Turmoil overtook other areas of CDRH’s bailiwick as well, such as its checkered enforcement of medical device reporting (MDR) requirements for ambulatory surgical facilities performing LASIK vision enhancement procedures, its slothful handling of device recalls, and its growing concern over regulatory standards for laboratory-developed diagnostic tests. Other sources of turmoil include the center’s controversial decision not to enforce its Good Laboratory Practice regulation, its scientifically flawed final rule on mercury-based dental amalgam, and on and on…

510(k) Reform

It broke out into the open during the transition to Obama’s administration in January, and by September it was a full-blown, $1.3 million Institute of Medicine (IOM) study commissioned by FDA: how to fix the 510(k) program at CDRH. Back on January 7, nine unnamed, dissident CDRH physicians and scientists wrote a six-page letter to the transition term leader, John D. Podesta, alleging “longstanding pandemic corruption” within the center “that cries out for new leadership at FDA from the bottom up.”

The complaints resonated with the incoming administration, especially then-acting commissioner Joshua Sharfstein, who is now an extraordinarily energetic effector of change as principal deputy commissioner. He was disturbed by their charges that scientific dissent on new product submissions was frequently overruled by managers at the behest of sponsors and politicians. Former CDRH director Daniel G. Schultz was depicted as complicit and he made no effort to deny it. Outgoing commissioner Andrew von Eschenbach offered to meet with the dissidents at the height of the publicity they generated, but they declined.

In May, after new public disclosures from the dissidents implicated a tortured 510(k) clearance that had been granted by Schultz over staff objections to ReGen Biologics for its Menaflex collagen scaffold, Sharfstein ordered a preliminary internal review of the matter. The company had enlisted no fewer than four New Jersey congressmen to show CDRH their “concern” over the company’s 17 years of efforts through four submissions to demonstrate “substantial equivalence.”

Whenever a regulatory agency doesn’t do its job properly, as CDRH hasn’t with its 510(k) program, there’s a higher likelihood that injured patients will sue a product’s manufacturer. This was the case in May, when the New York Times reported on 510(k)-related product liability litigation against Mentor Corp. that illustrated what Sharfstein’s review panel would later call “predicate creep.”

In September, Sharfstein’s review produced a report that found a “definite threat” that the Menaflex review’s integrity had been compromised. “We found that over the 17-year review history of the [collagen scaffold] device, multiple departures from processes, procedures, and practices occurred,” the report said. “Our ability to assess the effect of these departures on the decision-making process was in many cases undermined by the failure of important decision makers to sufficiently explain and document the bases for their decisions in an administrative record.” These actions constitute “a clear deviation from the principles of integrity used in this review and undermines the ability of the agency to counter the suggestion that lobbying on behalf of ReGen affected the decision.”

The report noted that several interviewees, including individuals with 30 years of FDA experience, described the ReGen matter as

Among the worst experiences in their professional careers, in large part because of the chaotic sense created by persistent pressure on agency decision makers and processes. The pressure came not only from congressional members and the company’s political consultant, but also from FDA leadership—in particular, the FDA commissioner (von Eschenbach). Beginning around this time and continuing until the months before clearance of ReGen’s final 510(k) on 12/18/08, the commissioner became involved in decisions typically committed to the review division or, if escalated, the center director.

Meanwhile, CDRH Office of Device Evaluation (ODE) director Donna-Bea Tillman in September told her staff she was taking immediate steps to strengthen the 510(k) program. In a memo that precipitated industry jitters that 510(k) reviews will be slowed down as center scientists examine them more carefully for signs of “predicate creep,” she said she had already established a center-wide 510(k) working group to look at ways to strengthen the program and expected to be “implementing recommendations from that group in the coming months.” In addition, Tillman wrote, ODE is planning to update the 510(k) modifications guidance next year.

Tillman’s memo told her division directors that she had asked their review branch chiefs to let her know when they get a new 510(k) for an indication that has never been cleared for that type of device. She stressed that this doesn’t mean she is actually going to do her own reviews, but that she is just gathering information. “I will be posting what I find in [an online location],” she wrote.

Daniel Schultz Resigns

Calling it “one of the hardest” decisions in his 35-year career, CDRH director Daniel G. Schultz told center employees on August 11 that he had resigned, effective at the end of the month. He said his resignation was based on discussions with commissioner Margaret Hamburg “and a mutual agreement that my stepping down at this time would be in the best interest of the center and the agency.”

Although AdvaMed and other industry voices made appreciative testimonial statements about his tenure, the activist Project on Government Oversight (POGO) called Schultz’s announcement a “long-awaited opportunity for openness and reform.” Schultz seemed almost to recognize this when he said “it is a decision that I am convinced is the right decision for me and for the special people at CDRH, who, over the last
15 years, have been my colleagues, friends, and second family.”

In an all-hands memo, Hamburg ignored the cloud of controversy over Schultz and instead lavished praise on his “tremendous legacy,” saying he had “worked tirelessly to advance the public’s health through the approval and monitoring of innovative and safe medical devices. The staff he has led for five years are among the world’s leaders in the evaluation of the design and the development of the next generation of advanced diagnostics and medical interventions.”

Schultz’s own announcement reflected a sunny view of his five years as center director and 10 more years in lesser positions. His record “is something that I will cherish and carry with me for the rest of my life,” Schultz told his
coworkers. “Anyone who has followed the course of medical care over the last two decades as an analyst, care provider, or patient will recognize the impact that device technology has had in improving healthcare delivery through advanced diagnostics, minimally invasive interventions, smart drug-delivery systems, etc.” But Schultz said that the staff at CDRH “have made [these products] safer, more effective, and more user-friendly.”

Associate commissioner for policy and planning Jeff Shuren, a neurologist and lawyer in his 10th year at FDA, is serving as acting CDRH director. A national search will be conducted for a permanent director.

LASIK Vision Enhancement Turmoil

Patient dissatisfaction with the adverse after-effects of LASIK surgery reached a critical tipping point at CDRH in 2009. Complaints include permanent quality of life issues like dry eye, night vision disturbances that prohibit driving, emotional depression, and unemployment. Patients have also criticized CDRH for collaborating with an ophthalmologists’ organization in dealing with these issues.

A potent Internet network of injured LASIK patients bombarded the agency with criticisms, petitions, and complaints until CDRH sent a letter in May to eye care professionals informing them about proper advertising and promotion practices related to the procedure. The agency acknowledged that eye care professionals’ advertisements for LASIK procedures failed to inform consumers of the indications, limitations, and risks associated with the procedure.

FDA has vigorously denied the injured patients’ charges that it has failed to follow up on the April 2008 advisory panel hearing. Among its follow-ups, FDA has cited developing an FDA LASIK Web site; updating LASIK-related information in the SightNet program for health professionals to emphasize that halos, glare, night vision, and dry eye problems from LASIK should be reported to FDA; and developing a patient information card with the American Academy of Ophthalmology to help LASIK doctors calculate the lens implant power should patients need cataract surgery in the future. FDA says that it has also recognized the new LASIK standard from the American National Standards Institute and opened a public docket for LASIK so that any interested person can submit comments.

None of this, apparently, was enough to placate the patients’ network. It kept up the pressure until, in October, FDA announced that it had sent warning letters to 17 LASIK ambulatory surgical centers after recent inspections revealed that they had inadequate systems for reporting adverse events related to the vision correction surgery. The letters did not identify problems with the devices themselves, but cited the recipients for failing “to develop, maintain, and implement written MDR procedures as required by 21 CFR 803.17.”

FDA also announced that it had begun a “collaborative study with the National Eye Institute and the U.S. Department of Defense to examine the potential impact on quality of life…” The project’s goals are to determine the percentage of patients with significant quality of life problems after having vision correction surgery and to identify predictors of these problems. The project will run until the end of 2012 and consists of three phases:

•Phase 1, which began in July, is to design and implement a Web-based questionnaire to assess patient-reported outcomes and evaluate quality of life issues after LASIK.

•Phase 2 will evaluate the quality of life and satisfaction following LASIK as reported by patients in a select, active-duty population treated at the Navy Refractive Surgery Center.

•Phase 3 will involve a national clinical trial and will study the effect of the procedure on quality of life following LASIK in the general population.

“The results of the project will help identify factors that can affect quality of life following LASIK and potentially reduce the risk of adverse effects that can impact the surgical outcome,” FDA said. “If any of these factors are related to the safety or effectiveness of the lasers used in LASIK surgery, the FDA will evaluate whether any action is necessary.”

Sloth in Responding to Recalls

CDRH has customarily had problems with promptly reporting medical device recalls. Its public postings lag behind its sister center’s drug recall postings by months and sometimes years.

In industry and Bush administration circles, this tended to be seen as “not a problem.” After all, medical device manufacturers conduct their recalls expeditiously within their own supply lines—reporting them equally expeditiously to FDA simply invites complications, like product liability lawsuits.

All this came to a head in March, when Public Citizen Health Research Group director Sidney Wolfe began a series of well-publicized complaints about CDRH’s tardiness in posting recalls. First, he complained, the center took nearly three months to tell the public about a Class I Covidien recall of Nellcor’s Shiley 3.0 PED tracheostomy tube. “Often the public does not become aware of a problem with a medical device until well after a company has already begun the recall process,” Wolfe said.

The next day, he asked why CDRH had waited for 47 days to classify as Class I a recall of Baxter Healthcare’s Colleague infusion pumps after the company warned users about serious problems “that lead to an interruption of therapy,” which itself “may lead to serious injury and/or death.”

And the day after that, Wolfe wanted to know why CDRH had not yet announced Welch Allyn’s Class I recall the previous month of 14,054 automatic external defibrillators (AEDs). In his third letter in as many days to FDA acting commissioner Frank Torti, Wolfe said the Welch Allyn recall was the largest of six recalls of “these dangerously problematic devices to date.”

Wolfe said the “recall once again makes it clear that the entire category of AEDs, a Class III medical device, is insufficiently regulated by FDA. Because of their risk, Class III devices are to be regulated under the [premarket approval] pathway; this requires direct evidence of safety and effectiveness before being marketed. However, because FDA has failed to meet statutory requirements established in 1990, AEDs and a handful of other Class III devices are still regulated under a less-stringent premarket review mechanism, the 510(k) pathway.”

Diagnostic Tests

Controversy over the bifurcated regulation of laboratory-developed tests (LDTs) increased in 2009 amid indications that new leadership at FDA may be less inclined than its predecessors to tolerate the status quo. Analysts have said confusion over the extent of FDA regulatory authority came up several years ago when the agency said it retains authority to regulate in vitro diagnostic multivariate index assays. The agency took several opportunities this year to send speakers out to industry meetings to say that, contrary to speculation, it still intends to regulate LDTs now regulated under the Clinical Laboratory Improvement Amendments (CLIA) by its sister HHS agency, the Center for Medicare and Medicaid Services (CMS).

The controversy gained momentum in December 2008 when Genentech filed a citizen petition asking FDA to regulate all LDTs, saying that this would provide greater consistency in FDA enforcement and better 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. The group also says that taking Genentech’s position would impose high costs on laboratories and put significant pressure on FDA’s budget and personnel.

However, CDRH Office of In Vitro Diagnostic Device Evaluation and Safety deputy director Alberto Gutierrez said in August that LDTs are often legally marketed for wider use without being subjected to the rigors of the FDA approval process. He says this “two-tier” approval system presents some unfortunate gaps in regulatory oversight: whereas FDA requires a research phase for approvals, CLIA does not; FDA requires analytical validations, while CLIA does not; FDA requires clinical validations, but CLIA does not. In addition, FDA requires reports on adverse events, but there is no such requirement for CLIA-approved tests, and no system in place for receiving or analyzing adverse-event reports.

Gutierrez noted that it is difficult or impossible for insurers to determine the true value of such tests in order to subject them to “pay-for-performance” reimbursement schemes, nor is there any good way to judge their comparative effectiveness. Since 1997, FDA has attempted to partially close the regulatory space that exists between laboratory tests that have been marketed through the FDA process and those that have come to market under CLIA rules.

The issue of whether—and to what degree—FDA may second-guess the use of CLIA-regulated tests in clinical practice remains a question of major interest for industry and for laboratories, Gutierrez said.

Then in September, CDRH acting director of chemistry and toxicology devices Courtney Harper amplified Gutierrez’s message at a Regulatory Affairs Professionals Society (RAPS) meeting. She said that CMS-regulated LDTs are tolerated under FDA “enforcement discretion.” They “present risks to patients,” she said, defining them as tests that have been fully developed in a single laboratory for use only in that laboratory, and that have no premarket review, no independent research basis, and no requirement for clinical validity. While the agency has no timeline to take over all LDTs—a step that doubtless would require notice-and-comment rulemaking—it’s clear that there’s a rising drumbeat at the center for this to happen.

Amalgam Turmoil

In August, FDA published a final rule reclassifying mercury-based dental amalgam as a Class II device. This action shocked many dental and toxicology experts, who quickly submitted two petitions seeking reconsideration before the rule’s effective date, November 2.

Two experts on mercury amalgams criticized the final rule’s literature-review and procedural foundations, saying that they upheld prior controversial agency assertions that continued use of mercury in amalgams is safe, except for allergic patients. In addition, dentists have long been retreating from amalgam in favor of safer, less-durable, and more-expensive alternatives.

Former International Academy of Oral Medicine and Toxicology resident David Kennedy, a San Diego-based preventive dentist and international lecturer on toxicology and restorative dentistry, told us he had read the complete document and had “found numerous errors in [FDA’s] assumptions.” In particular, he said, the preamble to the rule minimized the effect of mercury amalgams on children between the ages of two and seven as measured clinically in urine. He said the preamble discounted the significance of clinical studies that showed progressively less mercury leaking into the urine of children, particularly boys, year to year. “If less and less is leaking into urine, it’s obviously accumulating in the body,” Kennedy said.

Kennedy also faulted FDA for adhering to the agency’s 2006 white paper declaring mercury amalgams safe—even after it was soundly rejected by a joint meeting of its Dental Products Panel and Central Nervous System Drugs Advisory Committee. The second expert criticism of FDA’s rule came from University of Washington’s James S. Woods. The research professor said that the rule’s preamble had erroneously used three out of nine citations to his publications on the effects of mercury amalgams in humans.

All this and more had little effect on FDA’s public face. “The FDA does not agree with the characterizations of its rulemaking,” said agency spokesperson Mary Long. “The agency’s findings and conclusions are based on an extensive review and analysis of the scientific data pertaining to potential adverse health effects from exposure to mercury vapor from dental amalgams in the general population and in sensitive subpopulations. The FDA believes its rulemaking is in compliance with the Administrative Procedures Act.”

Moms Against Mercury national counsel Charles Brown then mounted a trenchant Internet campaign against agency commissioner Margaret Hamburg for having a conflict of interest on amalgam based on prior stockholdings in and employment by a major amalgam shipper. This campaign was also waged against deputy commissioner Joshua Sharfstein for being responsible, after Hamburg’s recusal, for such a scientifically flawed rule.

This campaign consisted of a flood of carefully orchestrated e-mails to both officials from members of Brown’s 5000-strong network of people opposed to mercury amalgam. The success or failure of this intense effort is to be seen in whether FDA accedes to two petitions seeking the final rule’s reconsideration.