The data do not reveal explicitly what actions each bonus rewarded. However, the perception created must be that being found wrong by a federal judge in a doomed prosecution did not hurt anyone's career or stipend. And, to be fair, many of the employees had other things on their plates besides that disaster.
Highest paid among these employees, the data show, was FDA associate chief counsel for litigation Eric M. Blumberg. He earned $266,161 after $58,733 in bonuses. More than anyone else, he was the person holding the most responsibility for the court case itself.
Second-highest paid among the bonused employees involved in the case was CDRH director of compliance Timothy A. Ulatowski. He earned $230,113 after receiving $34,623 in bonuses.
Next came regional director Dennis Baker. He had flown up from Dallas to lead an FDA listening session with Utah Medical that could have opened up the process to candor, but didn't do so. He received $206,337 after $1000 in bonuses.
Others in the Utah Medical case also got bonuses in 2005. They included the following employees: CDRH quality systems expert Kimberly Trautman with $128,251 (including $1450 in bonuses) and Denver district director Betsy Collins with $126,348 (including $1200 in bonuses). Denver district compliance director Howard Manresa received $113,385 (including $1000), and Denver district compliance officer Regina Barrell earned $99,297 (including $500). Atlanta-based national expert Karen Coleman earned $95,234 (including $600), and then– Salt Lake City resident post supervisor Teresa Thompson received $89,336 (including $250). Thompson is now stationed in Lenexa, KS. Finally, Salt Lake City resident post investigator Ricki A. Chase-Off earned $79,210 (including $250).
However, two notable FDA employees involved in the case did not receive bonuses in 2005. CDRH director Daniel Schultz earned $216,594 base salary, and former associate commissioner for regulatory affairs John Taylor received $222,330.
If FDA had shown any remorse over this case, it might be able to say that the bonused employees would have performed better if they had not been involved in it. But that is not the way this agency presents itself. This case, and the four similar ones that CDRH lost before it, simply are not on any FDA employee's mind today.
Expect more-stringent FDA attention to human subjects protection issues in clinical trials, warns the HHS Office of Inspector General (OIG). In December, OIG issued a report telling the agency to increase its efforts to implement corrective actions sought by the FDA commissioner in 2003. The actions are meant to address problems that had been identified in an FDA-sponsored bone-mass clinical study for the U.S. Army. In addition, the actions aim to prevent future problems from arising in FDA's human-subject research program.
The corrective actions directed each of FDA's six program centers, which include CDRH and the Office of Science and Health Coordination, to complete six tasks. First, they were to initiate an inventory and audit of clinical studies. They were also to examine research-monitoring programs and develop quality assurance programs, and then establish a policy of accountability to the commissioner. The centers were also to enlist the chief counsel's office's help to ensure appropriate regulatory schemes and to provide additional funding for oversight. Finally, they were to initiate a mandatory education and certification program.
OIG reported that after conducting inventories, the centers submitted 71 human-subject studies to the Office of Science. Those studies had neither been submitted to FDA for approval nor recorded in the agency's IRB database. The Office of Science added the studies to the database. The report said that from March 2003 to October 2005, FDA audited only three of the 297 studies listed in the database.
None of the centers reported having an operational research-monitoring program. Three had started to develop quality assurance programs but had not implemented them. And the Office of Science had drafted an agencywide quality assurance program but had not finalized it.
FDA did not have a written policy setting forth center directors' accountability to the commissioner for noncompliance with clinical research requirements. However, directors from three of the agency's centers did say that they were accountable to the commissioner.
The Office of Chief Counsel's IRB representative said she helped ensure that clinical research reviewed by an IRB complied with applicable regulations. No additional funds had been provided to the Office of Science to strengthen its oversight function, according to FDA officials. The Office of Science had not requested additional funds for this corrective action.
FDA told OIG that in 2002 it began requiring its researchers to complete a course on human-subject research issues. At the end of the course, they must pass an examination to receive a certificate of completion. FDA said it believed the course met the commissioner's directive.
The agency told OIG it agreed with the recommendation that efforts to accomplish the corrective actions be increased.
Von Eschenbach Confirmed over Objections
Over the strenuous objections of 11 dissenters, the U.S. Senate voted 80-11 on December 7 to confirm Andrew von Eschenbach as FDA's permanent commissioner. Senate leader Bill Frist (R-TN) used a cloture vote (89-6) to end all debate and thus lift three senators' holds on the pending nomination.
Grassley thinks the commissioner has shown disrespect for the law.
One of the three senators, Finance Committee chairman Chuck Grassley (R-IA), made a strong effort on the floor to dissuade his colleagues. “I've seen a complete and utter disrespect for congressional authority and hence the law” from the nominee, Grassley said. According to Bloomberg News, Grassley displayed enlarged versions of redacted documents provided to him by FDA in response to subpoenas. He complained that FDA's response to one of his document requests included a redacted version of a letter he had sent to the agency. “It's not OK to impede congressional investigations,” Grassley said. “It's not OK to limit the Senate's access to documents, information, and employees of the executive branch.”
Grassley claims that by denying the committee access to documents requested by the subpoenas, HHS and FDA have claimed “prosecutorial deliberative process,” “confidential communications,” and “agency prerogative to determine who will be interviewed or testify before a jurisdictional committee.” At his urging, the Congressional Research Service examined HHS and FDA's claims and found “no legal basis” for such “executive branch assertions.”
Nevertheless, industry organizations warmly praised the Senate's action. AdvaMed president and CEO Stephen Ubl issued a statement. In it, he said that von Eschenbach's “experience as a medical administrator, educator, urologic surgeon, and cancer survivor makes him keenly aware of the value of medical technology. AdvaMed looks forward to working with him to ensure patients have timely access to safe and effective lifesaving and life-enhancing medical tests and treatments. He is a stellar choice to lead the FDA of the twenty-first century.”
The Medical Device Manufacturers Association, representing smaller companies, did not issue a statement on the confirmation.
Stents Panel Plagued by Conflict-of-Interest Concerns
FDA's Circulatory System Devices Panel was convened to provide the public with a coherent, understandable explanation of the risks associated with drug-eluting stents, according to CDRH director Daniel Schultz. However, the panel has been plagued by conflict-of-interest concerns. (For more on the panel's results, see “Drug-Eluting Stents Come Under Fire.”)
Six panel members were issued conflict-of-interest waivers to allow them to attend the December 7 meeting. During a media briefing, a reporter asked Schultz why FDA redacted the specifics from the waivers about the companies and products that posed the conflicts. Schultz said the decision came from a broader policy and was not specific to this meeting. He said the intent was to have participation from panelists who could provide a balanced view on the issues raised.
Schultz said that although the experts were being asked for their opinions, no formal votes would be taken and their mission was clearly advisory. It would be up to FDA to determine what, if anything, should be done.
At least one critic charged that six waivers was excessive for the meeting. The panelists who received the waivers were Robert Harrington, Duke Clinical Research Institute; JoAnn Lindenfeld, University of Colorado Health Sciences Center; Richard Page, University of Washington School of Medicine; George Vetrovec, Virginia Commonwealth University; Judah Weinberger, Columbia University; and Clyde Yancy, University of Texas Southwestern Medical Center.
“I could think of 100 people who could qualify” as an expert and who would be without financial ties, Massachusetts General Hospital cardiologist Herman Gold told Bloomberg News. Gold presented research to the FDA advisory panel on how coatings on some stents raise the risk of patient blood clots.
FDA's role in allowing conflicted panel members to serve on advisory committees has drawn interest on Capitol Hill. Senate Finance Committee chairman Chuck Grassley (R–IA) has been a frequent critic of FDA's waiver practice on potential conflicts of interest. As recently as last month, the issue came up in a Senate HELP Committee hearing. Although not present at the hearing, Center for Science in the Public Interest project director Merrill Goozner provided written testimony to the senators. He rejected FDA's oft-expressed contention that it is difficult, if not impossible, to empanel a sufficient number of qualified experts as members of scientific advisory committees who have no conflicts in their areas of expertise. In particular, he criticized the “complicated scheme” (comprising four categories of conflict: low, medium, high, and nonwaivable) for managing conflicts of interest.
Goozner cited the experience of the National Institutes of Health Office of Medical Applications of Research (OMAR). It maintains a strict no-conflicts policy for its advisory bodies. “OMAR panels require the same specialized expertise found on FDA advisory panels: biostatisticians expert in interpreting clinical trial data, clinicians expert in treating disease, and scientists who understand the underlying biology,” Goozner said. “They perform the same tasks: understanding the science, evaluating clinical trials, weighing industry and public presentations, and synthesizing published materials. OMAR can find unconflicted scientists. So can FDA, if it just looks hard enough.”
A recent Institute of Medicine report recommended that FDA establish a requirement that a “substantial majority of the members of each advisory committee be free of significant financial involvement with companies whose interests may be affected by the committee's deliberations.” It supported 60% as a threshold for a “substantial majority.” And it said that a reasonable definition of “free of significant financial involvement” is those interests that currently require only disclosure and do not require a waiver. FDA should issue waivers for the remaining 40% “very sparingly.”
Revealing FDA's recent undertakings to address the criticism, FDA commissioner Andrew von Eschenbach said the agency will revise its guidance to identify more clearly the conditions under which conflict-of-interest waivers are granted. In addition, he said, FDA will revise the guidance that specifies when conflict-of-interest waivers will be disclosed to the public and what information will be made available. It will also revise the guidance that specifies when briefing materials used at advisory committee meetings will be made publicly available. FDA also plans to provide greater dissemination of advisory committee schedules through increased mailings to public groups and provide electronic notifications through an FDA advisory committee listserve. Finally, it will implement a more streamlined approach to appointment of members to the agency's drug-related advisory committees.
Radiometer Cited over QSR Problems
FDA in December announced that it had sent, on September 29, a warning letter citing quality system regulation (QSR) violations to Radiometer Medical ApS (Brønshøj, Denmark). The violations were found during an inspection conducted at the company in May. The company manufactures blood gas analyzers, transcutaneous pulse monitors, membrane accessory kits and related accessories, controls, and calibration products. The warning letter also said that an earlier inspection at Radiometer America (Westlake, OH) determined that the company distributes the firm's products in the United States and conducted 42 device corrections and updates between January 2005 and May 2006.
Violations noted at the Danish location included failure to establish and maintain adequate procedures for implementing corrective and preventive actions. The firm also failed to establish and maintain adequate procedures for verifying or validating its corrective and preventive actions to ensure that they are effective and do not adversely affect the finished device.
The warning letter said the firm's response was inadequate because it did not provide specific information on the corrective steps to be taken. The company was given 15 working days to indicate specific steps taken or to be taken to correct the violations. The new response must include an explanation of how the firm plans to prevent the violations or similar violations from occurring again. Documentation of actions taken was also to be included.
FDA and Japan Harmonize by Doing
The United States and Japan are participating in Harmonization by Doing (HBD), an international effort to develop global clinical trials and address regulatory barriers that may impede timely device approvals.
A November 28 update issued by CDRH says a pilot project, launched in December 2003, seeks regulatory convergence between FDA and Japanese agency premarket reviews of cardiovascular device technology. Instead of taking a theoretical approach to harmonization, HBD is using parallel development, application submissions, and review of actual device projects by FDA and the Japanese agencies in conjunction with other stakeholders.
The objective, CDRH says, is to eliminate redundancies, added costs, and time delays inherent in sequential trials. Rather than simply create guidance and discuss policy, HBD's intent is to develop common protocols for investigational clinical studies. These protocols would allow safe and effective breakthrough cardiovascular technologies to benefit patients worldwide, the update says.
For more on the project, visit www.fda.gov/cdrh/international/hbdpilot.html.
Orphan Technology Licenses Offered
The National Institutes of Health (NIH) has launched a Web site offering technologies for commercial licensing related to rare diseases or conditions. An NIH news release said there are more than 500 such technologies listed, including biologics, drugs, and devices. The technologies are available to be transferred from NIH and FDA to the private sector for further research and development, leading to potential commercialization.
NIH said rare disease is defined as one with a prevalence of less than 200,000 cases in the United States. Some 25 million to 30 million Americans have one of more than 6500 known rare diseases. The Web site was developed by NIH's Office of Technology Transfer and Office of Rare Diseases to provide a more collaborative, consolidated, and systematic approach to the development of products for rare diseases and conditions, NIH explained.
To access the listing, visit http://ott.od.nih.gov/licensing_royalties/raredisease_ovrvw.asp.
QSR Violations Alleged at Trionix
An FDA inspection at Trionix Research Laboratory (Twinsburg, OH) last July and August found QSR violations. Trionix manufactures nuclear imaging devices. A recently issued warning letter from FDA's Cincinnati District Office citing the violations included the following:
- Failing to establish procedures for and implement a corrective and preventive action to prevent recurrence of nonconforming product.
- Failing to implement procedures for receiving, reviewing, and evaluating complaints; to maintain complaint files; and to review and evaluate complaints to determine whether an investigation is necessary.
- Failing to ensure that the nuclear imaging device met all final acceptance and in-process acceptance criteria and to authorize device release by signature of a designated individual before distribution.
- Failing to ensure that equipment is routinely calibrated and inspected.
- Failing to control products that do not conform to specifications.
- Failing to use the design process for design changes made to the Biad nuclear imaging system, and failing to have written design change procedures.
- Failing to have management with executive responsibility ensure that an adequate and effective quality system has been fully implemented and maintained at all organizational levels.
The warning letter also said the firm failed to submit a written report to FDA on a correction made to the detector head of the Biad nuclear imaging device. The correction was initiated to remedy a violation caused by the device that could present a health risk. Specifically, the firm retrofitted the detector head with some screws and changed the gear and belt to prevent the detector head from dropping.
Trionix was told to submit a report within 15 days on steps taken to correct the violations. The company's report is to include an explanation of how the company plans to prevent these or similar violations from occurring again.
FDA Issues Final Breast Implant Guidance
FDA has issued a finalized guidance, Guidance for Industry and FDA Staff: Saline, Silicone Gel, and Alternative Breast Implants. It updates preclinical, clinical, and labeling recommendations laid out in a January 13, 2004, draft guidance. It may be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/04d-0002-gdl0002%20(2).pdf.
A Federal Register notice said the guidance reflects the latest scientific and medical thinking pertaining to breast implants. It is based on an April 2005 General and Restorative Devices Panel meeting, FDA's review of two premarket approval (PMA) applications for silicone-gel-filled breast implants, and comments received on the draft guidance. The notice said the primary changes to the guidance document since the 2004 draft version were to the Mechanical Data, Device Explant Analyses, and Core Study Clinical Data sections. (The Device Explant Analyses section was formerly called Modes and Causes of Rupture.) The agency also combined the former two clinical sections.
Some of the guidance's recommendations apply to all PMA applications for the devices, the notice said, while others are specific to a type of breast implant.
In addition, a new guidance for industry, Medical Device Tracking; Guidance for Industry and Staff, adds silicone gel implants to the list of devices that must be tracked when FDA orders manufacturers to do so. Tracking, the guidance said, is intended to facilitate notification and recall in the event a device presents a serious risk to health requiring prompt attention. It may be accessed at www.fda.gov/cdrh/comp/guidance/169.html.
FDA Deputy Commissioner Resigns
After holding positions at FDA and CMS, Gottlieb will rejoin AEI.
FDA deputy commissioner for medical and scientific affairs Scott Gottlieb announced his resignation in December to return to the American Enterprise Institute (AEI). During the long hiatus between FDA commissioners, Gottlieb was often the agency's primary public voice. He rejoined the conservative DC think tank effective January 16.
In 2003, former FDA commissioner Mark McClellan recruited him from AEI and took Gottlieb with him when he left for CMS in 2004. Gottlieb rejoined FDA in July 2005, from Forbes.com. There, he had been editing a popular investment-advice newsletter that specialized in medical technology stocks and frequently criticized slow approvals at FDA. A December 11 FDA statement on Gottlieb's departure said that during his latest term at the agency, he worked to improve the advisory committee process and to improve product-risk information disseminated to the public.
“Gottlieb also helped to facilitate implementation of important new regulations and policies, including the new drug and biologic products labeling rule and the expanded-access rules to help patients with life-threatening conditions gain access to drugs under development,” the statement added. Gottlieb also assisted with advancing FDA's Critical Path initiative. At AEI, he will rejoin McClellan, who recently resigned from CMS to accept a post as a visiting senior fellow at AEI-Brookings Joint Center for Regulatory Studies.
M&S Acquisition Cited for QSR Problems
An FDA inspection in September at M&S Acquisition's Mentor, OH, facility found quality problems, according to a recently released warning letter. That plant manufactures orthopedic implantable devices, including lumbar screws, rods, nuts, and plates. The warning letter was issued from FDA's Cincinnati District Office.
Violations cited included that changes to methods and procedures needed to correct and prevent identified quality problems were not fully validated and are not effective. The company also failed to validate certain processes. In addition, it failed to establish monitoring procedures and to monitor and control the process parameters for validated processes.
Cincinnati district director Carol Heppe said some of the firm's responses to the FDA-483 findings were adequate. Others did not address how the firm will ensure that corrective steps address all the identified problems. The company was told to respond within 15 days with a listing of steps already taken and those planned to correct the violations and to prevent them from recurring.
Counterfeit LifeScan Test Strips Recalled
FDA has classified two earlier recalls involving counterfeit blood glucose test strips as Class 1. The test strips are used in LifeScan's One Touch monitor. The first recall involves three suspect lots of One Touch Basic Profile test strips. “These counterfeit test strips could give incorrect blood glucose values, either too high or too low, which might result in a patient taking either too much or too little insulin,” FDA says.
The second recall involves one lot of One Touch Ultra test strips that have been found to “give erratic results that do not meet the manufacturer's specifications.”