Market return for Vioxx and Bextra?

Will the scorned painkillers Vioxx and Bextra ever get back on the market? Will Celebrex ever shake its black box warning?
These arthritis drugs, produced by Merck and Pfizer, are all members of the same class, known as COX-2 selective non-steroidal anti-inflammatory drugs, or NSAIDs for short. The popular painkillers raked in billions of dollars for their makers before they ran into regulatory trouble, and the Food and Drug Administration is holding a meeting on Friday to glean more information on health risks.
The FDA isn't going to make any decisions on Friday about the fate of these drugs. But experts have been weighing the possibilities of an eventual market return for Merck's Vioxx and Pfizer's Bextra, and whether Pfizer's Celebrex will improve its status in the eyes of regulators.
The future of Vioxx
Analysts are mixed on the prospects for Vioxx:
"I'm not holding my breath, but I think there is a chance that Vioxx could come back," said Jami Rubin, analyst for Morgan Stanley.
Rubin said the "huge body of data" about the risk profile concerning Vioxx could be used to bring the drug back into the fold. But David Moskowitz, analyst for Friedman, Billings & Ramsey, said that Vioxx will "certainly not" be brought back, because of a wealth of evidence pointing to the drug's cardiovascular risks.
"The product seemed to cause high blood pressure compared to the other drugs, and Vioxx would be implicated as the more dangerous product [compared to other NSAIDs,]" said Moskowitz.
When asked about a Vioxx market return, Robert Hazlett, analyst for Suntrust Robinson Humphrey, said, "There is a chance that could occur. It is an outside chance, but there is a chance."
The NSAID trouble began with Merck's (down $0.42 to $33.92, Research) Vioxx, which totaled $2.5 billion sales in 2003, its last full year on the market. Merck, based in Whitehouse Station, N.J., pulled the drug off the market in September, 2004, after a study showed increased risk of heart attacks and strokes in patients taking the drug for at least 18 months. Since then, nearly 10,000 lawsuits have been filed against Merck by plaintiffs who blame the drug for heart attacks, fatal and non-fatal. So far, Merck has lost one case, won two, is retrying another case that ended in a hung jury, and has another case ongoing.
The future of Bextra
The trouble for Pfizer (down $0.62 to $25.72, Research) came to light a few months later, in April of 2005, when the FDA asked the New York-based drug giant to take Bextra, which totaled $1.3 billion in 2004 sales, off the market. Pfizer's Celebrex remains on the market to this day, but sales have been cut in half, to $1.7 billion in 2005 from $3.3 billion in 2004. In July of 2005, the FDA had Pfizer add a "black box," the most severe type of warning, to its Celebrex label to reflect risks of heart attacks, strokes and gastrointestinal bleeding.
Analysts weren't so rosy about a market return for Bextra. While Vioxx has a wealth of data, positive and negative, Bextra does not, so Pfizer would have to invest in expensive studies to demonstrate the drug's safety to regulators.
"Pfizer would have to run more clinical studies for [Bextra's return to market,] and the market has really shrunk to the point where it's doubtful that Pfizer would ever return the product to market," said Moskowitz of FBR.
The future of Celebrex
Celebrex remains on the market with a black box that warns of possibly fatal heart attacks, strokes and gastrointestinal bleeding. Analysts are mixed as to whether the warning is a permanent or temporary.
Rubin of Morgan Stanley said that not only will Celebrex always have that black box, but that someday all NSAIDs will carry it, including the over-the-counter ibuprofen. But Moskowitz of FBR believes that Pfizer might shake the warning by tapping its wealth of safety data concerning Celebrex, particularly with regard to the gastrointestinal risks.
Dr. Eric Matteson, NSAID expert and professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minn., said that of all the major NSAIDs, Celebrex is definitely the safest and the only one that should still be available for patients.
"The concerns that led to Vioxx and Bextra being pulled from the market are grave concerns," said Matteson. "In my opinion, Celebrex is still on the market because the degree of cardiovascular events from Celebrex is not as high as Bextra and Vioxx. A drug like Celebrex is in a good position to remain on the market."
Dr. Mark Fendrick, NSAID expert and professor of internal medicine at the University of Michigan, said that Vioxx, Bextra and Celebrex were initially developed as alternatives to other NSAIDs like ibuprofen because they're easier, or intended to be easier, on the stomach. He said this fact is often overlooked amid the hype surrounding the fallen-from-grace blockbusters.
"If you have gastro-intestinal concerns, and you don't have heart concerns, and you're not taking aspirin, then that's where COX-2 inhibitors – Vioxx, Bextra, Celebrex – have a safety advantage," said Fendrick. "I do believe that in the absence of aspirin, Celebrex is safer for those with gastro-intestinal risk. They're no better in terms of pain relief, but they have an advantage for gastro-intestinal safety. If only we gave them to people to get the gastro-intestinal advantage, we wouldn't have this trouble."
To read about a study on NSAIDs and heart disease, click here.

The Merck Vioxx Litigation: Pathological Scouting

Here’s another dispatch filed by WSJ reporter Heather Won Tesoriero from the federal Vioxx retrial in New Orleans:
The issue of whether Merck & Co.’s troubled painkiller caused the 2001 fatal heart attack of Richard “Dicky” Irvin could come down to a battle of the pathologists. And it seems Merck isn’t taking any chances: while the plaintiff’s expert pathologist Michael Alan Graham took the stand, Thomas Wheeler, a pathologist who is likely to testify for Merck next week, sat in the gallery, taking notes and appearing to size up his opponent. There was a even a “small world” professional nod, with Graham acknowledging that he’s known Wheeler since his residency and that “he’s a good pathologist.” Wheeler testified on Merck’s behalf in the first federal trial in December.
Graham explained to jurors the mechanics of Irvin’s heart attack. Using large-scale slides from the deceased’s autopsy, Graham testified that Irvin had a plaque rupture in an artery which led to a fatal, heart-attack-producing clot. But Judge Eldon E. Fallon put strict limits on Graham’s testimony, ruling that while the doctor could testify about the presence of a clot and whether the clot killed Mr. Irvin, Graham was barred from linking Vioxx to that clot. Judge Fallon wrote that Graham lacked the qualification or preparation to offer an opinion on Vioxx’s role:
To compensate for his lack of education, experience and training, Dr. Graham spent approximately eight hours reviewing sixty-seven scientific medical articles, nine depositions, four expert reports, and three days’ worth of trial transcripts—far less than this Court or any attorney in this case has spent reviewing Vioxx related materials . . . While the Court could further explain Dr. Graham’s lack of qualifications or his lack of a reliable scientific basis, it is enough to say that he is not qualified to render an opinion as to whether Vioxx can cause a thrombotic cardiovascular event or whether Vioxx did cause Mr. Irvin’s death.
Ouch. Still, on the stand, Graham went as far as to say that it was unlikely that Irvin would’ve died absent a catalyst, though, sticking to the Judge’s ruling, no catalyst was named.
Dr. Wheeler was on a 5:30 p.m. Continental flight back to Houston, where he’s based. When asked about his appearance in court earlier in the day, he smiled and said, “I was just watching

Key Vioxx critic leaving clinic

Dr. Eric Topol, a world-renowned cardiologist who has taken on drug advertising and pharmaceutical companies but has faced questions about his own potential conflicts of interest, is leaving the Cleveland Clinic.


Topol — who attacked the pain reliever Vioxx while working as a consultant for a hedge fund that was betting against the drug's manufacturer — will become a genetics professor at Case Western Reserve University, the school announced Thursday. Topol has been a Case medical professor.
"We're delighted to strengthen our ties with Eric in the work we do," Case medical dean Dr. Ralph Horwitz said.
Neither Topol nor the clinic immediately responded to requests for comment.
Topol, 51, has led the Cleveland Clinic's distinguished cardiology program for 14 years and is known for his work on the role of genetics in heart disease. He used the clinic's prestige to raise awareness of heart disease.
Topol was one of the first scientists to raise doubts about the safety of Vioxx, and has been a key witness in lawsuits arguing that Merck & Co. concealed the dangers.
Topol also has criticized the $500-per-dose cost of the popular heart medication Natrecor and charged that is being given unnecessarily to some patients. He has also complained that advertisements by drug companies glamorize medicines.
In December, Topol lost two high-profile positions at the clinic when the medical school he helped establish there eliminated his dual position of provost and chief academic officer.
His departure comes as the Cleveland Clinic confronts questions about ethical conflicts between patient needs and profits among researchers such as Topol and Chief Executive Toby Cosgrove.
In December, a Wall Street Journal article detailed Cosgrove's relationship with AtriCure, a medical device company, and the clinic's role in a venture capital firm that invested in it. Cosgrove sat on AtriCure's board and served as a general partner.
The clinic announced Thursday it was tightening its ethics policies after a preliminary review found that poor disclosure practices by Cosgrove reflected problems throughout the clinic. Clinic spokeswoman Eileen Sheil said the clinic must correct the "imbalance between innovation and transparency."
Topol has said that he was unaware when he was working as a paid consultant to the hedge fund that was short-selling. He said that he had no financial interest in the fund and that he quit the work.
Merck pulled Vioxx from the market after its own study showed that the drug doubled the risk of heart attacks and strokes.

FDA: Merck Had Time to Warn About Vioxx

Merck & Co. could have warned that its popular painkiller Vioxx might increase the risk of heart attacks as soon as the first evidence showed up, rather than waiting two years for federal approval, a former Food and Drug Administration official testified Friday.


Richard Kapit said there was plenty of time to alert the public before Richard "Dickie" Irvin began taking Vioxx, which his widow claims caused his fatal heart attack after a month on the drug in 2001.
Merck says it alerted the FDA in 2000 that a study showed heart attacks occurred five times as often in patients taking Vioxx as those on another drug, called naproxen. The agency didn't approve the label change until April 2002.
The company pulled the drug from the market in September 2004, after another study showed that it could double the risk of heart attacks.
Kapit, who worked for the FDA for 16 years, mostly as a drug application reviewer analyzing adverse effects, said companies are allowed to change a drug label as soon as it applies for permission to add or strengthen a warning, precaution, or other information about a serious side effect.
"The FDA is a bureaucracy ... you don't want to wait until it goes through all the records," he said.
He said he saw hundreds of such applications during his years at the FDA, which he left in 2002. He did not work on Merck's application for Vioxx.
Under cross-examination, he said he based his analysis on about 80 pages of documents supplied by the plaintiff and his knowledge of FDA regulations.
The New England Journal of Medicine's Executive Editor, Dr. Gregory Curfman, also testified in a videotaped deposition played for the jury Friday, saying the information about the drug's effects should have been added to an article about the drug before it was published.
Merck contends it learned the information about heart attacks, which occurred after a reporting deadline set in the study. Curfman said scientific journals expect important updates.
More of Curfman's deposition will be played when the trial resumes Monday. Testimony is expected to last most of the week, with closing arguments expected Friday.
The initial case ended in a mistrial last year.