An Uptick in FDA Enforcement

Originally Published MDDI June 2004

WASHINGTON WRAP-UP

As FDA prioritizes its GMP inspections to conserve resources, the agency finds that collaborating with the SEC could benefit both agencies.

James G. Dickinson

Cordis Stent Approval Hostage to GMP Issues | Political Interference in FDA Abuse Probe? | Plus Orthopedics Penalized for Study Problems | Feigal Leaves CDRH to Follow Wife to Arizona | Couple Indicted for Defrauding Roche Diagnostics   

FDA is currently somewhat adrift, as all federal agencies are in an escalating political season. Plus, the agency is without both a permanent commissioner and a permanent director for its Center for Devices and Radiological Health. It's not surprising, then, that FDA in May showed signs of falling back on its traditional routines. This apparent uptick in enforcement activities, coincidentally, is unlikely to hurt the Bush administration's electoral image.

The days of the biennial GMP/QSR inspection have long given way to triaged inspections. Today's inspections are risk-based. They are used to increase public health and conserve scarce resources. In addition, they increasingly resort to leveraging with other agencies to gain, in former commissioner Mark McClellan's hard-worked phrase, “more bang for the buck.”

A good example of this is FDA's information-sharing collaboration with the Securities and Exchange Commission after the Martha Stewart scandal. The agency wants to make sure that what companies tell the financial markets about their FDA-related activities is the truth, the whole truth, and nothing but the truth.

The first example of this information sharing involved a medical device company, Biocurex (Richmond, BC, Canada). The company's Class I blood test, Histo-RECAFTM, had been featured in a news release to the financial community as a “universal cancer marker.” In fact, it had been accepted by FDA in 2001 for a far more specific use. FDA said it was “a qualitative ligand-binding histochemical kit for use as an adjunct to standard high microscopy staining methods for detection of alphafetoprotein binding on formalin-fixed, paraffin-embedded tissue sections as an aid in the identification of [cancerous breast] and axillary node tissues.”

Class I devices are exempt from 510(k) premarket notification requirements and do not fit FDA's current risk-based enforcement priorities. But cancer detection is a top public health priority. So rather than use its own scarce resources, FDA contacted the SEC. The commission suspended trading in Biocurex stock. The company then issued a corrective news release that said explicitly that FDA “has not ‘approved' the Histo-RECAFTM product for the diagnosis of cancer.”

We can expect to see more of this kind of interagency leveraging.

But another element may also be driving the FDA enforcement uptick. The violative rate for manufacturers of medical devices is 500 times that of manufacturers of pharmaceutical products. Discovered by CDRH bioresearch monitors, this information was shared with attendees at a Food and Drug Law Institute annual conference session in April 2004.

Michael Marcarelli, director of bioresearch monitoring, told the session that, although this huge disparity is “alarming,” his staff is unsure of its cause. “The difference may be due, in part, to the fact that manufacturers of medical devices tend to be much smaller, less well funded, and with smaller staffs for research oversight than is the case with drug companies,” he speculated. Marcarelli said smaller companies sometimes experience “sticker shock” when they realize the costs associated with a well-run clinical trial and may seek to economize or to “cut corners.” He cited one example of a firm that engaged untrained “Kelly temps” to manage the collection of clinical trial data. Their lack of understanding of certain technical aspects of the trial led to a serious compromise of the clinical data.

Jonathan Kahan, the Association of Medical Diagnostics Manufacturers' general counsel, suggested that there may be a reason for the disparity. He said that device clinical research affords more opportunity for deviation from protocols—inadvertently or otherwise—than most clinical studies of drug therapies.

In another example of enforcement leveraging of scarce resources, CDRH has mounted an outreach program to various industry-related professional organizations. Marcarelli hopes that this will forestall problems and raise awareness among their members of the importance of bioresearch monitoring, which accomplishes more than simply identifying violators and imposing sanctions. The agency has also developed a Web-based training course for clinical investigators, and has published a “Good Monitoring Practices Guidance Document.” These, Marcarelli said, can be a valuable resource for sponsors and researchers.

Also in April, Tim Ulatowski, CDRH director of compliance, told an AdvaMed workshop that his office is focusing on companies that continue to broaden claims about the intended uses of their 510(k)-cleared devices. He gave various recent examples of warning and untitled letters issued because of promotional claims.

These included a March 4 warning letter to Health Directions (Middletown, PA). Ulatowski said the company had broadened the intended use of its Health Pax cranial electrotherapy stimulator device. Its 510(k)-cleared use was as a cranial electrotherapy stimulator for applying electrical current to a patient's head to treat insomnia, depression, or anxiety. Company promotional materials said it was helpful in changing compulsive behaviors such as smoking. They also said the device was successfully used in treating epilepsy under clinical supervision where “both the frequency and severity of seizures were reduced.”

Twenty-six warning letters had been sent to respirator mask makers who claimed their masks could be used for preventing SARS, Ulatowski reported. The masks were 510(k)-cleared for such uses as “filter efficiency against particular aerosols free of oil” and “minimizing exposure to certain airborne particles.” He said currently there is no device cleared or approved to prevent transmission of SARS, and any such claim would require approval through the PMA process.

In another instance, CDRH sent an untitled letter to a maker of a reusable cold pack that was “marketed as a skin cooling system for laser treatments,” Ulatowski said. “Cooling devices for lasers are accessories to lasers and require premarket notification,” he said.

A February 12 warning letter was sent to Marine Polymer Technologies Inc. (Danvers, MA) because of claims that modified the intended use of its Syvek patch, a medical adhesive tape and bandage for patients on anticoagulation therapy or hemodialysis. The company's promotional material included questionable claims, the letter said, citing “vascular access site homeostasis” and “rapid cessation of bleeding at the vessel itself.” The claims, Ulatowki explained, were a significant modification in intended use because the device was intended only to manage external bleeding.

And Kegelmaster 2000 (Sarasota, FL) was sent an untitled letter for claiming that its 510(k)-cleared device was approved by FDA, Ulatowski said. “Substantially equivalent devices do not receive the same safety and effectiveness evaluation as do products subject to premarket approval requirements,” he said.

Cordis Stent Approval Hostage to GMP Issues

Cordis Corp.'s recent GMP and quality troubles followed it into an April 21, 2004, Circulatory System Devices Panel of the FDA Medical Devices Advisory Committee meeting. The panel voted 6–5 to recommend approval of the company's Carotid System. However, before premarket approval is granted, FDA must evaluate a corporate corrective and preventive action plan that addresses quality issues related to the company's Cypher stent.

Earlier in April, FDA had sent the firm a scathing eight-page warning letter after inspecting six Cordis facilities that manufacture the Cypher stent. In the letter, CDRH office of compliance director Tim Ulatowski said, “FDA is concerned with the breadth and scope of the specific violations noted in this letter and the inspectional observations noted on the form FDA-483s which we believe are symptomatic of serious underlying problems in your firm's manufacturing and quality systems.” The facilities inspected were located in Miami Lakes, FL; San German, PR; Warren, NJ; Roden, The Netherlands; Beerse, Belgium; and Latina, Italy.

Responses to the individual FDA-483s failed to “bring together the corporate corrective and preventive actions necessary to tie the operation of all these facilities together as they all contribute to manufacture this particular product,” Ulatowski wrote. He suggested that after the company responds to the findings in the warning letter, company executives and the respective FDA district offices should hold meetings to address outstanding concerns.

The warning letter charged that Cordis's quality board did not document the review of any additional thrombosis complaints from outside of the United States after reviewing an initial nine reports from the Roden facility. Ulatowski wrote that the quality board instructed the Roden facility to monitor these event types closely, “but gave no clear documentation or direction to Roden QA on how to monitor the situation.” 

The inspections, Ulatowski's letter said, found several problems with the way Cordis investigates out-of-specification (OOS) test results. For example, some OOS results at the San German plant were invalidated “without documented assignable causes or adequate scientific rationale.” In some cases, retesting had occurred with new samples rather than the original samples as required by its procedures.

On the production and process control side, FDA said Cordis's validation relating to its stent-coating process was inadequate. FDA also said that an Internet-based reporting system for clinical and postmarket events for physicians was not adequately validated. Additionally, the letter said an automated data acquisition system used to ensure the integrity of data from laboratory chromatography equipment was not adequately validated.

Once Cordis submits its quality plan, the company expects to meet with the agency. Participants will discuss exactly what effect the plan will have on the firm's submissions, according to Marty Schildhouse, company communications director. He also said that Cordis had not been told that its pending PMA is on review hold. 

Cordis's Carotid System is a two-component device made up of the company's Precise self-expanding nitinol stent and Angioguard emboli capture guidewire. It is intended for treating carotid artery disease in high-risk patients. The panel said conditions for approval “include a clarification of eligible patients, postmarket patient review, and appropriate use of the system's distal protection device to minimize the risk of stroke,” a company release said.

Political Interference in FDA Abuse Probe? 

An 18-month-old investigation by the HHS inspector general's office (IGO) into allegations of criminal misconduct by CDRH employees has stretched on and on, according to TMJ Implants Inc. (Golden, CO). The company's president, Robert W. Christensen, alleged that there have been no interviews of principal witnesses. On April 29, 2004, he sent a three-page letter to acting deputy Inspector 
General Martin A. Campbell. While praising the competence of the lead investigator in the case, Matt Kochanski, Christensen's letter said, “I have serious concern that political pressures from both within [FDA and IGO] have been operative and have prevented Mr. Kochanski from doing his job.”

TMJ Implants Inc. is currently under FDA investigation for allegedly failing to provide CDRH with 22 medical device reports. Denver district investigators found the reports in the company's files, but the company says that they do not implicate its products.

The investigation, which IGO acknowledged in an April 19 letter from Campbell to Christensen, was opened in late 2002. Christensen alleged illegal behavior by CDRH employees in refusing to approve his temporomandibular joint (TMJ) prostheses. He believes CDRH showed favoritism to a competitor's product and coerced committee members to vote against his device. In his letter, Campbell called the investigation “preliminary” and said that while he cannot provide a detailed status, “I can assure you that all steps are being taken to conclude it as quickly and efficiently as possible.”

Christensen's response questioned this assertion. While IGO had indicated that at least some of his allegations had been deemed serious enough to raise the potential for prosecutorial action, Christensen wrote that none of his requests for clarification as to which allegations were being investigated received a response. “This seems peculiar and unexplainably and unnecessarily secretive,” he said.

“We have serious doubt that certain individuals who are relevant to events of serious misconduct have, in fact, been interviewed,” Christensen wrote Campbell. As an example in the letter, Christensen named a member of the panel that reviewed the company's PMA. The panel member confided to Christensen that “he felt coerced by FDA employees to vote against approving the company's PMA, although his clinical, scientific, and professional judgment was that the PMA should be approved. [The panel member] explained to me that he voted against recommending approval because of his desire to be appointed to future panels and his belief that if he did not vote against recommending approval (according to the staff's desires) that he would be denied future appointments to FDA panels. Mr. Kochanski and Mr. Dennis were informed of this; yet [the panel member] has never been contacted by anyone from the IG's office.”

Christensen cited the example of an IGO investigation in the 1990s into misconduct by the same CDRH office with the same panel involving Myo-Tronics charges. After the investigation, “several individuals involved in the misbehavior were separated from the agency.” He said he has collaborated closely with Myo-Tronics president Roland Jankelson throughout his own company's CDRH ordeal. In doing so, he noted significant investigational discrepancies in the way the IGO treated each, including protracted noncommunication with TMJ Implants. Communication, he writes, “has been nonexistent for over a year-long period during the supposed investigation of our allegations. And it raises the question of how an investigation can be effectively carried on without communication with our company.”
The IGO declined to comment on Christensen's charges.


Plus Orthopedics Penalized for Study Problems 

Artificial hip and knee component maker Plus Orthopedics (San Diego) has been placed on FDA's application integrity policy list. The agency is now deferring substantive scientific review of its submissions and proceeding to withdraw certain approved applications.

The company received a warning letter last year over problems related to its performance of sponsor obligations involving investigational devices. The letter charged that Plus Orthopedics failed to submit an IDE application before shipping some of its investigational devices. Additionally, it did not ensure that clinical investigators participating in a company-sponsored study obtained IRB approval prior to use of an investigational device.

Plus Orthopedics also initiated two recalls last year—one involving its Hip Stem because of “design changes,” and the other involving the TC-Plus femoral component due to “inaccurate dimensions of the device.”

Feigal Leaves CDRH to Follow Wife to Arizona 

After five years as director of FDA's Center for Devices and Radiological Health, David Feigal resigned unexpectedly in April. He will follow his wife, Ellen, a National Institutes of Health cancer researcher, to Arizona. She has been appointed vice president of clinical sciences and deputy scientific director of Translational Genomics Research Institute (TGen) in Phoenix. 

Feigal will now focus his efforts on an earlier stage of medical product development. He has accepted a position with NDA Partners LLC (Falls Church, VA) as head of its medical device and biologics practice areas. NDA Partners advises midstage device and biopharmaceutical companies on discovery, preclinical and clinical strategies, and product development design and execution. The appointment was announced May 5, 2004, a week after Feigal stepped down from CDRH.

Feigal said he believes small and midsized firms will be at the forefront of product innovation across all areas of healthcare in the near future, particularly in combination products.

“I have always been interested in making product development more efficient and predictable and am looking forward to the opportunity to assist small and medium-sized pharmaceutical and device companies where many of the new therapies are being discovered,” he said. “These companies have great potential to positively impact public health as well as to open new markets.”

He noted that there are multiple paths to market and approval strategies for such firms. He wants to help small and midsized firms explore their options to the fullest extent.

Carl Peck, chairman of NDA Partners, said someone with the diversity of Feigal's background is necessary to advise industry as drugs, devices, diagnostics, and biologics converge. Before heading CDRH for five years, Feigal worked for FDA's Center for Biologics Evaluation and Research and its Center for Drug Evaluation and Research.

“Increasingly, innovative products blend devices and diagnostics with biologics or drugs,” Peck said. “Due to the complexity of these unique products, the development of a streamlined regulatory and scientific path is a strategic necessity. Dr. Feigal . . . will provide invaluable insight and guidance to our clients, who otherwise would be unable to afford or attract expertise of this caliber.”

Acting commissioner Lester M. Crawford praised Feigal for working with Congress and industry. He lauded the launch of a medical device user-fee program that “has laid the groundwork for CDRH's product approval program in the years to come. Drawing on his years of experience in academia, Dr. Feigal was a strong advocate of the Center's educational programs for the staff, and actively promoted a highly productive interchange between the academic community and the agency. He also championed major organizational change initiatives to help assure the future of CDRH through the successful deployments of key strategic initiatives.”

James S. Benson, former CDRH director and acting commissioner who is now retired after serving at AdvaMed as a senior vice president, had this to say about Feigal's departure:

“On the one hand, David has been at the helm when user-fee legislation was finally passed and implemented. He also had some major issues to deal with such as the terrorism threat. From my view, he handled a number of difficult issues very well. On the other hand, he has tried to instill the concept of ‘product life cycle' in the center. I'm not sure how well that has taken. Likewise, his strategic plan still seems to be on the drawing board.

“I don't think his management skills matched his ability to handle issues like the ones I mentioned. Too many people at CDRH are feeling disenfranchised. The only real commodity that CDRH, or the rest of FDA for that matter, has is the people that work there. 

Losing their dedication can never be made up by user fees or increased appropriations.”

Feigal's choice as Office of Device Evaluation (ODE) director, Daniel G. Schultz, was named to serve as acting center director for an indeterminate time, pending the appointment of a permanent director. Schultz, who is considered a likely candidate for the permanent appointment, began his FDA career as a medical officer in ODE's General Surgery Devices Branch in 1994 and has moved swiftly through increasingly important posts. In 1995 he began a three-year appointment as chief medical officer in the Division of Reproductive, Abdominal, ENT, and Radiological Devices, rising to acting director and then director of that unit. In May 2001 he was appointed by Feigal to be ODE's deputy director for clinical and review policy. He became ODE director in July 2002.

A 1970 graduate of City College of New York, Feigel secured his MD from the University of Pittsburgh in 1975 and joined the Indian Health Service that year. He served as a general practitioner until 1978. Then he moved to San Francisco, where he was a surgical resident at the U.S. Public Health Service Hospital at the University of California. In 1982, he did his fellowship in pediatric surgery at Denver Children's Hospital, transferring in 1983 to St. Joseph's Hospital (Denver) as chief resident in general surgery. From 1983 until 1994, he was chief of surgery and general surgeon at Santa Fe Indian Hospital. Between 1985 and 1991, he also served as attending surgeon at St. Vincent Hospital (Santa Fe).

Couple Indicted for Defrauding Roche Diagnostics 

Agents from FDA's Office of Criminal Investigative Division and the FBI have arrested a California couple indicted by a grand jury in Indianapolis on nine counts of mail fraud, money laundering, and conspiracy. The charges involve a scheme to fraudulently obtain and sell diabetic test strips from Roche Diagnostics Corp. (Basel, Switzerland).

Shirley and Jose Mendoza of Vallejo, CA were arrested at their home on April 20. At that time, agents seized about $2 million in assets including houses, businesses, and cars, according to Susan Brooks, U.S. attorney for the Southern District of Indiana. 

Brooks says the indictment alleges that between March 2002 and October 2003, the Mendozas devised a scheme to defraud Roche Diagnostics. The scheme involved stealing diabetic test strips that the company manufactures, markets, and distributes, and then selling them and using the proceeds for personal gain. She says Shirley Mendoza made false statements to cause Roche to send large quantities of test strips to a Roche facility in Berkeley, CA, where she was an independent contractor working as an administrative assistant. Roche sent the test strips to her, Brooks says, based on false and misleading purposes that Mendoza gave Roche for needing the strips, such as for use as samples at the request of physicians.

According to the indictment, after a shipment of test strips arrived, Mendoza sold the shipment to the Neighborhood Diabetes Shoppe (Wakefield, MA). At Shirley Mendoza's direction, the store sent a check to Jose Mendoza at their residence that then was deposited into Jose Mendoza's bank account. They reportedly used the proceeds to buy more than $1 million in real property and $450,000 in vehicles and equipment.

Government officials say if the Mendozas are convicted, they would face up to 20 years in prison for each of five mail fraud counts, 10 years in prison for each of four money laundering and conspiracy counts, and fines of more than $1 million. 

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