Originally Published MDDI December 2003

WASHINGTON WRAP-UP

FDA Enforcement Deeds Don't Match Words

The current perception of an “aggressive” FDA is inconsistent with the agency's own annual analysis.

James G. Dickinson

What FDA Can and Can't Do with PMAs | Misys Recalls Defective Software | Identification Sought on Reprocessed Devices | ASR Makers Seek DNA Guidance Clarification | FDA Closer to Approving Silicone Implants 

As high-ranking regulatory attorneys met in September to discuss what they and many of their clients deemed a newly “aggressive” FDA, the agency itself issued its annual analysis of enforcement performance. Ironically, FDA's report confessed continuing decline.

The apparent dichotomy reflects, in part, the approaching election season, during which the administration will seek to portray itself—among its many national-security concerns—as strong on enforcing laws that protect healthcare products. Such posturing explains the current rash of bold proclamations about security arrangements for FDA-supervised distribution pipelines and new collaborations between domestic and foreign trade agencies at ports of entry.

However, when John Scharmann, a former FDA Denver District director, looked into FDA's Enforcement Story for fiscal year 2002 (the latest available), he found a significant across-the-board reduction in three out of four measures of enforcement performance during the latest three-year period. Only court injunctions had increased, from 11 to 15. Criminal prosecutions had declined from two to zero, warning letters from 1154 to 756, and seizures from 36 to 13.

On the other hand, these reductions occurred in tandem with a 42% increase in product recalls, from 3532 in fiscal year 1998 to 5025 in fiscal year 2002.

The perception of increased FDA aggression was expressed by attorneys during FDLI's recent annual Conference on Enforcement and Litigation. Most of the meeting focused on a handful of high-profile GMP cases in which FDA has pioneered profit-disgorgement penalties.

FDA deputy chief counsel for litigation Eric Blumberg staunchly defended the strategy of seeking court orders to force companies to surrender to the U.S. Treasury any profits gained from selling violative products.

He called it “a long-recognized equitable remedy developed to prevent unjust enrichment and to deprive a defendant of ill-gotten gains.” He said this legal remedy is intended as a “deterrent” to future violations and should not be viewed as a “penalty.”

Pointing to a 1999 consent decree with Abbott Laboratories that provided for disgorgement, and a record-breaking $500 million disgorgement in a consent decree obtained from Schering-Plough Corp. in 2002, Blumberg said such settlements are designed “not only to remove incentive to break the law, but to reduce any incentive to delay compliance.”

Although some have disputed FDA's authority to seek disgorgement (it is not specifically provided for in the Federal Food, Drug, and Cosmetic Act), Blumberg cited at least three U.S. Supreme Court cases that he said uphold the agency's position. Included among these was Porter v. Warren, a 1946 decision the agency views as definitive.

Michael Labson of the Washington law firm Covington & Burling objected to Blumberg's application of the term ill-gotten gains to GMPs. Labson argued that GMP violations are not those to which this remedy has traditionally been applied. He also took issue with FDA's practice of naming individuals in consent decrees, stating that this can unfairly jeopardize their future employment prospects.

Blumberg retorted, “Why would anyone want to hire an . . . executive that had been involved in a major violation anyway?”

By not addressing the declining number of FDA enforcement actions and instead focusing on the perceived severity of the few actions that do occur, the FDLI conference discussions illustrated the Bush administration's enforcement philosophy: Get the “biggest bang for the buck” in an environment in which FDA simply cannot afford to even try to catch every violation.

Indeed, it may be fairly observed that by focusing on the “biggest bang” philosophy of enforcement, FDA is tacitly admitting that in the absence of human injury, most of the smaller, day-to-day breaches of its myriad regulations don't matter in the real world.


What FDA Can and Can't Do with PMAs

FDA's Center for Devices and Radiological Health and Center for Biologics Evaluation and Research have issued a new guidance, FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Performance Assessment. The guidance lists criteria for the various actions FDA can take during and after a PMA review, and the effect of each on the review clock and performance criteria set forth in the Medical Device User Fee and Modernization Act of 2002 (MDUFMA).

The guidance states that MDUFMA performance goals contain both cycle and decision goals for original PMAs, original expedited PMAs, panel-track supplements, and 180-day PMA supplements. After reviewing an original or supplemental PMA and considering any applicable advisory-panel recommendations, FDA can issue a written letter indicating that the application is approved, approvable, not approvable, or denied.

FDA should issue an approval order once it feels reasonably assured that the device is safe and effective for its intended use as prescribed in the product labeling, the guidance explains. Issuance of an approval order is also contingent upon the agency determining that the device company's manufacturing facilities, methods, and controls are in compliance with the quality system regulation. 

The agency should issue an approvable letter (different from an approval order) when it has determined that minor deficiencies remain that must be addressed before an approval order can be issued. If the agency has not yet determined whether the applicant's manufacturing facilities, methods, and controls are in compliance with the quality system regulation, it should issue an approvable letter as well.

The guidance says that FDA should issue a major-deficiency letter once it has determined that a PMA lacks any of the following necessary data: detailed reanalysis of previously submitted data, additional test data to demonstrate safety and effectiveness of the device, scientific justification for test data in the submission, new validation data and analyses, and/or any other substantive deficiencies that prevent FDA from making a determination about a device's safety and effectiveness.

A not-approvable letter, according to the guidance, tells a PMA applicant that FDA has completed a scientific review of the PMA and does not believe that it can be approved because of significant deficiencies identified in the letter. Applicants who receive a not-approvable letter may amend their PMA to address the deficiencies, withdraw the PMA, or consider the letter to be a denial of approval and request administrative review.

The guidance indicates that for original and panel-track supplements, a not-approvable letter is issued after FDA has conducted a complete review of the PMA application, including any recommendations by an FDA advisory panel, if applicable, and determined that the available data in the PMA do not support a determination of reasonable assurance of safety and effectiveness. Generally, according to the guidance, FDA has provided the applicant with an opportunity to address its concerns in a major-deficiency letter before the agency issues a not-approvable letter.

For 180-day supplements, a not-approvable letter is issued when an application lacks substantial information needed for FDA to complete its scientific review and render a final decision on the supplement, or after FDA has conducted a complete review of the supplement and determined that the available data do not support determination of a reasonable assurance of safety and effectiveness.

The guidance defines a denial order as a letter telling a PMA applicant that the agency has completed its scientific review of a PMA and, based on the review, has decided not to approve the PMA. Like a not-approvable letter, a denial order includes all deficiencies that must be adequately addressed by an applicant to bring the PMA into approvable form.

FDA may issue a denial order if (1) after reviewing an amendment submitted by an applicant in response to a not-approvable letter, the agency determines that a PMA still does not support a determination of reasonable assurance of safety and effectiveness; (2) FDA has received a written response from an applicant to a not-approvable letter stating that the applicant has decided not to submit an amendment; or (3) an applicant decides to regard a not-approvable letter as a denial and petitions for review.

An abandonment letter tells an applicant that FDA considers its PMA abandoned. FDA can issue it when it deems the PMA voluntarily withdrawn because an applicant failed to respond to a request for additional information contained in a major-deficiency or not-approvable letter. The agency can also issue an abandonment letter when other circumstances indicate that the applicant is not undertaking additional measures regarding the PMA, and when an applicant fails to communicate with FDA within seven days of the date on which the agency notifies the applicant that the PMA appears to have been abandoned.

To view the guidance, visit www.fda.gov/OHRMS/DOCKETS/98fr/03d-0434-gdl0001.pdf.  


Misys Recalls Defective Software

FDA said in October that Misys Healthcare Systems (Raleigh, NC) had recently recalled three versions of its laboratory software because of a defect that could lead to inaccurate results. The software compiles information from blood and urine tests and performs a quality assurance check to determine whether all procedures have been carried out properly. Misys said a software patch is available from the company to fix the glitch. No injuries have been reported as a result of the problem, FDA said.

To view FDA's notice, visit www.fda.gov/bbs/topics/NEWS/2003/NEW00956.html.  


Identification Sought on Reprocessed Devices

In comments submitted to an open docket, the Association of Medical Device Reprocessors (AMDR) told FDA that the agency should require identification of the OEM or the reprocessor on all devices as mandated by the Medical Device User Fee and Modernization Act of 2002. 

When the legislation was being drafted, OEMs sought a provision requiring identification of the reprocessor on reprocessed devices. However, AMDR argues that the provision was written to apply to all devices, reprocessed or otherwise. AdvaMed and the Medical Device Manufacturers Association have each argued that AMDR's interpretation of the provision places a significant burden on their members with no apparent benefit. But to require that the provision apply only to reprocessors would be “arbitrary and capricious,” according to AMDR.

To view their comments, visit www.fda.gov/ohrms/dockets/dailys/03/oct03/100203/02N-0534-emc-000007-01.pdf.  


ASR Makers Seek DNA Guidance Clarification

FDA needs to clarify that its draft guidance titled Multiplex Tests for Heritable DNA Markers, Mutations, and Expression Patterns does not apply to clinical assays that incorporate multiple analyte-specific reagents (ASRs), according to the American Clinical Laboratory Association (ACLA). In recent comments to the agency, ACLA argued that the guidance should apply only to “devices that incorporate multiplex technology and are complete ‘test systems.'” 

ASRs currently are exempt from premarket approval, but the group is concerned that the guidance may reverse the exemption. It asks FDA to clarify the boundaries of the draft guidance by stating in the final version that it is “not intended to revise the ASR rule and does not mandate FDA approval of multiplexed reagents where each of the multiplexed reagents otherwise meets the definition of a Class I ASR.”

To view these comments, visit www.fda.gov/ohrms/dockets/dailys/03/Aug03/082903/03d-0120-emc0005-01-vol2.pdf.  


FDA Closer to Approving Silicone Implants

Renewed FDA approval of silicone breast implants moved a step closer in October. A highly publicized meeting of the agency's General and Plastic Surgery Devices Panel resulted in a vote of 9 to 6 to recommend approval of a silicone-gel implant PMA from Inamed Corp. (Santa Barbara, CA). 
Marketing of such devices stopped in 1992 because of complaints that toxic silicone migrations from ruptured implants made the devices unreasonably unsafe.

FDA's panel now says that marketing could resume with strict conditions. They suggested requiring that women receiving the implants be fully informed about possible complications and be advised to have regular checkups following the surgery.

The panel heard testimony that major studies have found no evidence that implants caused chronic diseases, despite the fact that many women are convinced that they were sickened by silicone leaking from their implants.

Panel member Michael Miller said, “A large amount of latitude needs to be given to people to weigh the benefits and risks. The risks are well-defined and small. The patient can decide.”

After the vote, Inamed CEO Nicholas Teti told the media that the panel's suggestions were “fair” and seemed to reflect proposals advanced by the company. He said Inamed is committed to long-term research after approval, as well as to educating women about possible risks. The panel urged Inamed to follow some of its research subjects for at least 10 years. 

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