6

External Factors That Affect the Medical-Device Regulatory System

Chapters 3, 4, and 5 review and analyze how the Food and Drug Administration (FDA) regulates medical devices. However, that regulatory process does not exist in isolation. It is a part of a broad landscape consisting of such additional factors as the increasing complexity of medical devices, the process of innovation, the business environment in which medical devices are developed, and the international medical-device regulatory arena. This chapter explores those factors and how they have the potential to affect the regulation of medical devices in the United States.

THE GROWING NUMBER AND COMPLEXITY OF MEDICAL DEVICES

The number of 510(k) submissions to the FDA varies from year to year (see Figure 6-1). In 1976, fewer than 1,000 510(k) submissions were received by the FDA’s Center for Devices and Radiological Health (CDRH). The number of submissions reached about 7,000 in 1989 (in part because of a change in the status of examination gloves from 510(k)-exempt to non-exempt). In 2009, about 4,000 submissions were received (FDA, 2010a). The number of 510(k) submissions declined most dramatically from the early 1990s to the middle 2000s. At least three changes occurred during this time, which might have impacted 510(k) submission numbers.

The first change was publication of the Temple report in 1993, a review of the quality of clinical science submitted to CDRH in support of 510(k) submissions and PMA applications (FDA, 1993). The report was critical, observing (albeit on the basis of a small sample of PMA applications and



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6 External Factors That Affect the Medical-Device Regulatory System C hapters 3, 4, and 5 review and analyze how the Food and Drug Administration (FDA) regulates medical devices. However, that regulatory process does not exist in isolation. It is a part of a broad landscape consisting of such additional factors as the increasing complexity of medical devices, the process of innovation, the business environment in which medical devices are developed, and the international medical-device regulatory arena. This chapter explores those factors and how they have the potential to affect the regulation of medical devices in the United States. THE GROWING NUMBER AND COMPLEXITY OF MEDICAL DEVICES The number of 510(k) submissions to the FDA varies from year to year (see Figure 6-1). In 1976, fewer than 1,000 510(k) submissions were received by the FDA’s Center for Devices and Radiological Health (CDRH). The number of submissions reached about 7,000 in 1989 (in part because of a change in the status of examination gloves from 510(k)-exempt to non- exempt). In 2009, about 4,000 submissions were received (FDA, 2010a). The number of 510(k) submissions declined most dramatically from the early 1990s to the middle 2000s. At least three changes occurred during this time, which might have impacted 510(k) submission numbers. The first change was publication of the Temple report in 1993, a review of the quality of clinical science submitted to CDRH in support of 510(k) submissions and PMA applications (FDA, 1993). The report was critical, observing (albeit on the basis of a small sample of PMA applications and 149

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150 MEDICAL DEVICES AND THE PUBLIC’S HEALTH FIGURE 6-1 Original 510(k) submissions to CDRH, FY 1976–2009. Figure 6-1.eps SOURCE: FDA, 2010a. bitmap 510(k) submissions containing clinical data) that studies submitted in sup- port often failed to meet fundamental scientific standards. In response, the FDA initiated recruitment of additional scientists, including physicians and scientists, to perform premarket review of devices. While the review standard for 510(k) submissions was unchanged (that is, substantial equiva- lence), the review determinations began to shift from a descriptive to a data-driven base. The second change was issuance of FDA’s final guidance, in January 1997, advising industry as to when modifications to a cleared device could be made without submitting a new 510(k) notification (FDA, 1997).1 This guidance gave manufacturers autonomy in making decisions about devices with changes that were sufficiently minor as to preclude the need for premarket review. Finally, passage of the FDA Modernization Act in 1997 resulted in exemption of most Class I and many Class II devices from premarket review.2 This Act resulted in decreased numbers of low-risk and, in some cases, moderate-risk devices subject to premarket review. Those changes in administration, regulation, and statue might have had an effect on the volume of 510(k) submissions. The committee was unable to draw conclusions, however, on the basis of the available data as to whether innovation was influenced in any way by these changes. 1Updated guidance was issued by the FDA on July 27, 2011, after the committee had completed its work. 2Food and Drug Administration Modernization Act of 1997, Pub. L. No. 105-115, 111 Stat. 2296 (1997).

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151 EXTERNAL FACTORS FIGURE 6-2 Number of 510(k) product codes, 1990–2009. SOURCE: FDA, 2010a. Figure 6-2.eps bitmap The number of types of medical devices also has grown. The FDA uses product codes to identify generic categories of devices. The product codes are organized by 16 medical specialties (for example, cardiovascular, general and plastic surgery, and orthopedic), and the medical specialties are listed in the Code of Federal Regulations.3 From 1990 to 2009, more than 1,000 product codes were added (see Figure 6-2). In addition to the increase in 510(k) submissions to CDRH and the greater variety of types of products that CDRH must review, submissions have become longer and more detailed. As shown in Figure 6-3, the average number of pages per 510(k) submission in 2008 was more than seven times the number in 1983. In 2008, CDRH staff reviewed nearly 1.4 million pages of 510(k) submissions. Reasons for the increase in the length of 510(k) sub- missions are not readily apparent. The committee was not able to determine how often some types of data (for example, clinical data, bench-testing data, software-validation data, and labeling-comprehension studies) are included in 510(k) submissions, nor was it able to review a representative sample of complete (that is, not redacted) 510(k) submissions. The technologic complexity of medical devices has increased sub - stantially over the past 35 years as well. A 2010 FDA report states that “devices are unique among medical products in that they are defined by innovation, either through incremental evolution or disruptive revolution” 321 CFR §§ 862–892.

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152 MEDICAL DEVICES AND THE PUBLIC’S HEALTH FIGURE 6-3 Pages per 510(k) submission and total page volume received, 1983–2008. SOURCE: FDA, 2010a. (FDA, 2010b). Examples of new technologies in medical devices are soft- Figure 6-3 ware (incorporated in medical devices and as stand-alone medical devices), nanotechnology, and medical robotics. The evolution (and revolution) of science and technology creates many challenges related to the regulation of medical devices. As medical devices become more complex, so do 510(k) submissions. As a result of the complexity and the increasing number and size of 510(k) submissions received each year, the burden on CDRH review staff is increas- ing (see Chapter 3). The growing complexity of medical devices also affects how the medical-device industry approaches the 510(k) clearance process. For example, industry representatives have indicated that they view the increased length of 510(k) submissions as a response to the lack of predict- ability in decision-making by CDRH. To avoid delays in clearance of their products, industry includes more information in the submissions than it might have in the past.4 Multiple Predicates and Split Predicates As detailed in Chapters 3 and 4, predicates are used in the 510(k) clearance process as the basis for demonstrating substantial equivalence. The increasing complexity of medical devices is reflected in how predicates 4FDA Docket Number FDA–2010–N–0054.

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153 EXTERNAL FACTORS are selected and used. Applicants may submit more than one predicate for several reasons, including these: • he applicant is not sure which predicate is the most appropriate. T • he submission is part of a bundled submission. T • he new device combines functions of more than one predicate T device, so the applicant submits more than one predicate (termed multiple predicates) to demonstrate substantial equivalence of the new device. • he new device has the same intended use as one predicate and the T same technologic characteristics as another predicate (termed split predicates).5 Multiple predicates and, in some cases, split predicates are cited in more than half the 510(k) submissions (FDA, 2010a). In general, multiple and split predicates are used in 510(k) submissions for new devices that are more complex than the predicates. Using more predicates leads to longer CDRH review times (FDA, 2010a). It is not clear whether the increase in review time of devices that have multiple predicates is related to the number of predicates or to the increased complexity of the devices. It may be ap- propriate for multiple and split predicates to play a role in premarket review of Class II devices if the CDRH review team has the necessary expertise to ensure a high-quality review and if appropriate postmarket activities (for example, postmarketing surveillance) are used. Combination Products Combination products are therapeutic and diagnostic products that combine drugs, devices, and biologic products (FDA, 2008). As new tech- nologies emerge and older technologies evolve, combination products are increasingly complex. Over the past decade, it has been increasingly com- mon to enhance the performance of medical products by using multiple products together. For example, a genetic test that is a 510(k)-cleared or a premarket-approved (PMA) device may be used with a drug or biologic with the aim of identifying patients whose genetic characteristics place them at heightened risk for drug-related injuries, or a stent that is a medical device may be coated with a drug with the aim of reducing complications associated with the stent or altering the underlying pathologic condition for which the stent was placed. Combined uses of medical products present complex regulatory issues because the resulting treatment or diagnostic test 5In 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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154 MEDICAL DEVICES AND THE PUBLIC’S HEALTH incorporates multiple components that cut across the traditional categories of FDA regulation—drug, device, and biologic. In response to a growing trend toward combined uses of medical prod- ucts, Congress called for the FDA to establish an Office of Combination Products (OCP) in the Medical Device User Fee and Modernization Act of 2002. Combination product is a term of art that has a specific meaning.6 To qualify as a combination product, the two (or more) constituent prod- ucts need to be integrally combined or mixed with one another, packaged together in a single package as a unit, or, if packaged separately and in the particular circumstance of being used in combination, cross-labeled in a way that makes it clear that one is specifically intended for use with another product that is “individually specified” in the labeling. By that definition, the mere fact that products happen to be used together in clinical practice does not necessarily make them combination products for purposes of the FDA’s regulations. If products are simply used together in practice without constituting a combination product, each product retains its separate iden- tify and is regulated separately. For example, a drug would be regulated as a drug and a device as a 510(k)-cleared or PMA-approved device. However, even in that circumstance, OCP may play a role in the clearance or approval process for the device, as is discussed in more detail later in this section. When a pair or set of products does meet the definition of a combina- tion product, special regulatory provisions apply. The aim is to reconcile conflicts that would otherwise make it difficult to comply with drug, device, and biologic regulations. On the basis of the combination’s primary mode of activity—that is, whether the combination achieves its medical purpose primarily through the action of the drug, the biologic, or the device—pri- mary responsibility for premarket review is assigned to one of the FDA’s cen- ters—the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, or CDRH. The responsible center, while having primary jurisdiction over the combination, will work closely with the other centers to ensure appropriate oversight of issues related to the combinations of other components. Because postmarket regulatory requirements also dif- fer for drugs, biologics, and devices, OCP in 2008 prepared a proposed rule on postmarketing safety reporting for combination products (FDA, 2008).7 A final rule has not been published as of May 2011. Information for FY 2008 indicate that a large percentage of combination products involve 510(k)-cleared devices. There were 330 original applica- tions related to combination products. Of those, 120 were original 510(k) submissions, 2 were original PMA applications, 14 were original new drug applications, and 4 were original biologic license applications. The remainder 621 CFR § 3.2(e). 774 Fed. Reg., 50,744 (October 1, 2009).

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155 EXTERNAL FACTORS consisted of 158 applications for investigational new drug status and 32 for investigational device exemptions (FDA, 2008). Thus, many combination products enter the market on the basis of having the primary mode of activity of the incorporated 510(k)-cleared device. OCP also has a role in situations in which such products as medical devices and drugs are used in concert but not as true combination prod- ucts. OCP may act as a convener and facilitator in developing guidance documents. Guidance documents can influence the regulatory review of medical devices. For example, imaging tests use devices, such as magnetic resonance imaging (MRI) and computed axial tomography machines; they may use contrast agents, such as gadolinium and iodinated contrast agents that are regulated as drugs; and they may use software, which is regulated as a device, for the reconstruction and processing of the resulting data. Guidance coordinated through OCP has influenced the review of software devices on the basis of perceived limitations imposed by the specific lan- guage that describes the indications for use of the contrast agents (FDA, 2009a). For example, the use of MRI contrast agents that are approved for use in imaging of the abdomen, but not specifically imaging of the liver or kidneys, might limit the ability of CDRH to review a software tool that analyzes data produced by approved MRI machines after administration of the MRI contrast agents if the data analyzed pertain to the liver or kidneys. Guidance documents may stymie innovation in software tools that would be used merely to analyze data that are being acquired daily in a clinical setting. Because the contrast agent is readily available for use in clinical practice, there is no practical mechanism whereby the software company can influence the supplier of the contrast agent to apply for expanded or specific new label indications. Finally, the acceleration of device evolution is leading to increasingly novel devices that could not have been conceived of when the 1976 Medical Device Amendments and later amendments were written and enacted. For example, nanodevices include particles that are activated by biologic and pathologic processes, and some of them depend on metabolic pathways for the mechanism of action. Atomic and molecular computational platforms are under development. Complete “laboratories on a chip” are being deliv- ered and used in vivo. Even previously contemplated combination products, such as drug-eluting stents, have evolved in ways that stretch the capabilities of the current system. Some novel device–drug–biologic products—not truly combination products—are not well managed on the basis of the current combination- product concept. For example, nanoparticle drug-delivery systems (combi- nation products of a drug or biologic encapsulated in a device) could be activated by external ultrasonographic energy (delivered by a device) and monitored by software analysis of resulting real-time images (a device).

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156 MEDICAL DEVICES AND THE PUBLIC’S HEALTH Other than arbitrary assignment, there is no obvious lead agency for the review and approval of such a multipart product; in fact, the review might best be accomplished by multiple centers and branches. Finding 6-1 Medical-device technologies have evolved rapidly and devices have become increasingly complex since the 1976 Medical Device Amendments. Software Software is used in medical devices, as medical devices (for example, medical-device data systems), and as a tool in producing medical devices. Manufacturers are increasingly using software in their medical devices. An analysis by Fu showed that a milestone was reached in 2006: since then, more than half the medical devices on the market have relied on software in some way (IOM, 2011). Software offers many benefits over hardware in some situations, for example, flexibility, ease of change, and usability in other applications. To reduce costs, many software vendors produce “soft- ware product lines,” that is, software designed to allow ease of variation to accommodate similar, and perhaps tailored, product lines. In some cases, general-purpose, off-the-shelf (OTS) software is incorporated directly into medical devices. The FDA’s software validation guidance addresses that situ- ation, noting that “the use of off-the-shelf software in automated medical devices and in automated manufacturing and quality system operations is increasing” (FDA, 2002). Software Is Responsible for an Increasing Number of Recalls As software becomes more common in medical devices, it also is in- creasingly responsible for device failures and recalls. For example, CDRH (FDA, 2002) notes that the FDA’s analysis of 3140 medical device recalls conducted between 1992 and 1998 reveals that 242 of them (7.7%) are attributable to software failures. Of those software related recalls, 192 (or 79%) were caused by software defects that were introduced when changes were made to the software after its initial production and distribution. Fu noted that from 1999 to 2005, 11.3% of recalls were attributed to software, and 49% of recalled devices relied on software in some way (IOM, 2011). In the period 2002–2010, at least 537 recalls of software-based devices affected at least 1,527,311 devices. However, because of the limita- tions of recall data discussed in Chapter 5, there is insufficient information to determine the underlying issues in the increased rates. Because there is no

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157 EXTERNAL FACTORS FIGURE 6-4 Example of a medical-device software malfunction. Figure 6-4.eps SOURCE: Reprinted with permission from Halperin et al., 2008. © 2008 IEEE. bitmap way to know the number of devices on the market or how many of them use software, it is not possible to know whether the change is related to the increasing proportion of software in medical devices or whether it is a signal of new or different types of problems and vulnerabilities in medical- device software. A drawback of software is that it can be difficult to recognize problems, find their source, and fix them without adverse consequences. When soft- ware is used in medical devices, at least three outcomes are to be avoided: • Unreliable and unavailable devices.8 • Insecure devices. • Unpredictable behavior.9 Figure 6-4 is an example of how a software failure can be manifested. Here, the arrhythmia log is read from the bottom up. The episodes are in 8Reliability means that a system works as expected almost all the time; it rarely fails. Availability means that the system works whenever it is needed to work. There is no delay, and it is usable on demand. 9A device has unpredictable behavior if, for the same inputs, it gives different answers at different times.

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158 MEDICAL DEVICES AND THE PUBLIC’S HEALTH BOX 6-1 Example Recall Announcement URGENT: Medtronic Announces Nationwide, Voluntary Recall of Model 8870 Software Application Card MINNEAPOLIS, Sept. 22, 2004 - Medtronic, Inc. (NYSE: MDT) today an- nounced a voluntary recall that involves all Version AAA 02 Model 8870 software application cards in the U.S. that are used in conjunction with all Model 8840 N’Vision™ Clinician Programmers. This action has been classified by the Food and Drug Administration (FDA) as a Class I Recall. . . . a reasonable probability that the use of or exposure to the product will cause serious adverse health consequences or death. Medtronic became aware in August 2003 that some users had mistakenly entered a periodic bolus interval into the minutes field, rather than the hours field, potentially resulting in drug overdoses. Data entry errors have been related to seven serious injuries and two deaths. The previous model 8870 software application card did not provide a label for the hours/ minutes/seconds fields; the new software has this labeling. SOURCE: FDA, 2009b. chronologic order, and they inexplicably and suddenly move from 2007 back to 2005. Such an error can occur only when software is faulty. Similar software failures are noted frequently in recall announcements. For example, Medtronic issued a press release related to the Class I medical- device recall of the Medtronic 8870 Software Application Card Version AAA 02 (see Box 6-1). The Guidance for Premarket Submissions for Software Contained in Medical Devices for industry and FDA staff issued on May 11, 2005, poses questions about problems with OTS medical-device software (FDA, 2005a): What is it about “network-connected medical devices” that causes so much concern? . . . Vulnerabilities in cybersecurity may represent a risk to the safe and effective operation of networked medical devices using OTS software. Failure to properly address these vulnerabilities could result in an adverse effect on public health. A major concern with OTS software is the need for timely software patches to correct newly discovered vulnerabilities in the software. The “vulnerabilities” are problems with the software that can be ex- ploited by a malicious agent or can simply malfunction if the software is subjected to particular conditions. For instance, poorly designed software

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159 EXTERNAL FACTORS may malfunction if it receives a type of input that it does not expect or if it conflicts with other devices that are communicating along the same channels. A patch is the application of a software correction; the resulting modified software should work as desired. However, the FDA’s request for “timely patches” suggests that patching is straightforward. In the commit- tee’s opinion, it is not. Beattie et al. (2002) analyzed the timing of patch availability and ap- plication. The researchers concluded, “Patch too soon, and you may suffer from instability induced by bugs in the patches. Patch too late, and you get hacked by attackers exploiting the vulnerability.” And patches are not always available as soon as a problem is discovered. The second Tuesday of each month is known to Microsoft Corporation’s customers as “patch Tuesday”: the day on which patches are made available for application to existing systems. Only when a problem is considered an emergency is a patch offered off-cycle to customers. Microsoft is not alone. For example, Oracle (2010) notes that “Oracle Sun releases over 4,500 patches every year, for Solaris 8, 9, and 10, SPARC and x86, Solaris Cluster, Middleware, Developer, Storage, and other prod- ucts. Just 17 have been withdrawn after release in the last year due to seri- ous issues.” Software Is Different from Hardware Pfleeger et al. (2002) have written extensively on how software is dif- ferent from hardware. The authors identify three key characteristics of software that make it different from hardware: • oftware developers are overoptimistic. Careful empirical studies S have shown that software developers, particularly testers, often as- sume that they have found the last problem in the software under scrutiny. That is, they commonly stop looking once they find a prob- lem, not recognizing that other problems remain. Their optimism results in overconfidence in both testing techniques and the degree to which the tests exercise all the functions implemented by the software. Such optimism is shared by hardware testers but seems to be extreme in software testers. Indeed, Beck (2004) noted that “op- timism is an occupational hazard of programming, feedback is the treatment”; and Jorgensen (2010) has shown that, counterintuitively, identification of more risks can lead to developers’ overconfidence and overoptimism. • oftware is discrete, not continuous. Unlike hardware, software is S extremely sensitive to small errors. Off-by-one errors, negligible in hardware, can result in huge changes in software. Just as an off-by-

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178 MEDICAL DEVICES AND THE PUBLIC’S HEALTH with the essential requirement itself. Harmonized standards are developed and issued by the European Committee for Standardization (CEN) and in some cases the European Committee for Electrotechnical Standardization. Those two committees are responsible for writing the standards that deal with both entire classes of products and specific products. In some cases, the standards are adopted wholesale from the International Organization for Standardization (ISO). Manufacturers are free to use whatever standards they like, but if their devices meet the CEN or, where applicable, ISO stan- dards, they are judged to have met the essential requirements—often the easiest path to approval. Risk Classification14 A device is assigned to one of four groups, or classes, by using a set of rules that take into account the potential of the device to cause harm to a patient or user. This system is referred to as a “risk-based classification scheme” although it does not take into account the probability that harm will occur by modifying evidence requirements at the conformity-assessment stage. Risk is determined on the basis of the risk associated with the use of the device, whether the device is invasive, and the length of time it is in contact with the body (Table 6-1) (Chai, 2000). It is incumbent on the manufacturer to determine the level of risk associated with a device on the basis of the specifications laid out in Annex IX of the MDD (Grubb et al., 2011). As in the FDA classification system, there are three risk classes, and subdivisions of classes to delineate the magnitude of risk further. Class I devices are noninvasive, with some exceptions, and are judged to be of low risk. There is no explicit subdivision of products within Class I, but devices that are sterile or have a measuring function require greater oversight. Manufacturers are able to market Class I products that are non- sterile and do not have a measuring function without oversight from a noti- fied body (NB, defined below) but must keep documentation and technical specifications available for audit on request. Class I devices that are sterile or have a measuring function must be certified by an NB (Chai, 2000). Class II devices are divided into Class IIa and Class IIb. Class IIa devices require the involvement of an NB at the production stage but not the design phase. Class IIb devices are judged to have the potential to be of high risk and require NB approval at the design and manufacturing phases. Class III devices are deemed to be of high risk and require “explicit prior authorization” from an NB for all phases of development and production (European Commission, 1998). Manufacturers can also turn to guidance 14The essential requirements, classification rules, and conformity-assessment procedures are substantially different for in vitro diagnostic medical devices, which are regulated under their own directive. Some of the information in the following sections does not apply to these devices.

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179 EXTERNAL FACTORS TABLE 6-1 European Commission Risk Classification Scheme Class I Noninvasive devices except devices that are intended to store (low risk) or channel blood, body liquids, or tissues to be introduced to the body at a later time Class IIa Invasive devices intended for transient (<60 min) or short- (medium risk) term (<30 days) use except devices used to examine ear, nose, mouth, and throat, which are in Class I; all surgically invasive devices intended for transient use unless they emit radiation or have a biologic effect, in which case they are in Class IIb Class IIb Surgically invasive devices for short-term or transient use (medium to high risk) if they have a biologic effect, emit radiation, or administer medicines except devices that have direct contact with the heart or central circulatory system or central nervous system, in which case they are in Class III; all implantable or surgically invasive long-term (>30 days) devices unless they are placed in the teeth (in which case they are in Class IIa) or have contact with the heart, central circulatory system, or central nervous system (in which case they are in Class III); all devices intended to prevent conception or sexually transmitted disease unless they are implantable or long-term invasive devices (in which case they are in Class III) Class III All invasive surgical devices, whether for short-term or (high risk) long-term use, that come into contact with the heart, central circulatory system, or central nervous system; all implantable or long-term invasive devices that have a biologic effect, are absorbed, or undergo chemical change in the body; all implantable or long-term invasive devices intended to prevent conception or sexually transmitted disease; all devices that use animal tissues or derivatives except where they come into contact only with skin documents released by the overseeing body in the European Commission, the Directorate-General Health and Consumer that provide detailed instruc- tions on classifying devices, including diagrams and examples. The guidance is not legally binding but is provided for clarification purposes (European Commission, 2010a). Notified Bodies The directives contain provisions for the establishment of NBs, the backbone of the European regulatory structure for medical devices. An NB is a third-party private organization that is responsible for ensuring that a device meets the essential requirements laid out in the legislation. Each

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180 MEDICAL DEVICES AND THE PUBLIC’S HEALTH member state designates a competent authority (CA), an official government regulator, that is required to oversee the accreditation and designation of third-party organizations that will perform conformity assessments and various other tasks. The CA then notifies the European Commission and the other member states as to which private organizations have been judged to be competent according to the standards laid out in the directives and for which tasks. The commission maintains an updated list of the NBs and makes this information available to the public through the New Approach Notified and Designated Organisations Web site (NANDO, 2011). NBs are accredited under individual directives, and their number varies by directive. For example, although more than 70 NBs are accredited to examine prod- ucts under the MDD, only 19 are accredited for devices covered by the more specialized AIMDD (NANDO, 2011). The NBs compete with one another in that any manufacturer can go to any accredited NB in any member state and receive a CE marking. NBs must adhere to standards regarding conflict of interest and finan- cial incentives. NBs must be independent of manufacturers. Directors and assessment and verification staff must not be involved in the development of the device in question, nor can they represent any party involved in its development. Their compensation structure must not depend on the results of their evaluations or on the number of verifications that they provide. They must have the necessary staff and facilities to assess properly the devices for which they are designated. Any subcontractors retained by an NB must also meet all these requirements. Although an NB is responsible for ensuring a device’s conformity with the essential requirements, it also has a contractual relationship with the manufacturer, which pays for the work. That affords some protection to the manufacturer because, in theory, an NB that is inefficient or difficult to deal with will soon find itself without any customers. The accreditation proce- dures and standards of the European Commission ensure that the standards of safety are met, and the private status of the NB ensures efficiency and consistency for the manufacturer. As noted above, the level of involvement of an NB is determined by the classification of the product (Table 6-2). The NB has the responsibility to inform the CA if it withdraws a design examination certificate from the manufacturer. The CA then ensures that the device is withdrawn from the market. However, the manufacturer has the right to respond to a decision to restrict or withdraw a device before it goes into effect unless there is an urgent need to take such a step.

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181 EXTERNAL FACTORS TABLE 6-2 Conformity Assessment Procedure by Class Class I Manufacturer certifies that product meets essential requirements without involvement of an NB unless device has measuring function or is sterile; documentation of product specification must be kept for auditing purposes; Class I devices must be registered with a member state Class IIa Manufacturer prepares technical documentation to support a “declaration of conformity” and makes it available to the NB for inspection and adopts a quality-management system that applies to manufacturing and is subject to audit by the NB, or manufacturer adopts a full quality-management system that applies to both manufacturing and design control and is subject to audit by the NB Class IIb Manufacturer submits to type examination by an NB in which representative sample of product along with relevant technical documentation is examined to ensure that it fulfills essential requirements and adopts a quality-management system that applies to manufacturing and is subject to audit by the NB, or manufacturer adopts a full quality- management system that applies to both manufacturing and design control and is subject to audit by the NB Class III and Active Manufacturer submits to type examination by an NB Implantable Devices in which representative sample of product with relevant technical documentation is examined to ensure that it fulfills essential requirements and adopts a quality-management system that applies to manufacturing and is subject to audit by the NB, or manufacturer adopts a full quality-management system that applies to both manufacturing and design control and is subject to audit by the NB; NB also examines design dossier and issues a certificate to confirm that the device complies with all relevant essential requirements Postmarket Vigilance In addition to the postmarketing surveillance functions of the NBs, the MDD mandated the establishment of a European Databank on Medical Devices, a centralized database containing information on manufacturers, devices, conformity assessments and certificates, and clinical investigations. Its use is currently voluntary but will be required of member states in 2011 (European Commission, 2010c). The committee is not aware of any com- prehensive evaluations of the European system based on postmarketing surveillance or adverse-event reports.

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182 MEDICAL DEVICES AND THE PUBLIC’S HEALTH The Global Harmonization Task Force The multinational nature of medical-device manufacturing and distribu- tion has led governments, consumers, and industry to recognize the need for international cooperation regarding medical devices. In 1992, regulatory bodies and industry of the leading medical-device producer and consumer nations—Canada, the European Union/European Free Trade Association, Japan, Australia, and the United States—formed the GHTF. A collaborative body whose purpose is to improve public health and safety, promote inter- national trade, and provide guidance to countries with developing medical- device regulatory systems, the GHTF works to form consensus among the partners on regulatory and technical standards and postmarketing surveil- lance efforts. Many international agreements are in place regarding medical devices and their regulatory requirements for importation. The GHTF is an attempt to bring nations that tightly regulate medical devices into line with one another to ease the flow of devices between countries, manufacturers, and consumers while ensuring safety. In addition to participants from the founding members, the task force includes participants from non–founding members and liaison bodies, which include public-health organizations and international standard-setting organizations.15 The GHTF is structured around five study groups that are responsible for examining different issues and different paths and barriers to harmoni- zation within them. The study groups, made up of geographically diverse members from government and industry, are (GHTF, 2008) • tudy Group 1—medical-device regulatory systems, paths to harmo- S nization, and standards for premarket submissions and labeling. • tudy Group 2—adverse-incident reporting, postmarketing surveil- S lance, and harmonizing data-collection and reporting systems. • tudy Group 3—existing quality-system requirements. S • tudy Group 4—quality-system auditing practices. S • tudy Group 5—clinical safety and performance. S To date, the study groups have released 31 final documents providing technical guidance and standardized definitions and outlining generally agreed-on principles for use by regulators and manufacturers worldwide (GHTF, 2009). The GHTF has met with mixed success in its efforts. For example, the Summary Technical Document (STED) guidance is intended to 15In March 2011, the Steering Committee Chair of the GHTF announced that the organization would be developing and transitioning to a “regulator-led harmonisation and collaboration group.” According to the statement, the new entity would focus primarily on regulators of medical devices, including seeking new members in order to more accurately reflect the current medical-device market, while continuing to value input from industry and other stakeholders as appropriate (GHTF, 2011).

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183 EXTERNAL FACTORS standardize the format whereby a manufacturer submits technical informa- tion to a regulatory authority or conformity-assessment body (such as an NB). STED would allow manufacturers to save time and effort in preparing a product for market and allow better comparison and information-sharing among regulatory jurisdictions. Although the STED guidance has been ad- opted or implemented as a pilot program in all five GHTF founding-member jurisdictions, it has not been widely used (IOM, 2010). Nations that have highly developed regulatory frameworks agree in principle that harmoniza- tion is desirable, but differences in legal systems and regulatory cultures make implementation challenging. The Summary Technical Document Program In 2002, GHTF Study Group 1 proposed a pilot program for device premarket review known as the Summary Technical Document (STED), program (GHTF, 2008). The FDA then issued draft guidance to assist the medical-device industry and FDA staff in implementing a voluntary pilot program (FDA, 2005b). Not all devices are eligible to participate in the pilot. Eligible devices are limited to those which are seen to be the subjects of common and substantial interest by the member countries of the GHTF.16 The program, begun in June 2003, is intended to evaluate STED as an alternative premarket submissions process. Its objective is to decrease the regulatory burden and increase the efficiency of the approval process for manufacturers that operate within the international market (FDA, 2005b; GHTF, 2008). Industry groups have stated their support for the STED program, but the FDA has identified only 27 STED submissions17 (IOM, 2010). Of the submissions, 24 were 510(k) submissions, and 3 were PMA applications. The PMA applications were all approved. Of the 510(k) sub- missions, 20 resulted in a determination of substantial equivalence, 2 were not substantially equivalent, and 2 were withdrawn. Given the lack of data needed to evaluate the program and the small number of devices eligible, it is not possible to determine what factors contribute to the lack of industry participation in the program. Finding 6-8 Other countries that tightly regulate medical devices do not rely solely on substantial equivalence to a predicate for premar- 16A list of eligible devices and information on the alternative format (developed by the Global Harmonization Task Force) can be found in Appendix C of the Guidance on Traditional and Abbreviated 510(k)s. 17The FDA’s Document Mail Center identifies all submissions on receipt. STED submissions are flagged in the system. However, the FDA has stated that there are limitations in the system, and that the data on STED submissions may not be accurate (e-mail from Philip R. Desjardins, FDA, January 7, 2011).

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184 MEDICAL DEVICES AND THE PUBLIC’S HEALTH ket review of medium-risk devices. The Global Harmonization Task Force also does not offer as part of its guidance a predicate-based system for premarket review of medical devices. SUMMARY OF FINDINGS The Growing Number and Complexity of Medical Devices • inding 6-1 Medical-device technologies have evolved rapidly, and F devices have become increasingly complex since the 1976 Medical Device Amendments. • inding 6-2 Manufacturers are using increasing amounts of software F in devices and as devices; the increase is expected to continue. Soft- ware offers many benefits over hardware, including flexibility, ease of change, and the possibility of use in other devices. • inding 6-3 Software is responsible for an increasing number of F recalls. There are insufficient data, however, to determine whether the increase reflects the increasing proportion of software in medical devices or a new and different set of problems and vulnerabilities. • inding 6-4 Software is different from hardware and therefore re- F quires a different kind of evaluation. The Medical-Device Ecosystem • inding 6-5 Industry-funded assessments of the effects of the 510(k) F clearance process report that implementation of the process leads to a lack of predictability and transparency, which in turn has an adverse effect on venture-capital investment. • inding 6-6 The committee did not find assessments of how much F and in which way innovation is influenced by the 510(k) clearance process. • inding 6-7 There is little collaboration in collection of postmarket- F ing surveillance data among the FDA, healthcare facilities, healthcare providers, the medical-device industry, professional societies, payers, and patient-advocacy groups. Globalization of the Medical-Device Industry • inding 6-8 Other countries that tightly regulate medical devices do F not rely solely on substantial equivalence to a predicate for premar- ket review of medium-risk devices. The Global Harmonization Task Force also does not offer as part of its guidance a predicate-based system for premarket review of medical devices.

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