Originally Published MDDI September 2001
Proposed rule viewed by some as committing "too much to trust."
James G. Dickinson
Should FDA Device Reviewers Join Preapproval Inspections? | Seeking Vindication at FDA | Feigal Challenged on "Unfair" Enforcement | FDA Office for Combination Products? | Pre-IDE Meetings No Easy Fix
FDA should abandon its proposed 510(k) rescission rule because the agency already has specific enforcement tools to remedy problems with "bad devices," Washington attorney Mark Heller, of Hale and Dorr, told an AdvaMed submissions workshop in June. The rule would provide FDA with the authority to rescind a 510(k) if it finds that the marketing clearance was granted in error because of one of the following circumstances:
- The premarket notification did not prove that the device had the same intended use as the predicate device or the same technological characteristics.
- Based on new safety or effectiveness information, the device is not substantially equivalent to a legally marketed device.
- Predicate devices have been removed from the market for safety and effectiveness reasons, or a court has found them misbranded or adulterated.
- The premarket notification contained or was accompanied by an untrue statement of material fact.
- FDA finds that the rights or safety of human subjects in clinical trials supporting the device were not adequately protected.
- Clinical data in the premarket notification came from a disqualified investigator.
Heller told workshop attendees that a rescission would effectively reclassify the rescinded device and all other devices that claim it as a predicate as Class III devices. He said FDA could seek a rescission at any time during the marketing period of a device. Heller also warned that the rule would allow the agency to re-review 510(k) decisions and to change policies that were applied at an earlier time in order to pull products from the market.
CDRH premarket notification chief Heather Rosecrans assured the audience, however, that FDA will not embark on a witch hunt to re-review the more than 100,000 510(k) decisions that have been made. Fewer than 100 510(k)s have ever been rescinded, with 25% of these initiated by manufacturers and the remainder mostly related to fraud or public-health-related issues, she said.
More-appropriate enforcement powers already exist, Heller said, such as mandatory recall, prosecution and seizure. "This rule commits too much to trust, but that is not the way government is supposed to work," he argued.
Bernard E. Statland, CDRH Office of Device Evaluation director, thinks it would be a good idea if medical device reviewers were to join field investigators on preapproval site inspections. "Certain elements about the manufacture of a device might be very important in evaluation of the technology," says Statland. "There's nothing like actually seeing something, rather than just reading about it."
The concept, which is already in practice in Center for Drug Evaluation and Research, fits well with CDRH's growing emphasis on monitoring the total life cycle of approved products, Statland says. He also believes joint inspections would improve morale in CDRH review divisions and among field investigators, and could help break down barriers between reviewers and compliance officials.
In theory, it could cost more to conduct such joint inspections because of added travel and accommodation expenses, and because inspections conducted by novice reviewers could take longer. Statland says, however, that joint inspections could just as likely be shorter, with reviewers helping to "focus" investigators and resolving questions on the spot.
Will joint inspections come about? That's CDRH director David Feigal's decision, Statland says. He adds, "I'll support it. I'm sure the invitation is always there, but our reviewers are very busy."
Joint inspections might have helped avoid the alleged reviewer bias that is the subject of an ongoing protest by TMJ Implants Inc. (Golden, CO). Although the company's two jaw-joint prostheses were finally restored to the market in February 2001, TMJ Implants CEO Robert W. Christensen began a congressional-level campaign in July to punish the alleged perpetrators and retrieve some of his financial losses.
Christensen's targets are CDRH reviewer Susan Runner; her boss, Division of Dental, Infection Control, and General Hospital Devices director Timothy A. Ulatowski; and CDRH director David W. Feigal. He criticizes Runner for allegedly maintaining an undisclosed conflict of interest that affects his devices, Ulatowski for not adequately supervising Runner and assigning the review to somebody else, and Feigal for not intervening.
Christensen sent a barrage of letters to key senators and representatives to protest a decision made in June by acting Health and Human Services Inspector General Michael Mangano, which Christensen charges amounts to a cover-up.
In a June 25 letter to Christensen, Mangano said he had decided not to open a formal investigation into the manufacturer's complaints, but instead to conduct an evaluation of FDA's medical device approval process, including issues relating to patient safety.
Noting that Christensen's temporomandibular joint (TMJ) devices had been returned to the market, Mangano said he believed "that the best course of action for addressing the issues you raise is a broad-spectrum evaluation of FDA's device approval process. Such an evaluation will provide information that would be beneficial to the agency, to device manufacturers, and to consumers."
Mangano said the evaluation had already begun and "will examine the approval process for new and investigational devices, as well as the approval process for those devices, such as [Christensen's] Fossa-Eminence Prosthesis, that had been 'grandfathered' pending approval. It is our intention to use the review of the TMJ Implants Inc. devices as one of the case studies in our evaluation of the FDA approval processes. As is our customary practice, should the study find grounds for an investigation by our office or FDA, the matter will be appropriately referred."
Christensen, who estimates that the 20-month absence of his devices from the market cost his company more than $6 million and forced it to close temporarily, rejected this approach. In a written reply to Mangano's letter, Christensen said it was "an insult to our intelligence. We don't need an evaluation of how the FDA process is doing. We need an investigation of the wrongdoing of individuals' actions on our PMA process by CDRH." He noted that his experiences were strikingly similar to a 1997 episode involving the same CDRH division and Myotronics Inc. (Tukwila, WA), which resulted in vindication for the company and the removal of FDA employees.
Christensen attached a copy of an e-mail message sent by Susan Runner on June 22 to four academics and a naval dentist. The message included a request for TMJ patient experience data that could support her application for an FDA Office of Women's Health grant to set up a TMJ registry. Christensen told Mangano the e-mail "proves beyond a doubt that she has had an ongoing conflict of interest in review of our devices for approval."
"This e-mail shows that for several years she has been interested in obtaining grants... to study TMD [temporomandibular disease] implant patients and related matters," Christensen wrote. "This in itself is a conflict with approving our devices, which demonstrate the most successful treatment for TMD. Dr. Runner also was part of the interagency TMD group that organized two seminars in 2000 that we know of to study the TMD problem, and which specifically excluded from participation TMJ Implants Inc. or surgeons using its devices, which could have had valuable input into this problem. Obviously, Dr. Runner, the TMJ Association [a patients' group], and others saw the company's products as a threat to their ability to obtain grants."
In his letter to Mangano, Christensen said, "I ask you how is it, if you thoroughly investigated this matter, that you were completely unaware of Dr. Runner's involvement with the interagency group whose agenda was at odds with our approval and also with FDA's Office of Women's Health?" When Mangano failed to respond, Christensen began his high-level protests.
As this column went to press, Runner and Feigal had not responded to e-mail messages seeking their comments on Christensen's complaints.
When CDRH director David W. Feigal accused Washington medical device attorney Larry Pilot last October of using "misleading" FDA statistics to show that CDRH applies harsher sanctions against European Union (EU) firms than it does against domestic companies, Feigal was in error, Pilot contends. Ever since Feigal's charge was published in this column, Pilot has been trying to get him to acknowledge the CDRH bias against EU firms and to correct it. In a recent letter to Feigal, Pilot wrote that the "major source" of Feigal's confusion about the attorney's use of the enforcement statistics "resulted from comments made to you by your compliance folks."
At issue in the dispute is a statistical analysis presented by Pilot last October to a European meeting showing that, through the agency's use of import detentions, "European manufacturers that receive FDA warning letters after FDA inspections are more likely to be prevented from marketing devices in the United States than a U.S. recipient of a warning letter."
In comments to this columnist after Pilot's presentation, Feigal said the lawyer had used FDA statistics in a "misleading" manner, and Feigal appended internal comments from his compliance branch as substantiation of this charge. Those comments, however, falsely stated that Pilot had compared "120 import detentions over 10 years to 12 domestic detentions over an almost-10-year period" when he did not, Pilot told Feigal in the letter. "I did state that the yearly average number of import detentions for the 10-year period was 12," Pilot said.
Pilot then argued in his letter that a domestic administrative detention cannot be compared with an import detention as an equivalent sanction, because the latter has no due process and is of indefinite duration, while the former provides due process under 21 CFR Part 800, subpart C, and lasts for a maximum of 30 days. "I am quite familiar with this due-process procedure," Pilot told Feigal, "because this regulation was developed at my direction while I was employed by FDA."
Apart from getting Feigal to acknowledge that his characterization of Pilot's October presentation was in error, Pilot says he hopes to effect a change in CDRH policy toward EU device manufacturers so that sanctions are applied equitably to them and to U.S. manufacturers alike. At the time this report was written, Feigal had not yet responded to Pilot's letter.
FDA needs to create an Office of Combination Products to help eliminate premarket review delays for combination products with breakthrough technologies, a report from the Lewin Group recommends. These types of products, such as drug-delivery or drug-coated stents, don't fit neatly into existing regulatory structures and often face unnecessary delays, the report says.
Up to 13 months can be required to determine which center should have regulatory jurisdiction over some combination products. The report says the new office should be established within the Office of the Commissioner to clarify rules and assign products to the appropriate center.
The report suggests that PMA applicants pay a user fee to retain outside experts to help in the review of devices involving new technologies. "When FDA and the applicant agree that additional expertise is needed, funding by device sponsors should be permitted to pay outside experts selected by FDA to assist in the review process," the report states.
The group's report also recommends that the agency work with its international counterparts to harmonize inspection requirements. It adds that independent external organizations should be accredited to help meet FDA inspection requirements. This could help eliminate multiple inspections of U.S. manufacturers to verify that they meet global regulatory requirements.
Device manufacturers using pre-IDE meetings with FDA won't find them an easy fix for issues involving devices for new therapies or ambitious changes to existing devices, predicted Guidant CRM regulatory affairs and compliance director Nicholas Horvath in June at a submissions workshop in Washington, DC, conducted by AdvaMed.
For such devices, Horvath said, it often takes a series of meetings with CDRH to come to an understanding because "we're teaching everyone the technology as we are developing it." The pre-IDE meetings are likely to be more useful for small device development projects or device changes that can be very well defined, he said. Pre-IDE meetings are a means for a sponsor to get agency advice on proposed bench, animal, and clinical testing before submitting an IDE. The intention is to increase the likelihood of IDE approval on the first pass.
Horvath told the audience that his firm has attended 10 pre-IDE meetings during the past 18 months. Guidant found it was often difficult to get adequate time to present and resolve issues because "reviewers are strapped for resources and must focus on statutory deadlines," said Horvath. He added that certain issues tend to crop up late in the development process, such as design control issues. If firms proceed with pre-IDE meetings too early, they run the risk of "lost memory" if someone key to either FDA or the company becomes unavailable. This can adversely affect how the process moves forward, he warned.
Horvath outlined several guidelines to successful pre-IDE meetings. They are:
- Provide a clear description of the device features, target population, intended claims, and differences from an earlier device if the company's submissions will rely on that device's data.
- Limit surprises from the sponsor late in the process.
- Include only "working-level" personnel at the meetings—senior managers tend to turn working meetings into policy meetings and that makes FDA uncomfortable.
- Use an open, candid dialog and welcome FDA feedback.
- Continue to improve clarity and completeness of submissions.
- When using outside experts, involve only those who are recognized as qualified in the device or technology.
- Provide a device demonstration.
- Don't try to resolve everything in a single meeting; complex devices require input from many experts and FDA personnel.
- Use teleconferences to discuss smaller-scale products or modifications.
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