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Celebrex, approved by the FDA in 1998, was the first in a new class of painkillers designed to be tough on pain, but gentle on stomachs. Of the three approved drugs in that category, only Celebrex remains on the market. Merck & Co. removed Vioxx from the market on Sept. 30, 2004, after a company-funded study indicated it could double heart attacks and strokes. Pfizer pulled Bextra in 2005, after it was linked to heart problems and a potentially fatal skin infection.
Until September 2004, the volume of serious adverse event reports about Celebrex sent to the FDA had remained light. That changed when Merck removed Vioxx from the market. Between August 2004 and July 2005, the FDA added 2,000 reports about Celebrex side effects to its database. About 700 of them detailed heart problems, including heart attacks and strokes.
As Vioxx liability lawsuits began to flood courthouses, concerns about Celebrex rose. For example, in December 2004, the National Cancer Institute said a closer look at its data revealed high doses of Celebrex nearly tripled cardiovascular risks for patients taking it for three years. Ultimately, dozens of federally sponsored clinical trials stopped giving patients Celebrex.
WASHINGTON - The Tennessee woman wrote to the Food and Drug Administration, brokenhearted and mystified.
Her 66-year-old husband had taken Celebrex for arm and back pain. They talked, over coffee, about overgrown trees that needed trimming. It was their last conversation.
That day, the man suffered a stroke, robbing him of his speech and independence.
"He was like a child," his wife wrote in January 2005. "He could walk, but could not turn a light switch on or even brush his teeth." Her letter was among hundreds of reports sent to the FDA about Celebrex that were reviewed by The Boston Globe.
From August 2004 to July 2005, as consumers grew increasingly wary about Celebrex, they filed thousands of documents with the FDA. The reports raise heart attack and stroke concerns that are similar to those linked to two other painkillers, Bextra and Vioxx. But unlike those drugs, Celebrex is still sold.
Pfizer Inc., Celebrex's manufacturer, calls such side-effect reports "potentially misleading" because they do not include enough details to determine that the drug was to blame. And the New York drug giant points to studies that indicate Celebrex heart risks are no different than those associated with other widely used painkillers.
The FDA often gets its first hint that a drug may be unsafe by reviewing such problem reports, which are also submitted by doctors. The system works best when a product has unusual side effects, such as a severe rash. But slight increases in reports of more common ailments, such as heart attacks, strokes, and heart failure, can be overlooked, and clinical trials to confirm suspicions can take years.
"Just looking at these reports by doctors will miss most important adverse drug reactions," said Wayne Ray, who heads the Pharmaco-Epidemiology department at Vanderbilt University School of Medicine. It's "just not a good way to monitor the safety of drugs," Ray said.
At a National Academy of Sciences drug safety conference last summer, Dr. Steven Galson, of the FDA's Center for Drug Evaluation and Research, agreed that the reporting system is flawed. Galson also said the agency is "much more prone to error" when a drug sprints to blockbuster status - sales exceeding $1 billion annually. That's because the FDA approves treatments based on clinical trials that usually involve a few thousand participants. Once a drug hits the market and is used by millions of patients, rare side effects not seen during the trials can be revealed.
Celebrex, approved by the FDA in 1998, was the first in a new class of painkillers designed to be tough on pain, but gentle on stomachs. Of the three approved drugs in that category, only Celebrex remains on the market. Merck & Co. removed Vioxx from the market on Sept. 30, 2004, after a company-funded study indicated it could double heart attacks and strokes. Pfizer pulled Bextra in 2005, after it was linked to heart problems and a potentially fatal skin infection.
Nearly 19 million Celebrex prescriptions were sold in its first year - more than Lipitor and Viagra combined - thanks to an aggressive marketing campaign. At least 30 million Americans have used it to treat arthritis, menstrual cramps, and acute pain.
Until September 2004, the volume of serious adverse event reports about Celebrex sent to the FDA had remained light. That changed when Merck removed Vioxx from the market. Between August 2004 and July 2005, the FDA added 2,000 reports about Celebrex side effects to its database. About 700 of them detailed heart problems, including heart attacks and strokes.
In 2005, when Pfizer stopped advertising Celebrex due to heart concerns, Americans' spending on the drug tumbled to $1.3 billion, 46 percent lower than the year before.
Doctors wrote to the FDA on behalf of patients. Children wrote about deceased parents. Physicians and nurses reported heart problems they suffered personally. Doctors running clinical trials notified the FDA of heart problems in Celebrex-study participants. And attorneys, as part of preparations for legal action against Pfizer, reported details gleaned from clients' pill bottles, doctors' records, and autopsy reports.
The FDA, after redacting patient names and dates of birth, provided the reports to the Globe in response to Freedom of Information Act requests.
Nearly 300 of the reports blamed Celebrex for causing the patient's death; in more than half, the death came after a cardiovascular event, such as a heart attack or sudden cardiac death. Another 180 said Celebrex contributed to cardiac side effects that resulted in hospitalization. Seventy-one reports, including the letter from the Tennessee woman whose husband had two strokes, reported such disabilities as lost vision, mobility, memory, and speech. More of the heart problems were reported by people older than 50.
Dr. David Graham, an FDA drug safety reviewer initially prevented by the agency from publishing research pointing to Vioxx's heart problems, was deposed for Vioxx lawsuits - over FDA objections. "There is no question in my mind" that drugs like Celebrex increase heart attack risk "from the first tablet," Graham said.
The Vioxx effect
As Vioxx liability lawsuits began to flood courthouses, concerns about Celebrex rose. For example, in December 2004, the National Cancer Institute said a closer look at its data revealed high doses of Celebrex nearly tripled cardiovascular risks for patients taking it for three years. Ultimately, dozens of federally sponsored clinical trials stopped giving patients Celebrex.
Celebrex side-effect reports to the FDA for heart attacks, strokes, sudden cardiac death, and heart failure increased to 100 in January 2005, double the previous month. That February, when the FDA held a three-day meeting that ultimately led to the removal of Bextra from the market, side-effect reports for Celebrex hit 116.
Pfizer's Dr. Steven J. Romano said sudden jumps in the number of reports could have been driven by media coverage of Celebrex and related painkillers. "It is important to recognize that an increase in reporting rates does not necessarily mean an increase in incidence rates," Romano wrote in response to questions from the Globe.
"I'm not sure we can really make much of that data," said Dr. Scott Solomon, director of noninvasive cardiology at Brigham and Women's Hospital in Boston. Solomon led a study that prompted federal officials to closely scrutinize cardiovascular problems in Celebrex cancer prevention trials. He, too, said the volume of FDA reports likely grew due to news coverage.
Still, Solomon acknowledged that reports to the FDA did measure the pulse of panicked patients and doctors who, for the first time, were doubting Celebrex's safety.
According to Dr. Curt Furberg, a drug-safety expert at Wake Forest University School of Medicine, the reports actually underestimate harm attributed to Celebrex, since as few as 10 percent of doctors submit the time-consuming documentation.
Lawyers for Ken Kaye, a Connecticut man who used Celebrex, did not bother to deal with the FDA. They filed a lawsuit against Pfizer, which has not gone to trial, alleging the painkiller caused three strokes Kaye suffered in a three-week period six years ago. Kaye, 54, said he does not smoke and does not have diabetes or a history of heart problems. As a result of his attacks, he lost 20 percent of his vision, can no longer play basketball, and has to take a blood thinner.
"I was never sick a day of my life," said Kaye.
Others, such as the Tennessee woman, wrote to the FDA "in hopes that someone will take note and do something." Her husband's second stroke relegated him to a nursing home, where he received nourishment from a feeding tube. When she heard that Celebrex, like Vioxx, could increase heart risks, "a light came on in my head," she wrote.
Measuring the risks
Researchers, some supported by Pfizer, continue long-term clinical trials that could clarify Celebrex's heart risks and possibly position it as a cancer-prevention treatment. Precancerous tissues produce the same enzyme that Celebrex blocks to ease inflammation.
Pfizer communicates often with such researchers. But neither doctors running the trials nor the company have been eager to disclose what is discussed.
For example, M.D. Anderson Cancer Center, part of the University of Texas, refused to provide to the Globe correspondence between Pfizer and its scientists running Celebrex cancer-prevention trials. Through such e-mails and letters, Pfizer provides the doctors a tally of heart attacks suffered by trial participants that the company tracks in its private database. The University of Texas said releasing Pfizer correspondence could jeopardize its chance of receiving funding to conduct clinical trials for drug companies.
Pfizer, in a reply to the attorney general's office, agreed. Release of such correspondence by public universities "could affect the decisions of Pfizer and other companies seeking clinical research partners, leading them to choose private sites" that are not compelled by Freedom of Information Act requests and other means to divulge information, wrote Jeffrey R. Mastracchio, Pfizer assistant corporate counsel.
Pfizer, however, was eager to trumpet the results of a study, sponsored by the National Institute of Aging, that suggested Celebrex's heart risks were similar to another painkiller's.
Company officials sent a flurry of e-mails to Dr. John C.S. Breitner, the Seattle-based Veterans Affairs Puget Sound Health Care System researcher who led the study. Breitner, who was trying to determine whether Celebrex could help prevent Alzheimer's disease, found it was no more of a heart risk than naproxen, a painkiller sold as Aleve. Pfizer asked to see data that ordinarily would be kept secret. It also praised Breitner's presentation of the study's results to the FDA and encouraged him to repeat it when Canadian regulators conducted their own assessment of Celebrex safety.
When commenting about the study, Gail Cawkwell, Pfizer's senior medical director for pain and inflammation therapies, offered this summary of Breitner's findings: Neither Celebrex nor naproxen increased cardiovascular risk. Breitner sharply disagreed.
In fact, patients in the trial who took Celebrex were 1.5 times more likely to suffer heart attacks, stroke, or sudden cardiac death than those given sugar pills.
Early warnings
Before Vioxx raised fears of doubling cardiovascular risks, few suspected Celebrex carried any heart risk, and some of the first warning signs came from doctors reporting their own experiences.
A 46-year-old physician reported a heart attack he suffered in 2002 to the FDA in late December 2004, as news about Celebrex heart risks appeared on the front page of the nation's newspapers. The man had taken 400 milligrams of Celebrex twice daily - a higher-than-normal dose - to prevent a disease that causes polyps in the gastrointestinal tract.
"No risk factors. No smoking, family heart history, alcohol use," he wrote. The heart attack "happened on the last few days of my vacation and I was found to have no known coronary disease."
A few months later, when the FDA pushed Bextra off the market, another physician informed the FDA of her unexpected heart attack. She described herself as a healthy 35-year-old who took Celebrex for five months after bunion surgery.
"I had no pertinent risk factors. ... No meds. Nonsmoker. Nondrinker. Female. Not pregnant. No [family history] early cardiac disease or deaths," she wrote.
FDA critics say that career staffers were left in a leadership limbo because the agency lacked a Senate-confirmed commissioner for much of the past six years. According to critics, that made them vulnerable to influence from the Bush administration, which is seen as sympathetic to the pharmaceutical industry.
Without a real leader, "there is every reason to expect that [FDA staffers] would be somewhat passive and compliant," said Don Kennedy, FDA commissioner from 1977 to 1979.
The agency's harshest critics say it has become ineffective and point to a growing list of unsafe drugs and devices that still have the FDA's stamp of approval.
"They're pussycats at FDA," said Wake Forest's Furberg. "They have absolutely no clout."
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Diedtra Henderson can be reached at [email protected].
Caption: Ken Kaye suffered three strokes in a three-week period, which he ties to his use of Celebrex. Kaye, 54, of Bethany, Conn., said the strokes affected his vision and quality of life. He is suing Pfizer, the maker of Celebrex. JB Reed/Bloomberg News
Credit: Diedtra Henderson Globe Staff. Steven lee miller for The Boston Globe
(c) The Boston Globe Feb 25, 2007