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INTO THE INTERNET
Originally Published June 2000

FDAMA provision relaxes and clarifies manufacturers' device tracking obligations.

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FDA medical device tracking requirements are becoming easier, under the auspices of the FDA Modernization Act of 1997 (FDAMA), which relaxed and clarified contentious provisions of the Safe Medical Devices Act of 1990.

In certain circumstances specified in the earlier act, FDA required all device manufacturers to track their own products. FDAMA changed that rule, requiring manufacturers of Class II or Class III devices to track products only when ordered to do so by the agency.

In April, FDA formally proposed to implement this provision of FDAMA, saying it will issue such an order after making a determination on the device in question. The device would be examined to determine if its failure "would be reasonably likely to have serious adverse health consequences, or if the device is one which is intended to be implanted in the human body for more than a year, or is one which is life-sustaining or life-supporting and used outside a device user facility, and is one which warrants tracking."

This effectively relieves manufacturers of the obligation to study FDA regulations to determine if their device needs tracking. FDA proposes to delete all trackable device lists and tables from its regulations.

The lists and tables were useful, however, to interested parties other than manufacturers, such as various categories of device distributors who have tracking obligations. In the proposal, FDA states that it believes it is "more expeditious and effective to keep such interested parties apprised of revisions to device types subject to tracking orders through the use of guidance or periodic Federal Register notices than it is to undergo the process of changing a list in a regulation. Tracking guidance or notices will be made available to interested parties through the agency's Internet and Facts-on-Demand Web sites."

For purposes of the tracking requirement, FDA proposes to change the definition of a permanently implantable device to exclude devices that are intended to be explanted within one year. FDA said it continues to believe, however, that implanted devices that remain permanently in the body, but that have functions that may be replaced by natural or other processes after a given period of time, should not be tracked.

FDA acknowledges in the proposal that the cost to industry of maintaining device tracking systems will rise from about $40 million in 1999 to $71 million in 2006. An FDA analysis estimates that FDAMA-related changes will add about $1 million in new annualized costs to track the additional devices for which FDA orders were sent in December 1998 and September 1999. The same FDA analysis, however, claims industry would save about $19.2 million per year by eliminating tracking for a number of device types, and by limiting its scope for other devices to those used outside device-user facilities.

Mentor: "Criminal" Probe or Not?

Was Mentor Corp. the target of an FDA criminal investigation concerning its clinical studies on breast implants, or not? And if it was, were its vigorous public denials a ploy to defraud stockholders?

These extraordinary questions surfaced in April when House Commerce Committee chairman Thomas Bliley (R—VA) referred the matter to the Securities and Exchange Commission (SEC) on the basis of USA Today reports and cautiously worded correspondence from FDA.

The existence of the FDA investigation was confirmed in committee documents obtained by the on-line Internet news service FDA Webview (http://www.fdaweb.com). The documents said the investigation was "based on allegations of serious irregularities in breast implant studies." Despite this, however, Mentor continued to insist that FDA's investigation was not about implant studies, but rather "manufacturing issues" involved in the making of silicone breast implants.

Bliley told the SEC that this warranted its attention because "Mentor's public statement affected the trading of its stock, and material information in Mentor's public statement is in conflict with information provided by FDA." After USA Today published a report on the investigation on March 23, 2000, Mentor's stock plummeted. Trading was temporarily halted until the company's release, which denied the criminal investigation into irregularities in implant studies and characterized FDA's probe as "stemming from 1998 manufacturing issues." After the statement, the company's stock rebounded.

The company "unequivocally" stands by its original statement denying any knowledge of a criminal investigation into breast implant studies, Mentor general counsel Douglas Altschuler told FDA Webview. In fact, he said, the lead investigator from the FDA Office of Criminal Investigations (OCI) recently sent Mentor a letter asking for additional documentation related to its investigation of "manufacturing issues" surrounding silicone gel implants.

Bliley's referral to the SEC for investigation came after Melinda Plaisier, FDA associate commissioner for legislative affairs, confirmed that the agency stood by its memo indicating that an open criminal investigation of Mentor existed. In this FDA memo, dated March 9, 2000, the agency said the following: "We have an open investigation on Mentor Corporation at this time. Mentor is a breast implant manufacturer of saline and silicone breast implants with headquarters in Santa Barbara, CA, and a manufacturing plant in Irving, TX. The investigation is based on allegations of serious irregularities in breast implant studies. Consistent with FDA and OCI policy concerning ongoing criminal investigations we have no further comment at this time."

The USA Today article that caused the stock slump was partially based on a March 17, 2000, letter Bliley had written to FDA commissioner Jane Henney. In the letter, Bliley asked how a company under an FDA criminal probe could go before an FDA advisory committee (as Mentor had done on March 1) and present data regarding the safety and effectiveness of one of its products. While Bliley's letter did not name Mentor as the company being investigated, USA Today cited the March 9 memo from the OCI, which confirmed that an investigation was being conducted into alleged research irregularities at Mentor. The March 1 advisory committee was evaluating a Mentor premarket approval application for a saline-filled breast implant, which the panel recommended for approval.

Although not related to breast implants, Mentor's manufacturing of intraocular lenses was the subject of a five-page FDA warning letter in February 1997. In that letter, FDA said its investigators found significant GMP deficiencies at the company's Puerto Rico facility. "Since 1998 Mentor has substantially upgraded every aspect of its manufacturing facilities and overall compliance programs," Mentor stated in its March 23 statement. "Since that time, we have had two independent expert audits and one comprehensive FDA audit which have confirmed that the company is in substantial compliance with good manufacturing practices."

FDA frequently takes a multiple-site approach to serious manufacturing quality problems it finds in inspections, on the theory that the highest corporate management is responsible for the "culture of compliance." The assumption is that what is found in one facility is likely to be found in another, even if that facility is on the other side of the country or the world, and sometimes even if it is operated by a different entity within the corporate family. It is not as common, however, for FDA to take this global approach to clinical study irregularities.

Medtronic in FDA Cyber Trouble

Companies serving multinational markets but using a single Web site were watching in March when FDA lowered the boom on Medtronic (Minneapolis). The firm had posted product information that was acceptable to foreign regulators, but not to FDA. As a result, Medtronic removed all information about the company's Activa tremor control system from its Web site (http://www.medtronic.com).

According to a Medtronic spokeswoman, a March 23, 2000, FDA warning letter cast doubt on the company's presentation of information about products that are approved internationally and in the United States, but for differing indications. She said the company is discussing with FDA ways it can combine all product information on one site—information both about uses for all FDA-approved devices, as well as device uses approved in other countries.

At issue in FDA's warning letter was Medtronic's inclusion of the internationally approved uses in its presentation of information about Activa, the spokeswoman said. The device is indicated in the United States for "unilateral thalamic stimulation for the suppression of tremor in the upper extremity," Medtronic states. It is intended for "patients who are diagnosed with essential tremor not adequately controlled by medications and where the tremor constitutes a significant functional disability."

The Web site is not just for FDA-approved information, the spokeswoman said—it is designed for international use. She wasn't sure whether more disclosure would be necessary to comply with FDA regulations, or if Medtronic would have to launch a different Web site altogether, as some international pharmaceutical companies have done. Often these companies will direct visitors to different areas within a Web site, depending on the citizenship of the information seeker. For example, when providing product information, some drug companies have used buttons that say "click here if you are a U.S. citizen." "This is what we need to hear more about from FDA," the spokeswoman said. In the interim, the company has agreed to remove the offending material from its Web site until the matter is resolved.

FDA Guidances for Special Controls

FDA published six guidances on April 16, 2000, to serve as special controls for devices it had previously nominated for reclassification. On March 15, 1999, the agency proposed that the following devices be reclassified from Class III to Class II: pacemaker lead adapters, vascular graft prostheses less than 6 mm in diameter, annuloplasty rings, cardiopulmonary bypass defoamers, cardiopulmonary bypass arterial line blood filters, and cardiopulmonary bypass oxygenators. FDA has reopened the comment period on the proposed reclassifications until July 18, 2000, so that comments can include the guidance provisions. The guidances are available on CDRH's Web site at http://www.fda.gov/cdrh, or by contacting Joseph M. Sheehan, at the Center for Devices and Radiological Health (HFZ-215), FDA, 1350 Piccard Dr., Rockville, MD 20850; 301/827-2974.

A Recall's Ripple Effects

By April, seven secondary medical device companies had been publicly swept into a nationwide sterile-products recall initiated last year by Clinipad Corp. (Rocky Hill, CT). FDA named the companies in its weekly Enforcement Report.

The listing came as a follow-up to the agency's earlier announcement that Clinipad had notified its customers by certified mail that it was recalling all povidone iodine, tincture of iodine, benzoin tincture, acetone alcohol, and alcohol antiseptic products (swab sticks, prep pads, towelettes, and pouches), as well as all Cliniguard protective dressings that were manufactured over the past three years and were labeled as "sterile."

Clinipad said it had confirmed microbial contamination in some lots of its sterile products, including one lot— recalled in December 1999—with Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and coagulase negative Staphylococcus. "The potential for microbial contamination exists and we are unable to assure the sterility of products labeled and sold as sterile," Clinipad said. It added that it was also recalling certain lots of its nonsterile products because it could not assure that they meet their microbial release specifications.

FDA's list of secondary companies affected by the recall includes the following firms, which are also conducting product recalls: Cramer Products (Gardner, KS), 12,228 first aid kits; Sterling Medical Products International (Prophetstown, IL), 2280 sterile procedure kits/trays; Medline Industries (Mundelein, IL), 230,000 sterile procedure kits/trays; Premium Plastics (Chicago), 5280 sterile catheter irrigation trays and wound dressing trays; Molded Products (Harlan, IA), 51,650 on/off dialysis kits; Applied Medical Technology (Cleveland), 1982 medical PEG kits; and Acme United Corp. (Fremont, NC), 22 configurations of first aid kits containing more than 2.2 million products.

Abbott Troubles Drag On

During the month of April this year, FDA contemplated imposing a penalty of $15,000 a day on Abbott Laboratories. The penalty was in response to Abbott's failure to meet its March 1, 2000, deadline for compliance in correcting good manufacturing practices problems at its diagnostics operations in Lake County, IL. Abbott signed a federal court consent decree with the agency last November agreeing to the deadline.

Agency sources said the fine could be levied for Abbott's failure to bring its corrective and preventive action (CAPA) system into compliance with FDA's quality system regulation within 120 days after the consent decree was entered.

FDA inspected the firm after Abbott's expert consultants, Quintiles Inc., provided the agency with an audit report certifying that the firm was meeting the decree's CAPA conditions. FDA's inspection, however, documented continued deficiencies with the firm's CAPA system, a high official said. Abbott has responded to the inspection's FDA-483, and the fine has been put on hold until FDA completes its evaluation of the response and makes an official ruling.

The problem, according to another agency official, is that the CAPA system is very subjective, making it difficult to draw a fine line between compliance and noncompliance.

Abbott, reportedly dissatisfied with the FDA Chicago District's tough enforcement posture in the matter, requested a meeting with FDA senior associate commissioner Linda A. Suydam, which took place on April 14. Suydam was apparently unimpressed with Abbott's presentation. The fine, if levied, could continue until Abbott brings its CAPA system into compliance. But under the terms of the consent decree, the fine cannot exceed $10 million. The company did not respond to a request for comment.

Physio-Control Cited for Report Violation

FDA in March cited Medtronic Physio-Control (Redmond, WA) for a report violation involving its LifePak automated external defibrillator. Allegedly, the firm did not comply with requirements for a 10-day notification to FDA of a product correction or removal. A warning letter to the company said the product was first recalled in June 1998 because of the failure of a resistor that was damaged by an adjacent assembly. FDA said the product was misbranded because of the failure to make a required report.

In addition, the agency said, an FDA inspection lasting from October 21, 1999, to February 11, 2000, indicated that the device was adulterated because of quality system regulation violations. The agency said the corrective and preventive action taken for the resistor failure was ineffective: field failures of the resistor continued despite the June 1998 corrective action. Failures occurred in units that had not been checked, FDA said, and also in units that had been serviced. FDA added that regulatory action could be taken, including seizing product inventory, obtaining a court injunction against further marketing of the product, or assessing civil money penalties.

FDA's April 12, 2000, Enforcement Report said the company had recalled 8031 automated external defibrillators. Designed to be used by first responders to cardiac emergencies, the defibrillators were recalled because potential damage or failure of a resistor could fatally disable the device for its next use. The ongoing Class II recall was initiated by tech memos in June 1998 and February 2000, as well as the FDA warning letter issued in March of this year.

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

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