Originally Published MDDI April 2001

Washington Wrap-up

An FDA Veteran's Toughest Device Approval

James G. Dickinson

A 20-month, $6-million ordeal for TMJ Implants Inc. (Golden, CO) ended on February 27 as CDRH Office of Device Evaluation director Bernard Statland, MD, PhD, approved the last and most important of the company's two PMA applications—for the TMJ Fossa-Eminence prosthesis. Without his personal involvement in the review—including private discussions with several oral surgeons—the application would still be bogged down, observed TMJ Implants' attorney and former FDA staff member David Rosen, of McDermott, Will & Emery. Rosen and Mike Cole, of Bergeson & Campbell, helped propel the tortured review to its successful conclusion. The veteran Rosen ranks this FDA approval as the toughest he has experienced inside or outside the agency, including generic drugs and medical devices.

At one point, FDA reviewers allegedly predicted that the device would never be approved. The only device of its type ever marketed, the Fossa-Eminence prosthesis attracted significant reviewer skepticism.

Then, last month, the company's total joint, of which the Fossa-Eminence is a component, was approved. This seemed like a consolation prize because the total joint represented only a small part of the company's business. TMJ Implants CEO Robert Christensen recalls an FDA manager asking whether the company could be satisfied with just the total device while the agency continued to consider the partial. "I told them we could not survive on the total," Christensen explains, "but more importantly, I did not want patients to have the total as their only option."

The final product labeling of the Fossa-Eminence prosthesis now includes more indications than Christensen originally requested. It also effectively restores the device to all the marketed uses that were claimed before FDA's classification process removed it from commerce 20 months ago. The company had reduced the number of indications requested based on FDA and advisory panel suggestions. The final approval identifies the following indications:

Each of these indications had to be justified by a prospective clinical study that Christensen and oral surgeons using the device had provided, but that CDRH's Division of Dental, Infection Control, and General Hospital Devices had difficulty evaluating.

Statland states that he involved himself directly in the review process because it was "stuck." It helped that his wife once had a TMJ condition that did not require surgery. He learned as much as he could about "this very complex problem, which has many causes and many different treatments."

As Statland got deeper into the controversy, he discovered that the parties' positions had hardened due to communication breakdowns, which he was able to remedy. "There was venting on both sides," Statland says.

"The message," according to Statland, "is that those companies that are very conscientious in prospective studies and that have the data find that that speaks much louder than anything else. Anecdotal information is fine, opinions of various people and declarations are fine, but we have to look at the numbers. I think that's the take-home lesson."

Although he indicated to this reporter that the agency played a consultative role with TMJ Implants, Statland would not address Christensen's complaints that the early stages of the review were far from consultative. Says Statland, "I'm protechnology. I want good devices to be out there. Those things are going to help people. At the same time, I want full disclosure, so people can make good decisions."

Rosen acknowledged that after Statland began opening up the issues dividing the company from reviewers, there were holes in the company-provided data, such as patients lost to follow-up, that the reviewers apparently were unable to assess. After one roundtable discussion on February 9, Rosen and Cole worked through the weekend on the company's prospective clinical study data to extract a subset analysis of patients who had at least three years' experience with the Fossa-Eminence prosthesis. On February 13, Rosen presented this data subset to the reviewers and it answered their questions. That left only the labeling issue, which moved quickly to completion.

Christensen, who had enlisted legal, political, and media help in his frustration with the process, indicates that he is now "very pleased" with the result; however, he thinks FDA owes him for some of the excessive costs of restoring his two devices to the market. Although full marketing efforts have been resumed, he estimates that the company has $6 million to $8 million in losses to make up.

Improvements Cited in CDRH Annual Report

Modest processing-speed improvements of about 5% were achieved in the review of 510(k) and PMA submissions last year compared with 1999, according to CDRH's fiscal year 2000 annual report. CDRH also indicates that 4397 510(k) submissions were cleared in 77 days—4% faster than the 80 days it took in FY 1999. The average total elapsed time to clearance, including the time an application was on hold awaiting additional information, remained stable at 102 days.

Forty-three PMAs were approved in 2000, up from 39 the previous year, in an average total elapsed time of 11.9 months. The PMA review time was a 5% improvement from the 12.5 months it took in FY 1999. In addition, CDRH approved 474 PMA supplements—the most in any year since 1991. The average total elapsed time for approval of PMA supplements was 4 months, almost unchanged from the 3.9 months it took the previous year.

CDRH also indicated that it reviewed 320 original IDE submissions in FY 2000, "the second-highest number of reviews completed in any year since the IDE program began." In addition, 4335 IDE supplements were reviewed in FY 2000, more than in any prior year. The average review time for original IDE submissions was 28 days, compared with 27 days in FY 1999. The report added that 76% of original IDEs were approved for clinical trials in their first 30-day cycle, representing a larger percentage than in any other year.

Warning Letter Issued to Medtronic

FDA has charged the executive management of Medtronic Inc. (Minneapolis) with failing to find the underlying causes of GMP noncompliance and failing to provide sufficient resources for the firm's complaint-handling and quality assurance functions, leading to adulteration and misbranding of Midas Rex systems and power surgical devices made at the company's Fort Worth, TX, facility. The agency outlined its allegations in a warning letter sent to Medtronic CEO and chairperson William W. George.

The letter blamed unnamed executive management for not ensuring that established procedures were always followed (including the management review, quality system audit, training, design control, risk analysis, and corrective action procedures). The letter further claimed that employees were not properly trained, and that inadequate resources were allotted for complaint-handling activities, quality assurance functions, and assessment activities.

An FDA inspection revealed that Medtronic failed to submit at least 20 complaints under the agency's medical device reporting (MDR) requirements. For example, one complaint reported that a safety seal on the company's Midas Rex surgical instrumentation system broke and came out during a spinal-fusion procedure, and several other complaints concerning Midas Rex oil leakage during surgery were not submitted.

In the warning letter, the agency said it was troubled by the firm's responses to inspectional observations recorded on form FDA-483, which indicated that the 20 MDR reports were submitted after the inspection. "We would like to remind you that the 20 complaints identified were only a sample and that your firm should conduct a comprehensive review of all complaints for a decision on MDR reportable events and submit reports as required by CFR 803.50," FDA wrote.

The letter faulted Medtronic for failing to maintain adequate management and design results review documentation, review and update design plans, and establish and maintain procedures for approving design-input requirements. The company also failed to adequately validate the manufacturing process with a high degree of assurance, and establish and maintain corrective and preventive action procedures and processes for receiving, reviewing, and evaluating complaints, the agency charged.

In evaluating Medtronic's responses to the FDA-483, the agency indicated that more information was needed. "Your responses lack supporting documentation, and in some instances, do not address underlying issues that may have contributed to or resulted in the deficiencies," the warning letter stated.

The company had promised to review, maintain, correct, add, or delete standard operating procedures as necessary to establish relevance, and to submit an action plan by November 2, 2000. FDA said, however, that Medtronic's corrective action was inadequate because "you have not determined the possible root causes or why the [quality system] procedures were not always followed." The agency urged Medtronic to correct the violations promptly by developing and implementing procedures for production and process controls to keep such violations from recurring. Otherwise, the company would face regulatory action, FDA stated.

Medtronic spokesperson Bob Hanvick said at the end of January that company officials had met with FDA that month. "We went through every question that [FDA] had, answered all those questions, and then we submitted materials for their review on January 26," Hanvick said. He added that FDA was currently reviewing those materials, which he called "clarification information." As for operations at the Fort Worth facility, Hanvick said they were continuing.

$4.2 Million Complaint Filed

Worldwide Medical Corp. (Lake Forest, CA) stated in February that it would seek an administrative hearing in response to a $4.2 million civil money–penalty complaint filed against it by FDA. In its complaint, the agency seeks the penalty for Worldwide Medical's alleged marketing in 1999 and 2000 of an over-the-counter drugs-of-abuse test without agency approval.

The device, the First-Check home screening test, subsequently gained FDA clearance on June 23, 2000. An FDA notice of hearing published on February 6 gave the company 30 days in which to seek review by an administrative law judge. "Until we are formally provided with a copy of the FDA complaint, we cannot comment further; however, [Worldwide Medical] does intend to proceed with the internal process at FDA, and intends to address vigorously every concern expressed by that agency," says company president Daniel McGuire.

James G. Dickinson is a veteran reporter on regulatory affairs in the medical device industry.

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