WASHINGTON WRAP-UP

Golden, CO–based TMJ Implants Inc. (TMJI) claimed a small victory over FDA in February. FDA posted to its Web site TMJI's response to an “adulterated, misbranded” warning letter it received in December.

The victory was small, because it was deemed too little and too late. TMJI had asked CDRH Office of Compliance director Timothy Ulatowski to post its response beside the warning letter (which was being used in the marketplace against his company). Five weeks later, the response was posted without 10 pictorial attachments that president Robert Christensen felt were essential to the response.

Leaving aside for a moment the issue of the five-week delay, why were the pictures left off? They showed TMJI's devices in surgery and addressed the key issue in the warning letter. CDRH felt that pictures and statements on TMJI's Web site covered an unapproved indication. Christensen's response explained why TMJI felt the depicted use was within the approved indication, even though he had changed the site after learning of CDRH's objections.

Perhaps, unlike most firms dealing with an FDA enforcement action, Christensen wanted his response posted to mitigate trade damage. The longer his side of the dispute was not publicly available, the more damage he felt TMJI might suffer.

FDA Division of Freedom of Information (DFOI) acting director Fred Sadler spoke to me about the pictures. He said that Ulatowski's office didn't send them when it sent TMJI's written response to be posted. In any case, Sadler suggested, even if his office had received them, there probably would have been a few technical problems.

First, his office would have had to research possible file size limitations (the pictures totaled 655 Kbyte). Second, the pictures were in JPG format. FDA's warning letters Web site has been set up to handle only Microsoft Word and WordPerfect, HTML, and PDF files.

Theola Myo Khin, a DFOI specialist, corresponded with me about the division's policies. She wrote, “It is DFOI practice to post responses to warning letters promptly upon receipt, usually within five business days.” This response suggests to me that Ulatowski's office sat on Christensen's request for four weeks and then withheld the picture files.

The message to take home seems to be that, at best, it was all just an innocent oversight. At worst, it's that it doesn't pay to fight with that office.

Over at DFOI, Sadler pointed out that the entire program of posting responses to warning letters is still relatively new. Plus, requests for responses to be posted are unusual. Less than 5% of the warning letters on FDA's site have accompanying response letters from the subject companies. As reported last month, a random sampling I made suggested that less than 2% showed company responses.

One possible reason for the low numbers is that FDA warning letters do not offer companies the option of posting responses. They won't respond if they don't know they can. In addition, there are criteria that FDA says should be followed in getting a response posted. These include the need to assertively request posting. There is also a provision that the response must be in an acceptable format. In addition, there must not be anything in the response that FDA feels could mislead the public.

Another possible reason for the low numbers may be that in the vast majority of cases, FDA's warning letters are uncontested. Those firms therefore have no reason to want to see their responses exposed on FDA's site. However, this explanation may be premature. It won't be clear until companies are routinely informed of their right to have their responses posted alongside their warning letters.

Meanwhile, Christensen is insisting that FDA add five pictorial attachments to his posted response. He wrote FDA commissioner Andrew von Eschenbach to this effect on February 16. In the letter, he said that the omitted pictures “explain vividly how deficient temporomandibular joints are replaced in such patients who are developmentally deficient, i.e., Goldenhar Syndrome patients.”

Ex-employee Faults Medtronic Despite FDA Approval

FDA says it conducted a thorough investigation of complaints it received about Medtronic's recently approved Concerto implantable cardioverter-defibrillator. Nevertheless, the ex-employee who made the complaints now says FDA dropped the ball during its investigation.

Former Medtronic employee Chris Fuller spoke to me in February. He said the FDA technical inspector, Thomas Lee, refused to talk with him about the issues with Concerto. The exception, Fuller claimed, was one telephone conversation at the beginning of the investigation, in which Lee said, “Medical implants do not need to be tested as much as cell phones.”

“Mr. Lee's refusal to communicate with me prevented FDA [from] learning that Medtronic submitted false test results on radio-frequency (RF) stability for the Concerto implant,” said Fuller. “There are other Medtronic engineers who are equally concerned about Medtronic's testing of Concerto. One of those engineers agreed to talk with FDA. When I provided the Medtronic engineer's name and contact information to FDA, that engineer was fired within 48 hours. FDA never made an attempt to communicate with the engineer.”

Next, Fuller says he approached then–U.S. senator Mark Dayton (D–MN). Dayton contacted the HHS Office of Inspector General, which initiated an investigation that is still ongoing.

“FDA did not perform a thorough investigation and intentionally refused to hear evidence I have regarding the safety issues of Concerto,” Fuller continued. “Medtronic claims I am a disgruntled employee. That is untrue. I worked for years helping Medtronic understand the issues with RF design as part of my job.” When Fuller felt it necessary to resign in protest in December 2005, he tried for a year to help Medtronic quietly resolve the problems. That stopped when he learned that Concerto patients were starting to sustain injuries that could potentially be caused by RF instabilities.

At issue, according to Fuller, is Medtronic's failure to thoroughly investigate instabilities that occurred during testing. “I have not said the device is unsafe,” he said. Rather, his concern is that the device was tested far less than he believes consumer products, like a cell phone system, would be tested. “The device has not been tested enough to know whether it is safe,” he asserted.

Before Fuller's statements to me, FDA said it had investigated his complaints and was satisfied the device is safe for use. “FDA took the allegations made by the former Medtronic employee very seriously,” an agency spokeswoman said.

“The agency has completed a thorough investigation of the charges,” she continued. This investigation included a scientific review of the allegations and an inspection of the manufacturing facility. It also comprised a review of the data previously evaluated in support of the marketing application as well as a review of available adverse-event data. “All of this information was analyzed with respect to whether the allegations identified a safety concern for patients that substantively altered the risk-benefit profile for this device. To date, FDA has found nothing that would have influenced its decision to approve this device.”

FDA Agrees with Panel on Drug-Eluting Stents

FDA said in February that it agrees with recommendations it received last December from its Circulatory System Devices Advisory Panel. The panel suggested that large studies of drug-eluting stents are needed to accurately assess the risk of adverse events such as stent thrombosis.

The March 8 New England Journal of Medicine contained an article on the subject. It was written by Ashley Boam and Andrew Farb. They said the agency concurs with the panel's recommendation that larger and longer studies be conducted. Such studies would focus on important safety end points such as death and myocardial infarction, as well as on the appropriate duration of dual antiplatelet therapy. Boam is CDRH Office of Device Evaluation Interventional Cardiology Devices Branch chief, and Farb is a medical officer.

FDA also believes that randomized, controlled trials are needed to determine the best treatment strategies for lesions in certain patients. Such patients have common yet complex conditions, such as multivessel coronary disease, diabetes, and acute myocardial infarction.

Given the benefits and risks, the two wrote, physicians should consider certain patient characteristics in deciding whether to use a drug-eluting or a bare-metal stent. For example, patients who cannot comply with extended clopidogrel use may not be candidates for a drug-eluting stent. Also, those that have planned procedures requiring early discontinuation of antiplatelet therapy may be inappropriate.

Boam and Farb said that patients must be educated about the need for adherence to the recommended course of antiplatelet therapy. They should discuss any changes with their cardiologist. And healthcare providers considering stopping antiplatelet therapy to perform invasive procedures should consult with their patient's cardiologist.

The panel meeting focused on safety issues and the use of dual antiplatelet therapy. Discussions covered both on- and off-label use of drug-eluting stents. It is estimated that more than 60% of use is off-label, such as stents implanted in types of lesions that were excluded from the pivotal trials. Other off-label use involves patients who were not amply represented in the trials for a specific labeled indication, such as those with diabetes.

The panel and FDA agreed that when the stents are used for their approved indications, the risk does not outweigh the advantages in reducing repeated vascularization. But Boam and Farb said the panel also concluded that, compared with on-label use, off-label use increases the risks of both early and late stent thrombosis, as well as myocardial infarction or death.

The authors said that the absolute risk appears to be less than 2% throughout the first three years after on-label stent implantation. However, they continued, “Thrombosis with drug-eluting stents is a clinically important problem that may occur long after implantation. It is uncertain whether cases of late stent thrombosis will continue to accrue with longer-term follow-up.” The risk of thrombosis increases when drug-eluting stents are used in complex lesions and in patients with coexisting conditions, they said. But the magnitude of this risk compared with that posed by alternative treatments is unknown. “Early discontinuation of antiplatelet therapy is associated with an increased risk of thrombosis, but the optimal duration of clopidogrel treatment remains undefined,” the authors said.

FDA Enters Into Two Consent Decrees with Device OEMs

FDA and two device manufacturers entered into federal court consent decrees in February.

In one of them, Cardinal Health will have 90 days to recondition 1300 Alaris Signature Edition Gold drug infusion pumps. If the devices are not reconditioned, they will need to be destroyed. This decree also calls for a “qualified expert” to be retained by the firm. The expert will inspect the firm's drug infusion manufacturing operation to bring it into compliance with FDA regulations.

Once the facility has reached compliance, an auditor must annually inspect the facility for the next four years (twice in the first year). If any audit reports contain GMP deviations, FDA has the discretion to extend the audit cycle up to an additional four years. The pumps were seized on FDA's orders last year because of a design defect called key bounce that may cause drug overinfusion.

The other decree concerns Custom Ultrasonics and its president, Frank Weber. In it, the firm agreed to stop manufacturing and distributing its System 83 Plus washer and disinfector and System 83 Plus Mini-flex washer and disinfector until it complies with CGMP requirements. The devices are used to clean and disinfect endoscopes. The company also agreed to develop and implement adequate written medical device reporting procedures. An FDA news release said the company's actions posed a potential public health hazard.

Endoscopes that are not properly cleaned and disinfected can be a source of transmission of pathogens between patients, causing life-threatening infections. However, FDA said it is not aware of any adverse events that have occurred.

GHTF Study Groups Release Device Reports

FDA has released proposed and final documents prepared by three study groups of the Global Harmonization Task Force and will receive comments on them through May 7. Accessible at www.fda.gov/OHRMS/DOCKETS, the documents represent a harmonized proposal and recommendation from the study groups. Governments that are developing and updating medical device regulatory requirements may find the documents useful.

The documents were developed by Study Groups 1, 2, and 4. Study Group 1 was to identify differences between various regulatory systems. It would then propose areas of potential harmonization for premarket device regulations and possible guidance to help lead to harmonization. The group has developed a proposed document, the Role of Standards in the Assessment of Medical Devices, which provides guidance to manufacturers designing a medical device. It also offers guidance when firms are demonstrating that the device conforms to relevant essential safety and performance criteria.

Study Group 2 was charged with developing guidance documents to be used for exchanging adverse-event reports. Its document is called Medical Devices Post Market Surveillance: Global Guidance for Adverse Event Reporting for Medical Devices. It provides guidance on the types of adverse events that should be reported by a manufacturer to a national competent authority.

Study Group 4 looked at developing guidance documents on quality system auditing practices. The document that it developed is called Guidelines for Regulatory Auditing of Quality Management Systems of Medical Device Manufacturers—Part 3: Regulatory Audit Reports. It suggests a structure for audit reports used in multiple jurisdictions, promoting consistency and uniformity.

WLF Aids Abtox Convicts' Appeal

The Washington Legal Foundation (WLF) has filed a brief urging the U.S. Court of Appeals to overturn the criminal convictions of two Abtox Medical executives. The executives were convicted of having promoted an FDA-approved medical device for an off-label use.

WLF's brief argues that the First Amendment “broadly protects the right of individuals to speak truthfully about off-label uses of FDA-approved products, even in a commercial context,” WLF chief counsel Richard Samp said in a release. By prosecuting those engaged in truthful speech about off-label uses, he continued, the government is hindering healthcare delivery in this country.

Abtox principal Ross Caputo and vice president of regulatory affairs Robert Riley were convicted last year. They were found guilty of marketing faulty sterilization equipment to hospitals that left 18 people blind in one eye. Caputo and Riley had also been indicted on mail and wire fraud charges that arose from them selling hospitals FDA-unapproved sterilizers that deposited toxic copper and zinc salts on devices.

A district court denied the defendants' motion to dismiss the indictment on First Amendment grounds. According to WLF, the judge conceded that the defendants' statements regarding off-label uses were not misleading. Nevertheless, the judge held that prosecuting them for making those statements was constitutionally permissible. “It directly advanced the government's interest in encouraging manufacturers to seek FDA approval for known off-label uses,” WLF said.

WLF's brief also argued that the government's policy on off-label promotion is full of contradictions and exceptions. It cannot be said to materially advance any government interest, said Samp. The brief also argued that disclaimers could be used to notify recipients about off-label discussions in lieu of government-controlled speech restrictions.

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