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Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report (2010)

Chapter: Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips

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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 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

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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 monitor 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 weaknesses 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 radiation. The agency is also responsible for promoting the public health by helping 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 301(i), 403(f), 502(c), and 602(c)) means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or

1

Refer to FDA mission statement available at http://www.fda.gov/aboutfda/whatwedo/default.htm.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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,

  2. 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

  3. intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes 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, bandages 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, including 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

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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 potential 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, provisions 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 providing 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 substantial 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, including 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

2

Refer to Section 513(a)(1)(B) of the FDCA.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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 products 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 certain 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:

3

A 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×
  • 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 generally acknowledged state of the art, which changes as scientific knowledge changes. A 2007 revision of the directive in the EU placed considerableplaced considerable emphasis on clinical data and the necessity of keeping it up to date via postmarket 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 provide 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 information 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, differences remain.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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 standards 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 recognized standards to expedite the review of a submission.5

US DEVICE CLASSIFICATION PROCESSES

After May 28, 1976, the enactment date of the Medical Device Amendments of 1976 (MDA 76), FDA made a significant effort to group all medical 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 classification 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 classification 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

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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 (postamendments) 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 demonstrated. 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 distribution 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


  1. 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.

  2. Classification. Class II

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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 regulation. 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 successful means to adjust device classification over time.

8

A product code is a distinct three-letter code that is assigned by FDA at the time of clearance 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

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. Following 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 classified 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 bladder 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 substantially 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

Illustration 3

Ovarian adnexal mass assessment score test system.9

When Vermillion, Inc. wanted to market its OVA1™ Test as a diagnostic, there were no legally marketed devices to which the OVA1 Test could be compared. The OVA1 Test consisted of software, instruments, assays, and reagents all used to obtain the OVA1 Test result. The new device raised issues of intended use and technology that precluded a finding of SE. Although the OVA1 Test could not be found SE, FDA determined that the safety and effectiveness of the device could be ensured when regulated in class II subject to special controls. On this basis, FDA granted a de novo classification request and promulgated the following classification regulation:


21 CFR 866.6050 Ovarian adnexal mass assessment score test system.


An ovarian/adnexal mass assessment test is a device that measures one or more proteins in serum. It yields a single result for the likelihood that an adnexal pelvic mass in a woman, for whom surgery is planned, is malignant. The test is for adjunctive use, in the context of a negative primary clinical and radiological evaluation, to augment the identification of patients whose gynecologic surgery requires oncology expertise and resources.

Further, in addition to the general controls of the Act, the Office of In Vitro Diagnostic Device Evaluation and Safety developed the following special controls:

  1. “Class II Special Controls Guidance Document: Ovarian Adnexal Mass Assessment Score Test System,” which includes recommendations for performance validation and labeling;

  2. sale, distribution, and use in accordance with the prescription device requirements in 21 C.F.R. 801.109; and

  3. placement of warning statements that address the risks identified in the special controls guidance document in a black box.

TODAY’S PREMARKET NOTIFICATION PROCESS

At least 90 days before marketing a device in the United States for the first time, a manufacturer must notify FDA of its intent and obtain FDA authorization to do so. Furthermore, changing a legally marketed device’s design or intended use may render the device to be a “new” device, thereby requiring FDA authorization before the modified device is marketed in the United States for the first time. The agency has regulations that apply

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

to changes to legally marketed devices and has issued guidance to clarify requirements.

The objectives of the 510(k) program have evolved over time and are often the subject of debate among interested parties whose understanding of the program varies and whose expectations are not aligned. Initially, the congressional intent underlying the program was very simple; Section 510(k) was a means of classifying new devices, thereby ensuring that they were subject to an appropriate level of FDA regulation sufficient to ensure their safety and effectiveness. With the understanding that a new device found SE to (1) a class I device would be subject to general controls, (2) a class II device would be subject to general controls and the associated mandatory performance standards, and (3) a preamendment class III device would eventually be subject to PMA and that all NSE devices were automatically placed in class III, immediately subject to PMA, 510(k) was merely the means of ensuring that new devices are subject to appropriate FDA regulatory requirements. What this simplistic view did not consider was the rapidly evolving nature of the device industry, FDA’s inability to develop mandatory performance standards and the resource demands of PMA. Soon after enactment it became apparent that Congress’s initial vision for the program could not be fulfilled; in particular, the agency could not promulgate mandatory performance standards. This prompted the agency to develop program guidance to standardize 510(k) review and identify the key points to consider in determining SE (FDA, 1986). To a large degree, FDA’s guidance on the 510(k) program was accepted by Congress and codified in SMDA 90 and its implementing regulations.

From purely an industry perspective, 510(k) most often represents the desirable and most straightforward pathway to market. Yet, for many companies, specification developers and entrepreneurs, 510(k) is a means to elicit financial interest in new products. More specifically stated, 510(k) clearance is a commercially valuable event and often signals an investment opportunity, if only as a platform on which a more commercially appealing device can be built. While we do not know the number of 510(k) cleared devices that never go to market, we know that not all 510(k) cleared devices do and that there are often delays in market entry that are attributable to non-FDA related barriers to market entry.

Among the critics of the 510(k) program, there is a tendency to focus on specific clearances that are often associated with postmarket problems and attribute the observed problems to inadequacies in 510(k) review, thereby concluding that the objectives for the program are not being realized. As a generalization, program critics believe that there are too many new devices escaping PMA requirements and that the criteria for determining SE are skewed in a direction of inadequate public health protection. Of note is the fact that even the occasional critics of 510(k) decision-making appreciate the

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

concept of regulation based on device classification and do not argue that the 510(k) program is not largely fulfilling Congress’s intent.10

THE CONCEPT OF SUBSTANTIAL EQUIVALENCE

Between 1976 and 1986, substantial equivalence was not defined. In fact, the only guidance bearing directly on the issue of SE can be found in the Report of the Committee on Interstate and Foreign Commerce on the Medical Device Amendments of 1976 (Senate report) which offers the following unhelpful remark:

The committee believes that the term, substantial equivalence, should be construed narrowly where necessary to assure the safety and effectiveness of a device but not narrowly where differences between a new device and a marketed device do not relate to safety and effectiveness.

Despite the ambiguous nature of the words, during the very early years, determining SE was not a significant challenge for the agency as the magnitude and rapidity of change in use and design were not fully apparent, that is, devices that were the subject of 510(k) submissions did not initially differ appreciably from their preamendment counterparts. Because of the medical device industry’s desire for continuous improvement, the need to differentiate new devices from existing ones and the demands of a healthcare system for newer technology; it did not take long for the concept of SE to be challenged by the nature and degree of the change that was occurring, thus creating confusion in FDA and industry and a need for guidance. To complicate matters further, finding a new device NSE challenged FDA’s limited resources creating pressure to make Section 510(k) accommodate the majority of new devices entering the marketplace. To a large extent, the first decade of experience with implementing MDA 76 shaped the 510(k) program into the system that it is today, that is, a regulatory system that subjects new devices to appropriate preclinical and clinical testing and high risk devices that warrant class III regulation to the rigors of PMA. While the tendency is to judge the performance of the 510(k) program by the percentages of SE and NSE decisions, this approach ignores the percentage of devices that are withdrawn by their submitters before FDA renders a classification decision. The reason for withdrawals may vary, but many 510(k) submitters simply cannot perform the testing that is required for clearance or the testing is not supportive of a clearance decision.

10

Medical Devices: Are Current Regulations Doing Enough for Patients? Testimony of Peter Lurie, MD, MPH, and Jonas Hines, Health Research Group at Public Citizen before the US House of Representatives Committee on Energy and Commerce Subcommittee on Health, June 18, 2009.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
×

SE is always approached in the context of comparing a new device to at least one legally marketed class I or II device, referred to as a predicate device. In accordance with Section 513(i) of the act, a medical device is SE to a predicate device if it has the same intended use as the predicate device; and (1) it has the same technological characteristics as the predicate device or (2) it has different technological characteristics which do not raise new questions of safety and effectiveness and is shown to be “as safe and effective” as the predicate device. To fully understand how SE determinations are made, one must understand (1) the concept of “intended use,” (2) what constitutes “new questions of safety and effectiveness” and (3) how safety and effectiveness are approached.

INTENDED USE

Intended use is the first consideration when making a SE determination. Despite its importance, it has only been defined in the context of “postmarket” labeling requirements found in 21 CFR 801.4. In this context, the words intended use refer to the objective intent of the persons legally responsible for the labeling of devices, intent to be determined by such persons’ written or verbal expressions or the circumstances surrounding the distribution of the device. In the context of determining SE, this definition is often cited, contributing to significant confusion. In fact, the agency’s use of this definition in the context of 510(k) decision-making led to a change in the law under FDAMA 97 whereby intended use must be determined principally from proposed labeling provided in 510(k) submissions.

The words found in 21 CFR 801.4 are valuable for determining whether a manufacturer is promoting its device for a use other than the use for which the device is cleared, but are problematic for determining SE. Device manufacturers often envision multiple uses for their devices, but may not intend for them to be used for all envisioned uses until evidence can be gathered to support such uses. Some of these uses may be evident from patent materials, as well as the device’s design history file, neither of which establish the manufacturer’s intent to begin promoting beyond what is described in its 510(k) submission. In hindsight, the agency would have been better off developing a secondary definition of intended use specifically for use in the context of determining SE. In an attempt to define intended use in the 510(k) context, we believe that it may be helpful to initially focus on “indications for use,” a primary determinant of intended use that is relatively well understood.

Like intended use, the words indications for use are not defined in the context of 510(k), however, these words are defined in the context of PMA. According to the PMA procedural regulation, specifically 21 CFR 814.20(b)(3)(i), “indications for use” is a “general description of the dis-

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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ease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended.” This definition encompasses many indications-for-use statements appearing in labeling for class I and II devices, but overlooks the fact that not all devices require a level of detail in their indications-for-use statements that specifies diseases or conditions, or identifies a patient population. For example, indications for use for many general use devices (for example, scalpels, hypodermic needles and external infusion pumps) include “functional indications for use” that do not provide clinical specificity. Although not defined by regulation, the concept of functional indications for use is evident in labeling for many 510(k) cleared devices and has been advanced through agency guidance. In an October 6, 2005, draft guidance document titled Functional Indications for Implantable Cardioverter Defibrillators, FDA defined functional indications for use as “an indication statement for a medical device that describes what the device does and does not specify an indicated patient population.” As an example, many surgical sutures have indications-for-use statements that only specify that the device is to be used for the approximation of soft tissue, with no reference to specific tissues, anatomical sites or surgical procedures.

While a device’s indications-for-use statement represents a large part of a device’s intended use for determining SE, intended use in this context also encompasses: who is intended to use the device, where it is intended to be used and under what conditions the device is to be used. To ensure that the 510(k) system functions, each of these factors is constrained to an appropriate level of abstraction that has public health significance. For example, “who” is intended to use a device most often comes down to either a licensed health-care practitioner (prescription use) or a lay user (over-the-counter use); however, on occasion who can relate to someone with a minimum level of training or experience, or of a minimum age. In considering “where” a device is to be used, agency consideration most frequently relates to use either in health-care facilities or in the home; however, in some instances the location of use may require greater depth of review. In considering conditions of use, the domain may involve environmental conditions, for example, intended for use in the magnetic resonance imaging field or the number of times that a device is suitable for use (such as, a device that is “single-use” disposable).

In order for a device to be found SE, FDA must find that any differences in intended use between a new device and a predicate do not constitute a “new intended use.” In making this decision, the agency exercises considerable discretion and allows changes in intended use where the change does not introduce different types of safety and effectiveness questions compared to the predicate device’s generic device type.

To illustrate how the agency has accommodated differences in intended

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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use to meet changing public health needs, consider in vitro diagnostic devices. In the early years of the medical device program, the vast majority of IVDs were intended for use in hospital or contract service laboratories. Over time, there has been a shift to include physician office laboratories, point of care testing of patients, and lay use in the home. Rather than view any one of these changes as a new intended use worthy of class III status, the agency elected to require data to ensure that new devices function as required in each intended use environment. In so doing, FDA receives the data that it needs for decision-making and avoids the burdens of PMA.

After fully considering FDA’s approach to intended use within the confines of the 510(k) program, the concept of intended use as applied to determining SE becomes clearer. In essence, intended use is a regulatory concept that is the first consideration when determining the boundaries of a generic type of device and is most often constructed to encompass the widest breadth of use where the regulatory controls for the generic device type continue to provide reasonable assurance of safety and effectiveness. Again, surgical sutures serve as a simple example.

As previously stated, surgical sutures often carry a very general indication-for-use statement, that is, for the approximation of soft tissue. At the most fundamental level, this indication-for-use statement describes the functional capability of the device and also constitutes the device type’s intended use for the purpose of determining SE. Sutures carrying a more precise indication-for-use statement may reference specific tissues or surgical procedures, but are viewed for SE purposes as having the same intended use. It is on that basis that surgical sutures’ nonabsorbable poly(ethylene terephthalate) surgical suture is indicated for use “for the approximation of soft tissue such as the repair of meniscal tear injuries.”11

NEW QUESTIONS OF SAFETY AND EFFECTIVENESS

Under the law, if a device raises “new” questions of safety or effectiveness compared to a predicate device, that is, the new device raises a question that the old device did not raise, the new device cannot be found SE. Given that the detailed content and structure of any question can make it appear dissimilar when compared to questions raised in the past, and therefore “new,” FDA loosely interprets the word new. As evident in FDA’s program guidance to the review staff, the agency interprets “new questions” to be “new types of questions.” By inserting the word types, different questions can be grouped, thereby providing FDA considerable latitude in deciding what scientific questions justify making a new device NSE.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Advances in materials science provide examples of how specific scientific questions are addressed in the context of SE decision-making. In the medical device industry, manufacturers constantly search for new materials. As new materials are selected for use, questions often arise regarding their suitability for a particular use. While a new use for a material may raise questions, the questions are generally of the same “type” that previous materials have raised and, therefore, rarely justify an NSE decision. In the context of the latest material science, questions regarding a new material’s ability to meet the demands of a particular use environment are usually addressed through standard bench and animal testing. The vulnerability of course rests with the fact that in some cases, bench and animal testing reveal no concerns that later appear in actual use conditions. Although postmarket vigilance eventually provides feedback to FDA and the industry so that problems may be addressed, postmarket problems often suggest premarket weakness. Of course, to fully address this perceived premarket weakness, extensive premarket human testing for all new materials or compounds would be needed, thereby taxing FDA’s capacity to review products.

Historically, scientific knowledge pertaining to legally marketed class I and II devices has transcended generic device types leading to the appearance of comparisons to multiple devices in a single 510(k) submission. Frequently, devices subject to comparison are inappropriately referred to as predicates even though they may not share a common intended use. The motivation for this practice is efficiency. It often makes scientific sense to consider questions raised during the review of a 510(k) submission in the context of a broader array of legally marketed class I or II devices and not simply a single predicate. There is an obvious relevance to being familiar with the science that has supported a previous 510(k) clearance even if the subject device does not technically qualify as a predicate. An inherent part of today’s 510(k) program relies on an ability to answer scientific questions based on past practice. FDA’s experience in addressing scientific questions pertaining to any previous 510(k) clearance may support simply answering the question in an effort to avoid an otherwise unnecessary NSE decision. We note parenthetically that this represents a strength of the 510(k) in contrast to the current EU system that does not to allow prior knowledge to enter into decision-making outside of the application of the essential principles. An example of this problem can be found in the 2005 reclassification of orthopedic devices throughout the EU, including hips and knees.12 While the US FDA can perform such a reclassification device by device, the EU had to perform a “mass reclassification” in order to solve problems it believed it had in only a few devices.

12

D.F. Williams, The Classification of Total Joint Replacements in the European Union: An Independent Report on the European Commission Proposed Directive for Reclassification of Certain Total Joint Replacement Prostheses, at 44 (October 2003).

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Illustration 4

Tepha, Inc.’s TephaFLEX® line of surgical devices.

On November 11, 2005, FDA rendered an NSE decision for the TephaFLEX® Absorbable Surgical Suture (510(k) number K052225). Unlike other legally marketed class II surgical sutures, Tepha’s device was made from an absorbable poly(hydroxybutyrate) material comprising an isolate from prokaryotic cells produced by recombinant DNA technology. Rather than pursue PMA approval, Tepha pursued a de novo classification which FDA granted on February 8, 2007. FDA classified the TephaFLEX® Absorbable Surgical Suture in class II (21 CFR 878.4494) and established special controls in the form of a guidance document titled Class II Special Controls Guidance Document: Absorbable Poly(hydroxybutyrate) Surgical Suture Produced by Recombinant DNA Technology to address the specific risks to health associated with an absorbable poly(hydroxybutyrate) surgical suture produced by recombinant DNA technology.


Following FDA clearance of its suture, Tepha submitted a 510(k) for a surgical mesh made of its TephaFLEX® material, 510(k) number K070894. Given that the use of this material was as new to surgical mesh as it had been to surgical suture, the material could have resulted in an immediate NSE decision, but it did not. As disclosed in Tepha’s 510(k) summary for its mesh, the suture was cited as one of 5 predicate devices and the only predicate that was a suture. While a suture cannot be a predicate device for a surgical mesh due to their different intended uses, comparing the material used in the surgical mesh to the material in the cleared surgical suture represents good science and a proper regulatory decision.

SAFETY AND EFFECTIVENESS

The rules for determining safety and effectiveness are spelled out in regulation. Whether it is classification panels making recommendations to FDA regarding the proper classification of a device or agency employees determining the safety and effectiveness of a new NSE device, the rules are the same. In accordance with 21 CFR 860.7(b), when determining the safety and effectiveness of a device, the following factors are to be considered:

  1. The persons for whose use the device is represented or intended.

  2. The conditions of use for the device, including conditions of use prescribed, recommended, or suggested in the labeling or advertising of the device, and other intended conditions of use.

  3. The probable benefit to health from the use of the device weighed against any probable injury or illness from such use.

  4. The reliability of the device.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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The same regulation also defines reasonable assurance of safety and effectiveness. According to 21 CFR 860.7(d)(1), there is reasonable assurance of safety

when it can be determined, based upon valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks. The valid scientific evidence used to determine the safety of a device shall adequately demonstrate the absence of unreasonable risk of illness or injury associated with the use of the device for its intended uses and conditions of use.

Likewise, 21 CFR 860.7(e)(1) defines effectiveness as

when it can be determined, based upon valid scientific evidence, that in a significant portion of the target population, the use of the device for its intended uses and conditions of use, when accompanied by adequate directions for use and warnings against unsafe use, will provide clinically significant results.

While the objective of providing a reasonable assurance of safety and effectiveness is the same regardless of the pathway to market, the agency’s means of ensuring it is quite different when contrasting class I and II devices with class III devices that are subject to PMA. The safety and effectiveness of class I and II devices is ensured through conformance with the regulatory controls that are associated with a generic type of device and its regulatory class. In the case of class I devices, safety and effectiveness are ensured through the application of general controls. In other words, manufacturers of class I devices that abide by the rules against adulteration and misbranding, register their manufacturing facilities with FDA and disclose (“list”) the devices that are being manufactured in each facility, manufacture product under good manufacturing practices, label their devices in accordance with the labeling regulation and report deaths, serious injuries, and malfunctions in accordance with medical device reporting requirements will distribute a product that is reasonably safe and effective for its intended use. Section 510(k) is not applicable to the majority of class I devices making it incumbent upon FDA to monitor industry compliance with applicable requirements through facility inspections and postmarket vigilance. Manufacturers of class I devices, such as patient scales (21 CFR 880.2720), dental drills (21 CFR 872.4130), and nonprescription sunglasses (21 CFR 886.5850) go directly to market with no need for FDA authorization. We note that many of the essential principles are embodied within GMPs, or more precisely the Quality Systems Regulation (QSR). These have been largely harmonized with the EU system and though their application is most often thought of in the compliance or postmarket realm, they are in fact very powerful tools for

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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ensuring safety and effectiveness of products not only in the United States, but also worldwide. Conformance to quality aspects of manufacturing, which includes a feedback system coupled with corrective and preventive actions, assist in the assurance of device safety.

A particularly important provision of the QSR is known as design controls. The design control provisions of the QSR apply to select class I devices and all class II devices and contribute in significant ways to ensuring device safety and effectiveness, although they are often underappreciated. FDA reserved design controls for products where their application would be necessary to have full confidence in the manufacturer’s handling of the product.

For the majority of class II devices, reasonable assurance of safety and effectiveness is provided through the same means as class I devices with two distinctions: (1) most class II devices are subject to 510(k) requirements and (2) all class II devices are supposed to be subject to special controls. The original classification regulations were predicated on FDA’s eventually establishing mandatory performance standards for all class II devices. While many devices were placed in class II, FDA’s inability to follow through with establishing mandatory performance standards led to legislative change. With enactment of SMDA 90, performance standards were replaced with special controls in the hope that greater flexibility would afford FDA the opportunity to directly and consistently address the risks to health associated with class II devices. While the nature of class II controls has evolved, the basic premise remains: in order for class II devices to be safe and effective, regulatory controls beyond general controls are required. In today’s regulatory paradigm, 510(k) attempts to compensate for the lack of mandatory performance standards and special controls with higher expectations and more rigorous premarket evaluation associated with devices in class II. Otherwise, a distinction between class I and II would be nonexistent.

The exact number of class II devices for which FDA has established special controls is unclear and difficult to determine, but the percentage of the total number is small. The only class II devices that have special controls are devices that have been the subject of post-1990 rule-making. In essence, establishing special controls was done when “convenient” for the agency. How does FDA address safety and effectiveness issues relating to class II devices without having mandatory performance standards or special controls? The 510(k) review process compensates for this void through an increasing demand for performance data, including clinical data in select instances, before rendering SE decisions. Basically, 510(k) attempts to ensure the continued safety and effectiveness of each class II generic device type by requiring evidence that the risks associated with new devices are mitigated before they are determined to be part of an existing class.

In discussing FDA’s means of ensuring safety and effectiveness for medi-

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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cal devices, one should avoid comparing 510(k) and PMA as it is technically inappropriate to do so. Premarket approval, as its name implies, is an FDA “approval” that is granted on a device-by-device basis after FDA has determined that the manufacturer has demonstrated that the particular device is reasonably safe and effective. If we turn to 510(k), there is no FDA determination that the device is safe and effective. In fact, referring to an SE determination as an “approval” is prohibited by regulation (21 CFR 807.97). Why does this prohibition exist? Because general controls ensure the safety and effectiveness of class I devices and a combination of general and special controls ensure the safety and effectiveness of class II devices. Section 510(k) is but one of the general controls. By itself, 510(k) is incapable of ensuring safety and effectiveness. As part of the larger regulatory picture, 510(k) contributes to ensuring safety and effectiveness by documenting critical aspects of device performance and through the mitigation of risks. If Congress intends for 510(k) to ensure safety and effectiveness with a “lighter touch” than PMA, then both the regulatory requirements under this section of the act would need to change as would resources to accompany such expectations.

Although 510(k) is a general control, its role in the overall regulatory system has evolved over time. Today, the vast majority of class I devices are exempt from 510(k) as a result of FDAMA 97. This leaves the 510(k) process appearing more similar to a special control than the general control that it is under the law, particularly when one considers that FDA uses the 510(k) process to compensate for the lack of special controls.

If one wants to compare FDA’s means of ensuring the safety and effectiveness of class I and II devices with the means used for class III devices, there are similarities and differences (see Table C-1). Under similarities, virtually all medical devices, independent of their regulatory class, are subject to the general controls. How FDA ensures conformance with the general controls differs considerably by regulatory class. For class I and II devices, FDA must decide how to use scarce resources. This results in conformity assessment that is driven by current public health priorities. For all practical purposes, there is little or no relationship between 510(k) and this conformity assessment. This is not the case with PMA. Take conformance with GMPs as an example. For class I and II devices, FDA attempts to conduct manufacturing facility inspections on a biannual basis, though in reality this has been estimated to be on average between 5 and 7 years. This means that it can easily be a minimum of 2 years before FDA visits a manufacturing facility producing 510(k) cleared devices. For class III devices, conformance with GMPs is assessed on a preapproval basis. In other words, before a new class III device is sold in the United States, FDA has visited the manufacturing facility and determined that the facility is operating in conformance with GMP requirements.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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THE SCIENTIFIC INTEGRITY OF THE 510(k) PROCESS

The evidence requirements to establish SE vary depending on the class (that is, class I or II), device type, and the issues associated with the new device. For devices that are basically the same as legally marketed devices within the generic device type, the data and information reviewed in support of clearance are primarily descriptive in nature. For new devices in this category, it is not unusual for the review of a 510(k) to focus on the device’s intended use and technical specifications. When they are the same, or vary in ways that are not viewed to impact safety and effectiveness, FDA clearance is straightforward. We note that there is some subjectivity in the assessment of such views and this has led to inconsistency in reviews of some types of devices. This is an Achilles’ heel of the program and is in contrast to the advantage of a system based on essential principles.

For a new device that differs from devices within the generic type to which it is being compared, the nature and extent of the differences dictate review requirements. In most cases, differences can be categorized as those related to intended use or technology. If a difference relates to intended use and the intended use constitutes a “new” intended use, no amount of scientific evidence will support a finding of SE. In this case, the review of the submission ceases and an NSE decision is promptly issued. If the new device’s intended use (1) differs in ways that raise the same types of safety and effectiveness issues as the generic type to which it is being compared and (2) accepted scientific methods exist to answer the question, data are requested for evaluation. The same principles apply to new technology. As long as the technology does not raise new types of safety and effectiveness questions and the questions that are raised can be answered with established scientific methods, the agency usually requests that the submitter provide data. Most often data are from nonclinical studies, but the agency has the authority to require clinical data, if this is the appropriate way to address the question. One must realize that unless FDA’s issues are resolved with the type of data or studies that are requested, devices are not cleared for marketing. While FDA requests for data can be challenged, clearances are not forthcoming unless the requested data are provided or the data are determined not to be necessary for clearance.

Changes and Modifications to Legally Marketed Devices

Medical devices have a very short life cycle when one considers the number of changes that a typical device undergoes during the course of a year. Manufacturers often encounter issues with their suppliers, thereby creating a need for alternate sources of raw materials and components, embark on continuous process improvement to enhance manufacturing efficiency, and change or modify their existing product lines to remain competitive and

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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TABLE C-1 Comprehensive Comparison of the PMA and 510(k) Programs

Comparator

Premarket Approval (PMA)

Premarket Notification (510(k))

Devices eligible for review

Class III

Class I and IIa

Pathway to US market

Yes

Yes

Alternative pathways to market

Product development protocol (PDP), Reclassification or de novo classification

None

Opportunity for exemption from premarket review

No

Multipleb

Evidence required for FDA market authorization

Valid scientific evidence (21 CFR 860.7)

Descriptive and performance data (testing may involve prototypes)

“Least burdensome” provisions of the law apply

Yes—Section 513(a)(3)(D)(ii)—“effectiveness”

Yes—Section 513(i)(1)(D)—“substantial equivalence”

Threshold for FDA market authorization

“Reasonable assurance of safety and effectiveness”

“Substantial equivalence”

Regulatory Difficulties

Premarket Approval (PMA)

Premarket Notification (510(k))

Program complexity

High

Low to Moderate

Submission preparation complexity

High

Simple

FDA review cost (FY 2005)c

$870,000

$18,200

Team review required

Yes (multidisciplinary)

Generally no, but increasing in frequency

Statistical review of data

Yes

Not normally

Regulatory burden (premarket)

High

Low to moderate

Regulatory burden (postmarket)

High

Low

Changes and modifications

Changes that affect S&E require supplement approval

Changes that could significantly affect S&E require 510(k) submission

Annual reporting requirements

Yes

No

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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FDA Actions

Premarket Approval (PMA)

Premarket Notification (510(k))

FDA ability to request additional information (place submission on “hold”)

Yes

Yes

Panel review and recommendation

Yes (optional)

No (very unusual)

Favorable outcome

“Approval” allowing commercial distribution

“Classification” allowing commercial distributiond

Unfavorable outcome

Denial of approval

Not substantially equivalent (NSE) determination

Conditions of approval (COA)

Standard

NA

Postapproval studies

Frequently required as COA

NA

Control over promotion and advertising materials

Possible as COA

No

Authority to withdraw approval

Yes

No

Authority to temporarily suspend approval

Yes

No

Authority to rescind final decision

No

No

Review Times

Premarket Approval (PMA)

Premarket Notification (510(k))

FDA statutory review time

180 days

90 days

Total FDA average review timee

283 days

54 days

Submission Contents

Premarket Approval (PMA)

Premarket Notification (510(k))

Descriptive data

Yes

Yes

Performance data (bench and animal)

Yes

Frequently

Clinical data

Yes (original and panel track supplements)

Not usually required—FDA estimates <10% of 510(k)s

Human factors data

Increasing

Not usually

Final draft labeling

Yes

Not for compliance with Part 801

Manufacturing process details

Yes

No

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Submission Contents

Premarket Approval (PMA)

Premarket Notification (510(k))

Truthful and accurate statement

No

Yes

Trade name authorization

Requires FDA approval

No FDA authorization needed

Manufacturing facility inspection

Preapproval

Postclearance (biannual)

Premarket BIMO inspection

Yes

No (extremely unusual)

Contents available for future FDA decision-making

No (statutory prohibitions exist)

Yes (no prohibitions)

User Fees (2010)

Premarket Approval (PMA)

Premarket Notification (510(k))

Original application

$217,787 ($54,447)f

$4,007 ($2,004)

Panel track supplement

$163,340 ($40,835)

N/A

180 day supplement

$32,668 ($8,167)

N/A

Real-time supplement

$15,245 ($3,811)

N/A

30 day notice

$3,485 ($1,742)

N/A

Annual report

$7,623 ($1,906)

N/A

NOTE: BIMO = bioresearch monitoring; CFR = Code of Federal Regulations; FDA = Food and Drug Administration; FY = fiscal year; N/A = not applicable; S&E = safety and efficacy.

aVery few (continuously diminishing) number of 510(k) review eligible preamendment class III devices.

bClass I devices are generally exempt from 510(k) requirements as are other select class II devices. Other regulatory exemptions from 510(k) exist.

cGAO Report. Medical Devices—FDA Should Take Steps to Ensure That High-Risk Device Types are Approved through the Most Stringent Premarket Review Process. GAO 09-190. January 2009.

dManufacturers of class I and II devices are prohibited by law from referring to a finding of substantial equivalence as FDA approval (21 CFR 807.

eFY 2006 and 2007 ODE Annual Reports. PMA times are for original and panel track supplements.

fNote: Small business (≤ $100 million in gross receipts or sales per year) discounts provided in parentheses. Fee is also waived for first PMA submitted and approved by a business with ≤ $30 million in gross receipts or sales per year.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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meet users’ needs. With each change, manufacturers must consider whether the magnitude of the change creates a need to obtain FDA authorization before introducing the “new” device into the marketplace. The criteria for making this decision in regard to class I and II devices are found in regulation. According to 21 CFR 807.81(a)(3), a premarket notification must be submitted when the device

is about to be significantly changed or modified in design, components, method of manufacture, or intended use. To further clarify the regulatory standard, significant changes include

  1. A change or modification in the device that could significantly affect the safety or effectiveness of the device, for example, a significant change or modification in design, material, chemical composition, energy source, or manufacturing process.

  2. A major change or modification in the intended use of the device.

FDA and industry have struggled with the phrase “could significantly affect the safety or effectiveness of the device” and the use of the adjectives “major” and “significant.” The subjective nature of the wording leaves room for interpretation and is a continuous source of disagreement. To address this issue, FDA issued a guidance document in January 1997 (FDA, 1997). While this guidance document has been successful, contributing to a standardized approach to decision-making, one thing has not changed: manufacturers have to assess the significance of each change to their devices and make a decision whether to file a 510(k) with FDA. The details of this aspect of US device regulation go beyond the scope of this paper, however, the regulatory issues created when regulating rapidly changing products must be a consideration when exploring alternative regulatory schemes.

510(k): Strengths, Weaknesses, and Flexibilities

Unlike most FDA premarket review programs, the 510(k) process affords the agency great discretion in how it approaches decision-making. While the law and implementing regulations provide structure to the approach, the agency always focuses its attention on the scientific and clinical issues that are of public health importance. When important issues surface, FDA has the ability to request additional information, including clinical data, when it is essential to resolving them. In the end, FDA is in control. SE determinations are not automatic and 510(k) submitters are not authorized to market their devices until FDA issues a letter specifically authorizing them to do so.

Although an analysis of 510(k) decision-making that is far beyond the

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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) decisions,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 ability 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:

13

Refer 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.

14

Guidance 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/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073707.htm.

15

January 21, 1998, FR notice (63 FR 3142).

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 considered 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 intended 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 specified 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 appropriate, 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

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 postmarket 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 unnecessary regulatory burdens associated with the 510(k) and PMA processes. Although 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 equivalence determinations. In making such a request, the Secretary shall consider the least burdensome [emphasis added] means of demonstrating substantial equivalence and request information accordingly.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 likelihood 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 premarket 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 (including IVDs). In so doing, FDA believed that the statutory mandate could be accomplished without compromising scientific integrity in the decision-making 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 considering 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 intent 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 investigation. 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).

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 interference 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 during 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 knowledge 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 reviewer 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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We note that if new scientific knowledge suggests that devices on the market are not safe, then 510(k) is not the appropriate regulatory mechanism 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 seeking 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, requiring 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 management 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 declaration 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

16

Refer to Sections 301(x) and 501(e)(2) of the act. Submitting a false declaration in a premarket submission is a violation of the law.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 conformity. 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 standards 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 standards 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 submissions. This unwillingness is fueled by three risks: (1) the threat of immediate 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, including standards with “performance limits,” and to be willing to declare conformity in all premarket submissions. Taking this approach can encourage 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 technology 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 variable 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 information (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 authorization to add descriptive information to device labeling. In an FDA guidance document, the agency acknowledges this industry approach to differentiating 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 influences 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-

17

Refer to Guidance for Industry: General/Specific Intended Use at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073944.htm.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 technology fueled human factors considerations, all of which have created sudden 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 cardiovascular stents to prevent restenosis, or sophisticated drug and biologic delivery systems, an explosion of regulated entities that cross traditional FDA regulated 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.” Combination 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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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 complex 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 significant 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.

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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REFERENCES

FDA (US Food and Drug Administration). 1986. Guidance on the CDRH Premarket Notification Review Program 6/30/86 (K86-3). http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/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: Concept and Principles; Final Guidance for FDA and Industry. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc m085994.htm (accessed July 21, 2010).

Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 94
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 95
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 96
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 97
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 100
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 102
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 107
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 108
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 109
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Page 110
Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Suggested Citation:"Appendix C: Premarket Notification: A Key Element of US Medical Device Regulation--Larry Kessler and Philip J. Phillips." Institute of Medicine. 2010. Public Health Effectiveness of the FDA 510(k) Clearance Process: Balancing Patient Safety and Innovation: Workshop Report. Washington, DC: The National Academies Press. doi: 10.17226/12960.
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Next: Appendix D: Impact of the Regulatory Framework on Medical Device Development and Innovation--David W. Feigal, Jr. »
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The Food and Drug Administration (FDA) is responsible for assuring that medical devices are safe and effective before they go on the market. As part of its assessment of FDA's premarket clearance process for medical devices, the IOM held a workshop June 14-15 to discuss how to best balance patient safety and technological innovation. This document summarizes the workshop.

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