FDA's focus following the Senate Finance Committee hearing on the Vioxx withdrawal is on defending the safety of five other drugs challenged by one of its safety reviewers.

During a Nov. 18 hearing on the withdrawal of Merck's COX-2 inhibitor, Office of Drug Safety Associate Director for Science David Graham asserted that there are unaddressed safety issues with AstraZeneca's cholesterol agent Crestor , GlaxoSmithKline's asthma therapy Serevent , Pfizer's COX-2 inhibitor Bextra , Abbott's weight loss drug Meridia and Roche's acne agent Accutane .

Graham's assertion dominated the headlines following the hearing - and illustrates the stakes in the debate over how best to structure FDA's post-marketing safety review functions.

During the hearing, the Finance Committee leadership made it clear that it wants to see the Office of Drug Safety given genuine "independence" from the new drug review side of FDA (see ¹ Also see "“Independent” Drug Safety Office Is Goal Of Senate Vioxx Investigation" - Pink Sheet, 22 November, 2004. ).

In that context, Graham's testimony could be viewed as a taste of things to come if post-marketing safety regulators do win a separate platform to discuss their views of marketed products.

Graham was afforded star witness treatment by the Finance Committee in his status as an informal FDA whistleblower. He was featured on the first panel, before the committee took testimony from the official agency representative, Office of New Drugs acting Director Sandra Kweder, MD.

Finance Committee Chairman Charles Grassley (R-Iowa) highlighted Graham's special status by cautioning Kweder that he would be on the lookout for signs of retaliation by FDA.

Grassley also asked Graham to comment on speculation that he intends to leave FDA to make money as an expert witness in drug liability lawsuits.

"I'm sure FDA wishes that I would," Graham replied. "Anybody who knows me for more than five minutes, knows the answer to that question. It's a ridiculous question and the answer is no....That's not what my career is about, that's not what I see myself doing. I enjoy doing post-marketing safety."

Graham proved to be a compelling witness with a knack for eye-catching metaphors. He introduced himself by taking credit for the withdrawals of Omniflox , Rezulin , Redux and PPA, and for the restrictions on Trovan . He also said he "contributed to" the withdrawals of Baycol , Seldane , and Propulsid .

He asserted that Vioxx was responsible for as many as 88,000 to 139,000 excess heart attack cases. Using a figure of 100,000 cases, he declared that the Vioxx "disaster" is "the rough equivalent of 500 to 900 aircraft dropping from the sky. This translates to two to four aircraft every week" for five years.

Graham also put those figures into context for Grassley by noting that 100,000 people would represent 5% of the population of Iowa, or 67% of the population of Des Moines. Graham's written testimony included similar statistics for each of the states represented by members of the Finance Committee.

Graham first alluded to his belief that there are "at least five drugs" on the market with safety problems in response to questions from Ranking Democrat Max Baucus (D-Mont.) about his reasons for arguing that there is a systemic problem with drug safety regulation. He only identified the drugs by name later when asked to by Sen. Jeff Bingaman (D-N.M.).

Kweder disagreed with Graham's assessment. "I do not have reason to believe that that set of five drugs is specifically more concerning than any other drugs," Kweder said. "I believe that all drugs pose some safety risk and that some drugs pose a greater risk than others, but there is no magic formula for deciding what drug is the biggest risk of all. If there were a magic formula, our jobs would be very much easier."

Kweder acknowledged that the five drugs singled out by Graham have been the subject of "much discussion and activity" in the agency. However, "there are many more drugs about which we have much discussion and much activity over in the agency."

In addition, FDA issued a follow-up statement underscoring that Graham's testimony does not reflect agency views and that each named drug is approved by FDA as safe and effective.

The specific drug safety issues on each of the drugs named by Graham have been addressed by FDA (often more than once) under its current regulatory process. That history may only feed into Graham's implication that each of the drugs is a Vioxx waiting to happen.

Crestor is "the only cholesterol drug...that causes acute kidney failure" and it "has a higher risk of causing a very severe type of muscle injury called rhabdomyolysis" than other statins, Graham declared. Graham and other ODS reviews will be publishing a paper addressing rhabdomyolysis and statins in an upcoming issue of The Journal of the American Medical Association, he noted.

AstraZeneca released a statement the same day "reconfirming" the safety and efficacy of Crestor. "To date, the FDA has not given the company any indication of a major concern regarding Crestor, and comments today are inconsistent with past public statements from the FDA and our understanding of its current view of the safety and efficacy of Crestor."

Public Citizen has called for the drug's withdrawal and a criminal investigation into AstraZeneca's handling of adverse event reports about the statin (² 'The Pink Sheet' Aug. 9, 2004, In Brief).

AstraZeneca may face another communications challenge with the brand soon. During an industry conference several days before the Vioxx hearing, FDA's Crawford hinted that the agency may soon be contacting AstraZeneca about its DTC ads.

Graham cited Sereventas an example of a drug for which FDA's safety standards are too forgiving. The drug "has the unfortunate property that, I believe at least, it increases the risk of somebody that has asthma dying because of their asthma."

FDA requested that GSK conduct a large simple trial of Serevent (salmeterol) after receiving post-marketing reports of asthma-related deaths, Graham noted. "When you analyze the data, there is a statistically significant increase in serious asthma complications in the Serevent-treated group," he maintained. However, because of statistical penalties associated with unblinding the data early, "that conventional level of statistical significance...wasn't certain enough."

GSK halted the study in 2003, citing enrollment difficulties and the possibility that continuing the trial would not answer questions raised by an interim analysis. GSK said the excess risk appeared only in African-American patients and patients not taking concomitant inhaled steroids (³ Also see "GSK Serevent Safety Label Change Coming Soon; Will Advair Be Affected?" - Pink Sheet, 27 January, 2003., p. 10).

GlaxoSmithKline responded to Graham's comments by declaring that it "stands firmly behind Serevent."

For Pfizer's COX-2 inhibitor Bextra "I think we're in the same situation we are with Vioxx, needing to have good studies on cardiovascular risk, and I don't think we have them," Graham declared. Pfizer said it believes Bextra is labeled appropriately, and that an upcoming advisory committee review of COX-2 inhibitors is a better forum to discuss safety issues (⁴ Also see "Celebrex Long-Term Safety Monitoring Results Reassure FDA" - Pink Sheet, 8 November, 2004., p. 14).

In the case of Meridia (sibutramine), "I think we seriously have to consider whether there's a need for the product in the first place. It has to do with what's a reasonable balance of benefit to risk. I don't think that Meridia passes that test," Graham declared.

By Graham's analysis, few patients stay on the drug for more than a month because of the side effects. "So they get side effects, they get the risks of raised blood pressure and stroke, and they don't stay on it long enough to lose weight." Meridia was withdrawn in Italy in 2002, prompting Public Citizen to petition for its withdrawal in the U.S. (⁵ Also see "Meridia Fatality Rate “Substantially Lower” Than Obese Population – Abbott" - Pink Sheet, 25 March, 2002., p. 21).

Abbott also issued a statement standing behind Meridia, and noting the health consequences attributed to obesity in the U.S.

Graham described a long history of concerns with FDA's regulatory approach to Accutane (isotretinoin), including his view that the creation of the "SMART" risk management program "wasn't very smart. In my view, SMART was dumb," Graham said.

Although the media coverage focused on the five drugs discussed by Graham in Q&A, his written testimony identifies two more.

Graham noted that he recommended the withdrawal of Sanofi-Aventis' arthritis drug Arava (leflunomide); he was asked not to present his views when an advisory committee reviewed the issue in 2003, and FDA decided it could remain on the market (⁶ [A#00660140029], p. 29). Graham maintained that FDA also carefully managed an advisory committee discussion to consider the reintroduction of GlaxoSmithKline's irritable bowel syndrome agent Lotronex in 2002.

Crestor, Serevent Safety Issues Push Vioxx Out Of Spotlight In Senate Hearing

More from Archive

More from Pink Sheet