What's Left of the FDA After Vioxx?

By Edward J. Parr Jr., Esq.

In the end, the FDA decided to do nothing about Vioxx (unless and until Merck proposes to recommence marketing), to take Bextra off the market, and to relabel Celebrex and many other NSAIDs. In their April 6, 2005, memorandum entitled “Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk,” FDA officials concluded:

The three approved COX-2 selective NSAIDs (i.e., celecoxib, rofecoxib, and valdecoxib) are associated with an increased risk of serious adverse CV events compared to placebo. The available data do not permit a rank ordering of these drugs with regard to CV risk.

…

The agency should ask Pfizer to voluntarily withdraw Bextra (valdecoxib) from the U.S. market. In the event Pfizer does not agree to a voluntary withdrawal, the agency should initiate the formal withdrawal procedures; i.e., issuance of a Notice of Opportunity for Hearing (NOOH).

The professional labeling for all prescription NSAIDs should be revised to include a boxed warning highlighting the potential increased risk of serious adverse CV events. The boxed warning should also include the well described NSAID class risk of serious, and often life-threatening, GI bleeding, which is currently contained in a bolded warning.

…

The agency should carefully review any proposal from Merck for resumption of marketing of Vioxx (rofecoxib). We recommend that such a proposal be reviewed by the FDA Drug Safety Oversight Board and an advisory committee before a final decision is reached.

- Jenkins, J. and Seligman, P., “Decision Memo - Analysis and Recommendations for Agency Action - COX-2 Selective - Non-selective NSAIDs” (Apr. 6, 2005).

Bextra is now gone, and an FDA “Alert” published on April 7, 2005 states:

Celebrex has been associated with an increased risk of serious adverse cardiovascular (CV) events in a long-term placebo controlled trial. Based on the currently available data, FDA has concluded that an increased risk of serious adverse CV events appears to be a class effect of nonsteroidal anti-inflammatory drugs (NSAIDs) (excluding aspirin). FDA has requested that the package insert for all NSAIDs, including Celebrex, be revised to include a boxed warning to highlight the potential increased risk of CV events and the well described risk of serious, and potentially life-threatening, gastrointestinal bleeding. http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm.

We don’t yet know what will happen to Vioxx, but undoubtedly Merck will have been emboldened by the vote of the FDA’s Arthritis Advisory Committee and Drug Safety and Risk Management Advisory Committees that jointly met on Feb. 16, 17, and 18, 2005, to determine the future of Vioxx in the United States.

The basic question to be answered was “Does the overall risk versus benefit profile for [Vioxx] support marketing in the U.S.?” The voting by the Advisory Committees was a surprise to many, as news reporters rushed from the room to announce that 17 members voted “yes” and 15 voted “no.” The meeting transcripts and briefing materials can be viewed at www.fda.gov/ohrms/dockets/ac/cder05.html#DrugSafetyRiskMgmt.

When the committees’ votes are dissected, however, it turns out that 13 members voted “no, the overall risk/ benefit profile for Vioxx does not support marketing”; 8 members voted that the overall risk/benefit profile for Vioxx would support marketing under certain conditions (including “marketing” restrictions, boxed warnings, compassionate use programs, lower doses only, limited duration, and/or for juvenile arthritis and other limited indications); and 11 members voted “yes the overall risk/benefit profile for Vioxx does support marketing,” but 10 of the 11 favored certain conditions (again, boxed warnings, cardiovascular monitoring, informed consent).

Hence, the vote was 1 vote to support unlimited marketing of Vioxx, 18 votes for restricted use, and 13 votes that Vioxx should stay off the market.

As FDA officials noted in their April 6, 2005 memorandum:

[T]he recent advisory committee meeting was a general issues meeting, not one specifically devoted to the issue of resumption of marketing of Vioxx. While the committees narrowly voted in the affirmative that the overall risk versus benefit profile of rofecoxib supported marketing in the U.S., the committee members expressed a wide variety of often contradictory opinions on what regulatory actions (e.g., labeling changes, risk management efforts) would be appropriate to allow resumed marketing.

Nevertheless, the committees unanimously agreed “the available data support a conclusion that [Vioxx] significantly increases the risk of cardiovascular events.” There was also an acceptance that Vioxx has a lower incidence of adverse gastrointestinal effects than older NSAIDs like aspirin. But clearly the committees did not see a simple trade off of GI risk versus CV risk. All Cox-II drugs have other suspected risks and benefits, and some of the risks might be controllable — for example, taking something like Prilosec with aspirin might reduce the GI risk; likewise, taking something like Cardura with a Cox-II might reduce the blood pressure effects that increase CV risk.

In addition, it was clearly understood and communicated to the FDA that Vioxx should be reserved for appropriate patients, of whom there may only be a handful. Dr. Cryer indicated that only 1 percent to 4 percent of older NSAID users are at risk for having GI bleeding. Dr. Cryer also indicated that there is no data showing that Cox-IIs reduce the incidence of GI complications in patients who are at high risk for GI complications. Cox-IIs are not needed in low risk patients, have no benefit in patients taking aspirin, and may not have real benefits in high risk patients either.

The committees understood that there was massive over-promotion and overutilization of Vioxx, and that Merck’s direct to-consumer advertising contributed to that problem. It was also clear that physicians need more information in order to select appropriate patients in whom to use Vioxx and other Cox-IIs. So the committee votes have to be understood as affirming that the current warnings have been totally inadequate to inform prescribers and patients about the true risks of Vioxx and other Cox-II inhibitors, even though the benefits may outweigh the risks in some patients.

Neither the FDA nor anyone else at the meeting really addressed whether the cardiovascular risks were known, or at least knowable, before the Vioxx market withdrawal. However, recent reports and articles show that both Merck and the FDA were aware of the cardiovascular problems with Vioxx prior to its withdrawal and did nothing or little to protect the public from its harm.

As early as 2000, FDA was on notice of cardiovascular problems with Vioxx with the release of the VIGOR (Vioxx Gastrointestinal Outcome Research) data. The study was conducted to show that patients taking Vioxx had fewer stomach ulcers and bleeding than patients taking Naproxen. Although reduced gastrointestinal bleeding was seen, the study also revealed a statistically significant increase in the number of cardiovascular events, myocardial infarctions/heart attacks and strokes in patients taking Vioxx as compared to those receiving Naproxen. The committees, although concerned about the lack of evidence on the long term risks of older NSAIDs such as naproxen, clearly did not believed Merck’s old argument that naproxen is more cardioprotective than even aspirin.

Despite this data, the FDA did not get around to a label change until 14 months later, while Merck continued to claim no evidence existed that, in comparison with other NSAIDs, Vioxx increased the risk of cardiovascular events. It wasn’t until the APPROVe (Adenomatous Polyp. Prevention on Vioxx) study, that the FDA was ready to acknowledge cardiovascular problems associated with Vioxx. APPROVe was a study that Merck was conducting to see if Vioxx could prevent polyps of the colon and rectum. The data from APPROVe demonstrated that those individuals taking Vioxx for 18 or more months were at an increased risk of developing cardiovascular disease than those taking placebo. According to early reports about the data, those taking Vioxx were twice as likely to develop serious cardiac disease as those taking placebo. Only after the release of the APPROVe data did Merck withdraw Vioxx from the market, on Sept. 30, 2004.

The advisory committee discussions left no doubt that there were material warnings missing from the labeling of the Vioxx and other Cox-II inhibitors. Many members of the committee were critical of Merck and the FDA for having taken 14 months to get the Vioxx labeling first changed after the VIGOR study data was reviewed at the FDA meeting in February 2001. If you assume that Merck knew or should have known of the adverse effects of Vioxx sooner, then the clear implication is that FDA was also not doing what needed to be done. And, although it cannot bear the financial responsibility for this disaster, it surely must bear some of the moral responsibility, with Merck.

Traditionally, state courts have viewed FDA regulations as “minimum standards of due care.” Thus, mere regulatory compliance does not necessarily absolve the company of liability for its own negligent acts or omissions. Nowhere than in the case of Vioxx has the FDA’s regulatory oversight of a prescription drug appeared more minimal. Consider these statements:

• “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.

” - FDA Official David Graham, M.D., in testimony before the U.S. Congress

• “Neither of the two major forces in this five and-a-half-year affair — neither Merck nor the FDA — fulfilled its responsibilities to the public. . . . In my view, the FDA’s passive position of waiting for data to accrue is not acceptable, given the strong signals that there was a problem and the vast number of patients who were being exposed.”

- Eric Topol, M.D. in the New England Journal of Medicine

• “Our findings indicate that Vioxx should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified. . . . In some instances, important discrepancies were noted between published data and figures in FDA files.”

- Peter Juni, M.D., and others in The Lancet

• “After the FDA insisted for months that it did nothing wrong in its oversight of the withdrawn pain pill Vioxx, a top agency official acknowledged “lapses” in the agency’s actions before a Senate panel. Most witnesses testifying before the panel agreed, saying the agency should have the authority to force label changes and make companies conduct tests if safety issues arose after a drug was approved. [FDA Official] Dr. Kweder said the agency took too long to get information about Vioxx’s heart risks into the prescribing label that is provided to physicians.”

- The New York Times, March 2, 2005

• “In the past four years, the Food and Drug Administration has taken a noticeably less aggressive approach toward policing drugs that cause harmful side effects, records show, leading some lawmakers, academics and consumer advocates to complain that the agency is focusing more on bolstering the pharmaceutical industry than protecting public health.”

- The Washington Post article on Vioxx, November 18, 2004

• “One of my concerns is that the FDA has a relationship with drug companies that is too cozy. That’s exactly the opposite of what it should be. The health and safety of the public must be the FDA’s first and only concern.“

- U.S. Senator Chuck Grassley on Vioxx (Republican Senator from Iowa)

• “Given the amount of information circulating in regards to the potentially harmful effects of Vioxx, why hasn’t FDA, the agency that is supposed to protect the public, been more active in this area? This recall . . . raises troubling concerns as to the adequacy of FDA’s drug safety monitoring program.”

- Rep. Tom Davis (Republican Representative from Virginia)

The FDA and Health Canada have demonstrated their structural inability to do ongoing safety monitoring of new drugs and devices, and industry is far too conflicted to be able to carry out this important task. We need new national agencies to monitor drug safety independently from the approvals process. Only then can physicians and patients be assured an unbiased safety assessment of the drugs they are prescribing and taking.

- Canadian Medical Association

• “For an approved drug, the FDA currently engages in protracted negotiations with manufacturers rather than mandating manufacturers (1) to change a product label,(2) to conduct patient or physician education, (3) to limit advertising to patients or physicians, (4) to modify approved indications, (5) to restrict use to selected patients, (6) to complete post-marketing studies agreed on at the time of approval, (7) to conduct additional post-marketing studies or trials, and (8) to suspend marketing or immediately withdraw a drug. The FDA has recently claimed to lack adequate authority in these areas.”

- Bruce Psaty and Curt Furberg in the New England Journal of Medicine

The FDA’s lapses are not entirely of its own making – after all, the FDA did everything it is empowered by law to do, those laws are not comprehensive, and it was Merck – not the FDA – that sold Vioxx to millions of Americans. In essence, the prevailing opinion has come down that the FDA’s rules and regulations cannot protect us from a company determined to sell a dangerous drug to millions of Americans. Merck - not the FDA - should compensate the victims.

About the Author

Edward J. Parr, Jr., Esq., is a partner with the law firm of Ury & Moskow LLC in Washington, D.C. and Connecticut and manages the firm’s pharmaceutical mass tort litigation and regulatory/administrative law group. Mr. Parr is a former counsel at the U.S. Food and Drug Administration (FDA) who returned to private practice in 1998 to represent victims in the Diet Drug litigation. Since then, he has worked with MDL plaintiffs steering committees in the Rezulin, PPA, Propulsid, Baycol, Serzone, Hormone Therapy, and Sulzer product liability litigations, among others. Mr. Parr is a member of the Food and Drug Law Institute, the Drug Information Association, and the Association of Trial Lawyers of America.