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 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 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 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 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:

• 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.

The essential principles adopted in the GHTF (reference SG1/N41R9:2005) are modified from the EU but follow along the same lines. These principles fall in the following categories:

• General requirements.
• Design and manufacturing requirements:⁴
  • Chemical, physical, and biological properties.
  • Infection and microbial contamination.
  • Manufacturing and environmental properties.
  • Devices with a diagnostic or measuring function.
  • Protection against radiation.

• Requirements for medical devices connected to or equipped with an energy source.
• Protection against mechanical risks.
• Protection against the risks posed to the patient by supplied energy or substances.
• Protection against the risks to the patient for devices for self-testing or self-administration.
• Information supplied by the manufacturer.
• Performance evaluation including, where appropriate, clinical evaluation.

Could the current system of 510(k) be modified using regulations and not legal changes to bring products into the US system that have satisfied the essential principles? There are two ways this could occur. The Summary Technical Document (STED) developed by Study Group 1 of the GHTF, assigned the scope of premarket considerations, provides one such avenue. The document includes data demonstrating conformance to the essential principles. If a company wished to bring on a device and did not have a suitable predicate, then the agency could declare the device as nonsubstantially equivalent and request a 510(k) de novo application. The company could elect to submit a STED.

CDRH has encouraged medical device manufacturers to participate in the STED pilot program. Manufacturers would benefit from exposure to the STED preparation process, especially those seeking international regulatory approval or clearance for their devices. In addition, greater industry participation in this program would increase CDRH’s familiarity with STED submissions and would allow CDRH to provide constructive feedback to the 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 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.

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.

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.

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 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 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.

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 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 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.

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.

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.

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 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 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.

TABLE C-1

Comprehensive Comparison of the PMA and 510(k) Programs.

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.

CHALLENGES CREATED BY INDUSTRY, COST CONTAINMENT, AND THE PRACTICE OF MEDICINE

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.

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).

Footnotes

1

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

2

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

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.

4

The GHTF established a workgroup in 2007 to assess whether its guidance documents would address issues regarding safety and effectiveness with respect to computer software that were devices or operated devices. This workgroup made recommendations to the study groups to make modifications to documents for these issues and these have been resolved in revisions to study group documents.

5

Refer to How to Prepare Abbreviated 510(k) at http://www​.fda.gov/MedicalDevices​/DeviceRegulationandGuidance​/HowtoMarketYourDevice​/PremarketSubmissions​/PremarketNotification510k​/ucm134574.htm.

6

Refer to 21 CFR 860.3(i).

7

Refer to General Device Classification Questionnaire at http://www​.fda.gov/downloads​/AboutFDA/ReportsManualsForms​/Forms/UCM080858.pdf.

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.

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.

11

Refer to 510(k) number K082535 at http://www​.accessdata​.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn​.cfm?ID=28671.

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).

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).

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.

17

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