& DEPARTMENT OF HEALTH & HUMAN SERVICES Food and Drug Administration Rockville MD 20857 _ The Honorable Richard G. Lugar United States Senator NOV 05 2009 Washington, D.C. 20510-1401 Dear Senator Lugar: ‘Thank you for your letter of August 4, 2009, regarding a situation brought to your attention by Dr. Nalini Rajamannan involving the status with the Food and Drug Administration (FDA or the Agency) of the model 5100 McCarthy Myxo dEtlogix Annuloplasty Ring, manufactured by Edwards Lifesiences (Edwards) LLC, for use in heart valve repair. ‘The material you enclosed included a copy of a July 16, 2009, letter FDA had sent to a patient from Illinois, Ms. Atonista Vlahoulis, who had expressed concern about the use of the Myxo valve product by a surgeon who implanted this device inher. Below are responses FDA has made in reply to several follow-up questions the Agency received to the July 16, 2006, letter addressed to Ms. Vlahoulis. 1. The Agency says that sponsors are “encouraged to contact the Agency if they have questions regarding the appropriateness of a 510(K).” If there are no disincentives for making the wrong determination, why would manufacturers seek advance input from the Agency or submit a new 510(k) rather than wait for the FDA to request one? FDA believes that sponsors have disincentives to make the wrong determination. However, FDA has determined that its guidance to industry entitled “Deciding When to Submit a 510(K) for a Change to an Existing Device” is not sufficiently clear in describing when a sponsor must submit a 510(k) to FDA. For example, the changes Edwards made to its device were not clearly described as requiring the submission of a 510(k). In recognition of the rapid rate of device evolution, FDA’s regulations provide that ‘manufacturers need to submit a new 510(k) only when a change or modification, or the sum of incremental changes or modifications, could significantly affect the safety or effectiveness of the device. ‘This standard is contained in 21 CFR 807.81(a)(3). In our guidance document entitled “Deciding When to Submit a 510(k) for a Change to an Existing Device,” the Agency provided guidance on the types of labeling, technology, performance and material changes that may cross this threshold. We state in the guidance that if a firm, after consulting the guidance, still has questions on whether or not anew 510(k) is needed, they should contact our premarket review offices.Page 2 — The Honorable Richard G. Lugar In that guidance FDA also advised manufacturers that design control requirements applicable to all Class II and III devices, and to certain Class I devices, are required to identify, document, validate, review and approve design changes before their implementations. The device history file must contain or reference the records necessary to demonstrate that the design was developed in accordance with the approved design plan and quality system requirements. See 21 CFR 820.30(i), ()). FDA has access to the device history file upon inspection. ‘A manufacturer has strong incentives to comply with these 510(k) and design control requirements. Significant consequences flow from noncompliance. Ifa manufacturer implements a change or modification without submitting a new 510(k), and FDA subsequently determines the change required clearance of a new 510(k) before device marketing, FDA considers the unapproved device to be in violation of the Act, may advise the manufacturer to recall the product or take other measures to correct products already in distribution, and may take additional compliance action against the manufacturer and the product. In assessing the appropriate response in a particular situation, FDA must assess the risks to public health, and determine whether the company made a good faith effort to determine if the changes could significantly affect the safety and effectiveness of the device. FDA would consider the significance of the changes made and possible implications to the patient, whether a manufacturer had appropriate rationale and/or documentation to support its decision, and whether or not the manufacturer is taking steps to come into compliance. ‘The manufacturer's interest in avoiding such compliance actions provides strong incentive for diligence and good faith in making that initial determination. There are additional incentives that apply outside the FDA regulatory scheme, such as the incentive to avoid private lawsuits and other negative interactions with patients and the health care community. FDA is planning to update existing guidance in this area. We plan to take the lessons Jearned from these events and take the opportunity to communicate more clearly on these issues. 2. Did the FDA review any data on the patients who already had the device implanted prior to clearance by the FDA for marketing? If not, why not? ‘Yes, an overview of the elinical experience to date was reviewed in the 510(k) submission, This included a paper entitled “Initial Clinical Experience with Myxo- ETlogix Mitral Valve Repair Ring,” (J Thorac Cardiovasc Surg 2008:1-9) published by McCarthy et al., information from Edwards Lifesciences’ in-house registry, and a review of the Center for Devices and Radiologic Health’s (CDRH or the Center) Manufacturer and User Facility Device Experience (MAUDE) database. ‘The MeCarthy paper describes a two-surgeon, single-institution experience with 100 Myxo ETlogix (dETlogix) implants for repair of myxomatous mitral regurgitation over 18 months. ‘The authors reported no postoperative mortality, infection, myocardialPage 3 ~The Honorable Richard G. Lugar infarction, or renal failure. There was one reoperation for bleeding and one stroke. Ninety-ight percent of patients showed no residual regurgitation on intraoperative echocardiogram, with a mean transvalvular gradient of 3.0 mmHg. At hospital discharge (average 5.6 days later), 93.9 percent of patients had no regurgitation and 6.1 percent had + regurgitation. Follow-up was reported for an unknown number of patients with a total of 338 echocardiograms over an average time of 6.1 months (range unknown), Mitral regurgitation (MR) of 1+ was found in 18 percent of the Myxo ETlogix patients; itis stated that there was no statistical difference between discharge MR and follow-up MR, and that no patient had MR >2+. Persistent, obstructive systolic anterior motion was not seen. The safety and effectiveness outcomes reported in this manuscript are similar to what one would expect for mitral valve repair operations involving an annuloplasty ring. In the 510(k) the sponsor provided a summary of the data included in their in-house registry. The sponsor reported that a total of 667 units had been distributed with 10 observations. Four were complaints, including two cases of suture pull-out, one case of a systemic rash responding to steroids, and the fourth, a possible cause of “inflammatory response.” The sponsor reported that there were six device explants, Four devices were explanted during the procedure, but without report on whether the device was replaced with a different ring or by valve replacement. Details for the remaining two explants were not available. ‘The Agency also reviewed medical device reports (MDRs) submitted to the MAUDE database during our review of the 510(k). This database search returned five entries for four events (it appeared that the first two entries were for the same event). ‘Three of the four events occurred on the date of implant for suture pulling through the annulus or for “unknown reasons.” The fourth event was patient death and took place approximately six months after implant. The cause of death was not reported. Regarding our review of Edwards’ in-house registry data and the MDRs submitted for the dETlogix device, the Agency felt that the frequency and type of complaints and adverse events reports were consistent with the expected outcomes in this patient population, After reviewing all of the data described above, the Agency concluded that the clinical experience with the dETlogix device was similar to legally marketed annuloplasty rings. 3. Has the FDA required the company to take specific actions to prevent wrong determinations from occurring again in the future? If so, please describe what actions are being required of the company. Yes, FDA held a meeting with the firm to explain our decisionmaking process and expectations for determining when a new 510(k) is required. The firm must implement a corrective and preventive action to ensure that they have an appropriate process in place to correctly determine when a modification to a device requires a new 510(k). A. corrective and preventive action is an action to correct and prevent distribution ofPage 4 - The Honorable Richard G. Lugar products that do not meet specifications or have other quality problems. This is required by the Quality System regulation for medical devices. On a follow-up inspection FDA verified that Edwards had implemented an appropriate corrective and preventive action by changing its procedures for determining when a 510(K) must be submitted to FDA. 4, Has the FDA requested the company notify all patients implanted with the dETlogix ring before it was cleared by the FDA that they had received an experimental device? If not, why not? No, FDA has not requested that the company notify all patients who received the device prior to clearance. The Agency takes very seriously its responsibility for human subject protection. However, in this case FDA has determined that the device meets the standards for safety and effectiveness applicable to this class II device and that Edwards did not believe it was testing an investigational device. Therefore, in this case, we do not believe that notification would provide a benefit to patients, and instead may ‘unnecessarily alarm patients and raise unwarranted concerns. However, in cases where the evidence shows that patients may be at greater risk from the device or where we have identified steps that can be taken to ameliorate the risks to patients, we would generally request sponsors notify patients who received an unapproved or uncleared device. 5. According to FDA’s guidance, manufacturers are only required to maintain documentation of their analysis on whether or not a modification to their device requires the filing of a new 510(k) and to make that documentation available to the FDA during an inspection. Why are manufacturers not required to submit that documentation to the Ageney at the time that the determination is made so that the Agency is on notice and has a file of all modifications made to a device? One of the cardinal features distinguishing the medical device industry from the pharmaceutical industry is that design and manufacture of medical devices change and evolve at a much faster rate than for most pharmaceutical products. Modifications to a device can occur relatively frequently, and their impact can range from very minor to significant in terms of safety or effectiveness. Currently, approximately 3500 510(k) notifications are received every year, with over 120,000 cleared since the device amendments were passed in 1976. A requirement that manufacturers submit documentation every time a minor change is made to a marketed device would result in a Jarge number of paper filings. Handling and reviewing these paper filings would entail the redirection of limited resources to an activity with likely a small public health benefit. This is, however, an issue the Agency is revisiting. As noted in our response to question #1, we believe our current policy for what constitutes a minor change is not sufficiently clear. To address this deficiency we are in the process of revising our current guidance document. In addition, as CDRH moves towards the electronic submission of applications through rulemaking and investments in information technology, the Center will be in a better position to handle and analyze the larger volume of information that ‘would come from manufacturers submitting documentation of minor changes made to a devicePage 5 ~ The Honorable Richard G, Lugar 6. According to the Heartwire article, Edwards maintained in-house documentation ofits determination that the dETlogix ring did not require a new 510(k), and did not submit the documentation until FDA asked for that documentation last year during FDA’s investigation of the matter. . If allegations regarding the dE Tlogix ring had not been brought to the FDA’s attention, at what point in time might the FDA have discovered that a wrong determination had been made during a routine inspection of the manufacturer? In the above-mentioned guidance, we request that a firm, when submitting a 510(k) for a change or modification, identify previous modifications to the device for which they did not submit 2 510(k). If, during the review of the new 510(k), we find that one of the previous modifications did meet the criteria for a 510(k), we address that finding with the firm. In addition, FDA may become aware of changes made to a device by receiving a complaint, through our own investigation of adverse event reports or other reports to EDA, or during an inspection. Based on past experience, we would most likely have detected this kind of change/modification during our inspection. b. How comprehensive is FDA’s review of a manvfacturer’s analysis during a routine inspection? ‘The level of review varies. FDA may perform routine inspections at two levels of coverage: Level I or II. A Level I inspection covers corrective and preventive actions plus either design controls or production and process controls. A Level II inspection covers management controls, design controls, corrective and preventive actions, and production and process controls. During an inspection, if design controls are reviewed, the investigator will review one preproduction and one postproduction design change This review may lead to the collection of documentation of the design changes and the firm's documented rationale for determining whether these changes require a new 510(k). In addition, the investigator may review complaints or corrective and preventive action records, c. Does the FDA always request such documentation for review during each inspection? If not, how frequently does the FDA review such documentation? No, FDA does not always request such documentation for review during each inspection and we do not track how frequently we review such documentation. Instead FDA requests and reviews records using a risk-based approach, tailoring its review to the purpose of the inspection for that particular facility. As stated above, during an inspection, if design controls are reviewed, the investigator will review one preproduction and one postproduction design change. This review may lead to the collection of documentation of the design changes and the firm's documented rationale for determining whether these changes require a new 510(k). In addition, the investigator may review complaints or corrective and preventive action records.Page 6 ~The Honorable Richard G. Lugar 4d. Does the Agency maintain any database of all modifications made to devices cleared and/or approved by the Agency even if the Agency does not conduct a comprehensive review of all of the modifications? If not, why not? And how does FDA track what modifications have been made to each device? ‘The Agency does not maintain a database of 510(k) modifications. We do, however, track these changes through the review of the submission, For example, each time a new feature is added the FDA reviewer will typically describe the significance/evolution of the design history. As previously noted, in our above referenced guidance, we request that a firm, when submitting a 510(k) for a change or modification, identify previous modifications to the device for which they did not submit a 510(K). If, during the review of the new 510(k), we find that one of the previous modifications did meet the criteria for 2 510(K), we address that finding with the firm, For many of the same reasons described in our response to question #5, however, FDA does not maintain a database related to modifications not addressed or submitted as part of a 510(k) review. 7. Please describe in detail any steps the FDA plans or is planning to take to improve its oversight of manufacturer determinations on when to submit a $10(k) for a modification to an existing device. As noted, in our responses to questions #1 and #5, FDA is currently reviewing and revising the guidance document entitled “Deciding When to Submit a 510(k) for a Change to an Existing Device.” Furthermore, we have commissioned the Institute of ‘Medicine to conduct a comprehensive study of the 510(k) process and to make recommendations on appropriate administrative, regulatory, and legislative changes. FDA will also explore requiring the submission of documentation when minor changes are made to a device once electronic submissions are required and the necessary information technology system to handle these submissions is established. Thank you for your continued interest in this important matter. If we can be of further assistance, please let us know. Sincerely, b Abies Jeanne Ireland Assistant Commissioner for Legislation Enolosure