Originally Published MDDI August 2003

WASHINGTON WRAP-UP

A recent poll suggests manufacturers are increasingly satisfied with FDA's communication with industry and review times. Respondents support the agency's use of outside experts as reviewers.

James G. Dickinson

Guidant Pays $92 Million for MDR Failures | FDA's New ‘Economic' Role | FDA Cites Another Tyco Device Unit | Baxter Warned over Corrections | Complaints Received by FDA Decline 

A group of medical device manufacturers informally expressed satisfaction with efforts to speed up FDA approvals. Then a national columnist asserted that this agency should be “a superhighway, not a speed bump” on the way to market. These events suggest that a pivotal point may have been reached in regulatory reform. How fast is fast enough?
The industry endorsement of FDA's progress in expediting device review times came on June 5 during an unscientific poll taken at AdvaMed's 13th annual device submissions workshop, in the context of the agency's implementation of last year's Medical Device User Fee and Modernization Act (MDUFMA). With few exceptions, respondents indicated satisfaction with the quality of FDA's communications with industry, particularly the attention given by CDRH staff to industry queries regarding the 510(k) premarket notification process. The poll also indicated that, in the opinion of most industry representatives, FDA seems to be applying the “least burdensome” rule uniformly in its requests for information to be presented in premarket approval (PMA) applications. That is, most of the information requested may be fairly viewed as essential to the proper conduct of the review. 

Respondents to the poll were particularly supportive of the agency's increasing acceptance of outside experts as reviewers—a trend that may go far toward explaining the apparent increasing satisfaction with review times. In response to a question on the use of outside experts as reviewers, CDRH director David Feigal indicated that he intends to place even greater reliance in the future on this personnel resource. “Currently, the Division of Cardiovascular and Respiratory Devices has made the most use of outside review experts,” Feigal said. “But we intend to expand their use and to develop other mechanisms, including employing university faculty members, both as part-time consultants and possibly on a full-time basis during sabbaticals taken from their teaching duties.” Feigal indicated that the use of outside reviewers by CDRH currently totals only the equivalent of three full-time positions (FTEs). He expects to greatly expand their use to the level of 20 FTEs.

Even as this collaborative interaction was taking place at AdvaMed's workshop, columnist Gloria Borger's “FDA superhighway” exhortation was hitting the newsstands in U.S. News & World Report, in the context of Martha Stewart's fall from grace in the ImClone stock-trading scandal. (Stewart was charged with selling her ImClone stock on inside information that FDA had decided not to approve the company's cancer drug Erbitux.)

Yes, FDA caution in releasing new products to the market may be appropriate in some cases and for some patients, Borger wrote. But as an ImClone stockholder herself who had lost a dear friend to Erbituxresponsive cancer, she welcomed all the review-accelerating reforms being brought by the Bush White House's new commissioner at FDA, Mark McClellan.

“Standards are important,” Borger wrote, no doubt expressing the sentiments of millions, “but there is no time to spare. FDA needs to be a superhighway, not a speed bump.”

This provoked former FDA Denver District director John Scharmann to respond by citing the agency's mission statement that demands prompt review and timely marketing “in consultation with experts in science, medicine, and public health, and in cooperation with consumers, users, manufacturers, importers, packers, distributors, and retailers of regulated products.” Scharmann added pointedly: “Note, the word is cooperation, not capitulation.”

Noting the Bush administration's industry-friendly demeanor, Scharmann concluded, “Back in FDA history, one speed bump with the name Dr. Frances Kelsey on it kept thalidomide off the U.S. market despite strong pressure to approve it and in so doing spared many American families the pain of dealing with a lifetime of malformed children. Let's hope that there are still some ‘speed bumps' in the review process.”

Guidant Pays $92 Million for MDR Failures 

A medical device company that places an employee in the operating room while its device is being implanted can hardly have an excuse for not filing required medical device reports (MDRs) with FDA on any adverse events that occur. This was the basis of a guilty plea to 10 felony counts by Endovascular Technologies Inc. (Menlo Park, CA), a wholly owned subsidiary of Indianapolis-based Guidant Inc., in federal court in San Francisco in June.

The company agreed to pay the federal government $92.4 million to settle criminal and civil charges that it covered up thousands of incidents in which its Ancure Endograft system, used to treat abdominal aortic aneurysms, had malfunctioned. Federal prosecutors say that 12 deaths and dozens of invasive surgeries were among the thousands of incidents the company covered up and failed to disclose to FDA.

The $92.4 million settlement is the largest ever paid by a defendant for failing to report malfunctions of a medical device to FDA and one of the first felony convictions for such conduct.

Federal law requires companies to report any incidents in which medical devices cause or contribute to a death or serious injury, or experience a malfunction that would be likely to cause or contribute to death or serious injury if the malfunction were to recur. Prosecutors say that in this instance the company clearly was aware of every malfunction because, as a condition of FDA approval for the device, a company sales representative was present in the operating room during each surgery and reports of the failures were repeatedly tabulated and distributed to company officials.

The Ancure Endograft system was approved for commercial distribution in the United States in September 1999, but was withdrawn temporarily from the market beginning on March 15, 2001. Although the company filed 172 medical device reports during that 19-month period, it has admitted that there were an additional 2628 MDRs that it failed to file. 

The problems involved the delivery system for the Ancure stent, which sometimes became stuck or lodged in a patient's body and could not be removed without opening the patient's stomach during surgery and opening the aorta to remove the device and then repair the aneurysm. Federal officials say the company sales representatives who witnessed the problems attempted to keep doctors from converting operations into more-invasive procedures, which would be reportable to FDA, by instructing them in a technique to free the delivery system when it became stuck in a patient's body. Devised in part by a sales representative, the method involved breaking the handle of the device and removing the catheters housed within the delivery system individually from the patient's body. 

A U.S. Department of Justice news release says that during this time the handle-breaking technique had not been tested, doctors had not been trained in its use, sales representatives who described the technique to doctors during surgery had not been trained by the company on its use, the instructions accompanying the product did not explain the procedure, and the company failed to seek prior approval from FDA for the technique. “After a patient died in a case in which the handle-breaking technique was used,” the prosecutors said in their release, “a group of defendant's employees concluded that FDA had to be informed about its use. The company failed to do so, even as its sales representatives continued to describe the handle-breaking technique to doctors during surgeries.”

Endovascular Technologies pleaded guilty to nine counts of introducing a misbranded medical device into interstate commerce and one count of making false statements to FDA. The charge of making false statements stemmed from an FDA inspection in July 2000. At that time, FDA officials specifically asked for all complaints the company had received about one particular type of malfunction. The company provided a list of 85 complaints, prosecutors say, while knowing there had been hundreds of complaints about the malfunction.

Under the civil settlement, $49 million of the total $92.4 million is to settle claims that the firm's actions caused Medicare, Medicaid, and the Veterans Affairs programs to pay millions of dollars for the adulterated and misbranded devices. Endovascular Technologies and Guidant have both agreed to enter into a corporate integrity agreement with the Department of Health and Human Services Inspector General and will cooperate with an ongoing investigation into criminal activities associated with the Ancure product.

Government officials say they first became aware of allegations of fraud and cover-up in October 2000 when a group of seven anonymous Endovascular Technologies employees wrote a letter to FDA. Later, an investigation authorized by the company concluded that some of the complaints by the anonymous letter writers were accurate and that the company was significantly out of compliance with its own internal policies and FDA regulations.

On March 23, 2001, Endovascular Technologies told FDA it had failed to file 2628 MDRs and had inappropriately provided information to doctors about the handle-breaking technique. The Ancure device was suspended from sales at that time, but FDA later permitted it to be sold with modifications in its warnings to customers and the instructions provided to physicians. 

In a statement on June 12, 2003, Guidant said the issues outlined in the plea agreement related only to the delivery system of the Ancure device prior to the company's voluntary recall, and do not relate to the Ancure graft once it has been implanted. “No patient with the implant is at risk as a result of this matter, and the implant continues to demonstrate excellent long-term clinical results,” the company said. “While the settlement agreement includes a civil payment, the company remains in discussions with the Office of Inspector General of the U.S. Department of Health and Human Services concerning the nature and scope of any potential agreement.” On June 16, 2003, Guidant announced its intention to discontinue the Ancure Endograft product line.

Assistant U.S. Attorney General Robert McCallum said, “FDA requirements regarding medical devices are not mere technicalities, but can literally be a matter of life and death for patients receiving these devices. As today's guilty plea and civil settlement demonstrate, the Department of Justice will vigorously prosecute those who seek to evade FDA's requirements, as well as those who seek to profit by claiming payment from federal healthcare programs for potentially unsafe medical devices.

FDA's New ‘Economic' Role 

FDA Commissioner Mark McClellan, an economist who is also a physician, is breaking the mold set by his predecessors by openly moving this science-based public-safety regulatory agency into an unaccustomed role as a leader in national economic policy. 

Whereas past commissioners often pointed out that FDA had no business weighing economic cost-benefit issues arising from its decisions—beyond its statutory obligation to state the economic impact of its rules—McClellan frequently asserts an FDA responsibility to help reduce healthcare costs to the nation.

This new economic leadership role was most recently displayed when McClellan addressed the 2003 annual meeting of the Medical Device Manufacturers Association (MDMA; Washington, DC), which represents mainly smaller medical device manufacturers. In his presentation, McClellan cited the rising cost of healthcare, and its affordability to consumers, as “the most significant health policy challenge” confronting the nation. “Now is the most exciting time to be involved in healthcare, which currently accounts for fully 20% of the consumer economy,” he said. 
While acknowledging spectacular advances in medical technology in recent years, and citing potential benefits to be derived from new devices and other healthcare products in the future, McClellan said that, nevertheless, “future progress can't be taken for granted.”

A principal reason for caution in viewing the future prospects for innovative healthcare products, McClellan continued, is the fact that the product development process now seems to be getting increasingly longer and more costly. 

According to McClellan, solutions to this dilemma may be found, in large measure, in a regulatory process that is up-to-date and which expedites the availability to consumers of new products that are proven to be safe and effective, and in a patent process that gives incentives to industry 
to make needed investments in research and development to bring new products to market. He pledged strong support by FDA for both of these “solutions.”

Apart from the substance of his remarks, perhaps the most notable aspect of the commissioner's address was the highly favorable way in which he and his message were received by the MDMA audience. At the conclusion of McClellan's address, the founding chairman of MDMA, Tommy Thompson (not to be confused with the current secretary of the Department of Health and Human Services with the same name) expressed a sentiment that has been widely felt by MDMA members.

Thompson congratulated the commissioner on his understanding of the needs of the smaller medical device manufacturers—as represented by MDMA—who had largely opposed legislation allowing FDA to collect user fees from manufacturers to expedite product reviews (now enacted as the Medical Device User Fee and Modernization Act [MDUFMA]).

MDUFMA had been supported by FDA and representatives of most of the larger manufacturing firms, over strong objections from the smaller companies. Thompson said it was his belief that the earlier “adversarial relationship between FDA and MDMA is now past,” and that the MDMA membership looks forward to a more mutually beneficial and cooperative relationship with the agency. 

Attorney Larry Pilot, partner in the Washington, DC, law firm McKenna, Long & Aldridge, representing a number of clients who are MDMA members, agreed there has been a relaxation of tension and positive change in relations between the association and FDA over time. “The commissioner said the right things—his remarks were positive, cordial, and sensitive to the industry's position,” Pilot said. “But what will prove more important, in the end, is how effectively a better understanding of the needs of industry by FDA management is transmitted to the operational levels within the agency—to reviewers and inspectors. This will be the true measure of change.”

FDA Cites Another Tyco Device Unit 

FDA has issued a stern warning to Tyco International (Mansfield, MA) after a January inspection of a Kendall Division facility found quality system regulation (QSR) deviations in its polyurethane umbilical vessel catheter manufacturing processes. In a recent warning letter, New York District director Jerome Woyshner said that future violations at any other Tyco Healthcare division or facility “may result in the initiation of regulatory action by FDA.” He reminded the company about violations that were cited last year at a Radionics plant in Burlington, MA. 

The Radionics inspection brought into question whether a recent FDA policy on not providing violative firms with multiple warnings had any teeth. The facility had been cited previously by FDA, but before Tyco had acquired it. The 2002 inspection's findings led FDA to demand that Tyco retain an outside consultant to perform an audit of the firm's entire manufacturing and quality assurance systems under the QSR. At the time, FDA told Tyco that no Class III devices that may have related deficiencies would be cleared or approved.

In the recent Kendall inspection, the firm was cited for failing to have an adequate design change procedure, according to the warning letter. The facility did not adhere to its current procedures for validating and verifying a design change on a catheter line extension, FDA charged.
In addition, FDA said the firm failed to adequately establish and maintain procedures for finished device acceptance to ensure that devices meet all acceptance criteria. For example, the letter cited seven lots of finished catheters that had not been subjected to poststerilization acceptance criteria prior to distribution.

The warning letter also noted that the Kendall Division recently recalled all lots of catheters that were the subject of complaints that the catheters' lumens did not accommodate a designated sensor that was promoted with the product.

Baxter Warned over Corrections 

Deviations cited during an inspection of Baxter Healthcare Corp.'s Puerto Rico facility last October were considered by FDA to be recurrent deficiencies from an August 2000 inspection of the firm, prompting the agency to issue a recent warning letter. During the 2002 inspection, FDA noted quality system deficiencies related to both nonconforming product and corrective and preventive action (CAPA).

“For example,” the agency wrote, “a CAPA file including an evaluation of the significance of a failure mode based on a risk assessment was not initiated after obtaining a nonconformance product event. An event describing leaks at the junction of the male luer adapter and the lever lock cannula was reported as part of the final in-process inspection of the Interlink System 60-in. Micro-Volume Extension Set Lever Lock Cannula for batch U534784R. Although a recurrence of a nonconformance was attributed to the use of a same defective component, a CAPA file was not initiated.”

FDA said it disagreed with a response from Baxter last December that its “existing system did not indicate a need to generate a high-level CAPA after PRR 2001-243-FG was issued.” Company records “show the nonconformance event to be a recurrent and significant event requiring that a CAPA be initiated,” asserted FDA. 

Additionally, FDA cited the firm for the following: failure to have complete procedures for implementing CAPAs, as required by 21 CFR 820.100; failure to document nonconforming product evaluations and investigations, as required by 21 CFR 820.90(a); and failure to establish and maintain CAPA procedures to assure that other quality data sources were analyzed to identify existing, as well as potential, causes of quality problems. In a warning letter two years ago, FDA cited Baxter for failing to establish and maintain CAPA procedures that include requirements to analyze quality data sources. 

Complaints Received by FDA Decline 

The number of complaints received by FDA's Center for Devices and Radiological Health (CDRH) decreased by almost 50% from 2001 to 2002, while the number of disputes increased by almost 25%, according to the ombudsman's annual report. Forty percent of 2002 complaints and disputes with the center were resolved. This was a slight increase from the previous year (39%). Twenty-seven percent were withdrawn or deemed withdrawn, representing more than a 50% increase from 2001 (13%). 

Of the complaints and disputes cited, CDRH's Office of Device Evaluation was involved in the most (65%), according to the annual report, followed by the Office of Compliance (26%), the Office of Surveillance and Biometrics (4%), the Office of Health and Industry Programs (4%), and the Office of Systems and Management (2%). 

Presumably, because 510(k)s are the submissions reviewed most often by CDRH, they were found to be the subject of the greatest number of complaints and disputes in 2002 (42%). PMA and investigational device exemption applications lagged far behind as subjects at only 11%. 
Most complaints and disputes involved data and testing requirements to support a premarket submission (26%); miscommunication or lack of communication (16%); the lack of a level playing field (claims of unequal treatment) (14%); agency policies and procedures (12%); lack of timeliness (which included timeliness of approval or clearance, in setting up meetings, or in returning phone calls) (9%); the Freedom of Information 
Act (7%); difficult or unhelpful employees (6%); combination (drug/device) products (2%); and claims of reviewer conflict of interest, bias, or retaliation (1%).
 

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