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10 w w w . f d l i . o r gUpdate September/October 2010

FDA’s Preliminary Report and Recommendations for the 510(k) Program: Questions and Considerationsby Mark A. Heller, Stephanie Philbin and Kristin Davenport

In August, FDA’s Center for Devices and Radiological Health (CDRH) issued for public comment two prelimi-nary reports along with recommendations on the 510(k),

or premarket notification, program and utilizing science in regulatory decisionmaking.1 According to CDRH Director Jeffrey Shuren, the agency’s recommendations “advance three key objectives of a balanced public health approach: fostering medical device innovation, enhancing regulatory predictabil-ity, and improving patient safety,” and represent opportunities to increase CDRH’s effectiveness in carrying out its two-part mission of protecting and promoting the public health.2

Importantly, the foreword to these recommendations states they are preliminary and “CDRH has not made any decisions on specific changes to pursue.”3 Thus, CDRH requested com-ments on the recommendations, including the feasibility of implementing them and potential alternatives. Only after FDA has assessed the comments will it announce which changes it will make along with a projected timeline for the changes.4 CDRH is wise to seek comments from the public because the agency could encounter numerous problems in pursuing some of the proposed changes. Below we discuss some of the pre-liminary recommendations related to the 510(k) program that

Mr. Helleris a Partner at Goodwin Procter LLP in Washington, D.C., and is chair of the firm’s FDA Group.

Ms. Philbinis a Counsel in the FDA Group at Goodwin Procter LLP in Washington, D.C.

Ms. Davenportis an Associate in the FDA Group at Goodwin Procter LLP in Washington, D.C.

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September/October 2010 Update 11FDLI

Enforcement

may draw interest and would benefit from public feedback to ensure that changes, if any, achieve the intended goals.

Before we address specific preliminary recommendations, the two reports and the history of the 510(k) program beg the question of how much change is in fact needed for the efficient and effective op-eration of the program. Congress created the 510(k) classification system in 1976,5 and since its inception the agency has cleared over 120,000 510(k)s.6 Overall, FDA’s implementation of the program has resulted in the reasonably efficient management of a large annual volume of submissions and an apparently favor-able safety profile for 510(k) marketed devices. Thus, while the 510(k) program, like some other agency programs, may require some fine-tuning, there appears to be little basis for a large-scale overhaul.

Additionally, in the context of the 510(k) Working Group’s findings, and the repeated references to the need for ad-equate training of CDRH staff, the ques-tion arises whether some of the alleged deficiencies with the 510(k) program result from structural problems with the program, or instead from inadequate staff training on the 510(k) review process that undoubtedly is related, in part, to staff turnover and new hires. Indeed, the Working Group acknowledged that “[q]uality and consistency depend on a highly qualified, well-trained, and well-supported review staff” and thus recom-mended enhanced support for review staff training and professional development.7

Finally, because there was a low response rate from CDRH reviewers and managers in responding to the agency survey on their understanding of the 510(k) regulations, guidance documents and review practices,8 one must question whether the low response rate reflects a responder bias. In other words, the data

relied upon by the Working Group in making its preliminary findings and rec-ommendations may not have the validity that appears to be ascribed to them.

Thus, before CDRH implements any changes to its 510(k) program, CDRH management may want to consider redoing its survey and making responses mandatory; we suggest that this under-taking only occur after CDRH staff has been adequately trained on the current 510(k) program and has some further experience with it. In sum, more training on the 510(k) program, and changes predicated on a more fully trained review staff, may strengthen the 510(k) review process without significantly altering a well-established, longstanding device classification program.

CDRH’s Preliminary Recommendations

Proposal to clarify meaning of key terms in the 510(k) “substantial equiva-lence” review standard, including “in-tended use” and “different questions of safety and effectiveness”

The 510(k) “Working Group found that key terms in the statutory defini-tion of ‘substantial equivalence’ have not been consistently interpreted by” CDRH, including “what constitutes the same versus a new ‘intended use,’ and … when ‘different technological characteristics’ raise ‘different questions of safety and effectiveness.’”9 Thus, the preliminary recommendation is that CDRH create clearer definitions of these terms in guid-ance and training for both review staff and industry.

Specifically, the Working Group recommended that CDRH consolidate “indication for use” and “intended use” into the single term “intended use,” while retaining flexibility for 510(k) submit-ters to propose certain changes to the device labeling without such changes

necessarily constituting new “intended use[s].” Thus, the report suggests that CDRH consider what characteristics should be included under “intended use” so that modifications that currently are considered only changes in “indications for use,” and not new intended uses, likely remain that way in the future. The Working Group also recommended that CDRH carefully consider what it should call the existing “Indications for Use” statement in device labeling and the indi-cations form required for all 510(k)s. Fur-ther, the report states, the recommended training on how to determine “intended use” should clarify the elements of a 510(k) that should be considered when determining the “intended use,” such as product labeling, device design, literature and existing preclinical or clinical data.

The Working Group’s proposal to clarify these terms is based on the perception that there is a lack of clarity with regard to the meaning and proper application of the “indications for use” and “intended use” concepts. However, it is unclear from the report why any lack of clarity cannot be addressed through employee training that explains the terms and clarifies the meaning of each in guidance.

This would appear less disruptive to the agency’s premarket notification pro-gram than making potentially significant changes in the meaning of terms that were first defined in the 510(k) context in June 30, 1986,10 and subsequently ex-pressly adopted by Congress in the “Safe Medical Devices Act of 1990.”11 Although the agency seems sensitive to current practice, the preliminary report is not definitive about how, if the terms were consolidated, new devices with different indications for use from their predicates would be classified under the premarket notification process.



Enforcement

Insofar as a change in terms would entail a change in agency practice that imposes new legal or regulatory require-ments, it is important that the agency provide the public with a detailed notice and an opportunity to comment prior to making any changes.

The Working Group also recommended that CDRH reconcile the language in its 510(k) flowchart that asks whether the pending 510(k) device’s technological characteristics raise new types of safety or effectiveness questions from its predicate device, with the language in Federal Food, Drug, and Cosmetic Act (FD&C Act) sec-tion 513(i) that instead references “different technological characteristics” and “differ-ent questions of safety and effectiveness.” Specifically, the report suggests, CDRH should revise existing guidance to provide clear criteria for identifying “different questions of safety and effectiveness” and to identify a list of technological changes that generally raise such questions. Again, the Working Group recommended train-ing for CDRH staff and industry.

Insofar as CDRH believes that the terms in the flowchart have the same meaning as the terms in the statute and the proposed change will make the language consistent, the impact would be nothing more than administrative, e.g., requiring the updating of the 510(k) flowchart. If, however, CDRH’s proposal to change the flowchart is based on a belief that the current terms in the flow-chart are inconsistent with the statutory language and changing the terms would lead to a substantive change in interpre-tation and thus the meaning of the law, e.g., the term “different” is interpreted more broadly than the term “new,” then industry should expect notice and an opportunity for comment.

The Working Group also recom-mended that CDRH explore pursuing a

statutory amendment to section 513(i)(1)(E) of the FD&C Act that would provide FDA with broader authority to consider an off-label use when determin-ing a device’s “intended use.” To provide the agency with such authority would necessitate the elimination of section 513(i)(1)(E), which specifically instructs the agency to only consider the proposed labeling for intended use determinations. The suggestion of amending the statute would enable the agency to define the intended use of devices despite the intent of the 510(k) submitter; prohibiting this practice was the very reason for includ-ing section 513(i)(1)(E) in the FD&C Act in the first place. Importantly, under this section of the FD&C Act, the agency can limit the clearance of a device that it shows has a “reasonable likelihood” of an off-label use that “could cause harm.”12

In other words, current law empow-ers the agency to narrow a new device’s cleared use, if certain conditions are present, to eliminate or reduce off-label use without changing the intended use of a device that has yet to be placed in com-mercial distribution. Congress believed that justified labeling limitations, like contraindications, would effectively nar-row a new device’s indication for use.13 There would appear to be no need for a statutory amendment, unless the agency seeks to define the intended use of an unmarketed device independent of its proposed labeling and any appropriate agency additions to labeling now permit-ted by law.

Proposal to Establish a new Class IIbThe Working Group recommended

that CDRH explore the possibility of developing guidance to define a subset of Class II devices, defined as “Class IIb” devices, for which clinical data, manufacturing information or additional evaluation during the postmarket period

would typically be necessary in order for the device to be found substantially equivalent. Potential Class IIb devices may include implantable devices and life-sustaining and -supporting devices.

Imposing certain generic data require-ments for class IIb devices raises legal considerations that may make such a proposal difficult to implement with-out statutory regulatory changes. For example, current law separates the 510(k) determinations from Good Manufactur-ing Practices (GMPs) compliance, and thus manufacturing in the regulatory context.14 Specifically, under the law, “a finding that the facility in which the device is manufactured is not in compli-ance with good manufacturing require-ments” is “. . . unrelated to a substantial equivalence decision. . . .”15

In other words, in the context of prohibiting FDA from withholding substantial equivalence decisions because of violations unrelated to 510(k) deci-sions, Congress stated that GMPs were unrelated to, and therefore unnecessary for, substantial equivalence determina-tions. Moreover, the suggested proposal, to the extent it results in generic criteria with characteristics of a special control, would require a regulation for each type of device to which it would be applicable to be lawful. However, if Class IIb devices were evaluated on a case-by-case basis to determine if certain information such as clinical data was necessary for the substantial equivalence determination, the proposal may work.

Proposal Regarding Use of Multiple and Split Predicates

CDRH is concerned with the use of “split predicates.” That term refers to rely-ing on one predicate for intended use and another, with a different intended use, for a comparison of technological character-istics. The Working Group maintained



Enforcement

that this practice creates a nonexistent predicate device with unknown risks and benefits, and therefore CDRH should assess whether to disallow this prac-tice. Also, concern was expressed about “multiple predicates,” i.e., predicates that cover a new device’s technological characteristics with a composite of tech-nological characteristics from more than one device, with each device having the same intended use. To date, it does not appear that either practice has resulted in unsafe products reaching the market-place and the preliminary report does not contradict this conclusion. To the extent these practices have not resulted in the marketing of unsafe devices, and represent a part of the agency’s long-standing interpretation of the FD&C Act’s substantial equivalence provisions, the agency should take great care before changing them.

The Working Group also recommend-ed that CDRH develop guidance on the appropriate use of “multiple predicates” and train reviewers and managers on multiple predicates. As stated above, the use of multiple predicates refers to the practice of using more than one predi-cate where all the predicates fall within the same generic type of device. This long-standing practice, and interpreta-tion of the FD&C Act’s 510(k) provisions, is defensible under the law and there is no apparent reason to change it. If the multiple predicates share the same intended use, and therefore the same classification, and the 510(k) submitter has shown the new device is as safe and effective as the predicates, there should be no public health reason to discontinue this longstanding practice.

The Working Group also recom-mended that CDRH conduct additional analyses to better understand the appar-ent association between citing more than

five predicates and a greater mean rate of adverse event reports. Importantly, the Working Group acknowledged certain limitations relating to the collection and review of 510(k) data, including the lack of “ready access to meaningful ‘denomi-nator data’ . . . that could provide insight into the relative rates of reported adverse events and recalls” and the difficulty in deciphering the impact of adverse event reporting dynamics, e.g., bias, on the findings.16 We believe that because of the inherent limitations of the data, CDRH will likely be unable to firmly correlate the observed adverse event data to the use of multiple predicates.

Proposal to Require Reporting of Device Modifications

In addition to recommending that CDRH update its guidance on what modifications trigger the requirement for submitting a new 510(k), the Working Group also recommended that CDRH explore whether it could require manu-facturers to provide regular, periodic updates to the Center listing any modi-fications made to the device that did not trigger a new 510(k), and justifications for not submitting a new 510(k).

It is unclear whether and to what extent the Working Group considered CDRH’s resources when making this proposal. Requiring manufacturers to submit periodic updates on their device modifications would impose a significant burden not only on the regulated indus-try, but also on the agency.

As stated above, since 1976, over 120,000 devices have been cleared by FDA. Assuming 60 percent of these devices remain on the market today, this would result in over 70,000 currently marketed devices. Further assuming that modifications are made to about half of these devices annually, FDA would receive about 35,000 reports of device

modifications each year. Presumably, reviewers would be required to conduct substantive reviews and evaluations of these modification analyses and, to help gauge the significance of device changes, the underlying 510(k)s, assuming the justification of this annual reporting requirement is based on CDRH’s and a public health need to evaluate every unreported device modification. We believe that FDA must seriously consider whether requiring annual reports of 510(k) device modifications will create a cost without a benefit to the public health.

Proposal to Clarify CDRH’s 510(k) Rescission Authority

The Working Group recommended “that CDRH consider issuing a regula-tion to define the scope, grounds, and appropriate procedures, including notice and an opportunity for a hearing, for the exercise of its authority to fully or partially rescind a 510(k) clearance. As part of this process, the Working Group recommended that the Center should also consider whether additional authority is needed.”17

Although the FDA claims 510(k) rescission authority, the FD&C Act’s device provisions only inclde withdrawal authority for PMAs and IDEs, and no comparable authority for 510(k)s.18 Rath-er, more generally, the agency can only nullify a 510(k) substantial equivalence determination, like any other regulatory decision, if fraud occurred in procuring the substantial equivalence determina-tion or in very limited circumstances based on inadvertent administrative mistakes or errors.

Instead of expending resources seek-ing a rescission regulation on a dubious legal basis, FDA should consider using current authority to address what sec-tion 5.1.2.219 of the report describes as a very limited use of rescission to remove



Enforcement

inappropriate predicates from use. For example, if a device is ineffective or unsafe, FDA could remove it from the market under its misbranding and adul-teration authorities. A complaint alleging the device’s labeling is false or misleading in any particular, see FD&C Act § 502(a), or fails to have adequate directions for use, § 502(f)(1), or the device’s quality falls below “that which it purports or is represented to possess,” § 501(c), among other allegations, would result in the removal of the device from the market, if the agency can prove its case.

A successful case would accomplish the Working Group’s recommendation of eliminating devices “whose safety and/or effectiveness may be questionable”20 from being predicates.21 Relying on existing authority that explicitly pro-vides FDA with a legal basis to remove inappropriate predicates from use in the premarket notification process, instead of pursuing rescission authority that is not authorized by the FD&C Act and would illegally supplant the Act’s reclassification authority, is something CDRH should seriously consider.

Proposal to Consider Withholding Clearance on the Basis of a GMP Violation

The Working Group proposed that CDRH clarify when it is appropriate to withhold a 510(k) clearance on the basis of a failure to comply with good manu-facturing requirements in situations when there is a substantial likelihood that such failure will potentially pres-ent serious risk to human health. Even though the Working Group’s position statement relies upon the statutory crite-ria for withholding a clearance, and that provision does not require a regulation for implementation, we believe the agen-cy should seriously consider promulgat-ing a regulation to clarify the criteria for withholding 510(k) determinations and

establish a process to provide affected persons an opportunity for input prior to a decision to withhold a 510(k).

Consideration of a regulation of this type is merited because withholding a 510(k) decision based on GMP alleged violations would represent decisionmaking based upon the agency’s unilateral deter-mination and could have highly significant effects on 510(k) submitters, particularly small, single product companies.

Proposal to Create a “Notice to Indus-try” Tool to Communicate Changes in Premarket Expectations

The Task Force on the Utilization of Science in Regulatory Decision Mak-ing recommended that CDRH create a “Notice to Industry” tool to more rapidly communicate changes in premarket expectations. Specifically, the Task Force envisioned that this tool should be established as standard practice and that CDRH would send letters to manufac-turers of a particular group of devices for which the Center has changed its regulatory expectations on the basis of new scientific information.

While we believe that more infor-mation and greater transparency is important to quality industry submis-sions and FDA’s effectiveness, there are legal considerations that CDRH should closely examine before implementing the “Notice to Industry” tool. Insofar as the agency imposes new legal standards through a notice program that affect the regulated industry, the agency should consider the rule making aspects of such conduct and its obligations to use the notice and comment process.

ConclusionWe agree with these preliminary

reports to the extent that training and knowledge enhancement for CDRH staff should be crucial components of the 510(k) program, whether or not there are

modifications to the program. Indeed, if more training is provided, fewer changes may be necessary to address the perceived weaknesses of the 510(k) review process identified by these preliminary reports. In areas where the Working Group and Task Force determine changes are necessary despite adequate staff training, CDRH should ensure that any change improves the current 510(k) program and does not diminish it. FDA’s call for comments on the preliminary report and recommenda-tions on the 510(k) process was positive, and constructive public input and careful agency review of comments should lead to an appropriate outcome for this long-standing premarket review program.

FDLI

1 CDRH Preliminary Internal Evaluations – Volume 1, 510(k) Working Group Preliminary Report and Recommendations (2010); CDRH Preliminary Internal Evaluations – Volume 2, Task Force on the Utilization of Science in Regulatory Decision Making Preliminary Report and Recommendation (2010), available at http://www.fda.gov/AboutFDA/Center-sOffices/CDRH/CDRHReports/ucm220272.htm.

2 Foreword: A Message from the Center Director at 1, available at http://www.fda.gov/AboutFDA/Center-sOffices/CDRH/CDRHReports/ucm220272.htm.

3 Foreword: A Message from the Center Director at 5.4 510(k) Working Group Preliminary Report and

Recommendations at 4 (stating that CDRH may refer some changes to the Institute of Medicine for further review).

5 The Medical Device Amendments of 1976, Pub. L. No. 94-295, 90 Stat. 539.

6 See Comments of Donna-Bea Tillman, Director, Office of Device Evaluation, CDRH, Transcript of Open Public Meeting “Strengthening the Center for Devices and Radiological Health’s 510(k) Review Process” at 21 (Feb. 18, 2010) (“I believe we have cleared 120,000 510(k)’s since the beginning of the program. Last year, I think we had 3,700.”); see also Dr. Tillman’s Power Point presentation “Current Challenges for the 510(k) Program” at 11 (Feb. 18, 2010) (noting there are 3000 – 4000 510(k) submis-sions per year compared to 30 – 50 PMA applications).

7 510(k) Working Group Preliminary Report and Recommendations at 87.

8 510(k) Working Group Preliminary Report and Recommendations at 19 (explaining out of 308 reviewers in the Office of Device Evaluation (“ODE”) and Office of In Vitro Diagnostic Device Evaluation and Safety (“OIVD”), 215 reviewers took the survey but only 162 completed it, and out of 38 managers in ODE and OIVD, only 21 took the survey and only 13 completed it).




Enforcement

10 Guidance on the CDRH Premarket Notification Review Program 6/30/86 (K86-3), available at http://www.fda.gov/MedicalDevices/DeviceRegulatio-nandGuidance/GuidanceDocuments/ucm081383.htm

11 See S. Rep. No. 101-513 at 41 (1990) (stating the new law “is intended to codify the Secretary’s interpreta-tion of the term ‘substantially equivalent’ as used in the Act, including sections 513, 515, and 520.”); see also id. at 28 (“The Committee intends to incorporate the agency’s thinking into the determination of when a newer device is considered to be as safe and effective as a predicate device.”).

12 See FD&C Act § 513(i)(1)(E)(i).

13 See id.14 See FD&C Act § 513(f)(5).15 See id.16 510(k) Working Group Preliminary Report and

Recommendations at 20.17 510(k) Working Group Preliminary Report and

Recommendations at 58.18 See also Transcript for FDA’s Media Briefing on the

FDA’s Review of the ReGen Menaflex (Sept. 24, 2009) (In response to the question of “what legal authority FDA has to repeal a 510(k) clearance,” Dr. Shuren responded that “[If it would be appropriate to repeal a clearance, FDA] would move to reclassify the device.

And [FDA] would up-classify it to a Class III, and then it would be subject to a pre-market approval applica-tion, rather than a 510(k).”).



21 See FD&C Act § 513(i)(2) (stating that a device cannot be “substantially equivalent to a predicate device that has been removed from the market at the initiative of the Secretary or that has been determined to be misbranded or adulterated by a judicial order”).

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