Only two months into her appointment, FDA commissioner Margaret Hamburg found it necessary to recuse herself from a controversial rule making to reclassify dental amalgams containing mercury. The rule's proponents feared that Hamburg's move could delay a resolution, but FDA issued a final regulation in time for the July 28 deadline.
Mercury amalgams as tooth fillings are the leading source of Americans' exposure to mercury, a known kidney toxin, and a suspected neurotoxin that may be hazardous to fetuses and young children. An estimated 30–40% of new tooth fillings continue to use mercury amalgams, although the device is being gradually phased out.
The reclassification rule making began May 30, 2008, under a contractual settlement between FDA and Consumers for Dental Choice. Hamburg's recusal from the rule making shifts responsibility for it to principal deputy commissioner Joshua Sharfstein, according to acting chief counsel Michael Landa. He confirmed this in a terse June 8 letter to Consumers for Dental Choice national counsel Charles G. Brown.
Why did Hamburg recuse herself? According to FDA assistant commissioner for public affairs George Strait, in an equally terse e-mail to me, it was “based on the requirements of federal ethics laws and the standard of ethical conduct.”
Brown, however, says that a fuller explanation could be that for five years before she came to FDA, Hamburg was a board member at Henry Schein Inc. (Melville, NY). The company is the leading distributor of dental products including mercury amalgams.
In a June 9 letter to Hamburg, which Brown says Hamburg never answered, Brown cited a Forbes article that said Henry Schein paid her $285,365 in 2007, and he asked, “Was Henry Schein your number one source of earned income?” Brown also asked Hamburg the following three questions:
• Were you in any way involved in the mercury amalgam issue at Henry Schein?
• Did you ever contact FDA, the American Dental Association (ADA), or a dental manufacturer about amalgam?
• Were you involved in keeping amalgam unclassified by FDA or in keeping its mercury content away from consumer knowledge?
That last question is at the core of a long-running battle, which led to a federal court case against FDA. Brown has been waging that battle to get the agency to warn the public about mercury amalgams.
Brown's lawsuit alleged that CDRH Dental Devices Branch chief Susan Runner had initiated and sustained an effort to keep the amalgam's mercury content from the public, even proposing a rule in 2002 “directing dentists to instead disclose the nutrient zinc.”
Historically, Brown says, ADA has patented and promoted mercury's use in dental amalgams. Although less than half of its members still use it, he says that ADA continues to defend the toxin's use in dentistry.
Although Runner's effort was repudiated by two joint advisory committees four years later, Brown told me that it was supported by former CDRH director Daniel Schultz, his deputy Linda Kahan, and FDA associate commissioner for science and health coordination Norris Alderson.
“It's a huge problem at FDA,” Brown told me, adding: “They won't critique each other. Managers back up their scientists all the way to the top.”
The exception is deputy commissioner for policy Randall Lutter, whom Brown credits for breaking Runner's pro-mercury program and for setting in motion the change in policy that ended Brown's lawsuit and produced last year's agreement.
Lutter apparently saw CDRH's support of mercury amalgams as inconsistent with actions against using mercury by other FDA centers. Examples include the Center for Veterinary Medicine's 2002 ban on equine Miracle Leg Paint, a late 1990s ban by the Center for Drug Evaluation and Research on topical mercury-based treatments like Mercurochrome, and the Center for Food Safety Applied Nutrition's prohibitions and warning about mercury in fish.
GAO Sees ‘Serious Shortcomings' at CDRH on 510(k)s
FDA's premarket and postmarket activities continue to highlight “serious shortcomings” in the agency's ability to regulate medical devices, said Government Accountability Office (GAO) health director Marcia Crosse at a House hearing on June 18. She said that FDA should be reviewing all pre-amendment Class III devices through the premarket approval (PMA) process and not through the 510(k) process, unless the device is reclassified to a lower level (Class I or Class II).
Acknowledging that FDA began a process in April to reevaluate whether certain preamendment Class III devices should be approved under a PMA, Crosse still faulted the agency for not specifying a time frame for when this determination will be completed.
Device postmarket surveillance continues to be a challenge for the agency because the volume of adverse-event reports prevents the agency from analyzing many of them, Crosse told the House Energy and Commerce Health Subcommittee hearing.
Noticeably missing from the hearing was FDA. “If the hearing is about science and solutions, why wasn't FDA invited?” asked Representative Michael Burgess (R–TX). If the hearing is looking for a solution to gaps in the device approval programs, “then we need to hear from the FDA commissioner or [the agency's] surrogate,” he said.
Former CDRH deputy director Phil Phillips said at the hearing that the new FDA leadership should be given a chance to develop strategies to improve the agency's performance before any legislation should be drafted. He was one of several hearing participants that conflict-of-interest charges were levelled against (see the story, “Conflicts of Interest at Approval Hearing?
Public Citizen's Peter Lurie believes that FDA allows a too-permissive interpretation of a device's “same intended use,” which allows some devices to skip the more rigorous PMA process and proceed through the 510(k) process.
His testimony discussed unacceptable practices such as failure to randomize, after-the-fact examinations of data, comparing groups studied at different points in time, and failure to adjust for multiple statistical tests.
Lurie also told the hearing that the agency's “least burdensome” provision gives “the industry recourse to challenge many requests it regards as onerous.” He said that in the case of ReGen's Menaflex collagen scaffold, the firm invoked this language “when FDA considered the unfavorable findings of its randomized, controlled trial, asserting that the agency was ‘required' to consider the least burdensome information necessary to demonstrate substantial equivalence.” And, he said, FDA has permitted scientific approaches that fall well short of rigorous.
“These lax scientific standards can be the result of any combination of the lower standard for device approval, the inappropriate routing of devices through 510(k) instead of PMA, the ‘least burdensome' requirement, and lack of rigor at the agency level,” Lurie said.
Conflicts of Interest at Approval Hearing?
Phil Phillips's invitation to testify reportedly stoked a controversy between Republicans and Democrats after it was learned that he consults for ReGen. Apparently he was invited by the subcommittee's Republican members, who weren't aware of his ReGen affiliation and who said that Democrats should have advised them of the conflict of interest after vetting him for the hearing.
At the beginning of his testimony, Phillips said he was appearing on his own behalf based on the knowledge he gained while working at the agency and since moving to private consulting.
Ironically, subcommittee chairman Frank Pallone (D–NJ) was one of four lawmakers who intervened at FDA on ReGen's behalf to push its device through the 510(k) process. It has been disclosed that Pallone had earlier received almost $9000 in campaign contributions from the company.
“It is my job to ensure that FDA is abiding by the laws as they were passed by Congress,” Pallone said earlier when asked about his involvement. “In this case, I was obligated to get involved because FDA was applying an inappropriate and possibly illegal standard. I asked FDA to follow the law and provide a fair process for the review of this product, so that in the end only sound science would determine whether or not it was safe.” No lawmakers questioned Pallone's actions regarding ReGen during the hearing.
Pilot Challenges Safety-Efficacy Rule
Pilot says that FDA may not have the authority to issue an order that requires the device makers to submit more information.
Attorney Larry Pilot is challenging the legal basis of an FDA order to manufacturers of 25 pre-1976 Class III medical devices. The order requires them to submit information on the devices' safety and effectiveness in order to confirm or revise their classifications. FDA's action was a response to public criticism of the way the agency has allowed such devices to enter the market through the 510(k) “substantially equivalent” process.
In comments to the April 9 order's docket, Pilot suggests that FDA has no explicit authority now for the order. He bases this on the 1990 Safe Medical Devices Act mandate at sect. 515(i), which required the agency to complete the classification process for all devices by December 1, 1995.
In the order to 25 manufacturers, FDA did not mention the deadline date and gave as additional authority sect. 519, which empowers the agency to require reports bearing on classification. FDA can also require reports of any death or serious injury caused by a device or its malfunction.
Pilot, a former FDA director of medical device compliance, questions that foundation for the order as well. He says that sect. 519's scope as codified by FDA at 21 CFR 860.7(g)(2) is limited to individual manufacturers in specific cases and not to all manufacturers generally. He also says that sect. 519 applies only to manufacturers and importers—not to distributors.
Pilot says that because FDA's order “is vague and subject to possible challenge,” it is disappointing that the agency “threatens manufacturers that it ‘will use its enforcement power to deter noncompliance.'”
Quality System Violations Alleged at St. Jude Plant
An FDA inspection last March and April at St. Jude Neuromodulation Systems (Plano, TX) found quality system violations in the manufacture and distribution of a spinal cord stimulation system. Specific violations cited in the FDA-483 include the following:
• Failure to investigate the cause of nonconformities relating to product, processes, and the quality system.
• Failure to establish and maintain adequate procedures for validating the device design to ensure that devices conform to defined user needs and intended uses.
The warning letter says that FDA acknowledges the company's commitment to take all necessary actions to ensure compliance with the quality system regulation and provide quarterly updates until all corrective actions are completed. However, the agency is not satisfied with the company's response.
FDA told the firm to respond in 15 days with specific steps taken to correct the noted violations, along with documentation of the corrective actions taken and a timetable for their completion.
FDA Finds Violations at Frantz Design
A June 5 warning letter to Frantz Design (Austin, TX) says that agency inspectors in February and March found quality system violations in the specification developer's manufacture of the Elastic Mandibular Advancement Appliance Kit. The product is an oral device intended to treat obstructive sleep apnea and snoring.
The letter, issued by FDA's Dallas district office, says that the company verbally promised to correct the inspection observations listed on the FDA-483. The inspection also revealed, the letter says, that between March 31 and April 10, 2008, the company retrieved defective blue elastic device straps from dental laboratories and replaced them with new straps in response to several complaints of the blue straps breaking during patient use. The firm was encouraged to contact the district office recall coordinator to determine whether future product corrections or removals must be reported to FDA.
The company was told to take prompt action to correct all the violations. However, FDA says that further inspections will be needed to verify that the corrective steps have been taken.
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