of use, contraindications, and precautions. In the FDA’s view, approved labeling content was “authoritative,” not “definitive.” For medical devices, “indications for use” provides a description of the patient population and disease or condition that the device will diagnose, treat for, prevent, cure, or mitigate.27 The indications for use are meant to represent a relatively precise description of the clinical applications of the device. Indica- tions for use may be derived from clinical studies, may originate from the history of the predicate-device use, or may be defined by the manufacturer. A difference between intended use and indications for use from a regu- latory perspective is that indications for use are contained in the product labeling provided by the seller, whereas intended use may also be found in other marketing materials and activities of the seller. A 510(k) submission does not have to contain the full final labeling. However, the submission does include proposed labels, labeling, and advertisements, which should 21FFDCA § 201(h) (2), (3). 22FFDCA § 513(a) (2) (A), (B). 2321 CFR § 801.4. 2421 CFR § 814.20(b)(3)(i). 2521 CFR § 201.57. 2621 CFR § 201.5 7(c)(2). 2721 CFR § 814.20(b)(3)(i).

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95 THE 510(k) CLEARANCE PROCESS be in sufficient detail to describe the device, its intended use, and the direc- tions for its use.28 510(k) submissions have only to include a statement of the submitter’s intended use of the device. The distinction between intended use and indications for use is further complicated by the difficulty of clearly differentiating a medical device’s general “tool” use and its therapeutic or clinical applications (FDA, 2010b). Devices may span the spectrum of tool and clinical applications: • device that has a well-established general intended use as a tool A but does not have specific clinical indications for use, such as medical imaging platforms and general surgical devices (for example, suture material, clamps, and retractors). • device that has well-established general intended use as a tool and A has been expanded to include one or more specific clinical indications for use (such as a surgical laser that evolves to be used specifically for the removal of tattoos or an ablation device that has a general tool use of destruction of soft tissue and has evolved to be used for treatment for specific types of cancer). • device that would not be considered a general tool and has only a A specific clinical intended use and indication for use, such as a joint replacement. Determining the intended use and indications for use of medical devices at either end of the foregoing spectrum is relatively straightforward. Prob- lems can arise, however, with devices that fall in the center of the spectrum, that is, general tools that are evolving into devices that have explicit and specific uses that are no longer consistent with use as a general tool. Device types that are general tools can often be used for multiple clinical purposes, in multiple clinical disorders, and in multiple anatomic locations. In the 510(k) process, it is possible that those types of devices could be required to provide evidence to support the clinical utility of every possible indication, disease state, and anatomic location for the device even if the intended use has not changed. For many devices, that could be an onerous and unreasonable burden. Some devices, however, evolve so that new versions can be used only for specific clinical indications, such as an ablation device that evolves to be used only for tattoo removal. Given the structure of the 510(k) process (see Figure 4-1), these devices, which are used only for specific clinical in- dications, may still be able to cite a predicate with a general tool intended use. Manufacturers may not, however, promote an indication for use that is not cleared by the FDA through a 510(k) submission or approved as part 2821 CFR § 807.87(e).

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112 MEDICAL DEVICES AND THE PUBLIC’S HEALTH FIGURE 4-3 Number of 510(k) review cycles, FY 2002–2008. NOTE: NSE, not substantially equivalent; SE, substantially equivalent. Figure 4-3.eps SOURCE: FDA, 2010b. bitmap not meet the mandates (FDA, 2010d). The FDA has stated that its resources are strained, given the complexity of submissions for innovative devices; these submissions require more FDA staff time and generally involve more review cycles (see Figure 4-3). It is possible to assume that complex 510(k) submissions are skewing the response times and increase review cycles, but without a detailed file review it is not possible for the present committee to determine whether this is the case. Design Controls The committee was given findings of two studies of the FDA’s recall database (IOM, 2011). The studies assessed recalls associated with 510(k)- cleared products. Among the many measures assessed were the causes be- hind recalls of Class I 510(k)-cleared devices. Each study presented the recall data by reasons for the recall. The analysis conducted by Hall suggested that 55% of Class I recalls were related to postmarket issues and 45% to premarket issues (IOM, 2011). The analysis conducted by Maisel similarly concluded that about 57% of recalls were due to manufacturing process or device design (IOM, 2011). Given the results of those studies, it is clear that design issues and controls are worth examining more closely. The FDA requires manufacturers of medical devices to implement

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113 THE 510(k) CLEARANCE PROCESS quality system regulations (QSRs),43 which establish current good manu- facturing practice requirements for “methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, in- stallation, and servicing of all finished devices intended for human use.” The requirements are intended to ensure the safety and effectiveness of medical devices. 21 CFR Part 820 includes general descriptions and suggestions for establishing the following elements of a manufacturing process: • A management subsystem. • Design and development controls. • Production and process controls. • Corrective and preventive actions. The regulation requires manufacturers to have the QSRs in place but provides only general guidance for its implementation, not device-specific guidance. The adoption of design control requirements was driven by stud- ies performed by the FDA in the mid-1980s that evaluated the causes of recalls of medical devices. The studies revealed that almost 50% of recalls were attributed to the design and development phase of device manufacture. The FDA had no systematic means of tracking design and development is- sues. The controls described below would provide a paper trail for the FDA to follow if it inspects a facility involved in a recall. Despite the mandatory implementation of this requirement, device design is still responsible for almost half all Class I and Class II recalls (IOM, 2011; Shuren, 2010). Manufacturers are required to have design and development controls for all Class II and Class III devices and for several types of Class I devices: any device automated with software, catheters for tracheobronchial suc- tion, surgical gloves, protective restraints, a manual radionuclide applicator system, and a teletherapy radionuclide source. The ultimate implementation and approval of this management structure is left up to the manufacturer; the FDA provides only guidance and suggestions for implementation. A key element of the design-controls system is a list of documents that must accompany each device type produced by the manufacturer and must be maintained by the manufacturer and be available for review in the event of an inspection. The list includes the following: • Design inputs. • Design outputs. • Design review before transfer from design to manufacturing. • Design validation. • Design verification. 4321 CFR pt. 820.

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114 MEDICAL DEVICES AND THE PUBLIC’S HEALTH • Design transfer. • Design changes. This collection of documents forms what is referred to as the device history record and forms a portion of a larger device master record. The master record describes the life of the device through design iterations, modifications, as well as other documents, and it should contain all relevant information about the design of the device. The master record is what the FDA reviews during an inspection. Manufacturers typically have multiple products and multiple models of each product, however, and each model has a device history record (DHR). An FDA investigator is generally able to review only a small portion of all the manufacturer’s DHRs. It is not clear whether the documents required by the FDA are helpful in determining the reason for a recall or whether the documents provide the information necessary for improving the product or process to eliminate the reason for a recall. CDRH can request that design-control information be included in a 510(k) submission (FDA, 2010b). The committee did not find data on how often design-control information is requested by CDRH staff as part of 510(k) reviews. CDRH noted in its preliminary internal evaluation that center staff have not received sufficient guidance and training in requesting this type of information from submitters or in when such information is necessary for deciding whether to clear a device (FDA, 2010b). Device Labeling within the 510(k) Review General labeling requirements are applicable to various types of de- vices. There is one general set for over-the-counter devices and another for prescription devices.44 The prescription-device regulation, for instance, says that the label must “[bear] information for use, including indications, ef- fects, routes, methods, and frequency and duration of administration, and any relevant hazards, contraindications, side effects, and precautions under which practitioners licensed by law to administer the device can use the device safely and for the purpose for which it is intended, including all pur- poses for which it is advertised or represented.”45 This general rule would apply to any prescription device, whether 510(k)-exempt, 510(k)-cleared, or PMA-approved. Moreover, in a few cases, the FDA has issued specific labeling requirements for particular devices.46 Specifically for 510(k)-cleared devices, the 510(k) notification must include “proposed labels, labeling, and advertisements sufficient to describe 44See Chapter 2 and CFR pt. 801. 4521 CFR § 801.109. 46E.g., 21 CFR § 801.435 (device-specific labeling for latex condoms).

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115 THE 510(k) CLEARANCE PROCESS the device, its intended use, and the directions for its use.”47 The FDA is able to review the draft labeling and can negotiate with manufacturers on the text particularly for devices for which clinical study results are included. The final labeling is not cleared as part of the 510(k) clearance. The FDA, how- ever, uses the proposed labeling to determine a device’s intended use for pur- poses of determining substantial equivalence. Moreover, the draft labeling of a 510(k)-cleared device may be changed at any time—even before initial marketing—not only without FDA approval but even without submission to the FDA. The FDA’s guidance includes information about when labeling changes should be included in a new 510(k) submission. 510(k) sponsors are obliged to “maintain in the historical file any labeling or advertisements in which a material change has been made anytime after initial listing.”48 The FDA investigators might come across the change when conducting an inspection or when investigating a device problem. Otherwise, the FDA can be unaware of labeling changes made once a device is on the market. In comparison, for PMA-approved devices, labeling is approved as part of the PMA approval process. After PMA approval, all proposed label changes that affect the safety and effectiveness of a device must be submit- ted to the FDA, and, with a few exceptions (for example, newly acquired information that warrants an immediate strengthened warning or new contraindication), all changes must be approved by the agency before they go into effect. As discussed above, given that the FDA has relatively narrow mecha- nisms for addressing off-label use even when substantial risks are identified, it is often in the position of having to make decisions about substantial equivalence without complete information about how the device will be used once it is cleared. DE NOVO PREMARKET REVIEW The classification system introduced in the Medical Device Amend- ments of 1976 had provisions that designated all new medical devices that were introduced into the medical marketplace without predicates as Class III devices on the basis of their novelty regardless of risk. As a result, low- 4721 CFR § 807.87(e). 4821 CFR § 807.31(b). According to the FDA, material changes include any change or modification in the labeling or advertisements that affects the identity or safety and effectiveness of the device. These changes may include changes in the common or usual or proprietary name, declared ingredients or components, intended use, contraindications, warnings, or instructions for use. Changes that are not material may include graphic layouts, grammar, or correction of typographic errors that do not change the content of the labeling; changes in lot number; and, for devices whose biologic activity or known composition differs in each lot produced, the labeling that states the actual values for each lot.

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116 MEDICAL DEVICES AND THE PUBLIC’S HEALTH risk or moderate-risk but novel devices would require a PMA application (FDA, 2010g). The FDAMA remedied that cumbersome feature of classification by amending Section 513(f)49 to provide a new mechanism to reclassify statu- torily classified Class III devices. The new mechanism, referred to as the Evaluation of Automatic Class III designation (also called de novo or risk- based classification), allowed the FDA to streamline its approach to down- classification of devices that it deemed to be low or moderate risk. A device placed into Class I or Class II may be exempt from premarket review or be eligible for 510(k) review. A device placed into Class III will require a PMA application (FDA, 2010g). Under the de novo process, the manufacturer must first provide a 510(k) submission. Once the FDA has issued a not-substantially-equivalent (NSE) letter, the manufacturer has 30 days to request a risk-based classification determination be made for the device. The request must describe the device and provide detailed information and reasons for any recommended clas- sification. Not later than 60 days after the date of the submission of such a request, the agency must determine a classification by written order that places the device into one of the three statutory device classes: • Class I device and may enter the market with no special control. • Class II device for which a special control is required. • Class III device type and is required to go through the PMA process. Under the new classification provision, the FDA can assign new devices without predicates to Class I if the general controls are sufficient to provide reasonable assurance of safety and effectiveness and into Class II if special controls are needed to accomplish the same goal. In the absence of a predi- cate, substantial equivalence is no longer the operative review criterion. The submission must on its own (de novo) be found to be safe and effective. Once classified, the new product can serve as a predicate for future devices (FDA, 2010g). For the reclassified Class II devices, the de novo process can be cum- bersome and lengthy. As a part of the de novo review and classification, a special control needs to be developed and published before the classification is completed. In most cases, the device is new and no pre-existing special control is available. The FDA expressed concerns about the scientific chal- lenge of crafting special controls to address risks associated with new devices and about the time required to develop guidances (FDA, 2010b, 2010d). Manufacturers often know before they enter the 510(k) submission that a device will be found NSE and will require a de novo review. Many manu- 4921 USC § 360c(f).

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117 THE 510(k) CLEARANCE PROCESS 7 6 4 4 3 2 3 1 1 0 0 0 FIGURE 4-4 Number of de novo requests received, CY 1998–2009. Figure 4-5.eps NOTE: ODE, FDA Office of Device Evaluation; OIVD, FDA Office of In Vitro bitmap Diagnostic Device Evaluation and Safety SOURCE: FDA, 2010b. facturers have preliminary discussions with the FDA regarding the types of information needed for the FDA to assess a new device’s risk profile. That profile will be used to justify placement of the device into the appropriate classification (IVD Roundtable, 2002). An industry-sponsored report indicated that the long timelines required to process de novo submissions detracted from the value of the program (Ladin and Imhoff, 2010). From the beginning of the de novo program in 1998 to 2009, the FDA received 119 de novo requests (see Figure 4-4) (FDA, 2010b). The FDA found that the average review time for in vitro diagnostic devices going through the de novo process increased from 261 days in 2005 to 448 days in 2009 (see Figure 4-5). There was a greater increase in review time for therapeutic devices, from 254 days in 2005 to 752 days in 2009 (see Figure 4-5) (FDA, 2010b). An industry-sponsored review of the de novo process found that only 54 de novo requests had resulted in clearance; 38 referred to in vitro diagnostic devices, 16 to therapeutic devices (Ladin and Imhoff, 2010). Finding 4-9 Because of administrative constraints that make it bur- densome for both manufacturers and the FDA, the de novo process has not met its potential as an alternative regulatory pathway for moderate-risk but novel medical devices.

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118 MEDICAL DEVICES AND THE PUBLIC’S HEALTH FIGURE 4-5 Average total time from 510(k) receipt to de novo approval, CY Figure 4-6.eps 2005–2009. bitmap NOTE: IVD, in vitro diagnostic. SOURCE: FDA, 2010b. SUMMARY OF FINDINGS • inding 4-1 The 510(k) process determines only the substantial F equivalence of a new device to a previously cleared device, not the new device’s safety and effectiveness or whether it is innovative. Substantial equivalence, in the case of a new device with technologic changes, means that the new device is as safe and effective as its predicate. • inding 4-2 Current 510(k) decisions have been built on a chain of F predicates dating back to devices on the market in 1976. Because data systems in the FDA are inadequate, the agency does not have the ability to trace the supporting decisions. • inding 4-3 The key regulatory terms intended use and indications F for use are poorly defined and are susceptible to varying interpre- tations that lead to inconsistency in decision-making and create confusion among FDA staff, industry, Congress, the courts, and consumers. • inding 4-4 The 510(k) clearance process does not consistently F recognize distinctions among devices cleared solely as tools, those

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119 THE 510(k) CLEARANCE PROCESS cleared for specific clinical applications, and general tools that also have specific clinical applications. • F inding 4-5 There are no reliable tools for collecting data on the clini- cal use of and health outcomes related to devices cleared by 510(k) so that such data could become available for regulatory, healthcare policy, and medical decision-making purposes. • F inding 4-6 Insufficiency of information about how devices are used and perform once they are on the market adversely affects the ability of the FDA to evaluate devices’ intended uses, indications for use, and substantial equivalence in a 510(k) review. • F inding 4-7 A number of Class III devices continue to be cleared through the 510(k) process rather than, as Congress has always intended, through the PMA process. • F inding 4-8 There is no consistent approach for how the FDA de- termines the need for clinical data, the type of such data, and the manner in which such data, if available, are integrated into the decision-making process. • F inding 4-9 Because of administrative constraints that make it bur- densome for both manufacturers and the FDA, the de novo submis- sion process has not met its potential as an alternative regulatory pathway for moderate risk but novel medical devices. REFERENCES Bridges, J., and W. H. Maisel. 2008. Malfunctions and adverse events associated with off-label use of biliary stents in the peripheral vasculature. American Journal of Therapeutics 15(1):12-18. 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. FDA (Food and Drug Administration). 1997. Deciding when to submit a 510(k) for a change to an existing device. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ GuidanceDocuments/ucm080235.htm (accessed 08/20/2010). ———. 1998. Guidance for institutional review boards and clinical investigators: “Off-label” and investigational use of marketed drugs, biologics and medical devices. http://www.fda. gov/oc/ohrt/irbs/offlabel.html (accessed 03/7/2011). ———. 1999. Guidance for cardiovascular intravascular filter 510(k) submissions. http://www. fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ ucm073777.pdf (accessed 03/14/2011). ———. 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. Guidance for industry and FDA staff—Recognition and use of consensus standards. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Guidance Documents/ucm077274.htm (accessed 02/16/2011).

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