Harsh criticism lobbed at FDA in Senate Vioxx hearing

Janis Kelly

November 23, 2004

Nov 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 5 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.

The hearing contributed to a perception that the FDA is an agency in trouble. The Bush Administration has not appointed anyone to replace former FDA director Mark McClellan, who left in 2002 to head the Centers for Medicare and Medicaid Services (CMS), and there has been no director of the Office of Drug Safety for nearly 2 years. The Center for Drug Evaluation and Research (CDER) likewise has only an acting director.

The Senate Finance Committee is involved because it oversees the budgets for Medicaid (which helps provide healthcare for the poor and disabled) and for Medicare (which helps provide healthcare for the elderly). Together the programs cover more than 80 million Americans, and committee chair Sen Charles Grassley (R-IA) stated that Medicaid paid more than $1 billion for Vioxx during the time the drug was available in the US.

Vioxx is a terrible tragedy and a profound regulatory failure. . . . The FDA, as currently configured, is incapable of protecting America against another Vioxx. We are virtually defenseless.

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 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."

Grassley 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 1 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."

"It is my opinion that at this point in time, 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—and 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," Singh said. "Instead, the drug was approved by the FDA in a priority review within 6 months—with no discussion on the heart-attack trade-off. The prescribing physicians remained unaware of any of these data or discussions until much later—with the new label change in April 2002."

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.

Vioxx was a "fast-tracked" drug, given speedy consideration as a drug that could "treat serious and life-threatening illness and provide meaningful therapeutic benefit over existing therapies" under the FDA Modernization Act of 1997. That legislation requires that fast-tracked drugs be subjected to postmarketing surveillance, but this requirement was not enforced for Vioxx and has been loosely enforced for other fast-tracked drugs [ 2 ].

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 duration of exposure for many of the patients exceeded international standards for clinical trials of new drugs. At the time, when celecoxib was also under review, the data brought about tremendous hope for reducing the substantial morbidity and mortality associated with GI bleeding and ulcers associated with NSAIDs," Kweder said. "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.

"Simply put, the FDA and its Center for Drug Evaluation and Research 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.

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.

Graham pointed out that the VIGOR trial, published in November 2000, found a 5-fold increase in heart-attack risk with high-dose Vioxx [ 3 ]. 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 [ 4 ]. 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 myocardial infarction (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 undertook—with FDA approval and funding—a 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 [ 5 ].)

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 given clearance for 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. When FDA scientists learned that this paper had been accepted for publication in the Lancet despite not having gone through the normal peer-review process, the director of the FDA's Center for Drug Evaluation and Research [acting director Dr Stephen K Galson] contacted the journal's editor, out of respect for the scientific peer-review process."


Delay in changing the label questioned

The next question raised at the hearing concerned the 18-month delay between when Merck gave data from the VIGOR trial to the FDA (June 2000) and when the Vioxx label was changed to include information about increased heart-attack risk (April 11, 2002). In addition to the unusually long delay in finalizing wording for the label, there are questions about why the information did not merit a "black-box" warning (which would have ended direct-to-consumer marketing) or even inclusion in the "Warnings" section but was added to the "Precautions." In 2003 Merck spent $160 million for direct-to-consumer advertising of Vioxx, Grassley said.

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 [ 6 ]. "The public-health rationale for the 2 different approaches remains unclear," said Psaty, who is a noted expert on cardiovascular disease epidemiology, pharmacoepidemiology, and drug safety.

Singh was even more skeptical about the label change. "While the stomach-bleed safety data were added in a prominent fashion, the heart-attack information seemed to support Merck's contention that Vioxx did not increase the risk by adding statements such as, 'Because of its lack of platelet effects, Vioxx is not a substitute for aspirin for cardiovascular prophylaxis.' Was there a single physician in the world who had prescribed Vioxx for cardiovascular prophylaxis? Why not also say, 'Because of its lack of antitumor effect, Vioxx is not a treatment for brain cancer'?"

Singh recommended a public discussion of the role of FDA in approving drugs and labels. "As the delay in Vioxx label shows, the current process of labeling is of negotiations—if the 'sponsor' does not agree with what the FDA wants, it can continue to stall or worse. It took 2 years for the label change of Vioxx to take effect, and even then the label change supported mostly Merck's position, not the 1 advanced by the FDA's own reviewers in public hearings."

Was there a single physician in the world who had prescribed Vioxx for cardiovascular prophylaxis? Why not also say, 'Because of its lack of antitumor effect, Vioxx is not a treatment for brain cancer'?"

Kweder did not directly address the unusually long delay before the cautionary language was added to the label but did say that the FDA will be collapsing "Precautions" and "Warnings" sections into a single section under new guidelines now being developed, because dividing information between the 2 has not been clinically useful.

"When we sought to change the [Vioxx] labeling based on the VIGOR trial, our goal was to ensure that the information was accurate, provided enough data, and provided a perspective so clinicians could understand what we were concerned about. I believe the revised labeling for Vioxx did that," Kweder said. "We pursued that label change vigorously. We worked extremely closely with our colleagues in the Office of Drug Safety to make label changes when new signals were coming up in the adverse-events database, and we continued to monitor the literature."


Regulators seen as reluctant to act on safety problems

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."

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

Several members of the Senate Finance Committee were clearly interested in this approach, but it is likely to be resisted by the FDA. In a statement issued the day of the hearing, FDA's Galson said, "FDA's Office of Drug Safety (ODS), in the Center for Drug Evaluation and Research, is already an independent office separate from the Office of New Drugs, the office that reviews new drug applications. Both the Office of New Drugs and the Office of Drug Safety report directly to me as the director of the center. . . . [T]he premarket review divisions in CDER do not control the work of ODS. ODS has independent authority to perform its own research and does so everyday."

This is true, but it begs the issue of regulatory authority. At the hearing Kweder said, "The authority for making final regulatory decisions does rest within the Office of New Drugs."

Kweder also described new efforts CDER is taking to ensure that dissenting views such as Graham's are not swept aside. "CDER will implement a formal program for addressing differences of professional opinion . . . to absolutely reassure scientists who don't believe they are being heard," she said.



Vioxx situation may slow medical liability reform

Senate Finance Committee member Jim Bunning (R-KY) raised the issue of a possible effect of the Vioxx experience on attempts to pass legislation restricting some types of medical-liability lawsuits. Bunning said that the current proposal "provides that pharmaceutical companies be shielded from damages with respect to any drug that has FDA approval."

The bill (passed by the House of Representatives as HR5 and introduced into the Senate as S11) would eliminate civil monetary penalties for "products in compliance with FDA standards." It would forbid punitive damages against "the manufacturer or distributor of a medical product . . . on the basis that the harm to the claimant was caused by the lack of safety or effectiveness of the particular medical product involved " unless the claimant demonstrates that the product manufacturer failed to comply with a specific requirement of the Federal Food, Drug, and Cosmetic Act or the regulations promulgated thereunder and that the harm was due to this failure.

The bill also would exempt the FDA from actually having to demonstrate that the manufacturer met the required conditions and would forbid product-liability or class-action lawsuits against healthcare providers who prescribe a medical product approved by the Food and Drug Administration.



Graham lists 5 drugs of concern

Graham stunned the Senate Finance Committee hearing when he almost casually said, "There are at least 5 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.

All of the drug manufacturers involved have issued statements defending the efficacy and safety of their products, but Graham's remarks moved the stock markets because of his track record. Not only did he question Vioxx's safety before it was withdrawn, but his work contributed to withdrawal from the US market of the antibiotic temafloxacin (Omniflox, Abbott Laboratories; recalled for causing hemolytic anemia), the diabetes drug troglitazone (Rezulin, Parke-Davis/Warner-Lambert; acute liver failure), the diet drugs fenfluramine/phentermine (heart valve injury) and dexfenfluramine (Redux, Wyeth-Ayerst Laboratories; heart valve injury), the over-the-counter decongestant and diet drug phenylpropanolamine (hemorrhagic stroke in young women), the cholesterol-lowering drug cerivastatin (Baycol, Bayer; rhabdomyolysis, kidney failure), the antihistamine terfenadine (Seldane, Hoechst Marion Roussel; heart arrhythmias), and the gastrointestinal agent cisapride (Propulsid, Janssen Pharmaceutica; heart arrhythmias).

FDA tries to discredit Graham

Some of the controversy surrounding Graham is exposed in a new light by revelations in a news article published online November 27, 2004 in BMJ [ 7 ]. It quotes Graham's attorney, Tom Devine, legal director of the Government Accountability Project, a public-interest group based in Washington DC that helps whistleblowers to promote governmental and corporate accountability. Devine said that Graham, "fearingfor his job, had sought the group's help in connection with the rofecoxib study a month ago."

"The group's decision on whether to provide legal counsel for Graham was delayed after it received another request for aid for someone claiming to be an anonymous whistleblower at the FDA who was being 'bullied' by Graham," the article says. "The anonymous caller also said 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 FDA was employing a classic law of whistleblower appraisal—the smokescreen syndrome—which shifts the spotlight from the message to the messenger. The agency attempted to discredit Graham rather than provide any scientific evidence contradicting his conclusions."

Devine said that the FDA's attacks on Graham's credibility were implausible, and the article lists drugs he warned about that were subsequently withdrawn. The article also notes that when he returned to work on Friday after testifying at the Senate hearing, Graham was greeted by his colleagues with applause, which gives some measure of the esteem with which he is regarded.

"Something is rotten at the heart of the FDA," comments Dr Kamran Abbassii, acting editor of BMJ [ 8 ]. "As one of the world's leading drug regulators, the FDA needs to show that its primary role is to protect the public and not to protect the industry."


Sources

  1. Villalba ML. FDA Medical Officer Review of VIOXX (rofecoxib). NDA 21-042 (capsules) and NDA 21-052 (oral solution). Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_03_med.pdf

  2. Department of Health and Human Services, Food and Drug Administration. Report on the performance of drug and biologics firms in conducting postmarketing commitment studies: availability. Fed Regist 2003; 68:27822-27823, May 21, 2003.

  3. Bombardier C, Laine L, Reicin A, et al, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000; 343:1520-1528.

  4. Targum SL. Consultation on NDA 21-042, S-007. Review of cardiovascular safety database [on Vioxx or rofecoxib]. FDA Memorandum, February 1, 2001. Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_06_cardio.pdf.

  5. Topol EJ. Failing the public health—rofecoxib, Merck, and the FDA. N Engl J Med 2004; 351:1707-1709.

  6. Writing Group for the Women's Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333.

  7. Lenzer J. Public interest group accuses FDA of trying to discredit whistleblower. BMJ 2004;329:1255. Available at: http://bmj.bmjjournals.com.

  8. Abbasi K. Is drug regulation failing? BMJ 2004; 329: published online before print November 27, 2004. DOI: 10.1136/bmj.329.7477.0-g. Available at: http://bmj.bmjjournals.com.


Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....