FDA’s 510(k) Process: Reform or Ruin?

1. FDA’s 510(k) Process: Reform or Ruin? Richard J. DeRisio, DVP, Regulatory Affairs Abbott Medical Optics Inc.

2. 510(k) Background FDA News Release: January 22, 2010 The 510(k) process was established under the Medical Device Amendments of 1976 to achieve two goals: Make safe and effective devices available to consumers; and Promote innovation in the medical device industry. During the past three decades, technology and the medical device industry have changed dramatically, making it an appropriate time for the FDA to review the adequacy of the premarket notification program in meeting these two goals.

3. Congressional GuidanceInsights into the intent of the 510(k) process The statutory objectives for the 510(k) program and the Report by the Committee on Interstate and Foreign Commerce on the Medical Device Amendments of 1976 (House Report) The term “substantially equivalent” is not intended to be so narrow as to refer only to devices that are identical to marketed devices nor so broad as to refer to devices which are intended to be used for the same purposes as marketed products. If substantial equivalence were judged too narrowly, the marketing of devices that would benefit the public would be delayed; the device industry would be unnecessarily exposed to the greater burdens of premarket approval; new devices would not be properly classified; and new manufacturers of pre-Amendments-type devices would not have marketing equity.

4. FDA 510(k) GuidanceJudging Substantial Equivalence (SE) Thus, as a matter of practice, CDRH generally considers a device to be SE to a predicate device if, in comparison to the predicate device: The new device has the same intended use (as discussed below); and, The new device has the same technological characteristics, (i.e., same materials, design, energy source, etc.); or, it has new technological characteristics that could not affect safety or effectiveness; or It has new technological characteristics that could affect safety or effectiveness, and There are accepted scientific methods for evaluating whether safety or effectiveness has been adversely affected as a result of the use of the new technological characteristics; and There are data to demonstrate that the new technological features have not diminished safety or effectiveness.

5. Determination of Intended UseFDA Guidance: K98-I Update, December 3, 2002 FDA may issues an order of substantial equivalence only upon making the determination that the device to be introduced into commercial distribution has the same intended use as the predicate device and is safe and effective as a legally marketed device. “Ordinarily, intended use is determined by reference to ‘labeling’ or promotional claims; only in rare cases might it be necessary to infer intended use from other types of information.” The labeling includes the actual label for the device and any accompanying information such as directions for use and promotional materials. There may be rare instances in which the design of the deviceor published literature referencing the subject device or similar device, would lead one to believe that there may be an intended use different than that appearing in the label. The reviewer and division management should consider: Whether there is a reasonable likelihood that the device will be used for an intended use not identified in the proposed labeling for the device, and if such use could cause harm to the patient or the consumer.

6. 510(k) Public Meeting: February 18, 2010 Executive Summary In parallel with the IOM 510(k) study, FDA has initiated an internal review of the 510(k) process The Agency acknowledged that many 510(k) devices are cleared following submission of extensive data including, where appropriate, human clinical studies. Presentations by industry, trade associations, VC firms, physicians, consultants, private individuals, consumer advocates and university professors were overwhelmingly supportive of the 510(k) process. The consensus appears to be that there are no data to indicate that the 510(k) process is not working. There can be improvements, but many of these are under the control of the Agency itself. There are times when bench testing is more effective in predicting device safety than human clinical trials.

7. 510(k) Public Meeting: February 18, 2010 Executive Summary 120,000 510(k)s cleared since 1976; 3,000+ in last Fiscal Year. Is industry choosing “Lowest Common Denominator” predicates? An old predicate device might not reflect current medical practice Substantial Equivalence decisions are difficult with old predicate devices Are manufacturers innovating for innovations sake, but not necessarily developing devices that are better? Multiple predicate devices make it difficult to reach a Substantial Equivalence determination: Appears to create a new device using features from several devices FDA is concerned about “Device Creep”. With too many “Letters to File” documenting that a 510(k) is not needed for a device/process change, the currently marketed device might be significantly different from the original predicate. FDA can use judgment in clearing a 510(k) with a reasonable leap of technology where the risk fits the Class II profile e.g. manual laparoscopic instruments to robotic laparoscopic surgery.

8. 510(k) Public Meeting: February 18, 2010 Executive Summary Many comments identified management problems within FDA: Lack of updated guidance documents, poor training of new reviewers. Lack of management oversight is resulting is a lack of consistency and predictability among reviewers and branches: Treatment of manufacturers (level playing field) Cross-functional reviews among divisions Within brackets of different devices with different risks Over a period of time Lack of transparency/predictability due to changing internal standards without explanation – resulting in inconsistencies and time delays. Is direct communication with industry being discouraged? Is this partly an over-reaction to “Whistleblower” allegations?

9. Compliance RisksBeckman Coulter Troponin Diagnostic Test Company reports positive bias in its testing. Company issues a statement “thatcertain modifications…were made without obtaining appropriate product clearances.” Company will have to transition customers “to some other form of troponin testing.” Morgan Stanley analyst writes: “If the matter is resolved quickly, Beckman will likely be able to avoid major market share loss to competitors” and “The key question will be if this issue hinders overall immuno-assay sales momentum or market share?” Beckman reports we are “evaluating our internal processes and procedures regarding our product, quality and regulatory systems.” “It is possible that more of our products could be affected and the actions with respect to those products could adversely affect our operating results.”

10. Compliance Risks Guidant A Class III PMA product – Automatic Implantable Cardiac Defibrillator (AICD) FDA had previously cited concerns with Guidant’s AICDs; situation abetted by a New York Times investigation and report. FDA alleges that Guidant (now part of Boston Scientific) made changes to the device without filing the appropriate notifications of requests for approval: BSX identified two manufacturing changes that were never submitted to FDA for review. Analysts estimate the loss of sales at $5 million per day! FDA issues a statement that they are not expediting the firm’s submissions It is critically important to have qualified personnel and processes for continually and reliably assessing changes as to whether or not a regulatory change notification is needed for any market, and take all necessary actions in order to assure compliance.

11. Compliance Risks STERIS Corporation FDA Warning Letter cites: “The documents collected reveal that there have been significant changes or modifications in design, components, method of manufacture, or intended use, that require submission of a new premarket notification. Under that regulation, a new510(k) must be submitted for a change or modification in the device that could significantly affect the safety or effectiveness of the device, e.g., a significant change or modification in design, material, chemical composition, energy source, or manufacturing process. The changes described below are such significant changes. Therefore, until a 510(k) is submitted for the altered device and FDA issues a finding that this changed device is substantially equivalent to a legally marketed predicate, your device remains a class III device.” Changes included: Different pump design and performance characteristics Software changes Design modifications to accessories Change in chamber volume Change in sterilant concentration Change in sterilant formulation Other listed running changes

12. Compliance Risks STERIS Corporation (Cont’d) FDA cites examples of customer notifications and field-wide upgrades as actions that should have been reported and documented under 21 CFR 806,Corrections and Removals. 2009 – FDA issues a Safety Alert regarding the device to Healthcare Administrators and Infection Control Practitioners along with a separate Q&A document: Tells hospitals to transition to an alternative sterilizer Does not address actual patient harm due to a malfunction, only the potential Provides a link to the 2008 Warning Letter Solicits adverse event reports from user facilities 2010 – FDA publishes a safety alert providing Health Care Facilities and HCPs with a list of alternatives to the STERIS device.

13. FDA QuestionsIssues Related to Predicate Devices FDA maintains a searchable online database to provide interested parties, including prospective 510(k) submitters, with information about devices that have been cleared for marketing through the 510(k) process. How effective is the 510(k) database and search engine in helping prospective submitters find and evaluate the adequacy of predicate devices for 510(k) submissions, and write substantial equivalency rationales? How effectively do the publicly released documents listed previously describe the cleared indications for use of each device, the technological characteristics of the device, and the methods and type of information that were used to determine substantial equivalence to the device's predicate(s)? Should FDA require 510(k) holders who receive a substantial equivalence decision for their device to submit a redacted version of their 510(k) submission after clearance for public release?

14. FDA QuestionsIssues Related to Predicate Devices 2. Some 510(k) submitters do not accurately portray the similarities and differences between the device under reviewand the predicate device(s). Please comment on this problem and what steps FDA should take to address it. Stricter criteria? Problems and benefits of “outdated” predicates 3. Generally, a device that has a clearance under the 510(k) process may be used as a predicate, regardless of whether or not the device is still in use, remains relevant to current standards of care, or has been replaced by new technology. Please comment on the utility of this generally inclusive strategy and its positive or negative impact on achieving the two public health goals of the 510(k) program.

15. FDA QuestionsIssues Related to Predicate Devices 4. Incremental device changes may seem innocuous individually, but over time such changes may accumulate to create a device that is significantly different from the original device (referred to as “predicate creep''). Similarly, clinical non-inferiority studies may be submitted as evidence of substantial equivalence between a device under review and a predicate, the difference in effectiveness between device A and D may approach clinical significance (referred to as “non-inferiority creep''). Please comment on what if any changes should be made to the 510(k) program based on the occurrence of predicate creep and non-inferiority creep.

16. FDA QuestionsIssues Related to Predicate Devices 5. In some cases, more than one predicate device has been submitted by the 510(k) submitter in its evaluation of substantial equivalence. For example, if there is not a single predicate device that has the same indication for use and technological characteristics as the device under review, a submitter may cite one predicate device in an effort to demonstrate the same intended use, and a different predicate device in an effort to demonstrate the same technological characteristics. The use of more than one predicate has been referred to as using a “split predicate.” Please comment on whether the use of a split predicate or more than one predicate serves the public health goals of the 510(k) program. If possible, please include examples.

17. FDA QuestionsIssues Related to Predicate Devices 6. To find that a device is substantially equivalent, FDA must determine, among other things, whether or not a new device has the same “intended use” as the predicate device (Section 513(i) of the act). A device under review may have a different “indication for use” than the predicate, yet still be determined to have the same “intended use” and therefore may be found substantially equivalent. Please describe your understanding of an “indication for use” as compared to an “intended use”. What are the advantages and disadvantages of distinguishing between the terms “indication for use” and “intended use” during the review process?

18. FDA QuestionsIssues Related to new Technologies and Scientific Evidence The act defines the term “different technological characteristics” as “a significant change in the materials, design, energy source, or other features of the device from those of the predicate device.” What “other features” should FDA consider (or not consider) to be “different technological characteristics”? When a 510(k) submitter receives a Not Substantially Equivalent (NSE) determination from FDA, the submitter may petition FDA, if this type of device has not been approved through the PMA process, to classify this new type of device through the Evaluation of Automatic Class III Designation (or de novo) process. What criteria should FDA use to determine which risks can be mitigated through general controls alone or with special controls, and which risks are sufficient to make the device ineligible for de novo classification?

19. FDA QuestionsIssues Related to new Technologies and Scientific Evidence 3. If a device under review has “different technological characteristics” than the predicate(s), it may still be determined to be substantially equivalent if “the information submitted that the device is substantially equivalent to the predicate contains information, including appropriate clinical or scientific data if deemed necessary by the [FDA] * * *, that demonstrates the device is as safe and effective as a legally marketed device and [the device under review] does not raise different questions of safety and effectiveness than the predicate device”. Should FDA define “different questions of safety and effectiveness?” In some circumstances, FDA may consider data from one of the following four types of comparison studies, or a combination of any of them, to determine whether a new device is substantially equivalent to a predicate device: FDA-recognized standard; bench testing; bench and animal or bench and clinical testing; bench, animal and clinical testing.

20. FDA QuestionsIssues Related to new Technologies and Scientific Evidence 5. Has FDA established sufficiently clear guidelines concerning the provision of sufficient engineering and design information to provide FDA an understanding of how the device operates in 510(k) submissions? If not, what additional guidance might be helpful? 6. Would it be beneficial for FDA to have greater authority to withhold an initial classification determination based on a failure to comply with cGMP requirements or other provisions of the act? Please explain. 7. Currently, some 510(k) submissions include as the “indication for use'' a device function that is not associated with a specific clinical utility (e.g., treatment or diagnosis of a specific condition). For new devices, should a requirement of the 510(k) program be that a device's “indication for use” be proven to FDA to provide clinical utility? 8. How effective are FDA's actions with respect to curbing off-label use that could cause harm?

21. FDA QuestionsIssues Related to Practices CDRH has Adopted in Response to a High Volume of 510(k) Submissions 1. FDA receives a very large number of 510(k) submissions each year. In response to this high volume of work, CDRH has adopted a number of practices to allow for less resource-intensive reviews. Please comment on the advantages and disadvantages of each of these practices, as related to the quality and timeliness of 510(k) reviews. Third-party reviews Special 510(k)s Abbreviated 510(k)s Use of a single reviewer

22. FDA QuestionsIssues Related to Postmarket Surveillance and New Information about Marketed Devices FDA generally does not require postmarket surveillance studies as a condition of medical device 510(k) clearance. Might be beneficial for FDA to impose such studies as a condition of medical device 510(k) clearance. Should FDA allow for the rescission of 510(k) clearance decisions under a broad range of circumstances? If so, what specific criteria might justify the rescission of a 510(k) clearance decision? FDA obtains a significant amount of postmarket information for 510(k)-cleared devices, including adverse event reports, recalls, and inspectional findings. Should such information influence the premarket 510(k) review of similar devices? If so, how? FDA regulations require the submission of proposed labeling (including indications for use, directions for use, precautions, warnings, and contraindications) in a 510(k) prior to clearance of a device. However, 510(k) holders sometimes alter the labeling after clearance, so that the final printed labeling is different from that submitted to FDA in the 510(k). Please comment on whether or not it might be beneficial for FDA to review and clear the final printed labeling for all 510(k) devices or for selected 510(k) devices prior to marketing. FDA does not always know when there has been a purchase, sale, or transfer of ownership of a 510(k) for a particular device. Should FDA exercise more authority in this area? If so, how?

23. Summary and Conclusions Does CDRH/ODE want to preempt the IOM review? There will be changes to the 510(k) process, for example, a two-tier system: Higher-risk tier devices could have increased data requirements Periodic reports might be required to update FDA on device/process changes and post market performance. Review times could be longer. Design, process and test changes that could affect safety and effectiveness must be reviewed to determine if a 510(k) filing is required. Monitor the press and FDA’s website for CDRH compliance initiatives.