Most recently, the new spirit toward industry showed itself in the words of Commissioner Andrew von Eschenbach. He spoke via a prerecorded satellite feed to AdvaMed's annual meeting in Chandler, AZ, in March.
“It has been my experience,” he said, “that we have the opportunity to serve large companies that are addressing macro issues of complex product development as well as small companies that are really at the forefront of entrepreneurial innovation.” This notion of FDA in a service role for an industry it regulates is new. In my view, it flows from the introduction of user fees paid by industry for the review and approval of new products.
Indeed, barely a week after his AdvaMed remarks, von Eschenbach appeared before the Senate Health, Education, Labor, and Pensions Committee. There, he said that drug user fees are “specifically intended to be fee-for-service.” His testimony to the senators stressed that industry fees don't sway FDA's scientific decisions. However, von Eschenbach left unaddressed the vast nonscientific landscape on which FDA regulators and fee-paying industry people routinely make contact. That's where some industry watchers assert that a change of attitude has occurred among high-level FDA managers. That's also where the notion of FDA providing a service to the device industry has taken root.
The new dynamic's origins may be traced back to von Eschenbach's predecessor, Lester Crawford. In March 2004, he proclaimed—at AdvaMed's annual meeting—that his door was always open to industry. He also said that communication was the name of FDA's game. “We've had some great communicating commissioners,” he bragged, “but I'm still the only one that ever has had a listed phone number. So give me a call!”
Of course, even for FDA commissioners, talk may be cheap. Kevin Cornwell, CEO of Utah Medical Products, took Crawford up on his invitation and spoke to him twice. Cornwell says the commissioner twice committed to follow up but did nothing to avert the agency's legal action against his firm. This may raise a question about how useful to industry FDA commissioners really are.
Three years further down the FDA-as-servant road, von Eschenbach made his long-distance debut at AdvaMed atop the momentum of a just-concluded negotiation between FDA and industry to reauthorize MDUFMA.
In his video, von Eschenbach was effusive in his gratitude. “I wanted to take this opportunity to speak to you as the FDA commissioner,” he said, “to reaffirm how much I value the importance of the work that you are doing.” He said he particularly valued the strong partnership that has been formed between AdvaMed and FDA.
He briefly described how their interactions benefit patients. Then, von Eschenbach said he was “very, very gratified by the recent collaboration between industry and FDA as we have worked together to renew authorization of MDUFMA. I've been particularly gratified and grateful for the support and leadership of the AdvaMed board in helping to seek constructive solutions for many of the challenges that we have to face.”
Von Eschenbach described how the new user fees would improve CDRH's reviews of AdvaMed members' products and enhance FDA expertise. By means of these improvements, patients will benefit through FDA's service to all kinds of device makers. “FDA has a mission that's directed across the entire continuum of the industry,” he said, “and collectively that will enable us to be sure that we're bringing the most effective products to the marketplace.
He stressed that FDA and industry working together can save lives and can transform healthcare. “It's a privilege for me to thank you for the collaboration in the effort that we are embarked upon to make that a reality,” he continued.
He again praised AdvaMed's support of the MDUFMA “legislative package.” He said it creates “what we believe is an appropriate and exciting opportunity for both FDA and industry to have the resources that will enable us to enhance the regulatory process. I am committed to that relationship and to that outcome.”
He also promised FDA's full commitment to all the new FDA review performance goals set out in a separate letter to Congress alongside the MDUFMA reauthorization agreement. “If FDA says we will do it, we will do it,” von Eschenbach said. “Let me add that [we're] not just committed to meeting the goals; we're committed to exceeding the goals. I believe we have the opportunity for continuous quality improvement and continuous performance improvement at FDA.”
Meeting the goals will not only improve the MDUFMA relationship, von Eschenbach said. “It's really our commitment to bring to patients, the public that we serve, solutions to the problems that threaten their health and their lives.” Doing that more efficiently and more rapidly, he said, is core to FDA's mission. “That is a commitment that you and I share together. I look forward to a continued dialogue and conversation, and most importantly I look forward to the very collaborative and cooperative relationship that exists between FDA and the device industry—and particularly, AdvaMed.”
Daniel Schultz believes advisory panel reviews serve a necessary purpose.
There was much regulatory good feeling spread throughout the session. By the time CDRH director Daniel Schultz and CBER director Jesse Goodman had finished their presentations, one hopeful listener was moved to sound out the prospects for even better news.
Could we do away with advisory panel reviews? The advisory panel review process for new devices can seem “like going to Vegas,” he said. “I'm curious to hear your perspectives. Do you think it's a process that still serves its original intended purpose or one that needs to be embalmed or changed?”
But review changes were not in store. Although Schultz thought it a “great question,” he quickly reverted to FDA conventional wisdom. Panel review still serves a necessary purpose, he said, “from a number of different aspects. One is that it allows us to bring in specific expertise in a whole variety of areas that we may not have internally. Two, it provides an outside look at products. You may have been spending 10 years of your life developing the product, and we may have been spending five years of our life looking at that product. I think at that point, everyone develops a little bit of tunnel vision.”
Having others look at it from a public health perspective “is a good thing,” Schultz said. Panel reviews are important from both a communications and a public trust standpoint. “It's unique to our regulatory system, and a credit to it, that we do lay everything out in public.”
Goodman said he agreed “absolutely. Transparency is very beneficial to everyone.”
User fees have engendered a new attitude toward industry at the highest levels of the agency. However, the historic devotion to burdensome public transparency lingers on, to the cost of product sponsors and to the education of bystanders.
The question of the effect of commissioners on FDA operations remains unanswered. Nevertheless, a new tradition of FDA service to industry is being forged, at least at the upper-management level.
Virginia Gibson suggested that device manufacturers reward whistle-blowing.
“There's been a real failure of trust that has happened between the device industry and its customers.” That startling judgment was delivered on March 8, 2007, to AdvaMed's annual meeting by Assistant U.S. Attorney Virginia Gibson. Apparently referring to access restrictions imposed by hospitals against industry salespeople, Gibson asked: “Why is it that your customers are asking for so much verification just to let you in the door?”
Gibson is civil division chief in the U.S. Attorney's Office for the Eastern District of Pennsylvania. She was addressing AdvaMed on fraud penalties imposed on hospitals and other device users for failing to report purchase discounts and other cash incentives received from manufacturers. When claiming reimbursements under federally supported programs, users are required to report them. “You can be implicated in that,” she warned manufacturers. “You could have caused the failure to report, or caused the submission of false reports.”
Gibson's wide-ranging presentation also covered legal constructs of fraud arising from off-label uses and failure to report adverse events to FDA. “If a company is running its operations in a way that can keep hospitals from having problems from the enforcement authorities, then that is going to pay off on the business side,” she said. “Bring the hospitals and doctors back to the origins of your industry. It's a fascinating industry where you have a lot of collaboration between the inventors and the physicians who use your products. Access matters in that kind of collaboration, but make sure that the access is clean; make sure that it's not going to create risks for your customers and you.”
Gibson predicted that there would be increased pressure in the area of adverse-event reporting. Both the Justice Department and the HHS Office of the Inspector General could target industry. This is the result of a new law that requires hospitals to report patient outcomes to CMS on about 10 diagnoses. The Justice Department is interested, she said, because “the government is paying for an awful lot of healthcare in this country, and we care about the quality that is being delivered.”
She gave two examples. One involved a dental cement manufacturer that failed to report hundreds of adverse events to FDA. It was prosecuted under the Civil False Claims Act based on the theory that the claims submitted for reimbursement were fraudulent. “The government was paying for the devices in the first instance, and [then] paying for the replacements. There was a civil settlement in that case.”
The second case was criminal prosecution of Guidant for failure to report adverse events. “The company knew about the problem with the device,” she said. “The sales force tried to help fix the problem. Guidant didn't go to FDA about it; [it] basically did a shortcut around the science. There was an FDA inspection and the problems were hidden from FDA.”
Gibson warned that another area being watched is off-label marketing. “This is a very innovative industry, and we understand that you believe in your products,” she acknowledged. “But it is absolutely essential to avoid the risk of prosecution, to tell the truth, and not to substitute your own judgment for that of FDA's about a device's safety and efficacy.”
Gibson urged medical device companies not to wait for a U.S. Attorney's Office visit or a whistle-blower's lawsuit before taking action to update, enhance, and abide by a corporate compliance policy.
“Match the incentives of your sales staff to your compliance program,” she urged. “Reward whistle-blowing—what a concept! That's what we do. We reward whistle-blowing, and we have an awful lot of it. If companies rewarded whistle-blowing and addressed those problems, maybe less of it would come to us.”
Bausch & Lomb has recalled 12 lots of ReNu MultiPlus contact lens–care solution made at its plant in Greenville, SC, because they contain an elevated level of trace iron. The company says the trace iron may cause solution “discoloration.” The shelf life may also be shortened to less than its two-year expiration date. The solution was made “about a year ago,” with most of the product having already been used by consumers.
The Greenville manufacturing plant was at the center of last year's reports of Fusarium keratitis. The result was a market withdrawal of the firm's ReNu with MoistureLoc contact lens solution. FDA issued the company a warning letter late last year citing quality system deviations found at the plant. Bausch & Lomb has been awaiting a reinspection at the facility, which it expected during the first quarter of 2007.
In the latest recall, Bausch & Lomb says it began an investigation after receiving three customer reports of discolored solution. The root cause was determined to be an elevated level of trace iron in a single batch of raw material sourced from an outside supplier. “The elevated level of trace iron could combine with other compounds in the solution to cause discoloration. [This discoloration] signals that the solution may be losing effectiveness over time,” the firm explains.
Defibtech (Guilford, CT) has recalled 42,000 Lifeline and ReviveR semiautomatic external defibrillators that contain software versions 2.002 and earlier. “The self-test software for these devices may allow a self-test to clear a previously detected low-battery condition,” the company says. “If this situation occurs, the operator may be unaware of the low battery, and the device may be unable to deliver a defibrillation shock, which could result in failure to resuscitate a patient.”
An FDA notice says the company received three reports of malfunctions from end-users. “The company has provided a maintenance procedure that can be used to verify functionality of the device until the software upgrade has been installed, allowing the device to remain in service,” it says. A free software upgrade will be installed in the field within the next 10 weeks, according to the notice.
An FDA inspection last November and December at GE Healthcare's USA Instruments medical device manufacturing facility in Aurora, OH, found quality system violations. The violations center on the manufacture of coils used in MRI systems and breast biopsy plates.
Violations noted in a February 22, 2007, warning letter from FDA's Cincinnati district office included failure to ensure that only those devices that are approved for release are distributed. Also cited was failure to fully document validation activities for breast biopsy plates and to verify or validate corrective actions taken. GE also did not include complete acceptance records for the eight-channel Body Array Coil demonstrating that the device is manufactured according to the device master record. The firm did not investigate possible failure of devices to meet specifications when necessary, nor did it process complaints in a uniform and timely manner, the letter said.
The warning letter acknowledged a January 14 response from company officials and said some descriptions of corrections appeared to be adequate, while others didn't contain enough information.
The company was told to take prompt action to correct the violations. It must also submit documentation of corrective actions planned and taken.
FDA has issued a warning letter to BSD Medical Corp. (Salt Lake City) detailing problems found in conducting a clinical study at one site. Concerns addressed in the letter included monitoring, securing investigator compliance with the protocol, and reporting. BSD develops systems delivering precision-focused thermal cancer treatments.
BSD said the concerns are limited to conduct of the study and not to the safety, efficacy, quality, design, or manufacture of its equipment. Company officials said the research data from the site have not been used to seek FDA approval for any BSD product. The data also have not been used to statistically support the efficacy of BSD systems in treating patients.
Research at the site was not funded by BSD, the company said, and the site has been closed to treating patients since last September. The officials said they would provide FDA a complete report on actions taken and procedures implemented to address the deficiencies noted in the warning letter.
The company noted it has submitted a premarket approval (PMA) application based on a European study that was not the subject of the warning letter.
FDA has cleared a Baxter Healthcare 510(k) for the troubled Colleague drug infusion pump as part of the company's remediation under an earlier consent decree with the agency. The company says it intends to modify pumps currently in the market. It plans to submit manufacturing and service documentation to FDA in advance of deploying upgrades to U.S.–based pumps, which are estimated to number 200,000.
In January, FDA gave Baxter “conditional approval” for a plan to correct the Colleague pump. Although it provided few details of its corrective action plan, Baxter did say an updated 510(k) needed to be cleared before the agency would approve its plan.
The Colleague pump was at the center of a court-approved consent decree last year after FDA ordered U.S. marshals to seize several thousand units. At the time of the decree, FDA alleged, “none of the seized infusion pumps were manufactured under the proper controls.” It also noted that the Colleague pumps had a design defect that may cause the pumps to stop and shut down during infusion therapy. Additionally, FDA charged that Baxter failed to inform the agency about pump failures as required by the MDR rule. The decree also called for third-party expert reviews of Baxter's manufacturing operations and other measures to ensure compliance with FDA's quality system regulation.
FDA said in a release announcing the 510(k) clearance that “confusing display screens, software defects, swollen batteries, and other defects could have resulted in the pumps either shutting down or under- or overdelivering critical medication and fluids to patients and were associated with serious injuries and deaths.”
Baxter has a long history of running afoul of FDA manufacturing and promotional regulations. A 1999 inspection revealed similar battery problems with company-manufactured infusion pumps. In 2001, another FDA inspection documented additional battery and design concerns with Baxter's pumps. In fact, over the last decade, FDA has issued 15 warning letters to Baxter.
FDA has issued a guidance for industry and FDA staff titled Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests. It describes statistically appropriate practices for reporting results from different studies evaluating diagnostic tests. It also identifies some common inappropriate practices.
FDA says the guidance's recommendations pertain to diagnostic tests for which the final result is qualitative, even if the underlying measurement is quantitative.
Comments on a March 12, 2003, draft guidance asked for greater attention to use of standard terminology, FDA said. Where possible, this new guidance uses internationally accepted terminology and definitions.
The guidance covers benchmark and study population recommendations, reporting recommendations, and statistically inappropriate practices.
The guidance may be accessed at www.fda.gov/ohrms/dockets/98fr/03d-0044-gdl0002.pdf.
A new CDRH guidance provides criteria for sponsors and device reviewers to use in determining the type of PMA supplement to submit to FDA when changes are made to a device's design, manufacturing process or location, processing or packaging, or labeling. The document is called Draft Guidance for Industry and FDA Staff—Modifications to Devices Subject to Premarket Approval (PMA)—The PMA Supplement Decision-Making Process. It provides examples of device modifications, and it describes the types of testing needed to support the safety and effectiveness for each device modification. However, the guidance does not address how to test a specific device to determine the effects of modifications.
The guidance may be accessed at www.fda.gov/cdrh/ode/guidance/1584.html.
CDRH has issued a guidance for industry and FDA titled Class II Special Controls Guidance Document: Antimicrobial Susceptibility Test (AST) Systems; Guidance for Industry and FDA. It supports reclassification from Class III into Class II (special controls) of an AST system when the device employs short-term incubation (less than 16 hours). AST systems are intended to determine the in vitro susceptibility of bacterial pathogens from clinical specimens.
Following the effective date of a final reclassification rule, any firm submitting a 510(k) premarket notification for an automated short-term-incubation-cycle AST system needs to address the issues covered in the special controls guidance. Issues covered in the guidance include risks to health, device history, and study design. Data presentation, study result evaluations, labeling, labeling limitation resolution, and QSR considerations are also mentioned.
The guidance may be accessed at www.fda.gov/cdrh/oivd/guidance/631.pdf.