Critics Diagnose Systemic Maladies of FDA
A Senate Finance Committee hearing on Vioxx and a series of studies by a leading medical journal reveal systematic breakdowns in FDA's evaluation of drug safety, prompting advocates to call for an independent agency to review drug safety.Drug Researcher Testifies: The System is 'Broken'
In testimony before the Senate Finance Committee Nov. 18, FDA researcher David Graham said the current system for testing the safety of drugs is "broken" and incapable of preventing unsafe drugs from entering the marketplace. Graham's testimony came in response to an investigation into the agency's handling of Vioxx, which was pulled from the market last month after it was found that use of Vioxx led to increased risk of heart failure. Graham's research had found that users of Vioxx were 3.7 times more likely to suffer heart attack or sudden death compared to users of its competitor Celebrex. Though Graham presented these findings at a conference in France this summer, the FDA would not act on his findings here and instead asked Graham to soften his conclusions.
A Culture of Suppression
Vioxx is Not Alone
Although the Vioxx case prompted the hearing, Graham charged that the FDA's failure to serve the public extends beyond that one drug. Graham pointed to a systematic failure to warn the public about the dangers of drugs when such warnings go against the interests of the Office of New Drugs. Graham used the historical examples of Lotronex, which studies had shown caused severe constipation and ischemic colitis, and Rezulin, a diabetes drug that caused acute liver failure. In both cases, Graham stated, the FDA knew of problems with the drugs but stalled, allowing countless individuals to suffer needlessly before finally withdrawing the drugs.
Graham listed five other drugs that he believed had been proven to present a serious health risk that FDA was failing to act on:
- AstraZeneca's cholesterol drug Crestor, which has been linked to muscle degeneration and kidney failure;
- Abbott Laboratories' weight loss drug Meridia, which has been associated with high blood pressure;
- GlaxoSmithKline's Serevent for asthma, which can cause life-threatening lung spasms;
- Roche Pharmaceutical's Accutane for acne, which has been shown to cause serious birth defects; and
- Pfizer's Bextra, an arthritis drug similar to Vioxx, that may cause heart failure or stroke.
When questioned Graham asserted that the failure of FDA to protect the public is inherent in the current system. As Graham stated in his testimony, when FDA approves a new drug, "it is also saying the drug is 'safe and effective.' When a serious safety issue arises post-marketing, their immediate reaction is almost always one of denial, rejection and heat." Graham's charges were echoed as other news surfaced suggesting that top officials at the FDA are more concerned with industry profits and their own image than in protecting the public.
Killing the Messenger
FDA officials may have attempted to discredit Graham before the hearing took place, leading Senate Finance Committee Chairman Charles Grassley (R-IA) to call for the Department of Health and Human Services Inspector General to investigate the matter. According to the New York Times, when Graham realized he was potentially vulnerable to retaliation as a whistleblower, he contacted Tom Devine at the Government Accountability Project to seek protection. While considering whether to take on the case, Devine began to receive anonymous phone calls trying to discredit Graham's reputation. Devine was able to deduce through their phone numbers and documents they sent him that they were high-level FDA officials. The officials were never able to back up their claims against Graham.
Moreover, news is surfacing that FDA officials tried to discredit Graham's study before it was published in a medical journal. USA Today reported that Steven Galson, acting director of the agency's Center for Drug Evaluation and Research, contacted the editors of the London medical journal The Lancet while the editors were reviewing Graham's article for possible publication. Among other things, Galson charged Graham with manipulating the data in his study--a charge that the study itself lacks sufficient integrity to warrant publication in any serious scholarly journal. In fact, according to Graham, the basis of that charge was a "discrepancy" between an abstract of the study as published in materials for a conference and the final study itself. That "discrepancy" was the product of an error that he corrected before addressing that conference and before submitting the paper itself for publication.
The attack on Graham coincided with the FDA's decision to exclude from an advisory panel a scientist who has compiled evidence that yet another drug may, like Vioxx, be harmful to users. Curt D. Furberg, a professor at Wake Forest University, was booted from an FDA committee to review the safety of the Cox-2 inhibitors after he made public statements questioning the safety of Bextra, a Cox-2 inhibitor painkiller produced by Pfizer, Inc. Furberg, a leading expert on drug analysis, told the New York Times that he believed Bextra appeared to be similar to Vioxx. The statement prompted FDA to rescind his invitation to the advisory panel. Furberg told the Wall Street Journal, "I collected the evidence to contribute to the debate, I drew a conclusion, and I'm off."
Broader Failures in Drug Safety Evaluation
In a series of studies, the Journal of the American Medical Association (JAMA) illustrated the failures of FDA's current system of drug evaluation. Evidence of the failures of the current system revolved around the drug Baycol, which was pulled from the market in 2001. While one study demonstrated that the cholesterol-lowering drug had substantial risk of serious side effects, another pointed to evidence that the makers of Baycol had information in early 2000 that the drug was more dangerous than competing drugs but did not make the information known. Patients on Baycol were far more likely to be hospitalized with a rare, serious muscle disorder than those on Lipitor, Pravachol or Zocor.
Drug makers are largely responsible for evaluating the dangers of their own drugs. FDA may perform some drug evaluations, but it relies largely on the makers of the drug to evaluate the drugs safety and then report the information to the agency. The agency also relies on voluntary reporting from doctors, so the majority of cases go unreported or the reports are not thorough enough to accurately determine the potential side effects.
The editors of JAMA concluded that this system, too, is broken:
For instance, it appears that fewer than half of the post-marketing studies that manufacturers have made commitments to undertake as a condition of approval have been completed and many have not even been initiated. Moreover, despite the mandatory adverse event reporting system for companies subject to the FDA's post-marketing safety reporting regulations, drug manufacturers may be tempted to conceal available data that may signal the possibility of major risks. In some cases, the FDA and drug manufacturers may fail to act on that information and fail to conduct appropriate studies to examine a potential risk rigorously and promptly.
The Agency Responds to Criticism
The day before the hearing, FDA Acting Commissioner Lester Crawford issued a statement countering Graham's testimony. Crawford responded to criticism that the agency mishandled the Vioxx case, saying, "FDA has a well-documented and longstanding commitment to openness and transparency in its review of marketed drugs." Graham had contended that he was forced to revise the conclusions of his study, but Crawford countered that all revisions to Graham's study were done by Graham with his approval and without compromising his "deeply held convictions."
Sandra Kweder at the Office of New Drugs defended FDA's actions on the Vioxx case, saying, "FDA worked actively and vigorously with Merck to inform public health professionals of what was known regarding [cardio-vascular] risk with Vioxx, and to pursue further definitive investigations to better define and quantify this risk." Kweder also said that the FDA described by Dr. Graham "was not the FDA [she] know[s]."
Crawford also responded to statements that Dr. Curt Furberg had been removed from an advisory panel for publicly questioning the safety of Bextra. Backing away from the previous FDA position, Crawford said, "The advisory committee preparation process is still under way, so it was premature for any FDA official to suggest that Dr. Furberg could not participate in the upcoming meeting."
Crawford and Kweder also pointed out that FDA has taken steps to evaluate weaknesses in their current drug evaluation system. Early this month, FDA called on the National Academies' Institute of Medicine to review the agency's drug safety system. Responding to criticism that controversial scientific opinions of the agency's top scientists were suppressed or weakened by superiors, FDA is also establishing an internal appeals process. Through the appeals process, individuals within the agency who feel that superiors have allowed an unsafe drug to enter the market may present their case before an expert committee.
Calls for Change
In response to its findings that the public/private relationship in the drug evaluation system is deeply flawed, JAMA called for an independent agency to look at drug safety. The editors contended that it was unreasonable to have the same agency both approve drugs and "also be committed to actively seek evidence to prove itself wrong."
Other advocates have echoed the journal's request for an independent review of drugs, including Grassley. The Vioxx hearing before the committee pointed to mounting tensions between the FDA's Office of Drug Safety and the Office of New Drugs. Though the two offices are theoretically independent of one another, testimony revealed that the Office of New Drugs exerts considerable influence over the Office of Drug Safety. Many advocates believe such influence is inevitable when the same agency both approves drugs and evaluates their post-market safety. The agency is often reticent to release criticism of drugs already on the market, leaving patients at risk for side effects that can do serious harm.
Not everyone agrees that an independent group is necessary. University of Pennsylvania School of Medicine's Brian Strom, a consultant to major pharmaceutical manufacturers, countered the editorial staff with a commentary in JAMA. Strom argued that pre-market clinical trials will account for common side effects but may not catch rare side effects, which may only be detected through post-marketing surveillance. The current system "reflects a deliberate societal decision to balance delays in access to new drugs with delays in information about rare adverse reactions." Senate Health Committee Chairman Judd Gregg (R-NH) also disagreed with the need for an independent group to evaluate drug safety, saying Nov. 24 that "another layer of bureaucracy at the FDA is probably the last thing we need."
Gregg is set to step down as committee chairman in January. A new chair has yet to be announced.
Public interest groups have begun to take action against the host of problems within FDA. Among them, Consumers Union has launched a national grassroots advocacy campaign, Prescription for Change, which seeks reforms to ensure safe, effective and affordable prescription drugs. Echoing recent cries from Congress and several medical journals, the group calls "for a mandatory, public registry of drug companies' clinical trials to ensure that drug safety and effectiveness information is readily available to researchers, physicians and consumers." Over 25,000 citizens have already used the website to send emails to their representatives calling for action.