Medical Device & Diagnostic Industry Magazine
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Originally Published MDDI September 2005

WASHINGTON WRAP-UP

Margaret Glavin, FDA's new associate commissioner for regulatory affairs, wants to reorganize FDA's field command structure. The plan, announced in July, is the first major reorganization FDA has seen in several decades.

James G. Dickinson

Staar Surgical Faces FDA Enforcement| Device Sales Reps Jailed for Theft | Drug-Diagnostic Codevelopment | Too Many ‘Other' Responses on IVD MDRs? | Vail Recalls Enclosed Beds | Device, Drug Errors Are Different, Says AdvaMed| Boston Scientific in More FDA Trouble|

Barely on board six weeks, FDA's new associate commissioner for regulatory affairs (ACRA), Margaret Glavin, announced an FDA field command structure reorganization. The plan, announced in July, is the first major reorganization FDA has seen in several decades.

Traditionally, FDA ACRAs have been deeply experienced in FDA inspectional and enforcement work. Glavin had no such experience when she joined the agency two years ago to head up counterterrorism policy and planning. Before that, she had served as acting administrator of the USDA Food Safety Inspection Service. There, she worked with, and impressed, FDA Commissioner Lester M. Crawford.

In a July 6 memo, Glavin said she was creating three senior leadership positions in her immediate office. Those officers will help her “carry out the full range of activities and functions assigned to the ACRA.” Each will take lead responsibility for a major area of responsibility, she said. “In broad terms, the positions will focus on regulatory operations, field operations, and regulatory policy development.” The memo went out to all members of FDA's field organization, known as the Office of Regulatory Affairs (ORA).

Glavin said Steve Niedelman, FDA's current assistant commissioner for regulatory affairs, would take on the first position. He is known for his efforts to ban ephedra, develop and implement bioterrorism regulations, and promote third-party inspections under the Medical Device User Fee and Modernization Act of 2002. Niedelman “will oversee the day-to-day operations of the headquarters offices and the implementation of our regulatory policies,” Glavin wrote.

The second position will go to FDA Northeast Region director Diana Kolaitis. She “will oversee the day-to-day operations of the field and the resources needed by the field.” Kolaitis, who is based in Jamaica, NY, has specialized in good manufacturing practice issues at the International Conference on Harmonization.

FDA director of drug compliance David Horowitz will take the third position. Horowitz is an energetic lawyer who has been leading risk-based approaches to regulatory compliance. He “will concentrate on the development of policies and regulatory strategies that will identify and prioritize risks to enable us to work smarter and more successfully in achieving our public health mission.”

In essence, Glavin has split her job into three and lifted herself out of its details, in which she has no expertise. So, you may ask, why did Crawford select her in the first place? Probably because of how burdensome the ACRA position has been in the past.
Reorganization was on Crawford's mind when he chose Glavin. He had tried without success to persuade her predecessor, John Taylor III, to reorganize FDA's field operations.

Taylor allegedly resisted because he saw no need for such a shake-up. Additionally, he was close to a number of ORA people who would be affected by a reorganization. For example, Office of Regional Operations director Debbie Ralston had been close to Taylor for a number of years. In Glavin's proposal, Ralston's function will be greatly diminished.

Glavin was nudged by Crawford to do what Taylor wouldn't. She quickly saw in the ACRA position something that her predecessors may have been too close to the FDA forest to see: the position requires more than one person could do effectively. Taylor's main reason for leaving the position—there was no time for a personal life—supports her insight.

Glavin's recognition of the scope of the job and her decision to deal with it so boldly bodes well for her ability to handle the FDA field reorganization. Despite her inexperience, she may be able to face its biggest challenge: how to do a lot more with a lot less.

Staar Surgical Faces FDA Enforcement

FDA told Staar Surgical in July that it might be facing an enforcement action. The firm must provide proof that it had corrected or was correcting GMP deficiencies. The agency noted the problems during a September 2004 inspection of Staar's Monrovia, CA, manufacturing plant. A July 5 FDA letter said Staar “failed to adequately correct numerous violations” noted on the Form 483, according to the company. The letter added that FDA was “gravely concerned about Staar's serious, continuing violations,” and was prepared to seek the appropriate remedies.

The agency's letter gave the company 10 calendar days to provide its responses and supporting documentation. Staar said it would provide a response by the deadline. The response will include information about the company's ongoing corrective actions taken since its last response to FDA in February. The company said it believed that FDA would pursue an enforcement action if it found the response inadequate. It also believed that the agency will hold up final approval for its Visian intraocular lens until all compliance issues have been resolved.

Staar has been in hot water with FDA for the past few years. An April 23, 2004, warning letter to the firm cited it on objectionable clinical study conditions found during a December 2003 inspection. Before that, FDA sent the firm a warning letter for not reporting malfunctions related to its intraocular and implantable contact lenses. “In one case, a physician had to perform a vitrectomy on a patient after the lens delivery system failed,” the letter charged. “In another incident, a physician had to suture a patient after the cartridge failed.”

In a news release on the latest FDA letter, Staar said it will use all available resources to resolve the issues to FDA's satisfaction.


Device Sales Reps Jailed for Theft

A Miami federal court sentenced two former Ethicon Endosurgery salesmen to jail time for conspiring to transport and sell stolen medical devices. Francis Orlando and Matthew Smith, both of Las Vegas, NV, received five months in jail and five months home confinement. They also received fines of $10,000 each and two years supervised release with 200 hours community service in each of the two years.

According to a Department of Justice news release, the men were Ethicon salesmen in the Las Vegas area. From January 1997 through December 2000, Smith conspired with a third salesman, Gary Straus. They planned to acquire and provide medical devices to James Vogt to sell. Vogt was the principal behind International Surgical Supply Inc. (Miami). Smith and the others would keep medical devices manufactured by other companies when clients switched to Ethicon devices. They would also recover Ethicon devices from customers when older models were replaced with newer models. In addition, they would steal devices from customer facilities.

Court statements indicated Smith participated in 12 shipments of medical devices to Vogt. The shipments caused a loss of more than $120,000. Also, Orlando diverted medical devices worth more than $185,000 from April 2001 through August 2003. Straus already has been sentenced to one year and one day in prison and ordered to forfeit more than $1 million.

Drug-Diagnostic Codevelopment

FDA has released a draft concept paper called Drug-Diagnostic Co-Development Concept Paper. It contains FDA's thoughts on the codevelopment of a drug or biological therapy and IVD test. The concept paper focuses on development methods that are scientifically robust and efficient. FDA will solicit public input on the paper and then write a draft guidance for public comment.

Drug/IVD combinations might provide many clinical benefits to patients, including differential diagnosis of a disorder. Other benefits may include identifying a patient subset or recognizing likely responders to a specific drug. The products could also provide a way to target treatment or be a way to identify patients at risk for adverse events. Finally, they might be used to observe responses to drugs or a way to individualize treatment, FDA says.

FDA says codevelopment may involve cross-center product regulation. This is because it is an area of rapidly evolving technology and targeted treatment. The paper provides both process and scientific issues to consider when codeveloping drugs in which a diagnostic test may be critical to the drug's clinical use.

The paper addresses issues related to developing in vitro diagnostics for mandatory use. It also covers decision making about drug selection for patients in clinical practice. It deals only with developing a single test in conjunction with a single drug.
Covered are review procedure issues, analytical test validation, and preclinical pilot feasibility studies. Also covered are general approaches to define clinical test validation and clinical utility.

The concept paper may be downloaded online at www.fda.gov/ohrms/dockets/dockets/04n0279/04n-0279-rpt0001.pdf.

Too Many ‘Other' Responses on IVD MDRs?

Device companies are 15 times less likely than FDA to identify a reportable event as a product malfunction or patient injury. At least, this is the implication of a limited analysis recently conducted by CDRH. The analysis examined 155 medical device reports (MDRs) submitted by 12 manufacturers of certain in vitro diagnostics.

The exercise discovered that the manufacturers identified 35% of the MDRs as involving a product malfunction. But CDRH's Office of In Vitro Diagnostics (OIVD) Patient Safety Team analyzed the same data and identified 78% of the MDRs as malfunctions. Similarly, manufacturers reported “injury” in 4% of the MDR events, while FDA's team assigned that description to 18%. Manufacturers attributed a whopping 60% of the events to “other” causes. However, FDA attributed only 4% to “other”—a 15-fold difference.

“This work has not been replicated and so it is not possible to extrapolate to other products in OIVD or outside of OIVD,” cautions Sally Hojvat. Hoj-vat is OIVD director of microbiology devices. However, at the recent Orange County Regulatory Affairs Discussion Group meeting in Irvine, CA, Hojvat saw a warning sign with public health implications.

The analytical exercise showed an “obvious overuse of the word ‘other,'” she reported. “What's the issue here? Is it lack of understanding what these three different areas are? Or are we sort of doing, frankly, a bit of a cover-up? When we're talking about a potential public health issue, a very serious one, sometimes this can be something that really sends shivers through the OIVD environment. There's going to be a lot more attention paid here, and I think there's a guidance document in the works.”

Vail Recalls Enclosed Beds
FDA says Vail Products Inc. (Toledo, OH) has started a nationwide recall of 5000 enclosed bed systems. The agency says the systems have been found to cause patient entrapment that resulted in severe neurological damage or death from asphyxiation.

An FDA release says the products are canopy-like padded beds covered with nylon netting. The netting is zipped into place to enclose a patient. The beds are used for at-risk patients with cognitive impairment, unpredictable behavior, spasms, seizures, and other disorders. The beds are an alternative to physical or drug restraints to reduce falls or other injury to patients, FDA says.

The agency says the bed systems pose a hazard in that patients can become trapped between the side-rail and the mattress or between the canopy and mattress. Because of the canopy, if their head is entrapped, patients may experience asphyxiation, which can result in permanent neurological injury or death. FDA is aware of about 30 entrapments, of which at least eight resulted in death.

Under the recall's terms, the company has sent new instruction manuals and warning labels to its customers. The manuals inform them about FDA's advice to stop using the bed system, move patients to alternative bed systems if possible, and consult with the patients' physician. If no alternative bed systems are available for a particular patient, users are advised to follow the safety precautions contained in the new instruction manuals and warning labels to help minimize risk of injury.

FDA first issued a Public Health Notification about the potential risk posed by these bed systems last March. On June 23–24, Vail Products mailed corrected instruction manuals and labeling. This included warning labels to all users of its Vail 500, Vail 1000, and Vail 2000 enclosed bed systems.

Vail Products is permanently ceasing the manufacture, sale, and distribution of all Vail enclosed bed systems. Vail Products will no longer be available to provide accessories, replacement parts, or retrofit kits.

Device, Drug Errors Are Different, Says AdvaMed

Medical errors arising from devices are very different from those arising from drugs, notes AdvaMed. So, it says, the Institute of Medicine (IoM) should recognize the differences in any proposals to reduce errors. The association commented on IoM's Identifying and Preventing Medication Errors project on June 16. It stressed that IoM should acknowledge that device manufacturers are in the best position to address the safety issues with their own products.

“Unlike pharmaceutical products,” AdvaMed wrote, “medical devices tend to be unique in appearance, shape, construction, and configuration, as dictated by their intended uses.” Even different sizes or models of the same device often have physical traits that set them apart, it noted. Labeling usually appears directly on most devices, or their packaging, which clearly explains their intended use. Manufacturers perform risk analyses to study human factors that cause user error. In addition, they include mitigating design features if possible. International standards that apply to many devices require error-reducing design attributes.
Therefore, AdvaMed said, the potential for device mix-ups is much less than for medications.

AdvaMed included the following suggestions:

• Measures adopted to reduce medication errors should not be applied at random to medical products. Many root causes of errors are not factors in the safe and effective use of devices.
• Healthcare providers should not be subjected to new regulations governing their use of medical products.
• Practitioners and institutions need more financial flexibility to acquire new and improved medical technology.

The letter also provided examples of devices whose design features help reduce medication errors. Such devices include angiographic injectors and in vitro diagnostic products. Also included are infusion pumps with automated verification features and health information technology systems.

Boston Scientific in More FDA Trouble

Boston Scientific has been in regulatory troubles in the past. But none have been serious enough to prevent FDA from approving its new products.

In July, the firm reported a worldwide recall of all Hemashield Vantage vascular grafts used in peripheral procedures. Boston Scientific said it was recalling all such grafts manufactured in the last two years because of the devices' potential to fray or tear during suturing. Also, the grafts may lead to postoperative complications.

An FDA release said Boston Scientific was aware of three reported postoperative failures. All three occurred between three and seven days postprocedure. In each case, resuturing or replacing the graft successfully treated the patient.

This news came hard on the heels of an announcement that Boston Scientific had agreed to pay $74 million to settle a civil complaint. The complaint was related to the firm's continued distribution of coronary stent delivery systems in 1998. Boston Scientific distributed the stents despite a manufacturing flaw that prevented some of their balloons from deploying. The devices were subsequently recalled.

Seven days before that announcement, FDA disclosed that it had sent a warning letter to Boston Scientific after a month-long inspection that ended April 7. FDA found that the firm's Watertown, MA, facility had “serious regulatory problems involving [its] implantable Vaxcel Low Profile Infusion Ports.”

FDA found that methods, facilities, or controls used for manufacturing, packing, storing, or installing devices did not conform to current GMPs. Significant deviations cited include the following:

• Failing to establish ample management controls to ensure that an effective quality system has been established and maintained.
• Failing to validate the manufacturing process to ensure that specified requirements are met.
• Failing to establish and main-
tain an adequate corrective and preventive action procedure to identify actions to correct and prevent recurrence of nonconform-ing product and other quality problems.
• Failing to validate changes to the manufacturing process to ensure that specified requirements are met.
• Failing to identify the acceptance status of product throughout manufacturing, packaging, labeling, and servicing of the product to ensure that only product that has passed the required acceptance activities is distributed or used.
• Failing to establish procedures to address identification, documentation, evaluation, segregation, disposition, and investigation of nonconforming product.

The warning letter says the problems in the letter and in the FDA-483 issued at the end of the inspection may point to serious problems in the firm's quality system. FDA acknowledged an April 21 letter from the company's quality manager responding to the FDA-483 findings. But, the agency said, the response failed to address specific system-wide corrections needed to bring the facility into compliance.

Last September, Boston Scientific's Advanced Bionics subsidiary recalled unimplanted Clarion and HiResolution cochlear implants. The recall was started because of concerns the implants might malfunction owing to moisture inside them.

That same month, Boston Scientific's Galway, Ireland, plant passed an FDA inspection. The inspection was a follow-up on a 99,000-unit recall of its new Taxus Express2 paclitaxel-eluting stent produced at both this plant and a facility in Minnesota.

Throughout it all, though, FDA has continued to approve Boston Scientific applications. These include the Liberté bare-metal coronary stent system, Peripheral Cutting Balloon, and Express Bilary SD Monorail premounted stent system.

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