WASHINGTON WRAP-UP

There was a time when FDA leaders possessed and cheerfully used real, personal power. Regulated industry walked warily.

I was reminded of this while reading a newly filed lawsuit against the agency for its apparent refusal for 31 years to regulate mercury-based dental amalgams. The lawsuit likened FDA commissioner Andrew von Eschenbach to “the British Queen [who] chooses to reign but not rule, allowing his bureaucracy to set policy while he and deputy commissioner Lutter ignore repeated warnings of lawlessness beneath.”

This resembles some informal complaints about FDA and CDRH chiefs that were aired in the Utah Medical Products (Midvale, UT), TMJ Implants (TMJI; Golden, CO), and Myotronics (Tukwila, WA) cases. These companies also railed in vain at the impotence of high officials who, at least on paper, had the perceived power to right bureaucratic wrongs but chose not to.

In the Utah Medical case, former commissioner Lester Crawford twice verbally promised to “look into” the company's complaints and “get back to you,” but never did—and then the agency lost disastrously in federal court. Other FDA heavyweights, including associate commissioner for regulatory affairs Dennis Baker, promised an investigation into the company's complaints that never occurred.

In the TMJI case, CDRH director Daniel Schultz invited the company to appeal its concerns to the commissioner, who in turn never considered them. As a consequence, the company and its executives were slapped with civil penalties of $630,000.

In the 1997 Myotronics case, CDRH and FDA leaders failed to step in when lower-level procedural abuses were uncovered. Justice for the company was only secured after the HHS Office of Inspector General and congressional overseers got involved.

FDA leaders used to possess and wield personal executive authority, effective for implementing the administrative remedies that plaintiffs are expected to exhaust before resorting to the federal courts.

The new case was filed December 28 in the District of Columbia federal court on behalf of Moms Against Mercury, three other activist groups, and seven individuals. Defendants include von Eschenbach; deputy commissioner for policy, planning, and preparedness Randall Lutter; associate commissioner for science and health coordination Norris Alderson; and HHS secretary Michael Leavitt. Some CDRH officials are also named as defendants. They include director Daniel Schultz; director of anesthesiology, general hospital, infection control, and dental devices Chiu Lin; and dental devices branch chief Susan Runner, a dentist who was accused of bias in the TMJI case.

Filed by Consumers for Dental Choice national counsel Charles Brown, the 21-page complaint might bring to a head the issue of executive accountability at FDA and across the federal government—which has been waning since the Reagan presidency.

Even before Reagan's presidency, the suit contends, dentists within and outside of FDA worked together to keep mercury-based dental amalgams on the market in the face of widening efforts to eliminate mercury from other products. They did this, the complaint says, by concealing the metal's 50% presence in amalgams even though nonmercury resin is a plentiful alternative.

Brown says this effort was backed by the American Dental Association, which he says has always been controlled by mercury-favoring dentists and the makers of mercury amalgams. Dentistry has its origins in barbering and blacksmithing, and since 1859 the industry has shunned professional alliance with medicine in order to “march in lockstep” with the mercury amalgam producers, Brown says.

Misnamed “silver fillings,” the lawsuit says, amalgam arrives at a dentist's office with a skull-and-crossbones symbol beside the words “POISON, CONTAINS METALLIC MERCURY.” The warning calls mercury a “potentially hazardous substance” with “neurotoxic/nephrotoxic effects” and is known to the “state of California to cause birth defects or other reproductive harm.” The complaint says amalgam makers have “advised dentists in writing not to place amalgam in pregnant women, nursing mothers, children under six, and anyone with kidney disease.”

The lawsuit charges that repeatedly, “a rogue bureaucracy inside FDA sabotages pronouncements from the commissioner's office that FDA will act on amalgam.” It alleges that FDA leaders repeatedly promised to act—to litigants (1997), to Congressman Dan Burton (2002), to Senator Ted Kennedy (2005), and to the Court of Appeals (2007). In June 2007, facing a lawsuit by these plaintiffs, FDA allegedly promised to announce an advance notice of proposed rulemaking. The lawsuit calls this promise “a sham to buy more time to keep mercury fillings on the market.”

Von Eschenbach, the complaint says, promised Senator Michael Enzi in August 2006, during his confirmation hearings, that the scientific advisory panels convening in September “will be asked to answer specific questions concerning any possible adverse health effects of dental amalgam.” The lawsuit charges that such questions never took place; defendant Alderson sabotaged the order, turning the hearings instead into a referendum on a mysterious staff “white paper” (a vote Alderson lost). No record exists of von Eschenbach taking corrective action when “he broke that promise to Senator Enzi [and he] remains indifferent on whether FDA complies with its legal duty to classify mercury amalgam.”

Brown's complaint alleges that acting under a collectivist theory of unaccountability, where if everyone does it no one may be held to task, defendants Alderson, Lin, Runner, and Schultz have abused their high-ranking positions by “willfully and wantonly defying their statutory duty to regulate mercury amalgam.”

Runner allegedly sabotaged a 2002 order from former center director David Feigal to contract for an independent literature review of mercury amalgam's toxicity issues. Instead, working with dentists in other agencies, the lawsuit says that she handpicked an unqualified meetings planning company (Betah Associates) in order to avoid competitive bidding. She allegedly then directed Betah to subcontract the study to a Beltway tobacco consultant (LSRO Inc.), with whom “she or her coconspirators had conducted secret meetings to obtain an agreed-upon result.”

Brown told me that LSRO “flipped” its original directive from FDA, which was to find evidence in scientific literature that dental amalgam poses a health risk, to one that only required the consultant to determine whether the literature “supported hypotheses relating to adverse health effects.” This, he said, changed the question from “one that would certainly have to be answered yes, to one that could be answered no.”

His lawsuit charges that, “Fully aware that mercury can permanently harm the fetus or the developing brain of a child, Runner nevertheless led the effort in 2002 to conceal the presence of mercury from dental patients (even pregnant women and parents of young children) by naming zinc as the controversial product. This outrageous conspiracy to use zinc to cover up the mercury has been joined by defendants Alderson and Schultz.”

Top FDA officials have displayed real power only once in the 25 years since the Reagan administration. That was when David Kessler came to the agency in 1990 and proved to his startled conservative hosts to be a regulatory wolf in sheep's clothing.

As former Nixon White House aide John Dean writes in his book Broken Government, neoconservatives tried to emasculate the federal bureaucracy by implanting political appointees into its agencies even after Reagan's presidency. This move was intended to render the agencies incompetent, which was part of a strategy to return the regulation of industry to the states and, to use a Reaganism, “closer to the people.”

At FDA, this planned result met severe resistance from the industries that the misguided strategy was intended to help. In a globalizing world, health product labeling and tort
liability at the state level is exactly the wrong way to go.

However, on the regulatory enforcement side, FDA impotence and state ascendancy were seen as less objectionable, and FDA accelerated its outsourcing of food and medical device inspections to the states as appropriated funds were cut back. With political appointees focused on the product-
approval side of FDA's mission, their neglect of the enforcement side allowed mischief to grow out of sight.

When the mischief was pointed out, the politicos and their careerist helpers didn't know what to do, so they ignored it.

Now that the neoconservatives are retreating, the woes of protesters such as small device companies and Moms Against Mercury may meet with a newly accountable, hands-on FDA brain trust.

CDRH Plans Interactive Review Process

CDRH plans to use an interactive review process with industry to smooth out minor deficiencies and to request additional information to complete its review of premarket approval (PMA) and 510(k) submissions. The new interactive review is intended to help speed up submission reviews through “increased informal interaction between FDA and applicants, including the exchange of scientific and regulatory information,” according to a new guidance. It says the interactive review process will be designed to help

CDRH expects device application submitters to be up-front about “any major issues” prior to submission to ensure that the submission addresses relevant regulatory and scientific issues. The center's preferred communication tools for conducting interactive reviews are e-mail and fax transmission, according to the guidance. “One-on-one telephone calls should be used primarily for requests for clarification that the FDA reviewer can easily document (e.g., the location of specific information within the PMA, or interpretation of a graph). Any telephone call that leads to a request for data should be followed by an e-mail from the applicant to FDA that summarizes the commitment(s) made. FDA should respond via e-mail to confirm the accuracy of the commitment(s) and then add the e-mails to the submission's official administrative record.”

Face-to-face meetings are highly discouraged under the interactive model because of the difficulties in coordinating the availability of key staff between both the sponsor and the agency, the guidance says. “Therefore, FDA and the applicant should consider whether a meeting is the most appropriate and effective communication mechanism to resolve the issue(s),” it says. “Meetings are most effective when there are significant issues regarding the review that cannot be resolved by e-mail, facsimile, or telephone calls.”

CDRH's guidance says there is no appropriate timing interval for when an interactive dialogue should occur. Instead, “interaction should occur as needed to facilitate a timely and efficient review process.” Also, “when appropriate, FDA should wait until after the review of a particular topic or subject matter area (e.g., software, fatigue testing, device retrieval study) has been completed before interacting with the applicant regarding that topic. [This] ensures that the agency communicates appropriate and comprehensive deficiencies to the applicant.” In addition, timelines for sponsors to respond to FDA's informal requests for additional information will be set on a case-by-case basis.

The guidance also outlines when it is appropriate for applicants to contact the lead reviewer, such as

If a major review issue arises, FDA will likely communicate its concerns outside of the interactive review using a formal hold letter, according to the guidance. “Some major issues may be informally communicated in detail sufficient to permit the applicant to begin addressing the concerns before the issuance of a formal hold letter,” it says. “However, for major issues, FDA does not expect any response to be submitted within the current review cycle; thus, FDA should not provide a time frame for responding.”

Instead, applicants should submit a complete response to the hold letter, which will be reviewed under existing user-fee time frames. The guidance says that examples of major issues include “the need for additional preclinical testing; supplemental bench, animal, or clinical information to address a specific safety issue; a new statistical analysis of the submitted clinical data set; or additional manufacturing
procedures.”

More information about the program can be found at www.fda.gov/cdrh/ode/guidance/1655.html.

CDRH Issues User-Fee Guidances

CDRH has issued two guidances for industry and FDA staff dealing with MDUFMA provisions on user fees for review of certain marketing applications. A portion of the fees collected for reviewing PMAs will help cover costs associated with PMA bioresearch monitoring program (BIMO) reviews and any clinical or nonclinical preapproval inspections. A portion of the fees will also help cover costs related to reviewing information in the PMA's manufacturing section and to inspecting the applicant's relevant manufacturing facilities.

FDA notes that the HHS secretary told Congress when the user-fee legislation was approved that the agency is committed to “improve the scheduling and timeliness of preapproval
inspections.”

One of the guidances, titled The Review and Inspection of Premarket Approval Applications under the Bioresearch Monitoring Program, explains BIMO's process for reviewing PMAs and for assigning, scheduling, and evaluating related clinical or nonclinical preapproval inspections. It also applies to the BIMO review of certain PMA supplements and associated BIMO inspections. The guidance covers the sequence of events as the BIMO program within the Office of Compliance completes a PMA review. It also outlines the administrative process and the projected time frames involved with each step, and explains how the BIMO review of inspection results may influence PMA approval decisions.

The guidance may be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/06d-0228-gdl0002.pdf.

The second guidance, titled The Review and Inspection of Premarket Approval Application Manufacturing Information and Operations, explains the process involved with reviewing a PMA manufacturing section and inspecting the manufacturing operations described in that section. It is also generally applicable to the process involved with reviewing manufacturing information in certain PMA supplements. The guidance covers the sequence of events as the Office of Compliance or the Office of In Vitro Diagnostic Device Evaluation and Safety reviews a PMA's manufacturing section. It also describes the administrative process and projected time frames associated with each step, and shows how inspection of a manufacturing facility fits into the approval process.

This guidance may be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/06d-0063-gdl0002.pdf.

Stryker Division Receives Warning Letter

An inspection last summer at the Stryker Howmedica Osteonics facility in Mahwah, NJ, revealed quality system violations to which the firm's responses were inadequate, according to a recently released warning letter. The plant manufactures humeral stems, shoulder stems, acetabular shells, modular femoral components for knee
implants, hip implant components, hip implants with ceramic bearing components, and modular hip stems.

The warning letter says the inspection also found that the company failed or refused to furnish material or information regarding device corrections and removals. Four separate company responses to the cited violations were inadequate, FDA says.

The company was told that the violations and inspectional observations may reflect serious problems in Stryker's manufacturing and quality assurance systems. Stryker must determine the causes and must take prompt action to bring its products into compliance. The firm was told to respond within 15 days with a list of specific steps being taken to correct violations and prevent them from recurring.

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