Appendix C
Premarket Notification: A Key Element of US Medical Device Regulation

Larry Kessler, ScD, and Philip J. Phillips, MBA

EXECUTIVE SUMMARY

The regulation of medical devices in the United States is a complex system of interwoven requirements that are intended to be applied to industry based on the nature of particular devices that it makes and the degree of protection that is needed to provide the American public with reasonable assurance of safety and effectiveness. The main framework for this system is a classification scheme that dictates the overall approach to be taken to accomplish this goal.

Section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act) is but one of many controls that contribute to ensuring that medical devices that are used in the United States are among the safest and most effective in the world. While the US Food and Drug Administration (FDA) premarket review system may not be perfect, it represents a system that is at least as stringent as anywhere in the world. Coupled with the most extensive and utilized postmarket reporting system in the world, dangerous products do not make it to market or are identified and removed soon after distribution begins. Although Section 510(k) was initially intended to be the principal means by which new medical devices were classified, the 510(k) program has evolved in an effort to meet the challenges of a diverse and rapidly changing industry and a highly scrutinized regulatory agency that has never been provided with the necessary resources to meet everyone’s expectations.

Today’s 510(k) program is the result of a conscious effort to provide reasonable regulation in light of the agency’s inability to develop mandatory performance standards for class II medical devices and inadequate FDA resources to withstand any appreciable shift in the numbers of new



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Appendix C Premarket Notification: A Key Element of US Medical Device Regulation larry Kessler, ScD, and Philip J. Phillips, MBA EXECuTIvE SuMMARY The regulation of medical devices in the United States is a complex sys- tem of interwoven requirements that are intended to be applied to industry based on the nature of particular devices that it makes and the degree of protection that is needed to provide the American public with reasonable assurance of safety and effectiveness. The main framework for this system is a classification scheme that dictates the overall approach to be taken to accomplish this goal. Section 510(k) of the Federal Food, Drug, and Cosmetic Act (the act) is but one of many controls that contribute to ensuring that medical devices that are used in the United States are among the safest and most effective in the world. While the US Food and Drug Administration (FDA) premarket review system may not be perfect, it represents a system that is at least as stringent as anywhere in the world. Coupled with the most extensive and utilized postmarket reporting system in the world, dangerous products do not make it to market or are identified and removed soon after distribution begins. Although Section 510(k) was initially intended to be the principal means by which new medical devices were classified, the 510(k) program has evolved in an effort to meet the challenges of a diverse and rapidly chang- ing industry and a highly scrutinized regulatory agency that has never been provided with the necessary resources to meet everyone’s expectations. Today’s 510(k) program is the result of a conscious effort to provide reasonable regulation in light of the agency’s inability to develop manda- tory performance standards for class II medical devices and inadequate FDA resources to withstand any appreciable shift in the numbers of new 75

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76 THE FDA 510(k) ClEARANCE PROCESS medical devices that are subject to premarket approval requirements. Plagued with vague concepts such as substantial equivalence, intended use and predicate devices, the program is particularly vulnerable to intermittent inconsistencies in how each concept is interpreted and applied in agency decision-making, as well as misunderstanding by stakeholders that moni- tor FDA activity. Coupled with the fact that all medical devices are subject to eventual failure, and failure rates are among the most challenging data to understand, demand for regulatory reform is not unexpected. While the US system for regulating devices can certainly be improved, any attempt to reform the 510(k) program should be based on reality, not perception, and a clear understanding of how the components of the entire regulatory system interrelate and contribute to the overall goal of protecting and promoting public health. In summary, any regulatory framework will have strengths and weak- nesses and this applies to the 510(k) program and the rest of the regulatory structure at FDA’s Center for Devices and Radiological Health (CDRH). We show the 510(k) review program’s strengths and weaknesses and suggest important areas for consideration to improve the current system. Should an entire overhaul of the system be attempted, we provide information that may be useful in creating a new regulatory structure and process. OvERvIEW OF uS MEDICAL DEvICE REGuLATION FDA is responsible for protecting the public health by ensuring the safety, effectiveness, and security of human and veterinary drugs, biological products, medical devices, foods, cosmetics, and products that emit radia- tion. The agency is also responsible for promoting the public health by help- ing to speed innovations that make medicines, medical devices, foods, and radiation-emitting products safer, more effective, and more affordable; and helping the public to obtain accurate, science-based information necessary to use medicines, medical devices, foods, and radiation-emitting products to safeguard their health.1 Recently, FDA was given the authority to regulate tobacco products. In the context of medical device regulation, the word device is defined by Section 201(h) of the act as follows: The term “device” (except when used in paragraph (n) of this section and in sections 01(i), 0(f), 50(c), and 60(c)) means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or 1Refer to FDA mission statement available at http://www.fda.gov/aboutfda/whatwedo/ default.htm.

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77 APPENDIX C other similar or related article, including any component, part, or accessory, which is— (1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, () intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or () intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended pur- poses through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. Simply stated, a device is virtually any health-care product that fulfills its intended purpose by physical and/or mechanical means, rather than through chemical and/or metabolic activity. Although the mechanism of action may be chemical in nature, in vitro diagnostic (IVD) products also fit the definition of medical device. The breadth of products regulated as medical devices is tremendous; ranging from simple tongue depressors, ban- dages and gauze to complex implantable cardiac defibrillators, intraocular implants and DNA probes. To complicate matters, device components and accessories are also devices regulated by FDA. Most stakeholders, includ- ing health-care providers, consumers, and even members of Congress, have little appreciation for the breadth and diversity of medical devices regulated by the agency. FDA ensures that medical devices are safe and effective, under the authority granted by the act and in accordance with the implementing regulations found principally in Title 21 of the Code of Federal Regulations (CFR), Parts 800 through 1299. CDRH is the organizational component primarily responsible for ensuring that medical devices are safe and effective. A few medical devices are regulated by the Center for Biologics Evaluation and Research (CBER), including medical devices related to licensed blood and cellular products, while a small, but growing number of devices are combined with drugs and biologics (referred to as combination products) that are regulated by the FDA center with responsibility over the product’s primary mode of action. Medical devices are regulated by FDA through a classification system. While classification is commonly described as a risk-based system, this is an oversimplification. A device’s classification is actually based on (1) the risk(s) posed by the product, (2) the available knowledge related to the product’s intended use and technology, and (3) the level of regulatory control needed to adequately ensure safety and effectiveness. The objective of FDA device regulation is to provide the American

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7 THE FDA 510(k) ClEARANCE PROCESS public with a reasonable assurance of the safety and effectiveness for all medical devices (21 USC § 393(b)). The basic framework for achieving this objective rests on a classification system in which a particular device’s class designation dictates the applicable regulatory requirements. FDA’s approach to ensuring safety and effectiveness depends upon the class of the device, and varies with the level of concern that FDA has regarding the adequacy of existing controls to provide this assurance. The act defines three classes of medical devices: class I, class II, and class III. Class I devices are simple products that usually present minimal poten- tial for harm to the user. These devices are subject to “general controls”, a set of controls applicable to virtually all devices that involve substantive regulation by FDA. General controls include labeling requirements, provi- sions against adulteration and misbranding, good manufacturing practices (GMPs), establishment registration, medical device listing, medical device reporting and premarket notification (“510(k)”) prior to marketing a device. FDA has since exempted most class I devices from 510(k) requirements in implementing the FDA Modernization Act of 1997 (FDAMA 97). In general, class II devices present a greater level of potential risk than class I devices, but their safety and effectiveness can be ensured through a combination of general controls and additional regulatory requirements designed to mitigate the risks of concern that are associated with the particular device type. All class II devices should be subject to additional special controls to ensure their safety and effectiveness. Special controls include specific labeling requirements, mandatory performance standards, postmarket surveillance, patient registries, guidelines (such as for provid- ing clinical data in 510(k) submissions), recommendations, or virtually any other actions that the agency determines are necessary to ensure safety and effectiveness.2 By establishing special controls through notice and comment rule-making, FDA establishes a degree of enforceability. Despite the benefits of special controls, they have only been established on a case by case basis for select class II devices, most frequently associated with classification or reclassification actions after enactment of the Safe Medical Devices Act of 1990 (SMDA 90). Under US law, class III devices support or sustain human life, are of sub- stantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury to patients. It is on this basis that class III devices are subject to the highest levels of FDA’s regulation, in- cluding general controls and any relevant performance standards and special controls, and a “device-by-device” demonstration of safety and effectiveness through a regulatory process known as premarket approval (PMA). All new devices are class III by operation of law unless FDA (1) determines the new 2Refer to Section 513(a)(1)(B) of the FDCA.

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79 APPENDIX C device to be substantially equivalent (SE) to a device previously classified in class I or class II, (2) grants a risk-based (“de novo”) classification request, or (3) reclassifies the device into class I or II.3 THE EuROPEAN uNION SYSTEM OF DEvICE REGuLATION The European Union (EU) has adopted a very different paradigm than substantial equivalence. The use of “essential principles” that devices must meet before placement on the EU market does not depend on comparing to products on the market nor on any mechanism related to how those prod- ucts entered EU commerce. Each product must stand independently and have documentation verifying compliance with the essential principles. The essential principles ensure the safety and performance of medical devices by establishing minimum requirements that all devices must meet. We note that the EU uses the term performance rather than effectiveness. The expectation in the EU is that a manufacturer designs a product for a cer- tain functional use and that the device then can be demonstrated to perform in the manner so designed. For example, if a trocar is intended to puncture flesh in order to gain access to a body cavity, then the essential principles would require a degree of sharpness and stiffness in order to perform this function. How this product is used and whether it has “clinical utility” is not an explicit part of the principles of safety and performance. The clinical use and whether an EU country then includes this device in its “formulary” is a decision taken separately by organizations that are charged with technology assessment and purchasing for these nationalized systems. With respect to safety, the principles ensure that products are safe when used as intended. Although similar to the 510(k) system, the EU approach is somewhat different. In the EU system, the safety of a product is ensured by meeting the principles that describe whether the product would have any untoward effects on patients. In addition, the EU also requires that the solutions adopted by the manufacturer for the design and manufacture of the devices should conform to safety principles, taking account of the generally acknowledged state of the art. When risk reduction is required, the manufacturer should control the risk(s) so that the residual risk(s) associated with each hazard is judged acceptable. The manufacturer should apply the following principles in the priority order listed: 3A diminishing number of preamendment class III devices remain subject to 510(k) review. This weakness in the regulatory process was recently pointed out in a General Accounting Office report titled Medical Devices—Shortcomings in FDA’s Premarket Review, Postmarket Surveillance, and Inspections of Device Manufacturing Establishments. FDA is in the process of rectifying this irregularity. It is on this basis that the review of preamendment class III devices is not the focus of this paper.

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0 THE FDA 510(k) ClEARANCE PROCESS • Identify known or foreseeable hazards and estimate the associated risks arising from the intended use and foreseeable misuse. • Eliminate risks as far as reasonably practicable through inherently safe design and manufacture. • Reduce as far as is reasonably practicable the remaining risks by taking adequate protection measures, including alarms. • Inform users of any residual risks. Note the expectation that safety should be a function of the gener- ally acknowledged state of the art, which changes as scientific knowledge changes. A 2007 revision of the directive in the EU placed considerable emphasis on clinical data and the necessity of keeping it up to date via post- market surveillance in order to confirm the continued acceptability of the benefit:risk ratio. This links back to the current “state of the art.” As with everything pertaining to placing on the market in the EU system, this is the manufacturer’s responsibility and is constant across all classes of devices. . The expectation is that the organizations that audit manufacturers and pro- vide the CE mark (the notified bodies accredited by each EU government) will update their auditing procedures with changes in science. There is no literature based documentation that this has happened, per se. THE GLObAL HARMONIZATION TASK FORCE The Global Harmonization Task Force (GHTF) was established in 1992 as a joint venture between regulatory bodies and medical device trade organizations of Australia, Canada, the European Union, Japan, and the United States. The aim of the GHTF is to harmonize the regulatory systems around the globe in order to • Reduce redundant efforts regarding placing products on the market. • Ensure the safety of devices both by having a consistent set of safety principles and adverse event reporting and by sharing such informa- tion globally. • Facilitate international trade of medical devices. The GHTF is organized around study groups that have written over 30 guidance documents that, when adopted by GHTF partners, will bridge the different regulatory systems. The area of market entry has proved quite challenging. For example, much of the world uses a four class system for devices, whereas the United States uses a three class system. While one can create a map of requirements from one system and class to another, differ- ences remain.

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1 APPENDIX C The essential principles adopted in the GHTF (reference SG1/ N41R9:2005) are modified from the EU but follow along the same lines. These principles fall in the following categories: • General requirements. Design and manufacturing requirements:4 • o Chemical, physical, and biological properties. o Infection and microbial contamination. o Manufacturing and environmental properties. o Devices with a diagnostic or measuring function. o Protection against radiation. • Requirements for medical devices connected to or equipped with an energy source. • Protection against mechanical risks. • Protection against the risks posed to the patient by supplied energy or substances. • Protection against the risks to the patient for devices for self-testing or self-administration. • Information supplied by the manufacturer. • Performance evaluation including, where appropriate, clinical evaluation. Could the current system of 510(k) be modified using regulations and not legal changes to bring products into the US system that have satisfied the essential principles? There are two ways this could occur. The Summary Technical Document (STED) developed by Study Group 1 of the GHTF, assigned the scope of premarket considerations, provides one such avenue. The document includes data demonstrating conformance to the essential principles. If a company wished to bring on a device and did not have a suit- able predicate, then the agency could declare the device as nonsubstantially equivalent and request a 510(k) de novo application. The company could elect to submit a STED. CDRH has encouraged medical device manufacturers to participate in the STED pilot program. Manufacturers would benefit from exposure to the STED preparation process, especially those seeking international regulatory approval or clearance for their devices. In addition, greater industry partici- pation in this program would increase CDRH’s familiarity with STED sub- missions and would allow CDRH to provide constructive feedback to the 4The GHTF established a workgroup in 2007 to assess whether its guidance documents would address issues regarding safety and effectiveness with respect to computer software that were devices or operated devices. This workgroup made recommendations to the study groups to make modifications to documents for these issues and these have been resolved in revisions to study group documents.

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 THE FDA 510(k) ClEARANCE PROCESS GHTF on the current STED format. Even more can be done in this regard, and with constrained resources at FDA, all parties should seriously consider how to best use the work accomplished by the GHTF to mutually leverage the world’s available resources. This is a true opportunity to improve the entire regulatory process throughout the total product life cycle. An alternative is to make substantially greater use of international stan- dards and the abbreviated 510(k) submission, wherein a company represents issues of the safety and effectiveness of the device via complying with the essential principles (and completing a STED document) and submits that via the 510(k) abbreviated pathway. In an abbreviated 510(k) submission, manufacturers elect to provide summary reports on the use of guidance documents and/or special controls or declarations of conformity to recog- nized standards to expedite the review of a submission.5 uS DEvICE CLASSIFICATION PROCESSES After May 28, 1976, the enactment date of the Medical Device Amend- ments of 1976 (MDA 76), FDA made a significant effort to group all medi- cal devices in existence at the time, commonly referred to as preamendment devices, into generic device types with each generic type of device being “a grouping of devices that do not differ significantly in purpose, design, materials, energy source, function, or any other feature related to safety and effectiveness, and for which similar regulatory controls are sufficient to provide reasonable assurance of safety and effectiveness.”6 Each generic device type was then further categorized by medical specialty and referred to the appropriate classification panel(s) comprising independent experts, principally within the medical specialty. At the time there were 16 classifica- tion panels convened exclusively for the purpose of identifying device types’ proper classification. As guidance for formulating their recommendations to FDA, the panels answered a specific series of questions prepared by the agency, the Classification Questionnaire.7 The recommendations and the responses to the questionnaire aided FDA in determining the proper clas- sification for each generic device type. The final classification of each generic device type followed notice and comment rule-making and the promulgation of over 1,700 classification regulations. Since the early years, FDA has on occasion encountered additional preamendment devices that escaped the 5Refer to How to Prepare Abbreviated 510(k) at http://www.fda.gov/MedicalDevices/ DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/Premarket Notification510k/ucm134574.htm. 6Refer to 21 CFR 860.3(i). 7Refer to General Device Classification Questionnaire at http://www.fda.gov/downloads/ AboutFDA/ReportsManualsForms/Forms/UCM080858.pdf.

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 APPENDIX C initial classification and has subsequently classified them through the same process using the current advisory committee structure. The work of the original classification panels, and the agency actions that followed, form the foundation of the 510(k) program. As new (post- amendments) devices prepare to enter the marketplace, with few exceptions, they have been the subject of 510(k) submissions and have demonstrated SE to legally marketed class I and II devices. In fact, FDA has indicated that there have been over 300,000 510(k) clearances in the history of the 510(k) program. Immediately following enactment of MDA 76, SE to preamendment devices was routinely demonstrated as preamendment devices were the only devices that were available for comparison. Over time, the pool of legally marketed devices expanded with every 510(k) clearance, as did intended uses and technologies. The constant progression within the industry led to SE to recently cleared (postamendment) devices increasingly being dem- onstrated. In essence, the medical device industry came to quickly realize that there was a greater likelihood of their new devices’ being cleared if they were compared to legally marketed devices with similar intended uses and technological characteristics. While comparison to pre-1976 devices is not precluded, such comparisons in today’s 510(k) program are unusual. This evolution in the 510(k) program is often dismissed by critics of the program. Illustration 1 Surgical mesh. Prior to May 28, 1976, metallic and polymeric screens were in commercial dis- tribution to reinforce soft tissue or bone where weakness exists. These metallic and polymeric screens were categorized by the agency as surgical mesh. As part of the classification process this generic type of device was referred to three classification panels for review and recommendation: the Orthopedic Devices Panel, the General and Plastic Surgical Devices Panel and the Gastroenterology– Urology Devices Panel. All three panels recommended that this generic type of device be regulated in class II subject to performance standards. FDA accepted the panels’ recommendations and classified surgical mesh as follows: Sec. 878.3300 Surgical mesh (a) Identification. Surgical mesh is a metallic or polymeric screen intended to be implanted to reinforce soft tissue or bone where weakness exists. Examples of surgical mesh are metallic and polymeric mesh for hernia repair, and acetabular and cement restrictor mesh used during orthopedic surgery. (b) Classification. Class II

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 THE FDA 510(k) ClEARANCE PROCESS Over the last 34 years, FDA has cleared 547 510(k)s for surgical mesh devices. The clearances span nine product codes8 and cross virtually all medical specialties. Today’s surgical mesh has evolved to include some of the latest absorbable biomaterials. The agency has not given priority to developing performance standards or special controls for this generic type of device. Just as knowledge and experience influenced the initial classifications, information derived from experience with class III devices has paved the way for occasional reclassification actions. With the passage of time and an accumulation of experience, FDA has gained confidence that some class III device types can be safe and effective and that lesser FDA regulation will continue to ensure their safety and effectiveness. In essence, devices with uses or designs that were once thought to warrant their being subject to class III regulation and the rigors of PMA no longer require such regula- tion. The flow of devices from class III to class I or II was an anticipated outcome of FDA’s device regulatory system that has not been fully realized. Reclassification actions must be based on information in the public domain and significant legal impediments exist that preclude the use of data and information in PMAs for reclassification purposes. Furthermore, resistance by companies that have successfully navigated the PMA process and benefit from the significant barrier to competition that PMA affords and a lack of FDA incentive to pursue reclassification have rendered this less than a suc- cessful means to adjust device classification over time. 8A product code is a distinct three-letter code that is assigned by FDA at the time of clear- ance based on attributes of interest to the agency that are associated with the new device as it is included within an existing generic type of device. Product codes serve an administrative function allowing easy identification of devices with the attributes of interest within a generic device type.

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5 APPENDIX C Illustration 2 Extracorporeal shock wave lithotripters. Prior to May 28, 1976, mechanical devices were in commercial distribution that were inserted into the urinary bladder through the urethra to grasp and crush bladder stones. These preamendment medical devices were considered part of a generic type of device referred to as mechanical lithotripters. Fol- lowing enactment of MDA, the Gastroenterology and Urology Devices Panel recommended that mechanical lithotripters be regulated in class II subject to performance standards. FDA accepted the panel’s recommendation and clas- sified the generic type of device under 21 CFR 876.4500. The classification regulation describes the generic type of device as “a device with steel jaws that is inserted into the urinary bladder through the urethra to grasp and crush blad- der stones.” Performance standards and special controls were never developed for mechanical lithotripters. When the postamendment extracorporeal shock wave lithotripter, designed to use focused ultrasound to noninvasively fragment urinary calculi within the kidney or ureter, emerged in the middle 1980s, FDA did not find the device SE to the mechanical lithotripter. Based on differences in use and design, as well as different safety and effectiveness questions raised with the use of the new technology, FDA decided that this new device warranted the rigors of PMA. Over the next few years, clinical studies were conducted and PMA applications were eventually submitted and approved. Over time, postmarket experience with the FDA approved devices appeared in the public domain allowing the agency to reclassify extracorporeal shock wave lithotripters into class II subject to special controls (21 CFR 876.5990). Interestingly, the same technology for use in crushing gallstones remains in class III subject to PMA requirements. Since enactment of FDAMA in 1997, devices determined to be not sub- stantially equivalent (NSE) to legally marketed class I or II devices no longer have to face the rigors of PMA in all cases. The statutory provision, referred to as de novo classification, allows companies that receive NSE decisions to request that their devices be regulated in class I or II and allows FDA an opportunity to avoid unnecessary class III regulation. To date, there have been 55 de novo classifications that have been granted creating the same number of new generic device types.

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10 THE FDA 510(k) ClEARANCE PROCESS scope of this paper is required to assess the value of the program, the most recent data available from FDA demonstrate that the program is not merely a “rubber stamp” as is often suggested. For fiscal year 2007, the last year that the Office of Device Evaluation (ODE) published data on 510(k) deci- sions,13 of the 3,052 decisions rendered, 2,640 (87 percent) were SE, 95 (3.0 percent) were NSE and 317 (10 percent) were “other.” The basis for FDA’s NSE decisions is not public, however, the bulk of NSE decisions relate to either the new device’s having a “new” intended use or scientific and clinical issues relating to technology. Other decisions include 510(k) withdrawals and deletions representing manufacturers’ inability, or unwillingness, to meet FDA’s expectations for clearance. Freedom to Apply Knowledge from Precedent in Decision-Making Inherent in the 510(k) decision-making process, is the agency’s ability to apply the knowledge gained from the premarket and postmarket experience with class I and II devices to the review of new devices that are the subjects of 510(k) submissions. This is in stark contrast to the PMA process, where the agency is precluded by law from applying any information obtained in one PMA submission to the next without explicit authorization from the owner of the PMA with the information.14 This flexibility has lessened the regulatory burden associated with bringing new class I and II devices to market more than any other aspect of the 510(k) program. It has diminished the need for repetitive testing of new biomaterials to completely eliminate the need for redundant clinical studies. In the world of class III devices, every manufacturer must generate its own data on its own device and cannot rely on any data that are contained in competitors’ approved PMAs. Ability to Grant Exemptions When 510(k) no longer provides public health value, FDA has the abil- ity to exempt a device from premarket review. This option does not exist for PMA. The criterion for making the decision to exempt a device types from 510(k) was spelled out in the Federal Register (FR).15 The FR notice stated: 13Refer to the Fiscal Year 2005 and Fiscal Year 2006 Office of Device Evaluation Annual Reports at http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDRH/CDRHReports/ ucm127516.pdf. 14Guidance for Industry and for FDA Reviewers: Guidance on Section 216 of the Food and Drug Administration Modernization Act of 1997 available at http://www.fda.gov/Medical Devices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073707.htm. 15January 21, 1998, FR notice (63 FR 3142).

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10 APPENDIX C In considering whether to exempt class II devices from premarket notification, FDA . . . (1) . . . has considered the risks associated with false or misleading claims, and the frequency, persistence, cause or seriousness of the inherent risks of the device); (2) characteristics of the device necessary for its safe and effective performance are well established; (3) changes in the device that could affect safety and effectiveness will either: (a) be readily detectable by users by visual examination or other means such as routine testing, before causing harm, for example, testing of a clinical laboratory reagent with positive and negative controls; or (b) not materially increase the risk of injury, incorrect diagnosis, or ineffective treatment; and (4) any changes to the device would not be likely to result in a change in the device’s classification. FDA also considered that even when exempting devices, these devices would still be subject to the limitations on exemptions, as described in section III of this document. The agency’s position is that these same factors should also be con- sidered when determining if any additional class II device types should be exempted from 510(k) requirements. As a safeguard, all exemptions from 510(k) are subject to “limitations on exemptions” that prohibit industry from altering the intended uses or the fundamental scientific technology upon which the exemption was based. Determining Intended use from Proposed Device Labeling Section 513(i)(1)(E) of the act restricts FDA’s determination of the in- tended use of a device that is the subject of a 510(k) to the proposed labeling in the submission. The basis for this restriction relates to FDA’s historically withholding or delaying clearance of 510(k)s based on concern regarding off-label use of the device. In amending the law with FDAMA 97, Congress recognized the importance of allowing new medical devices that are SE to go to market even if a potential for off-label use is evident. Although the agency’s determination of intended use is restricted, FDA is empowered to consider the potential for off-label use and act on concerns that meet speci- fied criteria. In addressing off-label use issues, Section 513(i)(1)(E) requires FDA to consider 1. Whether there is a reasonable likelihood that the device will be used for an intended use not identified in the proposed labeling for the device, and 2. If such use could cause harm to the patient or the consumer. In situations that meet these criteria, the agency most often mandates the inclusion of warnings, precautions or contraindications, as appropri- ate, in device labeling through the SE letter, often referred to as “SE with limitations.” In order for recipients of these letters to modify or delete FDA

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10 THE FDA 510(k) ClEARANCE PROCESS mandated labeling statements, they are required to submit a new 510(k) with scientific evidence sufficient to justify their request. Following enactment of the statutory provision in 1997, critics of this statutory provision initially envisioned industry taking advantage of this “regulatory loophole” by labeling their devices one way to get clearance while really intending their devices for uses that do not appear in labeling. Manufacturers of biliary stents, a class II device, have engaged in activities that appear to support this concern. Many manufacturers of biliary stents have engaged in promotional activities geared toward the needs of cardiac surgeons and their patients. These practices suggest that obtaining FDA clearance for biliary use was a ruse to avoid the rigors of PMA approval for class III stents intended for use in the vasculature. Regardless of the manufacturers’ intent, the challenge relating to this situation affects the PMA path to market as well as 510(k). Devices in all regulatory classes that are labeled with legitimate indications for use can be, and often are, used for off-label uses. To completely avoid this situation, FDA would have to either prohibit distribution of the devices for the legitimate on-label uses or somehow interfere with the practice of medicine—two options that are subject to legal challenge and are not good for public health. While the merits of the way FDA handled the biliary stent situation can be debated, the biliary stent situation serves as evidence that there are post- market means of addressing an issue after FDA grants market authorization, as the FDA took the manufacturers to task via a systematic compliance action that effectively stopped the rampant off-label promotion and use of biliary stents for cardiac indications. Least burdensome Provisions of the Law With enactment of FDAMA 97, Congress wanted to reduce unneces- sary regulatory burdens associated with the 510(k) and PMA processes. Al- though the Congress did not change the statutory criteria for FDA decision- making, it sent a clear directive to the agency to eliminate any unnecessary burdens that contribute to delay in the availability of new medical devices. To this end and in regard to the 510(k) program, Section 513(i)(1)(D) of the act states: Whenever the Secretary requests information to demonstrate that devices with differing technological characteristics are substantially equivalent, the Secretary shall only request information that is necessary to making substantial equiva- lence determinations. In making such a request, the Secretary shall consider the least burdensome [emphasis added] means of demonstrating substantial equivalence and request information accordingly.

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105 APPENDIX C In regard to PMA requirements, Section 513(a)(3)(D)(ii) states that any clinical data, including one or more well-controlled investigations, specified in writing by the Secretary for demonstrating a reasonable assurance of device effectiveness shall be specified as a result of a determination by the Secretary that such data are necessary to establish device effectiveness. The Secretary shall consider, in consultation with the applicant, the least burdensome appropriate means of evaluating device effectiveness that would have a reasonable likeli- hood of resulting in approval. To implement these statutory provisions, the agency issued a guidance document for FDA staff and regulated industry (FDA, 2002). In defining the term least burdensome, the agency took great care to fulfill the intent of Congress while maintaining the integrity of the review processes. In this regard the term was defined as “a successful means of addressing a premar- ket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA.” In reality and recognition of the common sense nature of the provision, FDA applied the least burdensome concept to all devices regulated by FDA under the device provisions (includ- ing IVDs). In so doing, FDA believed that the statutory mandate could be accomplished without compromising scientific integrity in the decision-mak- ing process or FDA’s ability to protect the public health. Just as the words substantial equivalence often create visions of an inferior or out-of-date regulatory threshold for clearance, the words least burdensome create visions of scientific shortcuts or compromise. In consid- ering the least-burdensome provisions and need for regulatory reform, it is important to avoid perception and focus on fact. In this regard, we are fortunate to have detailed guidance that clearly articulates the agency’s in- tent in implementing the least-burdensome provisions of the law. When the guidance is carefully read, it is clear that only shortcuts and compromise that do not lower FDA’s standards fall within the meaning of the terminology. Accommodating New Scientific Knowledge in the Review Process Science is constantly evolving, creating new methods for conducting research, exploring what was thought to be known to a much greater depth than thought imaginable, and identifying new issues that warrant investi- gation. In a regulatory setting, this creates a significant challenge. On one hand, regulated industry appreciates new scientific methods that result in efficiencies and cost savings. On the other hand, industry resents having new products withheld from the marketplace pending the conduct of testing that the competition may not have conducted. While this issue is present across the board, including the PMA process, there is no simple way of addressing this dilemma within the system of device regulation embodied in 510(k).

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106 THE FDA 510(k) ClEARANCE PROCESS Interestingly enough, the challenge is less pronounced in regulating new devices with differing indications for use or technological characteristics. Under these circumstances, industry takes little issue with performing state of the art tests on the way to market entry. Ironically, the challenges most often surface with “me too” devices that are held to a higher standard than their predecessors because of new scientific information about the products or the materials, or new methods of assessing products. Take electromagnetic compatibility (EMC) as an example. Not too long ago, little attention was paid to electromagnetic emissions, giving way to devices that either interfere with other devices being used in close proximity or are themselves susceptible to interference. When electromagnetic inter- ference became a recognized environmental hazard the regulatory process was not prepared to respond. The initial response was to hold new devices entering the marketplace to a higher standard that included difficult to conduct EMC testing. This mindset delayed new products getting to market and prolonged the use of older designs. What is needed is a means of encouraging the development of improved technology that is not dependent on premarket review to implement. The development of performance standards or agency guidance that encourages product improvement over time with verification of company progress dur- ing FDA facility inspections is a viable model. Here the use of international standards would have some applicability as well, though ensuring those standards are kept up to date remains a significant challenge outside FDA purview. The development and issuance of guidance by FDA as new knowl- edge accrues would be a powerful tool and if communicated effectively to industry would promote innovation and also speed product to market while addressing new scientific concerns. Illustration 5 Computer assisted diagnostic (CAD) devices. Computer assisted diagnostic devices are a relatively new phenomenon. And as they have developed, FDA has been in the forefront of developing methods to evaluate these products. The research and attendant methods have changed significantly over the past decade and thus the questions that reviewers may be asking today about product performance parameters are dramatically different than what were asked previously. For example, in the early 1990s the focus was on sensitivity and specificity. Today, FDA has shifted to evaluating area under the receiver operator curve (ROC) and to assessing multiple case–multiple re- viewer study paradigms. Initially, not all of the appropriate questions relating to CAD were addressed in determining device safety and effectiveness. This means the evaluation methodology for CAD products has changed because of advances in understanding and science.

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107 APPENDIX C We note that if new scientific knowledge suggests that devices on the market are not safe, then 510(k) is not the appropriate regulatory mecha- nism to address the issue. If the new scientific information raises issues that would question prior decision-making, then FDA should resolve them without disadvantaging select companies and through maintaining a “level playing field.” If FDA has concerns with a group of devices, the agency has the means to rectify the situation without disadvantaging companies seek- ing market authorization for new devices. Promulgation of special controls, including mandatory performance standards, issuance of public health advisories, guidance documents and agency use of the “bully pulpit,” is an effective means of prompting change. If FDA has information that suggests that a product is not safe, a range of compliance actions can be selected from the menu, including issuance of untitled letters and warning letters, requir- ing mandatory recall, charging civil money penalties for every violation, as well as seizure and injunction. Ultimately, this is a challenge for FDA. Consideration must be given to establishing streamlined mechanisms for addressing issues recognized through new scientific means. The American public would be better served if FDA had more efficient and effective means of requiring companies to take corrective action. The promotion of voluntary consensus standards presents an unrealized opportunity for FDA reviewers to address scientific issues that the concept of substantial equivalence to marketed products does not. The unrealized Potential of National and International Standards in Review As of June 2010, CDRH recognizes 833 national and international device standards. These are largely of two types. Horizontal standards are broad and cover issues that affect many types of devices. Examples include the standards for safety of electrical products (IEC-60601-3) and risk man- agement for medical devices (ISO 14971). The third edition of IEC 60601 is an all-hazards standard for devices that use electricity and the standard is generally about the safety of these products. ISO 14971 is a relatively new standard and sets out principles for how to manage risk at all points across the medical device product life cycle. The other type is vertical standards which are less general and are very product-type specific. Failure to conform to a recognized standard after submitting a declara- tion of conformity in a 510(k) or PMA is a prohibited act, subject to FDA enforcement action.16 By declaring conformance to a recognized standard, a company can avoid submitting detailed documentation regarding the issues 16Refer to Sections 301(x) and 501(e)(2) of the act. Submitting a false declaration in a pre- market submission is a violation of the law.

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10 THE FDA 510(k) ClEARANCE PROCESS covered by that standard. In fact, Section 514(c) of the act directs FDA to recognize national and international standards, and mandates that FDA will accept a manufacturer’s declaration of conformity to an FDA-recognized standard to meet a requirement to which the standard is applicable. It also requires the manufacturer to maintain information demonstrating confor- mity. The manufacturer must have this information at the time a declaration is submitted and must provide the information to FDA upon request. By virtue of the rules of standards development organizations which generate the standards that FDA recognizes, it is clear that credible stan- dards do exist. However, the standards process is also burdensome and a theme with respect to standards, much like guidance, is that by the time a document is issued, the science may have changed making parts of these documents out of date. This heightens the need for the review teams in FDA to maintain a high level of current knowledge about science and stan- dards and to maintain some degree of review flexibility. More importantly, the FDA needs greater involvement in assisting in updating international standards. Are criteria for applying these standards transparent and grounded in good science and do they lead to good health care? All medical device standards are developed to help ensure safety and effectiveness leading to good public health. Many standards provide this information and others are improving. For example, if one follows AAMI/ANSI/ISO 10993-1:2009, a horizontal biocompatibility standard, the standard defines the principles and criteria for effective use of the standard with a flow chart summarizing the systematic approach to a biological evaluation of medical device materials as part of a risk management process. The rate limiting factor in the use of standards has been manufacturers’ unwillingness to submit declarations of conformity in premarket submis- sions. This unwillingness is fueled by three risks: (1) the threat of immedi- ate inspection, (2) the likelihood that a disagreement with FDA will ensue regarding conformity with a standard, and (3) the possibility of criminal prosecution should FDA conclude that conformity with the standard did not exist at the time that the declaration of conformity was submitted for FDA review. Fears of these risks persist and have resulted in low standards use. For consensus standards to optimally contribute to public health, industry needs to support the establishment of more robust standards, in- cluding standards with “performance limits,” and to be willing to declare conformity in all premarket submissions. Taking this approach can encour- age innovation and afford regulators the confidence that testing against the standard ensures that the device performs as intended and designed. Furthermore, FDA needs to expand the concept of conforming to standards to include conformance to FDA guidance as a viable and highly desirable approach to securing FDA market authorization.

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109 APPENDIX C CHALLENGES CREATED bY INDuSTRY, COST CONTAINMENT, AND THE PRACTICE OF MEDICINE Industry Competition Prompts Device Differentiation The medical device industry is a very competitive industry. While tech- nology has evolved at a tremendous rate ever since passage of the MDA 76, technology is only one part of the competitive equation that challenges device regulation. In fact, in some respects technology is the easiest vari- able to deal with in the confines of 510(k) review. New technology either is found to fall within an existing generic device type or raises significant enough public health issues to warrant premarket approval. Perhaps the most challenging aspect of competition in the industry relates to device labeling and promotion and advertising practices. As has been pointed out, in order for FDA to authorize a manufacturer to market a new device through the 510(k) process, the agency must conclude that the new device is SE to an existing class I or II device. While being SE is a prerequisite to obtaining FDA clearance, new devices can and do differ from the devices to which they are compared. In the highly competitive medical device industry, manufacturers attempt to differentiate their devices from the competition, but not to a degree where FDA finds them to be NSE. For devices that are similar in design and function to competitors’ devices, the most common way to achieve differentiation is through descriptive infor- mation (for example, “claims”) added to product labeling, or disseminated through promotion and advertising materials and activities. It is not unusual for manufacturers to attempt to use the 510(k) process to get FDA authori- zation to add descriptive information to device labeling. In an FDA guidance document, the agency acknowledges this industry approach to differentiat- ing devices in order to capture market share from competitors.17 Drivers of Change: Cost Containment and the Practice of Medicine The quest to control spiraling health-care costs is a major factor that in- fluences device design and use today. When combined with the ever changing demands imposed by the practice of medicine, significant forces are created that drive the medical device industry to innovate. The result stresses the FDA bureaucracy and slows progress. One need only consider the impact of medical errors on the evolution of medical technology. Everyone knows that the costs associated with medical errors are high, leading to escalating health-care costs and awards associated with expensive litigation. Pressure from the health-care community and insurance providers, along with prac- 17Refer to Guidance for Industry: General/Specific Intended Use at http://www.fda.gov/ MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073944.htm.

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110 THE FDA 510(k) ClEARANCE PROCESS titioners, to reduce medical errors incentivized the development of software controlled devices, networked systems and interdevice compatibility. More sophisticated device–user interfaces are associated with the resulting tech- nology fueled human factors considerations, all of which have created sud- den and significant challenges for FDA’s premarket review programs. Consider the evolution of single use devices (SUDs) and the reprocessing industry that was spawned to allow the reuse of SUDs as a means of cost containment. SUDs were initially developed to reduce the risks associated with hospital and doctor office cleaning and sterilization procedures and to eliminate the costs associated with these procedures. Escalating health-care costs soon after created opportunities for third party reprocessors to engage in activities designed to render SUDs suitable for unanticipated reuse. These dramatic shifts created major challenges for FDA that were only overcome through legislative change. Combination Products A scientific and regulatory complexity that has surfaced in the last 20 years with increasing frequency relates to combining drugs and biologics with medical technology. Whether simple antimicrobial coatings added to devices to increase resistance to infection, complex drug coated cardiovas- cular stents to prevent restenosis, or sophisticated drug and biologic delivery systems, an explosion of regulated entities that cross traditional FDA regu- lated product boundaries has created immense challenges for FDA. From a regulatory perspective, a device that contains, or is otherwise associated with, a drug or biologic agent may be a “combination product.” Combi- nation products present complex regulatory issues, including what FDA requirements apply to the combination product and which FDA center has responsibility for ensuring that the appropriate requirements are met. For combination products assigned to CDRH, the complexities go deeper when considering the proper device classification. For class III devices, regulation can be reasonably straightforward, but for simple devices, the addition of drugs and biologics can create complex scientific issues. FDA’s Office of Combination Products (OCP) determines which FDA regulated products meet the definition of a combination product, as well as which center assumes the responsibility for the combination product’s regulation. For combination products, typically one FDA center will have responsibility for the product’s regulation, but all centers with expertise relevant to the product play a role in the product’s evaluation. While a treatment of how this will play out with respect to various device regulatory approaches is beyond the scope of this paper, it seemed worthy of a mention within the broader context of considering whether the statutes that govern FDA’s device program provide adequate protection of public health.

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111 APPENDIX C A PERSPECTIvE ON FDA GuIDANCE DEvELOPMENT FDA guidance documents have been demonstrated to be a valuable way of articulating agency expectations while establishing a reasonable degree of consistency and predictability in the review processes. We hasten to add two points concerning agency guidance. First, in practice some members of both FDA and industry have interpreted guidance as de facto regulation. For guidance to be of maximum value, guidance must be treated as exactly that: “guidance”—information intended to help industry and FDA in achieving consistency in review and predictability in outcome. It should not be used as a straitjacket that hampers innovation or delays getting products to market. Guidance should facilitate development and, when used appropriately, lead to a streamlined means of developing data for regulatory submissions and improved submission quality, a source of significant delay in the regulatory process. The second point relates to the procedural issues in developing guidance in FDA. Guidance development has become as difficult as issuing a regulation. The current approach to development of guidance is needlessly burdensome on all parties and displays the bureaucracy failing in a simple, but effective means to promote and protect the public health. CONCLuSION Ensuring that all medical devices are safe and effective entails a com- plex system of requirements, with Section 510(k) being one component. A fair assessment of the US regulatory system requires careful consideration of each system component and the relationships between components that provide the system’s overall functionality. The 510(k) process differs from how it is often characterized. In fact, the most common characterizations of the rather complex concept of SE are as simple as the acronym and are often misleading. While the 510(k) program has strengths and weaknesses, without question the program makes signifi- cant contributions to public health. Whether the program is maintained “as is,” changed or totally abandoned, the US regulatory system for ensuring the safety and effectiveness of the diverse range of medical products that fall within the definition of device must be flexible enough to accommodate constant and rapid change, and have the integrity to fend off criticism. For FDA scientists and clinicians, making correct decisions is difficult enough without having the underlying regulatory process for those decisions under constant attack.

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11 THE FDA 510(k) ClEARANCE PROCESS REFERENCES FDA (US Food and Drug Administration). 1986. Guidance on the CDRH Premarket Noti- fication Review Program 6/30/86 (K86-3). http://www.fda.gov/MedicalDevices/Device R egulationandGuidance/GuidanceDocuments/ucm081383.htm (accessed July 21, 2010). FDA. 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 July 21, 2010). FDA. 2002. The Least Burdensome Provisions of the FDA Modernization Act of 1997: Con- cept and Principles; Final Guidance for FDA and Industry. http://www.fda.gov/Medical Devices/DeviceRegulationandGuidance/GuidanceDocuments/uc m085994.htm (accessed July 21, 2010).