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In February 2005, the U.S. Food and Drug Administration (FDA) called a three-day hearing to review the risks of three painkillers known as COX-2 inhibitors. From its inception, the hearing — conducted by an FDA advisory panel — was beset by controversy. One of the COX-2 drugs, Vioxx, had recently been withdrawn from the market for safety reasons. The FDA had also removed and then reinstated one of its own experts from the panel, and there were published reports of suppressed drug safety data regarding not just Vioxx, but another COX-2 inhibitor, Celebrex. Emotions were running high as the 32-member panel of outside advisers assembled in a Hilton Hotel ballroom in Gaithersburg, Maryland, to hear testimony from scientists, patients, and drug company representatives on the risks and benefits of the painkillers.

The previous September, pharmaceutical firm Merck had withdrawn Vioxx voluntarily, shortly before evidence surfaced to suggest that the drug caused an estimated 39,000 and 60,000 deaths from heart attacks and strokes. The advisory panel considered whether the other two COX-2s, Celebrex and Bextra, might also increase the risk of cardiovascular problems, including death, and whether any of the three drugs should be allowed to remain on the market. At the end of the hearings, the panel would conclude that all three drugs increase the risk of cardiovascular problems. Yet the FDA subsequently issued a decision that seemed to many observers to ignore an important conclusion by its own advisers. More worrisome, said critics, the FDA’s ruling sowed confusion among both doctors and patients about which painkillers are the safest.

Now, four years later, one of the key players in that drama is facing questions about the safety of a study he is leading that tests one of those painkillers on the very group of people at highest risk of dying from the drug. Dr. Steven Nissen, a top heart doctor at the famed Cleveland Clinic and sometime FDA critic well-known for his early warning about the dangers of Vioxx, is the principal investigator on the study known as PRECISION (the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen). PRECISION is a $100 million, multinational study of Celebrex and two other painkillers, ibuprofen and naproxen. The study is sponsored by Pfizer, the maker of Celebrex. And both Pfizer and Nissen believe the study is badly needed to find out which of these drugs is least risky. But critics argue that the trial is unethical. They say it puts patients who participate at unnecessary risk in order to get answers that, to a large extent, the medical community already has, and which would be clear to doctors if only the FDA had not muddied the waters with its 2005 ruling.

The story of the FDA’s hearing, the agency’s subsequent decisions on painkillers, and the PRECISION trial also illustrates larger, more complex problems at the agency, which is under constant fire from the press, members of Congress, and patient safety groups for being too close to the drug industry. That closeness, those critics say, has led the agency to be too quick to approve dangerous drugs and too slow to remove them from the market once danger signs appear. An agency spokesperson declined to comment. Former FDA commissioner Andrew von Eschenbach, who resigned in January, previously told reporters that the agency needs to work more closely with drug companies so that the FDA will be “a bridge to the future, not a barrier to the future.” But there’s no shortage of people who believe the FDA’s actions are failing to protect public health. “At the FDA,” says Dr. Curt Furberg, a professor of Public Health Sciences at the Wake Forest University School of Medicine, “they are judged by how many drugs they approve, not by how many lives they save.”

Ignoring the Advisers

Two of the COX-2 inhibitors — Vioxx and Celebrex — were brought to market amid great fanfare in the late 1990s. In November, 2001, Pfizer introduced a third COX-2, Bextra. These drugs, hailed as “super-aspirins” by the press, were invented in part to address the biggest drawback of an older category of painkillers known as non-selective non-steroidal anti-inflammatory drugs, or NSAIDs — a category which includes aspirin, ibuprofen (the active ingredient in Advil), and naproxen (the active ingredient in Aleve). The problem with these NSAIDs is that they can cause potentially life-threatening bleeding in the stomach and intestines in a small subset of people, particularly the elderly. Vioxx and its chemical cousins were designed specifically to avoid gastrointestinal bleeds.

Within a few years, though, evidence began to emerge that the super-aspirins weren’t so super. While Vioxx provided some protection against gastrointestinal bleeds, it increased the risk of heart attacks and strokes — a problem that exceeded its protective benefit. By the time Merck pulled Vioxx from the market, in September 2004, it appeared that Celebrex and Bextra also posed some of the same risks, and FDA was feeling mounting pressure to act. The agency pulled together two advisory committees, the Arthritis Committee and the Drug Safety and Risk Management Committee, and charged them jointly with the task of weighing the evidence for and against the COX-2s. The FDA has many committees, which are composed of outside experts and are charged with helping the agency make such decisions as whether or not to approve a new drug for market or withdraw one that is already there.

By the time the joint COX-2 committee was called to order, Pfizer, the manufacturer of Celebrex, had already laid plans for a “longer term study” of its drug, according to documents obtained by the Center. Slated to enroll 20,000 subjects, a process still ongoing, that study — PRECISION — is the largest trial ever involving a COX-2 drug. In the wake of mounting concerns about Vioxx and the safety of all the COX-2s, PRECISION is crucial to Pfizer’s ability to keep Celebrex sales afloat. Even if the trial were to show that Celebrex is more dangerous than its chemical cousins, so long as the study is ongoing the company can claim that there is still no solid evidence, thus signaling to physicians that they should continue prescribing it as long as the results are not yet in.

Whether or not Pfizer would be able to go forward with the PRECISION trial hinged in part on how the joint advisory panel answered three questions: Should Vioxx be allowed back on the market with stringent warnings and restrictions on its use? Should Celebrex and Bextra be permitted to remain on pharmacy shelves? How did the non-selective NSAIDs stack up in terms of safety? If the combined committee said Celebrex was clearly more dangerous than NSAIDs, the PRECISION trial would be difficult to justify, since it would mean putting patients at risk for the sake of a question that had already been answered.

The committee members sifted through a mountain of data, including a study conducted by Pfizer that the company had kept hidden from doctors for more than four years. That study, unearthed by the drug watchdog group Public Citizen, showed that Alzheimer’s patients taking Celebrex were twice as likely to die from a heart attack or stroke than patients taking a placebo, or dummy pill. The company did not publicly post its findings until January 24, 2005, after another study showed similar results. The data convinced the committee that all three COX-2s increased the risk of cardiac events, though of the three, Celebrex appeared the least dangerous. The committee also found that only Vioxx protected patients against a gastrointestinal bleed, but it posed the greatest cardiac risk.

The experts then turned to the question of safety of the non-selective NSAIDs. Aspirin clearly protected against heart attacks and some strokes, and it appeared as if naproxen might do so as well. The evidence on ibuprofen was murkier. The committee, while unanimously voting that Celebrex caused risk, voted 31-1 in favor of keeping the drug on the market for specially selected patients. The experts were split on keeping Bextra and bringing back Vioxx, with those in favor barely in the majority on both counts.

But one thing was clear to the committee: the COX-2s were potentially dangerous, clearly more so than one of the non-selective NSAIDs, naproxen, and likely more so than ibuprofen. The experts recommended that the COX-2s be allowed to stay on the market only if they carried a “black box” on the package “inserts” — a warning outlined in black to alert both physicians and patients to their dangers. At a press conference at the conclusion of the panel’s deliberation, Dr. Alastair Wood, committee chairman, and then professor of medicine and pharmacology at Vanderbilt University Medical Center, said, “I think physicians need to be more thoughtful about how they use [COX-2s] in the future. It would be a brave man or woman who started a patient with a clear history of heart disease on these drugs.”

The FDA, however, decided to heed only part of its own advisory panel’s advice. In April 2005, the agency ordered Bextra off the market, and Merck later voluntarily decided not to reintroduce Vioxx. But instead of urging doctors to consider alternatives, such as naproxen, the FDA ordered black box warnings on all non-selective NSAIDs along with the remaining COX-2s. The effect was to make the non-selective NSAIDs seem as risky as the COX-2s. Dr. Garret FitzGerald, professor of medicine and pharmacology at the University of Pennsylvania, and a consultant to the advisory panel, told the Center, “To lump all painkillers under a black box diluted the message about COX-2s and sowed confusion among practitioners and consumers.”

Boon to Pfizer

While the FDA is not required to take the advice of its committees, it rarely strays so far from their conclusions. Precisely how and why FDA officials decided to diverge from its committee’s findings in this case, and impose a black box warning on all painkillers, not just the COX-2s, remains a secret. Although the Center received 408 pages of documents under the Freedom of Information Act (FOIA) that relate to the agency’s final decision, hundreds of additional pages were excluded or redacted from release because they constituted internal deliberations by FDA. Such deliberations are exempt from release in order to protect government officials from operating in a fishbowl atmosphere. (The FDA has refused to release any documents relating to FDA oversight of the ongoing PRECISION trial on the grounds that the documents contain “confidential commercial information,” according to Karen Riley, spokesperson for the agency.)

In the view of many drug researchers and public safety advocates, the FDA’s decision reflects the degree to which the agency is influenced by the very industry it is supposed to regulate. “The decision to label all painkillers with the same warning has the effect of watering down the concerns about the COX-2 inhibitors,” charges Furberg, an advisory panel member for the COX-2 hearings. Pfizer, as the manufacturer of the only two COX-2s on the market at the time, stood to gain the most by the FDA’s decision.

This point is underscored by documents obtained by the Center. In a letter to the FDA dated March 10, 2005, a month before the agency acted, Pfizer agreed to re-label its drugs, Celebrex and Bextra. But the company also emphasized that because of “the potential for an increased risk of cardiovascular events for the older non-selective NSAIDs, Pfizer firmly believes that such products [the non-selective NSAIDs] must be included as part of the relevant class of products for which this issue is relevant.” In other words, if the FDA was going to require black boxes on the COX-2s, Pfizer wanted black box warnings on the patient information “inserts” of all the non-selective NSAIDs, including ones they manufactured, even though the weight of the evidence said that COX-2s were more dangerous than most NSAIDs, and naproxen might be neutral or even protect the heart. FDA spokesperson Riley stated there were no substantive communications with industry after the COX-2 advisory panel meeting other than the single letter from Pfizer that was released to the Center.

Celebrex is one of a group of drugs originally hailed as “super-aspirins.” But there is now some evidence that the painkiller manufactured by Pfizer may increase the risk of heart attack and stroke. Credit: Food and Drug Administration. Several drug research experts contacted by the Center believe that both Pfizer and the agency had reasons to want a black box warning on all the painkillers. From the company’s perspective, placing a warning on all painkillers could blunt any negative effect on sales of COX-2s, which have average wholesale prices 10 to 20 times greater than ibuprofen, the most commonly used generic non-selective NSAID. Pfizer needed to keep up its sales of Celebrex, which had plummeted 47 percent to $411 million in the first quarter of 2005, in the wake of the Vioxx scandal. The company would have been justifiably concerned that a black box warning on the drug’s package inserts would depress sales further. A warning on the other NSAIDs, drugs that patients had been taking over the counter for many years, might well make the warning on Celebrex seem less worrisome.

“Pharma has always pushed this strategy,” according to a pharmaceutical company researcher who asked to remain anonymous for fear of being unable to work for the industry. If they have to put a black box warning on their drugs, companies want warning labels to apply to all the drugs in a class. Their thinking, according to the researcher, is “the safety warning is going to hurt us, but at least it’s also going to hurt our competitors. With class labeling, all ships rise and fall with the tide so we’re all in the same boat.”

Sally Beatty, a Pfizer spokesperson, responded by noting that the black box warning on all the painkillers “was issued following a thorough review of the available…data.” The warning, she added, “was issued at the discretion of the FDA, not Pfizer.”

The pharmaceutical company researcher contends that the FDA, for its part, sees black box warnings on all drugs in a class as a way to avoid getting into hot water with industry, which often goes to Congress to complain when it does not like an agency ruling. The researcher said, “This is just another example of FDA basing policy on something other than science.”

Sowing Doubt

Pfizer had another reason to welcome a black box warning on the entire class of painkillers, in the view of critics. It allowed the company to maintain that doctors and patients can’t know which painkiller is safest without data from the company’s PRECISION trial. Without definitive evidence, doctors might assume Celebrex is no more dangerous than NSAIDs and continue to prescribe it.

Nissen, the trial’s principal investigator, has a different interpretation. “The trial is designed to answer a very critical scientific question: Which of the available drugs carries the lowest risk of heart-related complications?” he says. “The only way to answer that question is to do a massive head-to-head trial in people of sufficient risk to actually get enough cardiovascular events for precise results.” Other researchers support this reasoning. Colin Baigent, a professor of epidemiology at Oxford University in England, who recently completed a large analysis of the data on painkillers and safety, told the Center he believes the trial will be useful.

Beatty, the Pfizer spokesperson, rejected claims that the study is unethical, telling the Center, “We strongly support the risk-benefit profile of Celebrex for many patients suffering from arthritis as communicated in its approved labeling. As we have previously said, we, along with the Executive Committee of PRECISION chaired by Dr. Steve Nissen, believe the PRECISION study is not only ethical but extremely important to better understand the safety of NSAID pain relievers.”

Launched in December 2005, the PRECISION trial involves randomly assigning patients from 637 sites in countries that include the United States, Canada, Ukraine, Mexico, Peru, and Colombia to take Celebrex, naproxen, or ibuprofen. Neither patients nor their doctors will know which pill they’re getting. To be eligible, the patients must have had a either a heart attack, blocked arteries, or chronic chest pain; or diabetes, a stroke or clogged vessels in the neck or legs. By using high-risk patients, the study’s designers say they will acquire the answers to the study’s questions more quickly and definitively, because the subjects in the study will likely suffer a large number of cardiac events — on the order of 800 — during the course of the study. Nissen told The Associated Press, “We will have 10 times the statistical power of any trial ever done of these drugs.”

Regardless of the statistical power, say critics, the trial is more about marketing than science. “This trial is crucial to Celebrex sales,” says the University of Pennsylvania’s FitzGerald. PRECISION is a “post-marketing trial,” a study that is done after a drug has already come to market. Post-marketing trials can be especially helpful to extending a drug’s marketability when evidence surfaces to suggest that the drug may be dangerous or ineffective, even if the drug later proves to be harmful, said FitzGerald. “The whole idea is to sow doubt.” As long as the PRECISION trial is still ongoing, he and other critics charge, Pfizer marketers can tell physicians that the jury is still out with regard to the safety of non-selective NSAIDs, and claim that Celebrex hasn’t been shown to be any more risky. This uncertainty can only help Celebrex. The study is scheduled to finish in 2013 — the same year that Celebrex’s original exclusivity patent runs out.

Nissen insists that PRECISION is strictly about science. The trial will show which of the painkillers is the safest, he told the Center. “Are they all the same or are there differences? No one, including Dr. FitzGerald, knows the answer,” he says. Nissen pointed to the FDA’s decision to slap a black box warning on both Celebrex and the non-selective NSAIDs as justification for the trial — a decision requested by Pfizer. Nissen added, “The PRECISION trial is governed by an independent academic executive committee composed of highly experienced and respected physician-scientists, including an NIH representative.”

But Nissen’s claim that the governance of the trial is independent may not hold up. The Center has learned that two members of the executive committee resigned, because, sources say, they were upset over the degree of control that Pfizer had over the design of the study. Nissen called that claim “nonsense.”

Other critics charge that the PRECISION trial may be unethical because it puts patients who volunteer to participate at risk unnecessarily. The European Union found the risk of Celebrex to be sufficiently high that it has refused to allow the PRECISION trial to be conducted there. Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, believes the PRECISION trial exposes volunteers to unacceptable level of risk. He told the Center that the U.S. reviewers of the trial should also have “disallowed the study on ethical grounds.”

“In general, it seems ethical to do a study only if there’s reason to suspect benefit may outweigh harm,” agreed Dr. Jerome Hoffman, an expert in clinical epidemiology at the University of California, Los Angeles. In the case of Celebrex, he said, there isn’t any evidence of greater painkilling power compared with other drugs, though it’s possible that some people find it more effective than others. Celebrex isn’t any easier on the stomach than the non-selective NSAIDs. At the same time there’s strong, though not absolutely ironclad, evidence that the drug can cause harm. One study published by the American Heart Association showed that patients with pre-existing heart disease were two to four times more likely to die if they took Celebrex compared to similar patients who didn’t take the drugs, while patients taking non-selective NSAIDs had only 1.2 times the risk.“ People may argue about just how much risk is involved,” said Hoffman, “But it’s obviously not zero — especially in patients with heart disease.”

Since the test subjects enrolled in the PRECISION trial must have pre-existing heart disease as a condition of enrollment in the study, critics say that what they were told about the risks of the study is particularly worrisome. All patients who enroll in clinical trials must be fully informed about the potential risks, usually through talking with investigators and reading an “informed consent” document. When the Center requested a copy of the PRECISION trial informed consent document, Pfizer, Nissen, and trial-organizer Cleveland Clinic Coordinating Center for Clinical Research all declined to release it. The document was subsequently sent to the Center by an anonymous source. “At this time,” it states, “no studies have shown that celecoxib [Celebrex] causes more heart attacks or strokes than prescription ibuprofen or naproxen in the treatment of patients with chronic arthritis.”

“That’s just false,” says FitzGerald. “There is clear evidence that celecoxib [Celebrex] confers cardiovascular risk … so if you have had a heart attack you should avoid this drug. We don’t have similar evidence about ibuprofen and naproxen, although we have some suggestion that naproxen is less harmful.”

Nissen defended the language in the consent form, saying it had been approved by all institutional review boards at the study sites, which are required by the FDA to review informed consent documents to ensure they are accurate and provide patients with sufficient information before enrolling in a clinical trial.

In early March, Pfizer acknowledged that data from several studies of Celebrex sponsored by the company were fabricated. The studies will be withdrawn from the medical journals in which they were published. Some health experts said the revelation was stunning, and cast doubt on the body of evidence regarding Celebrex. Nonetheless, Pfizer maintains that “the fabricated data does not change the risk-benefit profile of Celebrex.”

Clearly, more reliable data on painkillers are needed, but in the view of several researchers, a better use of $100 million and thousands of human subjects than the PRECISION trial would be a study that compares naproxen, the NSAID that appears to be safest, to ibuprofen and acetaminophen, the active ingredient in Tylenol. Acetaminophen has no known serious cardiac effects, and for many people is just as effective as an NSAID at relieving pain. A study comparing naproxen and ibuprofen would be “reasonable and timely,” said FitzGerald.

But no such study appears to be in the works. Instead, the PRECISION trial continues to move forward — its outcome unknown and its justification under fire.

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