Originally Published MDDI May 2004
Two device companies are claiming FDA's inspections were mishandled, raising questions about the agency's image as an industry helper.
James G. Dickinson
There's a long and rich folklore in the FDA-regulated industries about abusive FDA investigators and their bosses. It tells of nitpicking and unfair inspections, products kept off the market until companies cave in, and a code of silence wherein complaining will only make the situation worse.
With the industry-friendly political climate that Washington has enjoyed in recent years, however, FDA has seemed to pull in its horns and don the mantle of industry helper. There has seemed to be little reason to complain the way you were once afraid to.
But wait! Two diverse cases—one new, one old—oozed up between the cracks in February, as if to say, “It ain't over till it's over.” Both of the companies involved—Utah Medical Products and TMJ Implants Inc.—are in FDA's Denver district.
In the more recent case, Utah Medical Products (Midvale, UT) took the extraordinary step of issuing a news release to complain about a succession of FDA inspections. The company asserted that FDA's refusal to issue certificates to foreign governments caused the company's foreign sales to be blocked. The dispute shut down its communications with the agency. The company had already filed suit against FDA in federal court—but everyone knows how long that takes.
As part of its lawsuit, Utah Medical filed a stunning statement from former FDA New England district director Ed McDonnell. A former director of medical device compliance with the agency, McDonnell stated that his inclination would be to reprimand the two FDA investigators who inspected the company for failure to follow FDA inspection policy. He testified that they made material omissions and misrepresentations, possibly intentionally, in their Establishment Inspection Report (EIR). These, he said, could not help but mislead their supervisors.
McDonnell's declaration named the two allegedly deficient investigators as Ricki A. Chase-Off, of FDA's Salt Lake City resident post, and Karen Coleman, of FDA's Atlanta district, a national expert.
Among Chase-Off's abuses, McDonnell said, was her review of quality data presented during a Utah Medical internal management review in February 2003. She insisted on the review despite it being explicitly precluded by FDA policy McDonnell helped write. Then, in writing the EIR, Chase-Off incorrectly described the prohibited material (a memorandum) she obtained as permissible material (an agenda).
McDonnell said Chase-Off “grossly distorted information excerpted from the management review to create the false and misleading impression” that Utah Medical's most recent quality system audit resulted in its ISO registration being discontinued, an action that would have prevented its products being sold in Europe. In fact, the company had merely discontinued its registration under ISO 9001 in order to register under the more stringent ISO 13485 standards, McDonnell's declaration said.
“In my opinion, the most troubling feature of the textual inaccuracies found in the EIR is the possibility that it represents an intentional misrepresentation by Ms. Chase-Off,” McDonnell wrote. He added that Chase-Off deleted, in her EIR, a plain statement in the management review that the ISO “registration was continued and there were no new observations that indicated significant system problems.” She replaced it with another statement out of context from four pages later that the registration would be discontinued. In addition, he said, Utah Medical personnel told him that this was verbally explained to Chase-Off during the inspection, but “there is no mention of this dialogue in the EIR.”
Coleman stated in the EIR that Utah Medical “could not provide any evidence they had ever validated their extrusion or injection molding operations.” However, McDonnell states, she had been provided with documents demonstrating that these operations exceeded FDA's own quality system regulation requirements. These documents, covering “hundreds and hundreds” of successful batch runs, were not included as exhibits to the EIR, McDonnell said. In addition, 4 out of 31 other documents provided were also omitted. These documents demonstrated, he said, that Utah Medical was using statistical process control to measure and monitor its injection molding process.
“Having reviewed all of the documents collected by Ms. Coleman, I believe that the documents that she omitted from the EIR are the most significant to anyone reviewing molding documents and attempting to determine the adequacy of the company's quality assurance processes,” McDonnell's declaration said.
He also described how Utah Medical conducted a special comparative resistance study during the inspection in response to Coleman's stated concerns about catheter construction and sterility, only to see its exculpatory results omitted from the EIR—despite their having been provided to Coleman in plenty of time for inclusion.
“As a District director at FDA, I would have found these misstatements and omissions in the EIR highly material because the new study shows that Ms. Coleman was wrong about her conclusions,” McDonnell declared. “An FDA compliance officer relying on the EIR's discussion of resistance testing would be misled by Ms. Coleman's narrative and could reach erroneous conclusions about the adequacy of sterilization validation.”
Other problems with Chase-Off's conduct of the inspection, McDonnell said, included her failure to provide notice of alleged objectionable conditions during the inspection, as required by FDA policy. The Sunday night before the scheduled Monday morning final close-out meeting, Chase-Off e-mailed management a request for 21 different categories of documents that had not been discussed during the inspection. “The company has informed me that it never had any opportunity to discuss these documents or the investigators' issues with these documents,” McDonnell said.
At the rescheduled close-out meeting two days later, Chase-Off and Coleman issued an FDA-483 that contained 54 observations grouped into 19 numbered items, McDonnell said. Of the 54, company officials told him 18 had never been discussed during the inspection “and came as a complete surprise.” This violates FDA's Investigations Operations Manual.
Transcripts of the close-out meeting, McDonnell said, “show that the investigators ignored the agency's policy requiring a dialogue with the company…Perhaps the most significant effect of the investigators' practices is that the EIR does not contain the company management's reaction and rebuttal because the observations were often surprises. The result is a biased EIR that contains material omissions and a one-sided presentation of the issues.”
In the case of TMJ Implants (Golden, CO), readers may remember how FDA shut down that company five years ago over the reclassification of its two temporomandibular joint prostheses. This cost the company more than $6 million and led to a marathon reinstatement battle that took nearly two years. The company alleged FDA had shown favoritism toward one of TMJ Implants' competitors.
With congressional and media involvement, TMJ's devices were eventually rehabilitated, but the long and bitter memories in CDRH apparently were not. Last summer, the center had the Denver district office conduct a two-week inspection during which 22 unreported “complaints” were unearthed. According to a warning letter issued six months later, they should have been reported under the MDR regulation but weren't.
A number of the so-called reportable device complaints involved extraction of the implants. For example, in one complaint, a company-made prosthesis was removed due to loose hardware and infection, the warning letter said. It said the physician noted that longer screws were needed for the explanted device, but TMJ Implants countered that the loosening was caused by disease progression and bone degeneration, not screw length. In another complaint, surgery was performed on a patient to replace fossa screws due to an “improper fit.” FDA charged that the firm did not include any information as to why there was an improper screw fit; the company, however, said the surgeon stated that the loose screw was not device-related.
FDA's warning letter reminded TMJ Implants that similar concerns about the lack of MDR compliance were communicated in letters from the agency three times in the preceding 16 months. Despite a company promise to “reassess” its MDR compliance, the warning letter said, “we note that you have not yet filed MDRs for these events.”
Company CEO Robert W. Christensen told me on March 10, 2004, that he had just met with district staff for two hours to explain that none of the complaints cited in the warning letter alleged his devices were the cause of reportable injuries under the MDR regulation.
He said the issue between his company and the agency centered on conflicting interpretations of what must be reported. FDA says that if disease progression requires that a device be explanted, that is a reportable event. But Christensen's reading of 21 CFR 803.3(d) limits the need to report to cases where “death or serious injury was or may have been attributed to a medical device or a medical device was or may have been a factor in a death or serious injury.”
Christensen said FDA wants to use MDR for its own trending purposes, a use that is not specified in the regulation. “They should have some other in-house method for trending and not use the MDRs for that purpose,” Christensen said. “Any MDR filed can be used by our competition to defame our product, and by attorneys wishing to file actions against the company, without basis of fact.”
He said the agency is applying a different reporting obligation on his company than it applies to his main competitor, TMJ Concepts (Ventura, CA), which has only three adverse-event reports in CDRH's public database. TMJ Implants has nine reports posted, and FDA's warning letter would have it add 22 more. TMJ Concepts is the company Christensen alleged FDA was favoring five years ago.
Needless to say, FDA is constrained from commenting on either of these “open investigatory files.”
FDA's Open Door
If medical device companies are worried about their access to the FDA commissioner's office now that Mark McClellan has gone, they can relax. Acting commissioner Lester Crawford assured AdvaMed's annual meeting in Scottsdale, AZ, in March that nothing will change, unless the change will provide even more access, especially during “the next few months.”
He was responding to a question from AdvaMed chairman Dennis Longstreet, group chairman of Johnson & Johnson, who took a floor microphone to ask Crawford in a satellite hookup about access: “I just wanted to emphasize that it is very important to our industry and individual companies that we have access to you as acting commissioner. Going forward, can we count on that from you?”
Crawford: “Yes—we have an open-door policy. Unfortunately, there are a lot of people in the door! You'll need to work with us in that regard. I'll promise this to you: We will never tear down a request for a meeting with me, as long as I am here…FDA is committed to communication. The way you experienced that under the previous time when I was acting for nine months, and also during the 16 months that Dr. McClellan was here, is the way it will continue to be.
“We have rearranged and reorganized the commissioner's office in order to make us a bit more responsive over the next few months,” Crawford continued, “because we have some major undertakings that we are going to be bringing to fruition, most notably good manufacturing practices and [state-of-the-art FDA product review] process controls for applications, and that will need a lot of input from industry. When we make a misstep, or you perceive that we may need special information, special knowledge that you have, you should be able to walk through that door. I assure you that that's the case. We've had some great communicating commissioners in [this office], but I'm still the only one that ever has had a listed phone number. So give me a call!”
In his satellite presentation to AdvaMed, Crawford stressed his, and FDA's, admiration for the medical technology industry and its many contributions to bettering public health. But he also voiced concern about rising costs, stressing the need to keep healthcare affordable while continuing to encourage biomedical progress.
“Millions of Americans are rightly worried,” he said, “that even as new medical technologies come along, they won't benefit from them because they won't be able to afford the high cost, now almost 14% of our spendable income.
“We've been taking some unprecedented steps at FDA to help address the problem. It is continuing to get more expensive and more uncertain to transform these discoveries into something that patients can use and benefit from. Because…the uncertainty of medical innovation means rising costs and healthcare access problems from a public health standpoint, this is just not acceptable. This is not a sustainable situation. Rising costs of discovery and developing new medical technologies combined with increasing pressure to contain rising healthcare costs is not a good combination for medical innovation.”
Crawford said FDA is committed to making the development process more predictable, “to quit moving the targets, and to [give] more-timely reviews.” He said the agency aims to improve its performance by 25% for 510(k)s and PMAs “and even more for breakthrough devices.” FDA is also committed to improving the scheduling and timeliness of preapproval inspections, Crawford told
AdvaMed, adding that the agency “has now exceeded all the goals established under the user fee program over the past year.”
FDA as R&D Expediter
As a parting legacy, on March 16, 2004, outgoing FDA commissioner Mark McClellan hosted the rollout of a major new agency initiative to help industry more rapidly convert technological advances into marketplace realities.
A 32-page report entitled Innovation or Stagnation?—Challenge and Opportunity on the Critical Path to New Medical Products was inspired by McClellan and FDA director of cross-center initiatives Janet Woodcock. The report says FDA is undertaking an initiative to identify and prioritize the most pressing development problems and the areas of greatest opportunity for rapid improvement and public health benefit. It identifies three dimensions along the critical path to be addressed: safety assessment, evaluation of medical utility, and product industrialization.
The report says the heart of the development slowdown problem is that the applied sciences that medical product development requires have not kept pace with the basic sciences. What's needed, FDA says, is a product development tool kit with powerful new scientific and technical methods such as animal- or computer-based predictive models, biomarkers for safety and effectiveness, and innovative clinical evaluation techniques.
“Scientists involved in reviewing medical devices at FDA report an urgent need for predictive software to model the human effects of design changes for rapidly evolving devices,” the report adds. “We believe that such software may be attainable with a concentrated effort by assembling currently available data and identifying existing data gaps.”
FDA says it will be working with relevant stakeholders in creating a “Critical Path Opportunity List” to identify the most important challenges. It also will refocus internal efforts to ensure agency staff are working on the most important problems, as well as intensifying support of key projects. The next steps include workshops and meetings to start development of the Critical Path Opportunity List and identify key priorities.
Application Integrity Policy Applied
FDA has placed Diagnostic Products Corp. (Los Angeles) on the agency's “application integrity” list after an inspection related to a recent 510(k) submission raised serious questions about the integrity of the data and information contained in the filing. The 510(k) in question is for the company's Chagas disease diagnostic test.
According to the company, FDA has suspended the review of the submission and will also “defer scientific review of any future submissions until these issues are resolved.” In a statement from the company, CEO Michael Ziering is quoted as saying, “We have initiated a process to identify and correct the causes of these issues. Our understanding is that a reasonable time for the resolution of these types of issues is approximately 12 months. Our new instrument, the Immulite 2500, and 74 assays which run on it, have already been cleared by the FDA.”
Embolization Device Guidance
FDA has issued Class II Special Controls Guidance Document: Vascular and Neurovascular Embolization Devices, a draft guidance for industry and FDA staff. The agency says the draft will be finalized only if a final rule is issued to reclassify vascular embolization and neurovascular embolization devices into Class II. If finalized, the guidance will supersede the November 1, 2000, Guidance for Neurological Embolization Devices.
FDA says vascular embolization devices, as proposed, are intended to control hemorrhaging caused by aneurysms, certain types of tumors, and arteriovenous malformations. Neurovascular embolization devices, as proposed, are intended to permanently occlude blood flow to cerebral aneurysms and cerebral arteriovenous malformations.
“FDA believes that the risks to health associated with the intended uses of the vascular embolization and the neurovascular embolization devices are the same, [and] therefore FDA believes that a single guidance document can serve as the special control for both types,” the guidance explains. Following the effective date of a final rule reclassifying these devices, any firm submitting a 510(k) for a vascular embolization or neurovascular embolization device will need to address the risks identified in the special control guidance document. “However,” the draft guidance says, “the firm need only show that its device meets the recommendations of the guidance document or in some other way provides equivalent assurances of safety and effectiveness.”
The guidance also states that FDA believes an abbreviated 510(k) provides the least burdensome means of demonstrating substantial equivalence for a new device, particularly once a Class II special controls guidance document has been issued.
The draft guidance reviews the content and format of abbreviated 510(k) submissions and the health risks generally associated with the devices, including blood vessel perforation or rupture, unintended thrombosis, adverse tissue reaction, infection, and hematoma formation. It also outlines measures to mitigate the risks as part of preclinical testing, animal testing, clinical testing, sterility, and labeling.
The draft guidance may be seen at www.fda.gov/cdrh/ode/guidance/1234.pdf.
Patient Lifts in Class 1 Recall
FDA reports that Moving Solutions Inc. (Downers Grove, IL) is recalling 865 Faaborg-model battery-operated patient lifts because of a faulty design. FDA says the Class 1 recall is due to excessive wear on the device's main bolt, which has led to the bolt breaking and causing the patient to fall. The bolt secures the lift arm to the main frame of the patient lift.
Because the malfunction can cause serious injury or even death, FDA says healthcare facilities should stop using the lifts until the problem is corrected. There has been one death reported from the bolt breaking and a resulting patient fall.
Moving Solutions notified users earlier this year about a “continuing problem with the bolt and included a nylon washer with its letter, instructing facilities to insert the washer between the hanger-bar bolt and the sling spreader arm,” FDA says. It adds that there is “no assurance that the washer will prevent the rubbing that caused the bolt to wear and break, and an investigation is under way.”
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