This story is told entirely from public documents. Everything you read here appears in the putative federal ERISA “breach of fiduciary duties” class action, presently pending in the Southern District of New York. In each case below, whenever Pfizer is mentioned, the reference would also (through and including April 16, 2003) ALSO refer to Pharmacia, then controlled by Fred Hassan, and Carrie S. Cox.
Okay, let’s start here — toward the end; when the rest of the world learned of the recalls. I’ll return to the beginnings — in the next post (with at least two more to come):
. . . .In June of 2003, Pharmacia co-authored an article on CABG Study #1. E. Ott, et al., Efficacy and safety of the cyclo- oxygenase 2 inhibitors parecoxib and valdecoxib (Bextra) in patients undergoing coronary artery bypass surgery, J. Thorac. Cardiovasc. Surg. 2003 Jun;125(6):1481-92.
The authors conceded that the “serious adverse events occurred twice as frequently in parecoxib/valdecoxib-treated patients. . . than in control patients.” Id. They downplayed the MI findings, lumping them in with other events: “The incidences of other individual serious adverse events, including cerebrovascular complications, myocardial infarctions, and renal function, were proportionally greater by not significantly different between the groups.” The MI rate between valdecoxib and placebo was 5 to 1, or 1.6% to 0.7% of their respective patient groups. Id. at 1487. The authors noted that the study was intended to direct only certain specific events and was only marginally powered to detect differences in serious adverse events. Id. at 1489. . . .
CABG Study #2 (2001)
Before submitting the NDA for Bextra, Pharmacia conducted a second clinical trial of post CABG surgery patients (“CABG Study #2”), which was [not timely] published. In 2004, Pfizer finally released information about CABG Study #2, including the finding that Bextra caused a “significantly greater incidence of events in the cardiovascular/thrombolic category” compared to a placebo (2.0% to .5%.). . . .
Information about the findings of CABG Study #1 and CABG Study #2 were not included in either the 2003 or 2004 Bextra product labels. “Cardiovascular events” were merely listed in the “Adverse Reactions” section near the end of the labeling. An accompanying table listing the percentages of specific adverse events only included data from “arthritis trials.” 2003 PHYSICIANS’ DESK REFERENCE for Bextra at 2703. . . .
The 2001 CLASS Study
In a paper published in the August 22, 2001/August 29, 2001, issue of JAMA, cardiologists Eric J. Topol and Steven E. Nissen, chairman and vice chairman, respectively, of cardiovascular medicine at the Cleveland Clinic, along with Dr. Debabrata Mukherjee, reported that the annualized myocardial infarction rate for Celebrex in the Celecoxib Long-Term Arthritis Safety Study (“CLASS”) of 0.80% was significantly higher than that in the placebo group of a recent meta-analysis of 23,407 patients in primary prevention trials of 0.52% (p=.02). The authors concluded that: “Current data would suggest that use of these so-called ‘COX-2 inhibitors’ might lead to increased cardiovascular events. . . .”
Throughout September of 2001, sales of Celebrex and Vioxx dipped. According to the Wall Street Journal, the JAMA article “appeared to exacerbate a slowdown in [COX-2] prescription growth some doctors and analysts say was occurring as the novelty of the drug wore off and patients with recurring pain sought new treatments.” S. Hensley, Pharmacia Plans to Show off its Research Pipeline Today, The Wall Street Journal, Nov. 28, 2001 at B4.
The 2004 APPROVe Study, The Withdrawal of VIOXX, and Concerns About Class-Wide Effects of COX-2 Inhibitors
In 2004, the Adenomatous Polyp Prevention on Vioxx (APPROVe) study revealed a statistically significant increased risk of confirmed cardiovascular events (principally heart attacks and strokes) in patients taking 25 mg/day of Vioxx compared to those ingesting a placebo. . . .
On September 30, 2004, Merck announced the withdrawal of Vioxx from the market. . . .
On October 8, 2004, Dr. Garrett FitzGerald published an editorial in The New England Journal of Medicine contending that the cardiovascular side effects that led Merck’s Vioxx to be pulled from the market likely affect all COX-2 inhibitors. K. Talley, Pfizer, J&J Fall, but Abercrombie Rises, The Wall Street Journal, Oct. 8, 2004 at C3. . . .
On October 15, 2004, Pfizer sent out a “Dear Doctor Letter” warning physicians that Bextra might increase the risk of heart attacks or stroke in coronary artery bypass surgery patients. However, Pfizer’s press release reassured that the, “available clinical information for Bextra suggests that there is no increased risk of cardiovascular thromboembolic events in people treated for osteoarthritis (OA) and rheumatoid arthritis (RA). . . .”
Pfizer was publicly criticized for not issuing this warning letter sooner because it was based on CABG Study #1, which had been completed in the spring of 2001. . . .
Meta-Analysis Presented to the American Heart Association
On November 9, 2004, Dr. FitzGerald presented a paper to the American Heart Association regarding the CABG studies and Bextra. The meta-analysis of the clinical trials showed increased heart attacks or strokes among patients given Bextra compared with those given placebo. Dr. FitzGerald stated that “the magnitude of the signal with Bextra is even higher than what we saw in Vioxx. This is a time bomb waiting to go off.” A colleague of Dr. FitzGerald who participated in the study, Dr. Curt Furberg, stated, “Basically, we showed that Bextra is no different than Vioxx, and Pfizer is trying to suppress that information.” G. Harris, New Study Links Pfizer’s Bextra, Similar to Vioxx, to Heart Attacks, The New York Times, November 10, 2004. . . .
The FDA Requires a Black Box Label for Bextra
On December 10, 2004, the FDA approved a new label for Bextra, which included a “black box” warning regarding cardiovascular risks for patients who recently had coronary artery bypass graft surgery and updating the warning on Stevens-Johnson Syndrome. . . .
Again, for the sake of clarity, recall that through mid-April 2003, all the references to “Pfizer” above apply equally to Pharmacia, and to Hassan and Cox, personally, as the two primary parties in control of Pharmacia (which company Pfizer acquired April 16, 2003).
In the next post, I’ll lay out the number of times — after late-2001, but before the withdrawal of Celebrex, and the “Black Box” warning on Bextra — that legacy Pharmacia made aggressively, and materially misleading statements about the safety of these two drugs. It even filed these statements with the SEC, thus arguably affixing securities fraud liability to them — long after the alarming cardiovascular event risk results from CABG Study No. 1 were known within many inner-circles of Pharmacia/Pfizer — and thus presumably equally well-known to Hassan and Cox.
And if these results were not known to them, they were both under a continuing duty to inquire, and inform themselves, before speaking to the press or Wall Street analysts — or making any filings with the SEC. More later — of the singular “hype machine” that was Pharmacia under “Fast Fred” Hassan, and Carrie S. Cox, from at least 2000, through 2003.
So do stay-tuned, but you will see why it is no wonder that this chain of interwoven events resulted in the largest criminal fine in corporate history.