Government Report Faults FDA on Drug Safety

August 2006, Vol. XXIII, No. 9

A recently completed report of the Government Accountability Office (GAO) lends support to an earlier editorial in the New England Journal of Medicine that characterized the FDA as “timid and toothless” in its failure to protect the public against unsafe drugs.¹

The GAO report, “Improvement Needed in FDA's Postmarket Decisionmaking and Oversight Process,” declares that the FDA “lacks clear and effective processes for making decisions about, and providing management oversight of, postmarket drug safety issues.”²

While acknowledging that the FDA undertook improvement initiatives last year, albeit amid congressional hearings on its performance (Psychiatric Times, July 2005), the report indicates that these “may improve the postmarket safety decision-making processes, but will not address all gaps.” The GAO finds, for example, that the Drug Safety Oversight Board, established by the FDA to function within its organizational structure, “may help provide oversight of important, high-level staff decisions, but it does not address the lack of systematic tracking of ongoing safety issues.”

The GAO investigation was requested by Sen Chuck Grassley (RIowa), Chair of the Finance Committee, and Rep Joe Barton (R-Texas), chair of the House Energy and Commerce Committee, after hearings on the apparent failure of the FDA to detect drug safety risks in several high-profile cases, including cardiovascular morbidity with Vioxx (rofecoxib).

Despite an initiative by the FDA to seek an organizational assessment by the Institute of Medicine, which is due in July, Grassley and Barton sought the probe from the GAO, as the office charged with measuring “accountability, integrity, and reliability” of government operations.

On receiving the GAO findings, Grassley told the Associated Press, “This report provides solid evidence that everything is not alright at the FDA and calls for long overdue reform. The FDA's problems are systemic and cultural, not isolated or easily fixed.”

An FDA spokesperson, Susan Bro, announced: “The FDA welcomes the GAO report and is currently leading a comprehensive and timely effort to transform the methods our medical and scientific staff use to manage safety issues.”

The FDA was provided a prepublication copy of the GAO report and invited to have its response appended to the published version. The agency's comment on the report was conveyed to the GAO on March 14 with a cover letter in which Acting Commissioner, Andrew von Eschenbach, MD, described it as “the tentative position of the agency and subject to reevaluation when the final version of this report is received.”

A “tentative position” conveyed by an acting commissioner may be indicative of an unsteady organizational structure underlying the questionable performance. There has been no permanent commissioner of the agency for most of President Bush's terms; the last permanent commissioner, Lester Crawford, resigned 2 months after being confirmed. The Senate confirmation hearings on von Eschenbach were scheduled for May but have been delayed as opposing factions battle over the prospect of the FDA not approving over-the-counter sales of the “Plan B” emergency contraceptive, in agreement with religious conservatives but in conflict with the agency's own staff recommendations.

An FDA advisor, and previously a suggested nominee for commissioner, Alastair Wood, MB, ChB, associate dean at Vanderbilt University School of Medicine, commented to the Los Angeles Times on April 30, “strong, continuing leadership . . . [at the FDA] is necessary to expeditiously address complex and contentious issues.”

GAO uncovers FDA inadequacies The GAO investigators evaluated the FDA organizational hierarchy and the responsibilities of staff and departments, particularly in 2 divisions within the Center for Drug Evaluation and Research (CDER): the Office of Drug Safety (ODS) and the Office of New Drugs (OND). Internal policies and procedures were examined, and FDA officials as well as outside drug safety experts were interviewed.

The investigators determined that there are insufficient criteria to establish what safety actions the agency should take, and when it should take them. The role of the ODS appeared unclear, even in regard to its participation in the scientific advisory committee meetings that it convenes.

“Insufficient communication between ODS and OND's divisions has been an ongoing concern and has hindered the decision-making process,” the GAO report indicates. “Specifically, ODS does not always know how OND has responded to ODS' safety analyses and recommendations. ODS management does not systematically track information about the recommendations its staff make and OND's response to them.”

There is also a lack of clarity about the recommendation practices of the ODS, according to the GAO investigators. “In practice, ODS often makes written recommendations of safety actions to OND, but there is some confusion over this role . . . and there is no policy that explicitly states whether ODS' role includes this responsibility,” the report observes.

In considering “data constraint” hindering postmarket safety decisions, the GAO found that the agency lacks the authority to require pharmaceutical companies to conduct the necessary studies, or the resources to directly obtain necessary data. Although the FDA can withdraw approval and order a drug to be taken off the market, the GAO report notes that the agency rarely exerts this authority, and more commonly negotiates a voluntary withdrawal. The FDA has no explicit authority to require manufacturers to take other safety actions.

“In the absence of specific authority, FDA often relies on drug sponsors voluntarily agreeing to conduct such post-market studies,” the GAO report indicates, “but [these] . . . have not consistently been completed.”

According to the FDA's own recent report, Performance of Drug and Biologics Firms in Conducting Postmarketing Commitment Studies, which the agency is mandated to issue annually under the FDA Modernization Act, 797 (65%) of 1231 stipulated postmarket studies had not begun, although they were not yet classified as “delayed.”³ Another 231 studies (19%) are proceeding as scheduled. Three studies had been terminated before completion, and the findings not yet reported to the FDA.

The GAO report recommends that Congress consider expanding the authority of the FDA to require pharmaceutical companies to conduct postmarket studies. It also recommends 4 executive actions by the FDA commissioner:

• Establish a mechanism for systematically tracking ODS' recommendations and subsequent safety actions.

• Revise and implement the draft policy on major postmarket drug safety decisions.

• Improve CDER's dispute resolution process by revising the pilot program to increase its independence.

• Clarify ODS' role in the FDA's scientific advisory committee meetings involving postmarket drug safety issues.

In its response to the GAO report, the FDA indicated that “the report is well done and . . . the conclusions reached are reasonable and consistent with actions we already have under way or planned.” The agency goes on to note, however, that evaluating drug safety is intrinsically complex; and argues that the agency, and specifically, CDER, should not be criticized for imperfect results, while it must balance risks and benefits “every day” using “whatever data are available.”

“This cannot be changed, and CDER should not be criticized for the task it faces,” the FDA claimed in its comment on the report.

The GAO investigators observe in the final published report that the FDA comments address some of the findings but none of the recommendations. The investigators concur with the agency's characterization of the postmarketing drug safety issues as complex, but disagree with the contention that the agency should not therefore be criticized for inadequately addressing them.

For the reason that drug safety issues are inherently complex, the GAO investigators indicate, “we believe that FDA needs to have greater clarity about how decisions are made and to establish more effective oversight of the decisionmaking process. Furthermore, we believe that our report fairly characterizes the limitation of the data that FDA relies on in this complex process.”

The merits of the GAO report notwithstanding, meaningful reform at the FDA could be less a function of the agency's acceptance of outside recommendations than compliance with legislated mandate. After the March 2005 hearings, and well before this GAO report substantiated impressions from the hearings, Sen Grassley and Sen Christopher Dodd (D-Conn) had drafted a bipartisan bill to reorganize the FDA with the intent of increasing the effectiveness of its drug safety programs. In addition to strengthening safety evaluations before approval, the bill would increase the power of the agency to require postmarket drug studies, relabeling, and warnings.

References

1. Okie S. What ails the FDA? N Engl J Med. 2005; 352:1063-1066.
2. Government Accountability Office. Drug Safety. Improvement Needed in FDA's Postmarket Decisionmaking and Oversight Process. GAO-06-402, March 2006.
3. Department of Health and Human Services (DHHS), Food and Drug Administration. Report on the Performance of Drug and Biologic Firms in Conducting Postmarketing Commitment Studies; Availability. Federal Register 10978; 71(42) notices. Friday, March 3, 2006.