After the apparent failures of the U.S. Food and Drug Administration to discern cardiovascular effects of COX-2 inhibitors and suicidality in children receiving antidepressants, critics of the FDA say that the agency has failed to protect public health. Read what advocacy groups are saying and Congress is doing to change the FDA.
The confirmation hearing for the nomination of Lester Crawford, D.V.M., Ph.D., to head the U.S. Food and Drug Administration was conducted by the same Senate committee that had two weeks earlier probed the agency's capability to weigh drug benefits against risks and evaluate postmarket safety.
Apparent failures of the FDA to discern cardiovascular effects of COX-2 inhibitors and suicidality in children receiving antidepressants prompted the Consumers Union to demand that the Senate Committee on Health, Education, Labor and Pensions (HELP) "vet the vet." Janell Mayo Duncan, counsel for Consumers Union, indicated in a press release:
Under Dr. Crawford's watch, the FDA has failed to protect the public from dangerous prescription drugs, dietary supplements and contaminated animal feed that could car mad cow disease.
Critics of the FDA were joined in March by the New England Journal of Medicine (2005;352:1063-1066), which published an editorial characterizing the agency under acting director Crawford as "timid and toothless." The same issue carried two other editorials assessing the lapse in drug safety represented by the COX-2 inhibitors, which had also been published online in February, preceding the FDA advisory committee meeting on the cardiovascular risk of the agents.
Susan Okie, M.D., wrote (N Engl J Med 2005;352:1063-1066):
[T]he need for better surveillance of approved drugs is only one of the FDA's ills. Another is the lack of strong and independent leadership, which has contributed to an atmosphere that stifles debate and discourages some employees from expressing scientific concerns about drugs.
Okie offered the example of FDA epidemiologist David J. Graham, M.D., M.P.H., who, according to his testimony to the Senate Finance Committee, had been pressured by the agency to revise his conclusion that rofecoxib (Vioxx) increases risk of myocardial infarction.
Okie faulted the Bush administration for leaving the FDA without permanent leadership. She noted, further, that for more than a year before the 1.5-year tenure of the previous appointee, Mark McClellan, M.D., Ph.D., the highest-ranking appointed administrator at the FDA had been chief counsel Daniel E. Troy, J.D., who had previously represented tobacco and pharmaceutical manufacturers in actions against the agency.
Abbey S. Meyers, president of the National Organization for Rare Disorders, testified in the March 1 Senate HELP hearing that the long period without a permanent FDA director "sends a sad and dangerous message that the public health is not a high priority to our government. Without a Presidentially-appointed, Senate-confirmed FDA Commissioner, no one knows where the buck stops."
In his confirmation hearing, Crawford acknowledged concerns about the agency and described several planned measures, which he has previously announced. "I am committed to addressing existing concerns regarding post-market safety of FDA-regulated products, both in medical products and food, respectively," he testified.
On February 15, the day President George W. Bush announced his nomination and a few days before the advisory committee meeting on the cardiovascular risk of COX-2 inhibitors, Crawford and U.S. Department of Health and Human Services (HHS) Secretary Michael Leavitt unveiled their plan to create a new, independent Drug Safety Oversight Board. The Board will oversee management of drug safety issues and provide emerging information on medical risks and benefits to health providers and patients.
Although the new oversight board is characterized as "independent" in FDA and HHS press releases, it is proposed to function within and as a part of the agency's Center for Drug Evaluation and Research (CDER). The CDER currently encompasses an Office of Drug Safety (ODS), for which there has also been a vacant director's position.
Other measures proposed by Crawford include a "Drug Watch" Web site to increase the transparency of the agency's decision-making process and health care professional and patient information sheets for all drugs on the FDA's Drug Watch. In addition, the agency is preparing final versions of three guidances to help pharmaceutical firms manage risks involving drugs and biological products; it is planning to sponsor an Institute of Medicine study to evaluate the current drug safety system; and it has recently implemented a program to address differences of professional opinion within the agency.
The FDA has also submitted a budget for the 2006 fiscal year that would increase funding for the ODS by $6.5 million, including $1.5 million in user fees from drug sponsors under the Prescription Drug Use Fee Act. Although interaction of the ODS with the newly proposed Drug Safety Oversight Board remains to be defined, the increased ODS budget is intended to "increase the number of staff with expertise in critical areas such as risk management, risk communication and epidemiology, and ... increase access to a wide range of clinical, pharmacy and administrative data bases," according to Steven Galson, M.D., M.P.H., acting director for CDER, in a statement before the Committee on Government Reform in May.
The prospect of increased funding, supported by President Bush's recent call for increasing FDA postmarketing safety programs, was welcomed by Meyers. She remarked in her testimony that funding for the FDA has never appeared to be a high priority, irrespective of what party has had the majority in Congress.
"A major problem is that the Agency is not funded through any of the health-related appropriation committees," Meyers explained. "Rather, it is funded, for historical reasons, by the agriculture appropriations committees. There, FDA's funding must compete against fish farms, diseases of peach trees, and the tobacco subsidy."
Remedies From Witnesses
The Senate HELP committee held two hearings in March on the FDA: "FDA's Drug Approval Process: Up to the Challenge?" on March 1, and "Ensuring Drug Safety: Where Do We Go From Here?" on March 3. Testimony was heard from FDA administrators and from several witnesses with different and sometimes opposing perspectives.
Bruce M. Psaty, M.D., Ph.D., co-director of the Cardiovascular Health Research Unit at the University of Washington, who appeared at the invitation of Democrats, advocated that a fully independent safety group replace the existing ODS. Thomas Fleming, Ph.D., chairperson of the department of biostatistics at the University of Washington, invited by the Republican majority on the committee, argued against creating an oversight function outside the agency.
Two patient-consumer advocates called for strengthening FDA capacity to ensure drug safety; but Nancy Davenport-Ennis, CEO of the National Patient Advocate Foundation, cautioned against implementing too cumbersome a process, which might delay needed new products.
"We would advise against any effort that creates new regulatory or bureaucracy that isolates or further separates either the drug safety function or the drug efficacy function from the overall drug review process," Davenport-Ennis told the committee. "Safety and efficacy must never be viewed in isolation from each other."
Meyers agreed with the need for timely and efficient review of new drugs, but was critical of the FDA plan to establish a drug safety monitoring board within its own structure and staffed with its employees.
"Rather, we believe it should be composed of medical and scientific experts from outside the federal government, and it should report directly to the Commissioner's office, with FDA employees serving in an advisory capacity only," Meyers testified.
The American Medical Association was represented by Cecil Wilson, M.D., a trustee, who cautioned against reforms that might interfere with physicians' prerogative to prescribe medications "off-label" for unapproved indications.
"Given the disparity between the actual submission of [Supplemental New Drug Applications] and the evolution of evidence-based medical practice, physician prescribing for unlabeled uses should not be impeded by any actions taken to improve drug safety," Wilson told the committee.
A proposal that would necessarily interfere with off-label prescribing, at least in the initial market release, was described by Raymond L. Woosley, M.D., Ph.D., president of the Critical Path Institute at the University of Arizona, Tucson. Woosley explained that the FDA is under competing pressures to review and approve new drugs more rapidly, while conducting more exhaustive safety assessments of the new products. A "staged approval" process could support both these requirements, according to Woosley.
In the proposed staged approval process, an investigational medication evidencing greater potential benefit than available products could receive early approval, but would then be more tightly controlled, with new usages allowed gradually over time.
"There is an earlier and more gradual rise in the number of patients treated in this model," Woosley explained. "This allows time for more complete safety testing and assimilation of the drug into the practice of medicine before millions are exposed to the drugs."
Pursuing Postmarket Safety
In a prepared, shared statement submitted in the March 1 hearing by CDER deputy director, Sandra Kweder, M.D., and on March 3 by FDA acting deputy director for operations, Janet Woodcock, M.D., the FDA assured the HELP committee that drug safety is a high priority of the agency and an objective of both pre-approval screening and postmarket assessment.
"No amount of study before marketing will ever elucidate all the information about effectiveness or all the risks of a new drug," the FDA statement indicated. "Therefore, post-marketing surveillance is extremely important."
The post-approval assessments of the agency, according to the statement, include reviewing periodic safety updates received from drug sponsors and the voluntary MedWatch reports of adverse drug reactions. Agency actions based on these reports and subsequent evaluations, according to the hearing statement, may be to "ask" the manufacturer to revise the labeling, and can include withdrawing approval for the drug to be marketed.
Several of the Senate hearing witnesses decried the lack of FDA effectiveness in postmarket safety surveillance, however, and the inadequacy of voluntary adverse reaction reporting. They also testified that drug sponsors do not necessarily comply with FDA requests for Phase IV, post-approval clinical studies.
Senate witnesses also criticized the necessity for the agency to "negotiate" with drug sponsors to obtain revised labeling when new safety information emerges after drug approval. Psaty commented that a revised Vioxx product label in 2002 had followed more than two years of negotiation during which 20 million patients were exposed to unnecessary cardiovascular risk.
Psaty also indicated that the FDA's MedWatch system has been characterized as a 1950s-era approach. This voluntary reaction reporting system, Psaty testified, "lacks many of the features of high-quality epidemiologic studies, including validation of events by standard criteria, complete ascertainment of cases, population-based controls, comparable assessment of drug use and risk factors, and so forth."
William B. Schultz, J.D., an attorney who has practiced in public interest as well as serving as a congressional staffer and FDA official, spoke to the limited capacity of the agency to detect and act on postmarket drug safety issues. "There is no explicit authority for the FDA to order that the label be changed to include new information or new warnings," Schultz testified.
"The FDA's only recourse is to withdraw the drug from the market or to bring a misbranding action. These options are usually inappropriate and cumbersome," Schultz indicated. "Thus, the FDA is left to negotiate labeling changes with the company and it does not have sufficient leverage to require the changes that it deems appropriate."
Meyers concurred, telling the committee, "This means that labeling changes are often needed after a drug reaches the market, but the FDA does not 'tell' companies to add changes to their labels. They 'negotiate' the changes with manufacturers. Meanwhile, more patients may suffer adverse events because doctors are unaware of the problems associated with that particular drug."
Meyers and other witnesses called for the Senate committee members to draft legislation that would empower the FDA to mandate such post-approval label changes. "The FDA must be given the authority to require manufacturers to do things that will enhance patient safety without delay," Meyers urged.