Forbes has a story this month about a Cox-II inhibitor, Celebrex. While mostly used for arthritis pain, this drug is of high interest to cancer patients as a possible tumor inhibitor (for background on the cancer connection see
Cancer Patients … and Celebrex in Anti-Cancer Trials Nov 2004

Matthew Herper, 12.13.05, 3:00 PM ET
NEW YORK – On Aug. 22, the Monday after Merck was slammed with a multimillion-dollar verdict in the first trial related to Vioxx, Pfizer brought a team of academic researchers to meet with the U.S. Food and Drug Administration to discuss a gigantic clinical trial to try to prove that low doses of Celebrex do not pose the same heart attack and stroke risk that Vioxx does. The talks were left unfinished then, but now just such a trial is being announced.

The big surprise: Pfizer (nyse: PFE – news – people ) has enlisted one of Celebrex’s first critics to run the 20,000-patient study.

Steven Nissen of the Cleveland Clinic, who co-wrote with his boss Eric Topol a 2001 journal article that raised the alarm on both Celebrex and Vioxx, will be running the big study. It will compare Celebrex to two other popular arthritis drugs, the active ingredients in Aleve and Advil, in patients who are already at high risk for heart attacks. Says Alastair Wood, associate dean at Vanderbilt University Medical School, “That’s the study Merck said couldn’t be done.”

The trial, dubbed Precision, may not be finished until the middle of 2009, but when it wraps, Nissen says patients will have finally answered raging questions about which arthritis drugs are safest for those in pain. “If you have arthritis, you’re going to have to take something,” says Nissen. “So what do you take? Celebrex, ibuprofen or naproxen?”

Daniel H. Solomon, a Harvard rheumatologist who is not involved in the Pfizer study, says, “As a physician, I’ll tell you that’s the decision I make. I am deciding what to prescribe in high-risk people, because those are the people who have arthritis.”

The stakes are incredibly high. In September 2004, Merck (nyse: MRK – news – people ) did an about-face and pulled Vioxx from the market after its own study showed a definitive link between Vioxx and cardiovascular problems after long-term use. That has exposed Merck to thousands of lawsuits that could cost it billions, and started a drug safety firestorm.

As more data came to light, studies also linked Celebrex to a heart risk, and Pfizer’s Bextra was pulled from the market. Questions also arose about older drugs like ibuprofen, the active ingredient in Motrin and Advil, and even naproxen, or Aleve, which most researchers still believe is the safest painkiller for the heart.

To head off any criticism based on conflicts of interest, Nissen is taking the unusual step of forbidding the nine researchers planning the trial from taking consulting or speaking money from the companies that make the drugs, Wall Street or law firms. Financial relationships related to Wall Street, hedge funds or Vioxx lawyers will likewise be forbidden. “The controversy and the issues have been so intense that I just think it’s necessary,” Nissen says.

The researchers intend to make all raw data available through the National Institutes of Health (NIH).

Nissen’s study will enroll patients who either have had heart attacks already or have multiple risk factors like high blood pressure, high cholesterol or being overweight. It could take a year and a half to find 20,000 such people. Patients will receive aspirin for their hearts and Prilosec to guard their stomachs against potential side effects of the pain pills. Then they will be followed for an average of two years until about 700 patients in the study have died or had heart attacks or strokes. At that point, probably in 2009, Nissen promises a “clear answer” as to which drug is safest.

One representative of the NIH will be on the executive committee of Nissen’s study, but the NIH will not be contributing any money. The NIH had been approached about doing such a big study but declined. Such a gigantic trial could easily cost $100 million.

“My overall reaction is that I’m pleased, because we need the data,” says Charles Hennekens, a professor at the University of Miami who helped prove that aspirin can benefit the heart.

Already, the study is facing criticism. The trial will be conducted in Australia, the U.S., Eastern Europe and Switzerland, but not in most countries in the European Union, where Celebrex’s labeling says it should not be given to patients at risk for heart attacks. Garret FitzGerald, the University of Pennsylvania pharmacologist who raised the first alarms that the drugs might pose a heart risk, says he thinks giving the drug to patients at high risk of a heart attack or stroke may be “ethically questionable.”

FitzGerald also expressed concerns that the study could be just a way to buy Pfizer more time. Previous studies of heart risk with painkillers that were conducted by drug companies, such as Novartis’ (nyse: NVS – news – people ) trial of its own experimental drug that was similar to Celebrex and Vioxx, have been criticized for not recruiting enough patients at risk to see a difference. FitzGerald has favored studies that would try to use small groups of patients to decipher what the differences between the drugs are as they act in the body.

“I think it’s absolutely an ethical study,” says Wood. Statistician Tom Fleming of the University of Washington, one of the leaders in monitoring clinical trials for safety, says he hopes to lead the committee that will make sure this trial is safe as well.

Others, like Hennekens, would have liked the study to include Tylenol or aspirin–options that the planners considered but decided would be too difficult. Testing Tylenol required giving patients too many dummy pills, because the drug must be given so often, and they worried about bleeding with high doses of aspirin.

The story behind the study shows how difficult it was to get done at all. Pfizer had been planning to do a clinical trial to prove Celebrex’s safety at least since last year, when it announced a trial called 4C that would attempt to prove the drug actually benefits the heart. That became impossible after the link to a heart risk showed up. But last February, Jeffrey Borer of Weill Cornell Medical College told Forbes.com that a second version was being planned that would involve 20,000 people and would test Celebrex’s safety (see: “How Celebrex Could Recover Its Sheen”).

Six months later, at the time of the FDA meeting, the details of Pfizer’s trial still hadn’t been finalized, although Borer, who was present at the meeting, said at the time that a commitment was made to go forward. Nissen says Pfizer approached him and Topol in August (Topol is not participating in the study). “We were very early in representing the potential hazards,” Nissen says, “and they needed to work with an outside group.”

Even so, getting to the point where he felt comfortable making an announcement took another four months, and the first patient will not enter the trial until next year.

“I’m very enthusiastic,” says Harvard’s Solomon. “I would have great confidence this would yield important information.”