Originally Published MDDI July 2004
While FDA has been involved in its share of cover-ups, the public rarely hears about such practices.
James G. Dickinson
CDRH Moves to Risk-Based Inspections | Abbott Gets a Break| Class I Cordis Stent Recall | “Objectionable” Clinical Study by Staar Surgical | FDA Guidance on Pediatric Devices | Bone Cements Warning Is Expanded
When it comes to keeping lower-level employee misconduct quiet, the Pentagon is not alone. For many years, FDA has been doing the same—as have, surely, other government agencies.
Historically, the public rarely hears of such practices by FDA. Statistically, they are more likely to affect the agency's regulation of medical devices than of other kinds of products.
In 1996, a CDRH employee leaked a competitor's review documents to Summit Technology's CEO. Although the documents were quickly returned to FDA, somehow the envelope they were mailed in had already disappeared. The sender was never identified. An internal investigation was opened promptly, but its findings were kept under wraps.
Ten months later, investigations were opened first by the FBI, then by the House Commerce subcommittee on oversight and investigations. Likewise, these went nowhere. Although the subcommittee held an inconclusive hearing, thereafter it deferred to the FBI. The bureau then closed the case because the monetary value of the paper in the leaked documents did not meet its $5000 action threshold.
The managerial adequacy of FDA line officers in this case was never questioned. CDRH director Bruce Burlington now holds a senior executive position at Wyeth Pharmaceuticals (Collegeville, PA), and commissioner David Kessler is dean of Yale University School of Medicine. Neither was held to any accountability, and both proceeded in their distinguished careers without a blemish from the episode.
Fast-forward to today and you see the same pattern of denial. It's usually cloaked in managerial concern for employees' privacy rights and the integrity of FDA's investigational processes (which never produce public results). A current case in point is the sustained CDRH actions against TMJ Implants Inc., previously reported in great detail here. [For more information, see MD&DI May 2004, p. 50, and June 2004, p. 39.]
This case concerns the company's alleged failure to report 18 adverse events under CDRH's medical device reporting regulation. TMJ Implants contends that this is just an outgrowth of a previous cover-up. The company alleges that reviewer Susan Runner unsuccessfully attempted to prevent its prostheses from returning to the market in 1999.
But nobody seems to know what actually happened next. Some say that an FDA Office of Internal Affairs investigation was never opened because the company's evidence didn't warrant it. Others believe an investigation was opened but failed to substantiate the company's complaints. CDRH director David Feigal declined to discuss the matter, as did CDRH compliance director Timothy Ulatowski, who had been Runner's immediate supervisor. TMJ Implants is now protesting an HHS Inspector General's failure to interview any of the principals in the case for more than a year.
Feigal has now moved on, amid high praise from acting commissioner Lester Crawford, to a prestigious appointment at NDA Partners (Falls Church, VA). Ulatowski was promoted to compliance director, and Runner took Ulatowski's former position in an acting capacity. Both retain influence over TMJ Implants' continuing protest.
A House Commerce oversight and investigations subcommittee informal review of the TMJ Implants matter never reached public hearing status. This may be because the political landscape has changed since 1996, and there's little interest in embarrassing a friendly administration in an election year.
There are other examples, too. One, a near-replica of the TMJ Implants saga, involved a gutsy fight by Myotronics Inc. (Tukwila, WA) in 1996. The case resulted in FDA's public defeat, employee punishment, and the company's complete vindication.
CDRH Moves to Risk-Based Inspections
CDRH says it has created a work group to move the center to a risk-based inspection planning process. According to a “process improvement” notice posted on the center's Web site, the work group has received center approval for a new definition of the term risk. The following definition is to be used when planning inspections:
Risk is a combination of the probability of occurrence of harm and the severity of that harm. Harm is a negative effect on a person or person's health due to an unsafe or ineffective device; or reduction in a device's safety/effectiveness, clinical benefit, fitness for use, improper use, or quality.
In March, CDRH held its first internal Annual Inspection Workplan Prioritization Meeting. Risk-based inspection assignment proposals were reviewed at the meeting, according to the notice, for inclusion in FDA's FY 2005 work plan.
Abbott Gets a Break
Abbott Laboratories (Ashland, OH) seems to be getting some leeway from FDA with GMP deficiencies. The problems were found at its Hospital Products Division (HPD) during FDA inspections over the past two years. This is despite the company operating under a consent decree for past problems at its Diagnostics Division.
An inspection at an HPD drug manufacturing facility in Austin, TX, last August revealed significant GMP deficiencies. These led FDA to issue a six-page warning letter in October. In it, FDA cited the firm's quality assurance unit, a lack of validation, and incomplete complaint handling. FDA also conducted two inspections at a Chicago-area HPD administrative facility where manufacturing records are maintained, which resulted in a four-page warning letter dated March 25.
HPD was recently spun off from Abbott and now operates under the name Hospira. Although the inspections took place under Abbott's management, a Hospira spokeswoman said in May that it now assumes full responsibility for resolving any outstanding issues.
The inspections that provoked the latest warning letter took place at the Lake Forest, IL, facility. One occurred April 2003, and the other, begun a month later, went on for three months. The letter took issue with Abbott's continuing distribution of several Lifeshield intravenous (IV) sets for two weeks after the first inspection ended. “Your firm's management with executive responsibility failed to ensure that the quality policy was understood, implemented, and maintained at all levels of the organization as required by 21 CFR 820.22,” FDA charged.
The Hospira spokeswoman said that in the spring of 2003, Abbott notified FDA that certain HPD IV sets contained discolored drip chambers. “We conducted internal and external assessments of the chambers and did conclude that the discoloration was cosmetic in nature, and most importantly would not cause any risk to patient health and safety.” She said the product was subsequently recalled.
The warning letter said Abbott failed to revalidate the manufacturing and sterilization procedure for a process change involving drip chambers on certain IV sets. It also failed to maintain procedures to ensure all purchased and received products conformed to the company's specifications. Additionally, FDA cited the firm for failing to ensure that all personnel were adequately trained to perform their responsibilities. “For example, the Supplier Quality Assurance Engineering Project specialist & supervisor…had not been trained” on required procedures for auditors of suppliers, the letter said.
Hospira's spokeswoman said the firm has “fully implemented all necessary improvements.” The company has also “met with FDA to rapidly facilitate resolution of this matter.” The warning letter mentioned that Abbott responded to the inspections' findings in numerous letters and meetings with FDA. “Although it appears from your responses that you are working toward correcting the deviations noted at your firm, you must adequately implement and maintain each corrective action to ensure its effectiveness,” FDA reminded the firm. The agency said it plans to verify that all corrections have been made during its next inspection.
Class I Cordis Stent Recall
Johnson & Johnson's Cordis Endovascular unit has issued a Class I recall of recently revised instructions for its Precise RX nitinol stent transhepatic biliary system. According to the company, the instructions did not warn “strongly enough against the device's use in the vascular system.” A Class I recall is FDA's most severe classification, reflecting a high potential to cause serious harm or death.
The instructions were sent to Precise users in a company-prepared medical device notification dated March 29. FDA did not approve the instructions.
“Cordis is aware of nine patient injuries due to air embolism, including seizure and coma, as well as seven incidents of device malfunction in connection with the use of this system outside of its approved indication,” the company said in announcing the recall. The company's May 4 follow-up notice about the severe adverse events also advised users to limit use of the device to the FDA-cleared uses only. The stent's labeling already contained a warning that the device's safety and effectiveness have not been established for use in the vascular system.
“We regret our initial communication did not more strongly reinforce against off-label use,” Cordis said. Cordis said it is working with FDA to ensure that all physicians are aware of the problem.
“Objectionable” Clinical Study by Staar Surgical
A recent FDA warning letter to Staar Surgical (Monrovia, CA) details objectionable clinical study conditions found during an inspection last December. However, the agency indicated that the firm's responses to the findings generally have been adequate.
FDA conducted the inspection under a program designed to ensure that data and information submitted to the agency are scientifically valid and accurate. Such data are contained in requests for investigational device exemptions (IDEs), premarket approval applications, and premarket notification submissions. The program also ensures that human subjects are protected from undue hazard or risk during scientific investigations.
Three major areas of concern were cited in the warning letter:
• Staar provided an investigational device to a physician and started its study before FDA approval had been obtained.
• Staar failed to ensure that continuing institutional review board (IRB) approval review was received before continuation of the study.
• Staar failed to comply with sponsor responsibilities such as obtaining signed agreements from each investigator and identifying all exclusion criteria for the device.
The warning letter contained some responses from Staar vice president of scientific affairs Helene Lamielle. She said that executive staff no longer with the company had misinterpreted FDA regulations regarding custom devices. These staff members had allowed two devices to be provided to a clinical investigator before approval had been received. When the firm became aware of the situation, she said, it asked the investigator to return the devices.
Lamielle told FDA the company has revised procedures and added staff training. Such training, she added, should ensure that the staff fully understands regulations regarding devices intended for use in IDE clinical trials. The training will emphasize “the fact that investigational devices may only be shipped to designated personnel or to a site specified by those personnel and not to any other individual within or without the organization.”
FDA said Lamielle's responses “appear adequate. However, the fact remains that the devices were shipped to be implanted prior to FDA approval. FDA regulations clearly state that a sponsor shall submit an application to FDA if the sponsor intends to use a significant-risk device in an investigation, and may not begin an investigation for which FDA's approval of an application is required until after FDA has approved the application.”
Lamielle also said the failure to have continuing IRB review was an isolated incident that has been covered in staff and contract personnel retraining. And, she said, procedures have been revised and clinical investigation sites contacted on the sponsor responsibilities that were not followed.
FDA Guidance on Pediatric Devices
FDA has issued a guidance for industry and staff, titled Premarket Assessment of Pediatric Medical Devices. The guidance is designed to help achieve the intent of provisions of the Medical Device User Fee and Modernization Act of 2002 (MDUFMA). These provisions are designed to promote safe and effective pediatric devices and to protect pediatric patients during clinical trials.
In the guidance, FDA notes that MDUFMA requires it to ask the Institute of Medicine to conduct a study. The study should address whether the existing postmarket surveillance provisions of the act provide “adequate safeguards regarding the use of devices in pediatric populations.” FDA says representatives of both agencies have met to formulate the study's scope and objectives. The institute is now engaged in planning activities for the assessment.
FDA says it considered and responded to comments from stakeholders in writing the guidance, whose goals are to
• Help define the pediatric population and pediatric use for medical devices.
• Help identify the types of information needed to provide reasonable assurance of pediatric medical device safety and effectiveness.
• Help define the guiding principles and protections sponsors should consider for pediatric subjects in device clinical trials.
The guidance recognizes four pediatric subgroups—newborn (neonate), infant, child, and adolescent—with approximate age ranges for each. But it notes that the age descriptions are somewhat arbitrary. A subject's weight, body size, physiological and neurological development, and neuromuscular coordination may often be more-appropriate indicators than chronological age and should be taken into consideration.
The guidance may be accessed at www.fda.gov/ohrms/dockets/98fr/2003d-0319-gdl0002.doc.
Bone Cements Warning Is Expanded
FDA has expanded an earlier warning on serious complications that may arise from the use of acrylic bone cements in treating spinal compression fractures. The warning now includes all forms of bone cements and bone-void fillers.
Use of bone cements and fillers in such procedures has primarily been performed off-label, the agency says. FDA noted, though, that as of April 1, “a bone cement was cleared by the FDA for the treatment of pathological fractures of the vertebral body due to osteoporosis using a kyphoplasty procedure.”
The complications reported with bone cements typically center around “leakage,” which leads to soft-tissue damage and nerve root pain and compression. Other reported complications include pulmonary embolism, respiratory and cardiac failure, abdominal intrusions and ileus, and death.
FDA's notice can be viewed on FDA's Web site at www.fda.gov/cdrh/safety/bonecement.html.
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