The center director is too well liked among industry executives to be popular with an activist like Wolfe, of course. But now he has also become the target of dissident scientists and physicians in his own shop who have complained about his sponsor-serving overrides of their decisions about contentious products.

The most famous of these was his 2005 override of more than 20 FDA scientists, managers, and medical and safety officers who reviewed data for Cyberonics' vagus nerve stimulator. The Centers for Medicare & Medicaid Services later made the decision to not provide national coverage for the device's FDA-approved indication: treatment-resistant depression. Schultz readily admitted that the Cyberonics device was probably ineffective against it.

Other examples of overrides under Schultz, according to Wolfe, include Neuronetics' NeuroStar Transcranial Magnetic Stimulation device cleared under 510(k) on December 16, 2008, and ReGen Biologics' collagen scaffold cleared under 510(k) two days later.

These instances are in addition to the example that was publicly cited by the nine dissenters in January: Nashua, NH–based iCAD Inc.'s SecondLook Digital, which is a computer-aided detection system for mammography. The device was approved for use with Fuji Medical Systems' Computed Radiography for Mammography system.

There can be little doubt that Schultz's management, including facilitation of an “ambush” civil money penalties case against TMJ Implants that had been incubating in his center for two years, has attracted deserved criticism.

Is it fair to expect the center director to know about and control everything that's going on below? President Harry S. Truman had a block on his desk bearing the answer to that: “The Buck Stops Here.” I expect the new Democratic regime in Washington to try to apply that standard when their attention finally comes round to CDRH.

Dissidents May Have Misjudged a Product

The one-sided publicity given to the CDRH dissidents' complaints about their management in January might suggest that right is inevitably on their side. By taking up the dissidents' cause in a product review that is ongoing, as opposed to over, Public Citizen may have erred. And in not questioning the group's judgment, I also did indeed err in my column in MD&DI's January issue.

This column reported on a November 13, 2008, letter from the Health Research Group at Public Citizen to CDRH director Daniel Schultz. The letter expressed concern over the center's willingness to back further study and possible approval of Acorn Cardiovascular's CorCap cardiac support device.

No doubt seeded by CDRH dissidents (that's how Public Citizen and Congress get most of their information about internal agency controversies), the letter contained “factual errors and fails to provide an accurate description of the review process conducted by the FDA and its advisory panels,” according to an Acorn statement in response (see the sidebar, “Acorn's Rebuttal”). “The letter included a concluding quote from a Circulatory System Advisory Panel member that was taken out of context from a panel transcript that was hundreds of pages long and represented nine hours of panel discussion,” according to Acorn's statement.

Did FDA's Ombudsmen Take Sides?

Instead of maintaining a mediator's neutral stance, CDRH ombudsman Les Weinstein and FDA Office of the Ombudsman regulatory counsel Laurie Lenkel may have helped FDA in a case against embattled Golden, CO–based device maker TMJ Implants Inc. (TMJI). According to agency documents obtained under pretrial discovery, FDA management helped prepare the agency's civil money penalties (CMP) case in November 2004. Oral arguments in the case were set to be heard in March by the U.S. Court of Appeals for the Tenth Circuit, in Denver.

The documents include a four-year, 141-page FDA “privilege log” of internal e-mail and other communications related to the case. They show that starting November 23, 2004—six months before FDA filed its then-incubating CMP case—Weinstein received an “e-mail chain re correspondence re FDA interactions with TMJI in response to” a November 16, 2004, letter from TMJI president and CEO Robert Christensen. The letter requested an appeal from a CDRH determination that he must file 17 medical device reports (MDRs).

Log entries suggest that thereafter, Lenkel, who is now director of FDA's Office of the Ombudsman (“Chief Mediator” has been dropped from the name) and Weinstein were part of an intensive, two-pronged strategic FDA effort to ignore the appeal while the CMP case was finalized.

Two months later, the log says, Weinstein participated in several meetings and e-mail chains with other center officials “and agency counsel” on the appeal. The appeal went unanswered until after the CMP charges were filed (at this point the appeal was rejected as “inefficient and duplicative”). An undated entry in the log by Weinstein mentions the CMP matter, but the context was redacted by the agency. However, a three-page e-mail chain authored by both Weinstein and Lenkel referenced “opinions and recommendations of agency counsel re appellate procedures.”

One entry tersely describes 11 pages of handwritten notes from the previous day about a meeting involving Weinstein, CDRH director Daniel Schultz and deputy Linda Kahan, CDRH compliance director Tim Ulatowski, and others. The meeting centered on TMJI's “compliance issues, proposed CMP recommendation, and 11/16/04 request for appeal with attached notes re opinions, suggested elements, and charges, etc., for proposed CMP; chronology concerning TMJI MDR issue; and document entitled SMDA CMP Decision Tree.”

Contrary to provisions of the U.S. Model Statute for Ombudsman Offices—which has been adopted at the state but not the federal level—that require ombudsmen to be independent and impartial, nothing on FDA's ombudsman Web site stipulates such a standard. Instead, the agency's newly posted Ombudsman brochure simply says the office coordinates “appeals to the Office of the Commissioner after a final center-level decision has been made (21 CFR 10.75)...” Under the heading “Cases We Handle,” the brochure lists “Disputes [and] complaints from regulated industry regarding agency product center actions, or lack of action, and those issues that cut across center jurisdictions.” According to the brochure, the ombudsmen also handle “disputes [and] complaints from regulated industry related to interactions with agency field offices, including inspection and compliance issues.”

Separately, in a 57-page 1998 guidance on CDRH dispute resolution, the center incorporates language from FDA's Office of the Chief Mediator and Ombudsman that it seems to have since forgotten: “The office's goal is to facilitate a constructive resolution to disputed issues. The office is neutral in that it has no vested interest in any particular outcome, but is a strong advocate for fair processes and fair outcomes.

“The office serves as a resource to regulated industry when disputes arise, such as concerns, for example, that FDA has not: determined the relevant issues; obtained accurate and complete information; applied relevant information properly; informed affected parties accurately and adequately; or revised past actions where appropriate.”

However, TMJI's Christensen says he was not steered by anyone to that office, and after Weinstein's office failed to help him in an earlier dispute with the agency over reclassification of his devices, he did not seek Weinstein's services in his dispute with the same center over medical device reporting. Christensen says he instead followed Schultz's advice to appeal to the commissioner.

Without a brief from Christensen, on behalf of whom were Weinstein and Lenkel acting in the privilege log disclosures about the CMP case? Weinstein did not respond to my request for elucidation, but it would seem that both were acting at the invitation of the same center management that was preparing the CMP case.

In an e-mail, Lenkel said her office “does its best to uphold the essential characteristics of the ombudsman function and therefore does not confirm or deny its involvement on any specific case.” And FDA Office of Public Affairs device specialist Peper Long, responding for Weinstein, said his participation in regulatory meetings can be as an “advocate” for companies, whether formally engaged by them as such or not (see the sidebar, “Weinstein's Involvement,” on p. 30).

After his first year in office (2000), Weinstein introduced himself to the industry in an article published in MD&DI. In this, he acknowledged that “ombudsmen who work in government agencies are supposed to be neutral and impartial. Their goal is to work toward the resolution of disputes without taking sides.”

His article showed an earnest and conscientious approach to the job, but he also noted that his office “reflects the way CDRH operates, and I try to meet the needs of CDRH and the medical device industry.” Without pledging impartiality, he concluded his article by saying that his “mission is to promote and support fairness, accountability, and equity at CDRH.”

But that was then, and this is now. If, as some critics say, CDRH is the most broken part of a broken agency, Weinstein's article might have served as a confession that reflected that condition. In addition, the privilege log that FDA has been compelled to disclose in the TMJI case appears to substantiate it.

Utah Medical Products CEO Kevin Cornwell, who famously won in federal court against many of the same FDA players and says he has read every brief in the TMJI matter, sees similarities in the agency's behavior in both cases. As it has with TMJI, he told me, in his case CDRH rejected mediation. “In mediation, you have to put all your cards on the table—and they didn't have any cards!”

CDRH does have a formal independent scientific dispute resolution process that is coordinated by Weinstein, which is mandated in the 1997 FDA Modernization Act. But it is biased toward medical device approval issues, and a center guidance says it “excludes matters relating to potential criminal activity, allegations of intellectual or regulatory bias, ... and legal issues.”

Christensen's assessment is sharp. As a small medical device manufacturer with fewer than 20 employees, he told me, three letters to the commissioner, including an appeal, should be more than enough to get a scientific question answered before the agency resorted to litigation.

“We requested dialogue for clarification,” Christensen said. “Our request was in line with the European Union standards for reporting events. TMJI's major scientific question that needed to be answered was whether a device removed as a result of disease progression needed to be a medical device report. The other questions had to do with usually less serious, but most frequently expected events, such as swelling, bleeding, and even post-op infections, to mention a few.”

Rather than engage in such a dialogue, the agency pressed ahead with the CMP process that CDRH compliance officials had been planning for two years, Christensen said. His reasons for not filing the contested 17 MDRs—although he has repeatedly offered to if FDA would drop its charges—were that, as a clinical expert, he had judged them not to be device related. As a result, he did not want to expose his products to competitive disadvantage without cause.

Lab-Developed Diagnostics Ignite Controversy

Genentech has ignited controversy with a citizen petition asking FDA to regulate all laboratory-developed diagnostic tests (LDTs). Some manufacturers of tests, whose validity Genentech questioned in the petition, said that the company is simply looking for a marketing edge, and that their laboratories are adequately regulated by the Centers for Medicare and Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments.

The December 18, 2008, petition said that FDA has the legal authority, expertise, and resources to regulate all predictive tests used to guide treatment. FDA regulates test kits as medical devices and has exercised enforcement discretion over LDTs. Most laboratory testing services are overseen by CMS.

Analysts have said confusion over the extent of FDA's regulatory authority came up several years ago when the agency said it retains authority to regulate in vitro diagnostic multivariate index assays. Genentech says that greater consistency in FDA enforcement would protect the public health.

The Coalition for 21st Century Medicine, which represents diagnostics firms, clinical laboratories, researchers, physicians, venture capitalists, and patient advocacy groups, has said that if FDA agrees with Genentech, it would result in delayed introduction of critically needed diagnostic tests. Such an agreement would also impose high costs on laboratories and put significant pressure on FDA's budget and personnel, the coalition says.

“Genentech wrongly asserts that FDA approval is a prerequisite for claims to be considered scientifically proven,” the coalition said in a statement. “FDA approval is not needed for an LDT's performance to be demonstrated. There are many other methods of establishing a test's performance, such as the publication of reproducible research findings in peer-reviewed publications.”

According to the coalition, a lack of information about some diagnostic tests does not justify what it calls a revolutionary change in the regulatory regime for laboratories. It also noted that the Federal Trade Commission already has authority to ensure that diagnostic company claims are truthful.

Finally, the coalition asserts that even if FDA were to seek to regulate the tests, it would have to go through notice-and-comment rule making.

FDA Issues Premarket ANA Test Guidance

FDA has issued a guidance for industry and FDA staff, Recommendations for Anti-Nuclear Antibody (ANA) Test System Premarket (510(k)) Submissions, to give device manufacturers and agency staff information on premarket submissions for various types of in vitro diagnostic (IVD) tests for antinuclear antibodies.

The guidance updates a 1992 guidance on issues associated with new developments in ANA testing. It addresses IVD devices that detect antinuclear antibodies as an aid in diagnosing autoimmune disease and is not meant to address tests that differentially diagnose autoimmune diseases.

FDA's most recent guidance includes an introduction and background as well as information on scope, device description, performance characteristics, method comparison, and labeling. Access the guidance at www.fda.gov/cdrh/oivd/guidance/848.html.

FDA Faults I-Flow Corp. on Quality System

In what may fall into the category of FDA bureaucratic sloth, the agency posted a warning letter on its Web site in February that was issued six weeks earlier by its Los Angeles district office to I-Flow Corp. FDA took issue with the Lake Forest, CA–based company's responses to an inspection conducted between March 11 and May 12, 2008.

By the time you read this, nearly a year will have passed since the inspection. Asked about the multiple delays in making this public, FDA's Freedom of Information Office did not respond.

The tardy warning letter noted violations including the following:

•Failure to establish and maintain procedures for verifying the device design.

•Failure to establish and maintain procedures for identifying, documenting, validating or verifying, reviewing, and approving design changes before implementation.

•Failure to ensure that when results of a process can't be fully verified by subsequent inspection and test, the process is validated with a high degree of assurance and approved according to established procedure.

•Failure to ensure that for validated processes, the monitoring and control methods and data, the date performed, and the individuals performing the process or the major equipment used is documented.

•Failure to maintain device history records.

The warning letter said the inspection had determined that the devices were misbranded because the firm failed or refused to furnish information required under the medical device reporting (MDR) rule.

Many of I-Flow's responses to the quality system violations were inadequate, the letter said, and adequacy of the remainder could not be determined. The response to the MDR violation appeared to be adequate.

Ironically, the letter told I-Flow to take prompt action to correct all deficiencies and to respond within 15 days with a listing of specific steps to be taken, an explanation of how the company will prevent these and similar violations from occurring again, documentation of all steps taken, and a timetable for implementation.

Many in industry have asked what FDA's purpose is in publicly posting such letters. The only purpose I know of is the legal status they have: they are public documents. The law does not say anything else about that, nor does it address promptness.

Some have postulated that because these letters are legally public, it follows that the public embarrassment that might come from such exposure could have deterrent value. Others have suggested that the letters can have educational value for other companies that might be in need of staff training in such matters.

But posting the letters a year after the events described in them would not seem to enhance either benefit, and in some cases could punish a company that had promptly achieved full compliance many months previous.

As 19th-century British prime minister William Gladstone once famously said: “Justice delayed is justice denied.”

“In support of the CorCap, Acorn conducted one of the largest premarket, concurrent controlled cardiothoracic surgical trials in device history,” the company said in a statement. “This trial was designed in conjunction with FDA and yielded statistically significant results. Acorn and its clinical investigators were commended by the panels for investigating an extremely ill heart failure population that is worsening and does not have therapeutic options.”

The company says that both FDA and its advisory panels felt that the CorCap therapy was promising; however, additional confirmatory clinical data were needed because the trial was an unblinded surgical trial.

Acorn quotes Clyde Yancy, MD, cochair of FDA's Circulatory System Advisory Panel as saying that “the answer here really should not be yes or no, but how this technology should move forward—as an unlimited approved indication, or as a promising ongoing intervention with provocative preliminary data worth pursuing.”

Further, Acorn said that the trial Public Citizen referenced “was designed in close collaboration” with staff from various divisions of FDA. In addition, the company cited significant input from representatives of the advisory panels and said that “no conclusions can be drawn until the trial is complete and the data fully analyzed.”

FDA press officer Peper Long said that Weinstein's “participation in an issue is not limited to a company's request. As an advocate of fairness, he often participates (by center request or on his own initiative) in discussions that may be about a particular company or companies.”

Further, Long said that the CDRH 1998 guidance predates the existence of a CDRH ombudsman, and that the guidance pertains to the Office of the Chief Mediator and Ombudsman at the agency level. “As you point out, the 1998 guidance refers to the ombudsman role as ‘a strong advocate for fair processes and fair outcomes.' However, the same advocacy role underpins Les's participation in meetings of this nature,” Long said, “where he may point out ways that center staff may wish to act differently or he may suggest relevant issues, from a company's perspective, that the center may not have considered.”

Long said that Weinstein is sometimes “an advocate” for a company even if it hasn't yet requested ombudsman help. In addition, Weinstein's involvement offers background on the case in the event that he is later asked to step in. “But, as ombudsman, he remains committed to fair resolution regardless of who invited him to participate.”

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