The Development of a New 510(k) Program

Medical Device & Diagnostic Industry Magazine
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An MD&DI June 1999 Column

Device companies stand to benefit by important changes in the premarket notification process that were initiated by FDA reengineering and codified in FDAMA.

The 94th Congress showed considerable foresight in 1976 when it drafted the Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act. Before this time, the medical device industry was largely unregulated. As a result, Congress had little experience in dealing with the industry and, understandably, an uncertainty about the breadth and complexity of the task at hand. Despite this handicap, Congress drafted an enormously flexible statutory framework intended to ensure that the American public is protected from unsafe and ineffective medical devices.

In the 1976 amendments, the legislators developed a creative scheme that allows the level of regulation to vary according to the risks inherent to different types of devices. The new statutes addressed both the diverse nature of existing devices and the rapidly expanding device industry. General controls, such as good manufacturing practices (GMPs), would be relied upon to provide a reasonable assurance of safety and effectiveness for those devices that pose the least amount of risk. For more complex and riskier devices, performance standards, in addition to the general controls, would be used. Finally, for the most complicated and riskiest devices, performance standards, general controls, and premarket approval would be required.

Using this statutory framework, FDA's Bureau of Medical Devices designed and implemented a premarket review program responsible for the regulation of all medical devices. Serving as the foundation of this program was the premise that the lowest level of regulatory control sufficient to provide a reasonable assurance of safety and effectiveness should be used. Thus, the premarket notification (510(k)) process became the predominant method for device entry into the domestic market.

The flexibility of the 510(k) process has served the device industry, the healthcare community, and the American consumer well through the years. It has permitted numerous substantially equivalent or "me-too" devices to enter the marketplace in an efficient manner, thus keeping down the costs to consumers and the healthcare community. In this way, it has facilitated technological innovation, while at the same time permitting FDA to responsibly regulate the rapidly progressing medical device industry.

THE 510(k) PROCESS REENGINEERING INITIATIVE AND FDAMA

In December 1996, the director of FDA's Center for Devices and Radiological Health (CDRH) instituted an unprecedented reengineering initiative. Fifteen teams were formed, and major program areas were targeted in an effort referred to as "Organizational Transformation." Quite naturally, the 510(k) program—with its large volume of submissions and growing demand for resources—was one of the first areas identified by the center for reengineering.

The 510(k) Process Reengineering Team (the Team) comprised representatives from CDRH as well as from the Center for Biologics Evaluation and Research (CBER) and FDA's Office of Chief Counsel. Although the Team's attention was directed to the 510(k) program in general, it quickly became apparent that the largest gain from reengineering would not come from revamping the review process, but rather from reconsidering the need for certain 510(k)s and examining the content requirements of the 510(k) application itself.

In early 1997, the 105th Congress began its own evaluation of FDA. After months of deliberation and discussion with the agency and the device industry, Congress passed the most sweeping legislation since the original device amendments. This new legislation, the FDA Modernization Act of 1997 (FDAMA), affected virtually all device programs. Perhaps just as importantly, however, is that the new law codified agency reengineering initiatives in several areas, including 510(k)s, thus demonstrating a common direction by both FDA and Congress. The new 510(k) initiatives—those resulting from reengineering as well as from FDAMA—are discussed in this article.

CONFORMANCE WITH GMPS

One of the first issues undertaken by the Team was an evaluation of the link between the substantial equivalence (SE) determination and compliance with GMPs. In 1992, CDRH established the 510(k)/GMP Preclearance Program under which all 510(k) submissions were checked against a database to verify compliance with GMPs. The purpose of this program was to ensure that all devices going to market through the premarket notification process were manufactured in compliance with GMPs. In theory this was a good idea; in practice, there were problems. For example, under 21 CFR 807, 510(k) submitters are not required to identify a manufacturing site. Nevertheless, submitters often do identify their site. For submissions in which a site was identified, if any issue of GMP noncompliance was found, the substantial equivalence determination could have been delayed. On the other hand, SE determinations for submissions without a manufacturing site were not affected by the Preclearance Program.

In addition to the inequities of the Preclearance Program, the Team considered its cost-effectiveness. To implement the program, CDRH spent approximately $300,000 per year. This estimate only reflects those costs incurred by the center and does not include costs incurred by the various field offices, which would push the total even higher. During the 18-month period selected for analysis, 47 SE determinations out of the 8259 rendered were deferred, yielding a deferral rate for this time period of 0.6%. Moreover, the determinations that were deferred were for Class I and Class II devices, not for the riskier Class III devices that the check was intended to focus on.

As a result of its analysis, the Team recommended that the 510(k)/GMP Preclearance Program be discontinued for Class I and Class II devices until 21 CFR 807 was amended to require that 510(k) submitters identify their manufacturing and/or sterilization sites. The Team, however, did not include Class III 510(k) devices in its recommendation. These Class III devices are subject to a separate and distinct 510(k) preclearance program that generally involves a GMP inspection similar to the premarket approval (PMA) application program. In March 1997, the 510(k)/GMP Preclearance Program was discontinued for Class I and Class II devices.

THE NEW 510(k) PARADIGM

Considered the most innovative of all the efforts undertaken by the 510(k) Process Reengineering Team was that resulting in the document "The New 510(k) Paradigm." For the first time since the SE determination scheme was developed in 1985, alternatives to the traditional submission were developed. By taking advantage of other regulatory controls as well as the use of consensus standards, 510(k) submitters could pursue alternative approaches to demonstrating substantial equivalence.

Before discussing these alternatives, however, it is important to understand the new 510(k) paradigm as it was initially proposed. In the original document, the Team recommended a new regulatory structure in which Class I devices would be exempt from 510(k) requirements. Additionally, certain Class II devices would be reclassified into Class I and subsequently be exempt as well. Finally, Class III devices would be subject to PMA requirements. Thus, under this proposed scheme, only a select group of Class II and some Class III devices (until the PMA applications were called for) would be subject to 510(k) requirements. It was believed that this would allow FDA to achieve the maximum public health impact with its scarce resources.

The draft document was released for public comment in the spring of 1997 and was widely disseminated, including on Capitol Hill. By the time the new 510(k) paradigm was ready to be issued in its final form, the document had gathered considerable support among many interested parties in the medical device industry and Congress. It is not surprising, therefore, that the idea to transform the 510(k) program in the manner described above was reflected in FDAMA. By including many of the concepts first proposed by the 510(k) Process Reengineering Team, it provided a statutory basis to ensure acceptance and implementation of these center initiatives, thereby helping to streamline the process even further. For example, FDAMA eliminated the requirement for notice and comment rule making to exempt Class I devices from 510(k) requirements and eliminated the need to down-classify Class II devices before exempting them. In this regard, FDAMA enhanced a reengineering goal through streamlined statutory mechanisms.

Reliance on the Quality System Regulation. FDA believes that the design control provisions of the new quality system regulation will make significant contributions toward ensuring the safety and effectiveness of medical devices. This belief—coupled with the fact that design controls are required for all Class II and Class III devices—led CDRH to accept reliance on a manufacturer's "Summary of Design Control Activities" as a basis for making substantial equivalence decisions for certain types of device modifications.

Under this "Special 510(k)" alternative, manufacturers that are modifying their own legally marketed device and that determine that a new 510(k) is required for the modification can use design control procedures as the basis for demonstrating substantial equivalence. This can be done as long as the modification does not alter the fundamental scientific technology of the device or change its intended use. This type of submission has been successfully used for modifications such as changing the materials in a bone screw from stainless steel to titanium or altering a single-lumen catheter to have a dual lumen.

CDRH believes that the Special 510(k) alternative offers benefits for both FDA and the regulated industry. In many respects, this approach—which involves a risk analysis of the device modification as well as verification and validation activities— provides more evidence of substantial equivalence than that which is generally provided under the traditional 510(k). This approach will also allow CDRH to direct more resources to clearing new and innovative devices as opposed to simple design modifications of approved technology.

For device manufacturers, the Special 510(k) alternative should save not only financial resources but also time. The process allows design control activities—which are already required—to serve as the basis for the SE determination, and thereby may obviate the need for comparison testing to support a device modification as mandated under 21 CFR 807.87(g). Device manufacturers should also find the shorter review times for Special 510(k)s attractive. To date, the average FDA review time for this type of submission is 26 days, compared with 111 days for the traditional 510(k). Although Special 510(k)s have generally been submitted and cleared for fairly conservative changes to devices, it is hoped that the use of design controls in 510(k) decision making will soon be routine for more 510(k)s, including more-significant device modifications.

Streamlining with Consensus Standards, Special Controls, and Guidance Documents. Under the Medical Device Amendments of 1976, devices were classified into Class II when performance standards were thought to be necessary to ensure safety and effectiveness. However, the time and effort required to promulgate mandatory performance standards, coupled with the rapid rate at which technology was advancing, all but precluded the development of such standards. In fact, only one mandatory performance standard (dealing with cables and leads) has been developed under section 514 of the FD&C Act.

Despite the difficulty in developing mandatory performance standards for Class II devices, the center has devoted considerable effort to the development of national and international voluntary consensus standards. It should be noted that the usefulness of these voluntary standards is limited because the majority are not performance standards but rather methods standards—that is, they establish a test method but not accompanying performance criteria.

Given the situation described above, one can see why standards have not been factored into the device evaluation process in any routine or regular fashion. Despite the limited success of standards, the Team believed that their use could contribute to device safety and effectiveness and added this concept to the new 510(k) paradigm by way of the "Abbreviated 510(k)." CDRH bolstered this effort through its development of formal procedures for relying on declarations of conformity to voluntary standards and through its recognition of more than 400 of these standards.

As with several other reengineering efforts, this concept was incorporated into FDAMA. The new law not only gave FDA the authority to rely on a manufacturer's declaration of conformity in lieu of reviewing the underlying data, but also provided the administrative procedures for officially recognizing voluntary standards. Before the full benefit of a standards-based review can be realized, however, considerably more effort needs to be expended in developing performance standards and standards that address pertinent issues of safety and effectiveness.

In addition to consensus standards, the 510(k) Process Reengineering Team recognized that device-specific guidances and special controls could be used to streamline the approval process, and so incorporated these concepts into the Abbreviated 510(k). Special controls are a relatively new addition to the statute. Under the Safe Medical Devices Act of 1990, FDA was provided with an additional way to address safety and effectiveness issues when classifying or reclassifying a device into Class II. Under the amended statute, the agency was permitted to use "special controls" to provide reasonable assurance of safety and effectiveness for Class II devices. Special controls include—but are not limited to—performance standards, postmarket surveillance, patient registries, guidance documents, and labeling recommendations. Since 1990, FDA has taken advantage of this statutory provision to the extent that, for all reclassification actions in which a device was reclassified from Class III to Class II, the agency has identified a special control or controls to support the down-classification.

Under the new 510(k) paradigm, manufacturers of Class II devices that are subject to special controls can elect to submit an Abbreviated 510(k) rather than a traditional 510(k). In the Abbreviated 510(k), the manufacturer would include a "summary report" that describes the efforts taken to comply with the established special control(s). For example, in Abbreviated 510(k)s for contact lenses, manufacturers would describe how the special controls for preclinical and clinical testing as well as for labeling were applied.

Finally, manufacturers can also use device-specific guidance documents to shorten their submissions through the Abbreviated 510(k) pathway. Over the past few years, CDRH has developed numerous guidance documents for individual device types. In these guidances, the center has identified the risks associated with a particular device type and has suggested ways in which the manufacturer could address them. Manufacturers of devices for which such guidances exist can submit Abbreviated 510(k)s that include a summary report outlining how the guidance was used in the device development process to address the risks associated with the device. This approach should allow manufacturers to shorten their submissions while still providing FDA with adequate information upon which to base its regulatory decisions.

As is often the case with something novel, the new 510(k) paradigm has taken a while to catch on with the device industry. The Special 510(k) alternative has been the most popular and, as of the end of calendar year 1998, FDA had reviewed 146 applications—representing 5% of all 510(k)s— of this type. Twenty-two Abbreviated 510(k)s had also been processed; it is anticipated that as more performance standards and special controls are established, this type of submission will be used more frequently.

THE USE OF ENFORCEMENT DISCRETION

FDA exercises "enforcement discretion" when it decides to not enforce a particular regulatory authority. Until recently, enforcement discretion as a written policy was used rarely by the agency. However, one outcome of the 510(k) reengineering effort was an acknowledgment that such inaction is an acceptable regulatory position for CDRH to take while formal procedures are being established.

An example of one of the first applications of enforcement discretion was the convenience-kit policy. Convenience kits are devices composed solely of legally marketed products that are assembled in kit form for the convenience of the user. CDRH's Office of Device Evaluation reviews approximately 300 510(k)s each year for this type of device. Because the components of these kits had previously been reviewed by the agency, the Team questioned the benefit gained by essentially rereviewing the same information.

In May 1997, the Team issued a guidance document titled "Convenience Kits—Interim Regulatory Guidance." In this guidance, CDRH announced its intention to exercise enforcement discretion by not requiring 510(k) clearance for convenience kits that met certain criteria. Premarket notification would not be required if the convenience kit was for a designated intended use and included devices that had been previously cleared for market or were exempt from 510(k) requirements, and if the assembler/manufacturer reasonably concluded that any further processing of the kit and its components would not significantly affect the safety or effectiveness of those components. Although enforcement discretion is not a long-term solution for convenience kits, this policy continues to be in effect until FDA formally exempts these devices from the 510(k) process.

This guidance represents the first time that the center proposed relying on conformance with the quality system regulation and other general controls to reduce the premarket burden. Although this action affects relatively few 510(k)s—300 out of the 5000 submitted annually—it demonstrates FDA's acknowledgment that little value was being added by the traditional approach. Such action also shows the agency's willingness to be creative and look for innovative solutions to such situations. Recently, CDRH took this same "interim" position with regard to external penile-rigidity devices. As in the case of convenience kits, the agency adopted an interim policy under which 510(k) requirements for certain devices of this type would not be enforced while formal 510(k) exemption procedures are being pursued.

Enforcement discretion is a valuable regulatory tool and offers benefits to both FDA and the device industry, such as eliminating 510(k)s for which agency review contributes little to the public health and safety. Use of this tool also allows the center to redirect its scarce resources to areas where they can have a greater impact. For the device industry, enforcement discretion offers an alternative with an expedient path to market as opposed to the traditional approach, which can result in administrative delays.

THE CLASSIFICATION OPPORTUNITY FOR NSE DEVICES

From time to time, CDRH has come across a device for which there was no legally marketed predicate device, but which would have otherwise been appropriately placed in Class I or Class II. Without a predicate, however, the device had to be found not substantially equivalent (NSE), leaving the reclassification or premarket approval processes as the only viable paths to market. Because both of these processes can be burdensome to a manufacturer, the center has long looked for a reasonable alternative; that is, a regulatory path that would allow resolution of the scientific issues but that would not be overly burdensome given the nature of these devices.

In section 207 of FDAMA, "Evaluation of Automatic Class III Designation," Congress provided for such a mechanism. Section 207, which amended the FD&C Act to add section 513(f)(2), permits recipients of NSE decisions to present their argument for a Class I or Class II designation in response to the automatic Class III designation that is usually associated with the NSE determination. Under this new provision, requests for such consideration by FDA must be submitted within 30 days of the firm's receipt of the NSE decision. The agency has 60 days to either classify the device into Class I or Class II or to determine that the device should remain in Class III. Within 30 days of issuing its decision, FDA must notify the public through an announcement in the Federal Register.

Although this provision will most likely have limited applicability, FDA has already experienced early success with this new process. The Diamond Probe/Perio 2000 system (Diamond General Development Corp.; Ramsey, NJ) for use in assessing periodontal disease and the Doc Band (Cranial Technologies Inc.; Phoenix) for use in correcting some forms of nonsynostotic positional plagiocephaly (malformity of the skull) in infants are two devices that were recently classified in Class II through this mechanism. These decisions suggest that this aspect of FDAMA provides a viable alternative path to market for devices that do not warrant the level of regulatory control associated with the premarket approval process.

THE LEAST BURDENSOME PATH TO MARKET

CDRH has not formally announced its plan for meeting the FDAMA directive to establish "the least burdensome path to market" for 510(k) submitters (see section 513(i)(1)(D) of the FD&C Act). However, many of the changes resulting from the reengineering initiative are contributing to the establishment of a less-burdensome process.

For example, the premise behind the new 510(k) paradigm was to reduce the redundancy between 510(k) requirements and other regulatory imperatives, thus streamlining the overall process for establishing substantial equivalence. Specifically, data generated by design control procedures can now be used to support certain device changes. Because device manufacturers are required to comply with the quality system regulation, relying on design controls—rather than on additional testing—to provide substantial equivalence data for a modification enables companies to follow a less burdensome path to market. Similarly, adopting a declaration of conformity to standards that reduces the amount of testing needed to demonstrate substantial equivalence to a predicate device is another approach to achieving the least burdensome path. Other measures that can reduce regulatory burdens include the provision for automatic evaluation of Class III designation and FDA's use of enforcement discretion. Both of these mechanisms allow the agency to match the risks posed by a device with the level of regulatory control needed to address those risks, while still providing an expedient path to market.

CLAIMS

The last issue examined by the 510(k) Process Reengineering Team was that of claims made by manufacturers about their medical devices. Certain claims, in their effect on the intended use of a device, can affect the substantial equivalence determination. For this reason, reviewers must consider a manufacturer's claims and the evidence supporting those claims during the review process.

The issue of claims consumes a great deal of resources on the part of agency staff as well as the regulated industry. Reviewers evaluate numerous claims in 510(k) submissions, and FDA's district and regional offices constantly assess various postclearance claims to determine if they require submission of a new 510(k). Device manufacturers use claims to differentiate their devices from those of their competitors and so are continuously faced with deciding whether a particular claim requires substantiation or a new 510(k). For these reasons, the Team concluded that guidance on the issue of claims needed to be developed in order to assist reviewers, compliance officers, and the regulated industry in making their respective decisions.

Because of the demands of implementing FDAMA, the development of this guidance document has not received high priority and it remains in the draft stage. However, CDRH intends to release a draft in the very near future for comment by both its own staff and the regulated industry. Until the guidance is completed, FDA can rely on the guidance titled "Determination of Intended Use" to partially address this issue. Section 205 of FDAMA (new section 513(i)(1)(E) of the FD&C Act) limits the agency's determination of intended use to the labeling for the device. Thus, under the new law—and as described in the guidance—FDA may only take exception to an off-label use if that use has a reasonable likelihood of occurring and could cause harm. As mentioned previously, certain claims can affect the intended use of the device, and thus may present an off-label-use issue if the statutory threshold is met. For such cases, the agency may need to issue a special SE letter to address the off-label use.

CONCLUSION

The 510(k) Process Reengineering Team and FDAMA have created a 510(k) program vastly different from the one originally conceived in 1976. In the past year, CDRH has developed numerous policies and guidances that offer opportunities for both FDA and the medical device industry to better utilize resources and to focus their attention on the most pressing public health issues.

To be most effective and efficient, however, it is incumbent upon the medical device industry to be thoroughly familiar with all of these new provisions as well as with FDA's interpretation of them. But familiarity is not enough: for the initiatives to be successful, the device industry must actively participate in shaping the future of the agency. It will only be through such a concerted effort that both FDA and the regulated industry will be able to realize their mutual goal of providing the American public with safe and effective medical technology in an expeditious manner.

Philip J. Phillips is deputy director for science and regulatory policy in the Office of Device Evaluation (ODE), Center for Devices and Radiological Health, and has been with FDA for 18 years. Joanne R. Less, PhD, is director of ODE's investigational device exemption and humanitarian device exemption programs.

Illustration by Lael Henderson

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