Harsh criticism lobbed at FDA in Senate Vioxx hearing

Janis Kelly

November 23, 2004

Washington, DC - The November 18, 2004 hearing of the powerful US Senate Finance Committee produced harsh criticism of the role of the US Food and Drug Administration (FDA) in the rofecoxib (Vioxx®, Merck) debacle and likely accelerated Congressional pressure for creation of a drug safety division with independent authority to act on safety concerns about FDA-approved drugs.

Controversial FDA scientist Dr David Graham stunned the hearing when he warned that five drugs currently on the US market (among them valdecoxib [Bextra®, Pfizer] might pose significant risks and should be reconsidered (see sidebar at end of article).

FDA safety system described as "broken"

Witnesses and Senate Finance Committee members charged that the FDA's Office of New Drugs:

  • Rushed Vioxx through the new drug approval process with unnecessary haste and in the face of concerns about cardiovascular risk raised by the agency's own reviewers.

  • Missed or ignored "red-flag" safety warnings after the drug was on the market and tried to silence an agency scientist whose analysis raised additional concerns about the drug.

  • Delayed too long in adding a cardiovascular warning to the rofecoxib label and allowed Merck too much control over what the label would say.

  • Is generally reluctant to act on safety problems that might cast doubt on previous regulatory decisions.

Star witness and a major source for committee investigators was Graham, associate director for science and medicine in the FDA's Office of Drug Safety. Graham described the FDA and its Center for Drug Evaluation and Research (CDER) as "broken" and said, "Vioxx is a terrible tragedy and a profound regulatory failure. I would argue that the FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless."

Sen Charles Grassley (R-IA) charged that the FDA, among other failings, permitted Merck to delay for 14 months before adding information about cardiovascular risk to the Vioxx labeling, during which time the company "aggressively marketed Vioxx, knowing that consumers and doctors were largely unaware of the cardiovascular risks." This delay, like the apparent discounting of bad news from the FDA's own researchers, mirrors problems the Finance Committee had already investigated with regard to the increased suicide risk associated with use of some antidepressants in children and adolescents.

Too hasty to approve drugs?

Dr Gurkirpal Singh (Stanford University School of Medicine, CA) suggested that one factor in the Vioxx problem was undue haste to approve the drug. The most important reason for development of the selective COX-2 inhibitors was safety: the hope that they would avoid the GI damage associated with nonselective NSAIDs. However, by the time Merck filed for approval of Vioxx in 1999, internal studies by Merck researchers had uncovered suggestions of a "heart attack-stomach bleed" trade-off, Singh said.

Furthermore, the FDA's own reviewer, medical officer Dr Maria Lourdes Villalba, noted at the time that data in the Vioxx new drug approval (NDA) application showed that "thromboembolic events are more frequent in patients receiving Vioxx than placebo," with cardiovascular event rates of 0.24% among patients receiving placebo vs 0.74% for those receiving 12.5 mg or more of Vioxx daily.[1]

Villalba wrote, "With the available data, it is impossible to answer with complete certainty whether the risk of cardiovascular and thromboembolic events is increased in patients on rofecoxib. A larger database will be needed to answer this and other safety comparison questions."

Larger and more definitive studies should have been done before the drug was approved. After all, the drug was no more effective than any other available painkiller.

"It is my opinion that at this point in time, larger and more definitive studies should have been done before the drug was approved," Singh said. "After all, the drug was no more effective than any other available painkillerand there were nearly 30 such drugs available in the US. . . . There was certainly no emergent need to approve Vioxx without further studies if there were lingering safety concerns. The trade-off of heart attacks for the rare instances of stomach bleeds is not a reasonable one."

The charge of hasty approval was stoutly rejected by Dr Sandra Kweder (deputy director of the FDA's Office of New Drugs). Kweder said that the agency conducted an "intensive review" of the Merck NDA data for over 5000 patients seeking any indication of cardiovascular risk. "The cardiovascular risk was examined with a fine-toothed comb. The company provided a database of over 5000 patients. That's quite a large database for any drug. . . . The results of the [Vioxx Gastrointestinal Outcomes Research] VIGOR study were the first clinical indication of an increase in cardiovascular risk.""

No bad news allowed?

The Grassley committee's next concern was whether the FDA had missed or ignored "red-flag" warnings it should have noticed after Vioxx came onto the market. According to Graham, this is exactly what happened.

The organizational structure within CDER is entirely geared toward the review and approval of new drugs. When a serious safety issues arises, their immediate reaction is almost always one of denial, rejection, and heat.

"Simply put, the FDA and its CDER are broken. The organizational structure within CDER is entirely geared toward the review and approval of new drugs. When a serious safety issues arises, their immediate reaction is almost always one of denial, rejection, and heat. They approved the drug, so there can't possibly be anything wrong with it. The same group that approved the drug is also responsible for taking regulatory action against it postmarketing. This is an inherent conflict of interest. At the same time, the Office of Drug Safety has no regulatory power and must first convince the new-drug-reviewing division that a problem exists before anything beneficial can be done to help the public," Graham said.

Graham pointed out that the VIGOR trial, published in November 2000, found a fivefold increase in heart-attack risk with high-dose Vioxx.[2] A letter from Grassley to acting FDA head Dr Lester M Crawford also cited the "Targum memo," an analysis by FDA medical officer Dr Shari Targum of Vioxx-related cardiovascular risk that was considered at the February 2001 Arthritis Advisory Committee meeting that made recommendations for post-VIGOR Vioxx label changes.[3] Targum, who is in the FDA's Division of Cardio-Renal Drug Products, concluded, "there is an increased risk of cardiovascular thrombotic events, particularly myocardial infarction, in the [Vioxx] group compared with the naproxen group" in the VIGOR study. Targum further pointed out that although Merck was attributing the difference in MI rates to a protective antiplatelet effect of naproxen, "this hypothesis is not supported by any prospective placebo-controlled trials with naproxen."

Graham said that after VIGOR, he undertookwith FDA approval and fundinga collaborative epidemiologic study with Kaiser Permanente in California to examine cardiovascular risk. He emailed study results to a supervisor on August 11, 2004.

"We concluded that high-dose Vioxx significantly increased the risk of heart attacks and sudden death and that the high doses of the drug should not be prescribed or used by patients. This is exactly the finding of VIGOR: high dose increases the risk of heart attack," Graham said.

According to his analysis, Vioxx increased the risk of heart attack and sudden death by 3.7-fold for high dose and by 1.5-fold for low dose, compared with celecoxib. This led to an estimate of nearly 28 000 excess cases of heart attack or sudden cardiac death attributable to Vioxx. However, Graham said that this is an extremely conservative estimate, and using the risk levels seen in the Merck VIGOR and APPROVE clinical trials gives "an estimate of 88 000 to 139 000 cases, 30% to 40% [of whom] probably died." (Similar work by Dr Eric Topol [Cleveland Clinic, OH] estimated that up to 160 000 heart attacks and strokes were due to Vioxx.[4])

This conclusion triggered an explosive response from the Office of New Drugs, which approved Vioxx in the first place and was responsible for regulating it postmarketing.

Graham added, "This conclusion triggered an explosive response from the Office of New Drugs, which approved Vioxx in the first place and was responsible for regulating it postmarketing. The response from senior management in my office, the Office of Drug Safety, was equally stressful. One drug safety manager recommended that I should be barred from presenting the poster [of the study results] at the [International Conference on Pharmacoepidemiology] meeting and also noted that Merck needed to know our study results. I guess that Merck needed to know the results, but the public didn't."

Graham described feeling pressured to water down his conclusions and referred to an August 13 email from Office of New Drugs director Dr John Jenkins saying that Graham's conclusion used "pretty strong language since to my knowledge, the FDA is not contemplating such a warning or labeling." Graham did present the poster and submitted a manuscript of the study to the Lancet, which accepted it for publication, but he told the Senate Finance Committee that "senior managers in the Office of Drug Safety have not authorized its publication."

The day before the hearing, Acting FDA Commissioner Crawford released a statement saying that Graham submitted his findings for publication "without going through the long-established peer review and clearance process established for scientific papers submitted by FDA scientists."

Dr Bruce M Psaty (University of Washington, Seattle) commented on the contrast between the changes to the Vioxx label and the black-box warning about an increased risk of cardiovascular events added to labeling for estrogens and progestins soon after publication of data from the Women's Health Initiative.[5] "The public-health rationale for the two different approaches remains unclear," said Psaty.

The FDA should regulate the drug companies, not collaborate or negotiate with them if there is any question of public safety.

Singh recommended that the FDA be given the authority to make unilateral decisions on issues of public-health safety, without having to negotiate and reach agreement with drug companies. "The FDA should regulate the drug companies, not collaborate or negotiate with them if there is any question of public safety," Singh said.

Psaty and Singh both recommended establishing a new "Independent Office of Drug Safety" separate from the Office of New Drugs to handle postmarketing surveillance and to make "decisions about label changes, new studies, suspension of sales, or withdrawal of drugs."

Graham lists five drugs of concern

Graham stunned the Senate Finance Committee hearing when he almost casually said, "There are at least five drugs on the market today that I think need to be looked at quite seriously to see if they belong there."

After a bit of prodding from Sen Jeff Bingaman (D-NM), Graham named the drugs:

  • Valdecoxib (Bextra, Pfizer).

  • Sibutramine (Meridia, Abbott).

  • Rosuvastatin (Crestor, Astra-Zeneca).

  • Isotretinoin (Accutane, Roche).

  • Salmeterol xinafoate (Serevent, GlaxoSmithKline).

Graham's concerns about Bextra are because it is in the same drug class as Vioxx and because Pfizer is already considering a "black-box" warning about Stevens-Johnson syndrome.

FDA tries to discredit Graham

Allegations have also come to light that FDA management tried to discredit Graham. In a news article published online in BMJ November 27, 2004, Graham's attorney, Tom Devine, legal director of the Government Accountability Project, a public-interest group that helps whistleblowers to promote governmental and corporate accountability, says that Graham had sought the group's help in connection with the rofecoxib study.[6]

But the group then received an anonymous call from someone at the FDA claiming that he was being "bullied" by Graham and that Graham's study could reflect scientific misconduct. After investigating, Devine and colleagues found out that these anonymous charges actually came from FDA management. "We made demands to call whichever side was bluffing," said Devine. "The FDA flunked every test of credibility while Graham passed all of them. The agency attempted to discredit Dr Graham rather than provide any scientific evidence contradicting his conclusions." Devine said that the FDA's attacks on Graham's credibility were implausible.


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