May 17, 2006
Although Merck has long maintained that the risks associated with Vioxx occur after long-term use, a recent study in the Canadian Medical Association Journal, says the drug may raise the risk of heart attack for patients taking Vioxx for less than 2 weeks.
The study published online this month, found that more than 25% of 239 patients who had heart attacks did so in less than 13 days of being on the drug.
The study followed patients for about two and a half years and included 30,200 Vioxx users and 45,000 Celebrex patients. It found no statistically significant increase in heart attack risk with Celebrex patients.
In addition, on May 12, 2006, Dr Steven Nissen, interim chairman of cardiology at the Cleveland Clinic in Ohio, said Merck recently misrepresented an analysis of data from a follow-up review of patients who participated in the 3-year study called, Approve, that led to Vioxx being pulled off the market on September 30, 2004.
"It's important that we inform people about this because patients who have taken the drug will need increased surveillance by their physicians and increased awareness of their risks in the year subsequent to stopping the drug. And that risk may extend beyond a year; we simply don't know," Nissen told Reuters in a telephone interview.
"In the one year after Vioxx was stopped there was a 75 percent greater risk of having an adverse event," he said.
"What this means is that, surprisingly, in the year following discontinuation of Vioxx the relative risk remains approximately as high as it was when people were actually taking the drug," Dr Nissen explained. "That is very clear from the data," he said.
Critics say the cozy relationship between the pharmaceutical industry and the FDA is evidenced by the large number of industry connected members on the agency's advisory panels. A study conducted by the Public Citizen's Health Research Group in the April 26, 2006 issue of the Journal of American Medical Association analyzed the transcripts of 221 FDA drug advisory panel meetings that involved 16 committees, listed on the agency's web site as taking place between January 1, 2001 and December 31, 2004.
The analysis revealed that in 73% of the meetings, at least one member of the panel or one voting consultant disclosed a conflict, and yet only 1% of the members recused themselves from participating.
In all, 28% of committee members and voting consultants disclosed a conflict, the most common involving substantial financial dealings from consulting agreements, contracts or grants, and investments. For instance, the study found that 19% of the consulting agreements were worth over $10,000, 30% of the investments involved over $25,000, and 23% of contracts or grants exceeded $100,000.
In the case of Vioxx, ten of the 32 members on the FDA advisory committee that voted to allow the continued sale of Cox-2 pain drugs, including Vioxx, had previously acted as paid consultants for the drugs' manufacturers.
And true to form, the members with industry ties voted to return Vioxx to the market. Dr Marcia Angell, a senior lecturer in social medicine at Harvard Medical School and author of "The Truth About the Drug Companies: How They Deceive Us and What to Do About It," said in a March 10, 2005 editorial in the Boston Globe: "It is hard to see how the panel could have concluded that the benefits were worth those risks, especially given the fact that taking over-the-counter Prilosec in addition to an older pain reliever would probably have provided as much protection from stomach ulcers."
Dr Angell says advisory committees should not include paid consultants for drug companies. "Their conflict of interest is real, not 'potential'," she wrote.
"The excuse that they are indispensable," she says, "is not only self-serving but insulting to the experts who don't consult for industry."
However, in what critics call a rare occurrence, and no doubt because the agency was under intense public scrutiny, in this instance the FDA did not follow the recommendation of its advisory panel and Vioxx was not approved for a return to the market.
In light of the evidence of Merck's total disregard for patient health that has surfaced in Vioxx litigation thus far, the public needs to take a good hard look at any proposed legislation or action by Congress or the FDA that would shield drug companies from accountability based on the FDA's approval of a drug.
According to Attorney, Karen Barth Menzies, a partner in the Los Angeles based Baum Hedlund law firm, "the Vioxx public health debacle, has served to highlight deep-seeded problems within the FDA."
She says, "drug companies are profit-driven and are loath to issue warnings about risks associated with their drugs, even those that become quite clear."
"And it is precisely for this reason," Ms Menzies says, "that the public is in such desperate need for an agency that advocates for them, rather than the drug industry."
The FDA played a big part in the Vioxx disaster and allowed Merck to get away with murder. A new report released on April 24, 2006, by the Government Accountability Office is deeply critical of the FDA's approach to drug safety and specifically Vioxx, and lists organizational dysfunction, bureaucratic politics, and ineffective enforcement over drug companies as factors compromising drug safety.
The report was commissioned by Senator Charles Grassley (R-Iowa), in response to findings at a November 18, 2004, Senate Finance Committee hearing titled, "FDA, Merck and Vioxx: Putting Patient Safety First," where reports of mismanagement surfaced regarding the FDA's failure to implement safety measures to protect the public against the dangers of Vioxx.
Citing "recent controversy about drug safety," the report illuminates the weaknesses of the FDA in monitoring the safety of drugs once they are approved.
The report states that the FDA "lacks a clear and effective process for making decisions about, and providing management oversight of, postmarket drug safety issues."
It highlights the communication problems between the two FDA offices that handle postmarket safety concerns and advises that "insufficient communication" between the Office of Drug Safety and the Office of New Drugs "has hindered the decision-making process."
"Specifically," the GAO wrote, "ODS management does not always know how OND has responded to ODS's safety analyses and recommendations."
Ms Menzies says the FDA has sided with industry for years. "The recent GAO report," she says, "confirms many of the problems that we have been shouting about for years and illustrates that, contrary to FDA's preemption arguments, FDA's decisions must be second-guessed for the safety of the public."
The report comes almost two years after the hearing that revealed the FDA had not acted promptly to protect the public when it first became aware of information that Vioxx might pose risks to cardiovascular health.
The Senate Finance Committee got involved in the Vioxx matter because it has jurisdiction over the Medicare and Medicaid programs. "Accordingly," Senator Grassley informed the audience at the start of the November 18, 2004 hearing, "the committee has a responsibility to the more than 80 million Americans who receive health care coverage — including prescription drugs — under these programs."
"Of the 20 million Americans who reportedly took Vioxx, an untold number are Medicare and Medicaid beneficiaries," he advised. "I was told that the Medicaid program paid in excess of $1 billion for Vioxx while Vioxx was on the market," he said.
To demonstrate the value of government payments to Merck, at the beginning of the hearing, Senator Grassley described a June 4, 1999 Merck document titled "IN IT TO WIN IT" that said: "As of yesterday, Vioxx became reimbursable on Medicaid in 42 states with the other 8 states close behind."
"The Medicaid market was clearly going to be a money maker for Merck," he said, "and Medicaid has paid Merck well for Vioxx."
When the FDA approves a drug, Senator Grassley said, it's considered a "Good Housekeeping Seal of Approval."
"However," he told the audience, "what's come to light about Vioxx since September 30th makes people wonder if the FDA has lost its way when it comes to making sure drugs are safe."
It looks like the FDA, he said, allowed itself to be manipulated by Merck on labeling changes that became necessary after a review by Merck that's known as the VIGOR trial.
He explained how Merck completed the VIGOR trial in March 2000 and gave the findings to the FDA in June 2000, and was the subject of an advisory board meeting in February 2001. "But it was April 11, 2002," he told the audience, "before the Vioxx label was actually changed."
"During these 22 months," Senator Grassley said, "Merck aggressively marketed Vioxx, knowing that consumers and doctors were largely unaware of the cardiovascular risks found in the VIGOR trial."
The bottom line is, consumers should not have to second guess the safety of what's in
their medicine cabinets," he said. "The public should feel confident that when the FDA approves a drug, you can bank on it being safe, and if a drug isn't safe, the FDA will take it off the market."
The first witness called to testify at the hearing, was Dr David Graham, a scientist with an 18 year career at the FDA, who blew the whistle on the FDA' s handling of the safety issues related to Vioxx.
Right off the bat, he warned the committee: "we, are faced with what may be the single greatest drug safety catastrophe in the history of this country or the history of the world."
He called the Vioxx tragedy "a profound regulatory failure."
"It is important," Dr Graham said, "that this Committee and the American people understand that what has happened with Vioxx is really a symptom of something far more dangerous to the safety of the American people."
"Simply put," he told the panel, "FDA and its Center for Drug Evaluation and Research are broken."
Dr Graham discussed the studies that demonstrated that Merck and the FDA were aware of the Vioxx risks since before the drug was approved.
He told the panel of a Merck study named 090, that found a nearly 7-fold increase in heart attack risk with low doses of Vioxx conducted before the drug was approved and yet the labeling at the time of FDA approval said nothing about the risks.
In November 2000, he said, the VIGOR study found a 5-fold increase in heart attack risk with high-doses of Vioxx and yet the company said Vioxx was safe.
In fact, it was not until about 18 months after the VIGOR trial was published, that the FDA made a label change to include the heart attack risk, but even then the agency did not place it the "Warnings" section.
"Of note," Dr Graham told the committee, "FDA's label change had absolutely no effect on how often high-dose Vioxx was prescribed, so what good did it achieve?"
He informed the panel that a large study in 2002 also reported a 2-fold increase in heart attack risk with high-doses of Vioxx.
In March of 2004, he said another study determined that both high-dose and low-dose Vioxx increased the risk of heart attack and sudden death.
In this study, users of Vioxx were compared with users of another COX-2 inhibitor, Celebrex. The analysis found that Vioxx at doses of 25 mg or less daily was associated with a 50% increase in the risk of heart attack; and doses of greater than 25 mg daily were associated with a 370% increase in the risk of heart attacks.
Yet a report describing these findings was not posted on the FDA website until November 2004, on election day.
"In my opinion," Dr Graham said, "the FDA has let the American people down, and sadly, betrayed a public trust."
In regard to injuries, Dr Graham told the panel that Dr Eric Topol of the Cleveland Clinic estimated that there were up to 160,000 cases of heart attacks and strokes due to Vioxx, in an article published in the New England Journal of Medicine.
"This article," Dr Graham said, "lays out clearly the public health significance of what we're talking about today."
At the November 18, 2004 hearing, to illustrate the significance of 100,000 people being affected by Vioxx, Dr Graham presented charts to show that when looking at Florida or Pennsylvania, it would mean that 1% of the entire population would have been affected. For Iowa, the charts showed it would be 5%, for Maine 10%, and for Wyoming 27%.
"If we look at selected cities," Dr Graham told Senator Grassley who resides in Des Moines, Iowa, "67% of the citizens of Des Moines would be affected, and what's worse," he continued, "the entire population of every other city in the State of Iowa."
The VIGOR study started in January 1999, and included patients over 40, with rheumatoid arthritis who were given either Vioxx or Naproxen. Patients with recent cardiovascular events and patients taking aspirin were excluded from the study.
In the combined outcome of all cardiovascular deaths, heart attacks and strokes, Vioxx patients had higher rates than Naproxen patients. For the outcome of heart attack alone, the rate was five times higher in Vioxx patients than in Naproxen patients
In 1000 patients followed for one year, Vioxx treatment was found likely to be associated with 6 more heart attacks than Naproxen treatment.
Dr Graham said he became concerned about the public health risk after the VIGOR study indicated that the heart attack risk was increased 5-fold in patients who used the high-dose strength of Vioxx.
The safety question was important he explained because (1) Vioxx would be used by millions of patients; (2) heart attack is a fairly common event; and (3) even a small increase in risk could mean that tens of thousands of patients might be seriously harmed or killed.
"If these three factors were present," Dr Graham said, "I knew that we would have all the ingredients necessary to guarantee a national disaster."
To get answers, he worked with Kaiser Permanente in California to perform a study that took nearly 3 years to complete and concluded that high-dose Vioxx significantly increased the risk of heart attacks and sudden death and should not be prescribed or used by patients.
"This conclusion," Dr Graham said, "triggered an explosive response from the Office of New Drugs, which approved Vioxx in the first place and was responsible for regulating it postmarketing."
The response from senior management in the Office of Drug Safety was equally stressful he said. "I was pressured to change my conclusions and recommendations," he told the panel, "and basically threatened that if I did not change them, I would not be permitted to present the paper at the conference."
In fact, one Drug Safety manager recommended that he should be barred from presenting the poster at the meeting, and also said that Merck needed to know about the study results.
Finally, he said they wrote a manuscript for publication in a peer-reviewed medical journal and senior managers in the Office of Drug Safety would not grant clearance for its publication, even though it was accepted by a prestigious journal after rigorous peer review.
"Until it is cleared," Dr Graham told the panel, "our data and conclusions will not see the light of day in the scientific forum they deserve and have earned, and serious students of drug safety and drug regulation will be denied the opportunity to consider and openly debate the issues we raise in that paper."
As for the FDA conduct in responding to the studies that showed the dangers of Vioxx, Dr Graham discussed what he referred to as two "revelatory milestones," in 2004.
"In mid-August," he said, "despite our study results showing an increased risk of heart attack with Vioxx, and despite the results of other studies published in the literature, FDA announced it had approved Vioxx for use in children with rheumatoid arthritis."
"Also, on September 22," he told the committee, "at a meeting attended by the director of the reviewing office that approved Vioxx, the director and deputy director of the reviewing division within that office and senior managers from the Office of Drug Safety, no one thought there was a Vioxx safety issue to be dealt with."
At this meeting, the reviewing office director asked Dr Graham why he had even thought to study Vioxx and heart attacks because the FDA had made its labeling change and nothing more needed to be done.
At the same meeting, a senior manager from ODS labeled the latest Vioxx study conducted by Dr Graham's team, "a scientific rumor."
"Eight days later," Dr Graham told the panel, "Merck pulled Vioxx from the market."
"My experience with Vioxx is typical of how CDER responds to serious drug safety issues in general," he said.
On December 31, 2004, Dr Graham told Inter Press Service that the Vioxx debacle did not phase the FDA. "You have an agency in denial," he said in the interview with IPS, "the FDA still maintains it made no mistake in the approval or regulation of Vioxx."
He said, "intimidation of scientists who threaten the status quo at FDA is routine," and described how, his FDA superior reacted after he sought withdrawal of another arthritis drug called Arava.
"The division director spent the first 10 minutes of that meeting screaming at me," he said. "Basically, standing up, jugular veins bulging in his neck, eyes sort of bugging out of his head, screaming," he recalled, "basically trying to intimidate me so that I'd change my conclusion."
In fact, once Dr Graham went public, history shows that there was a full-court press by FDA officials against the agency Whistleblower.
Dr Steven Galson, the acting director of the FDA drug-evaluation division at the time, told reporters that Graham's work "constitutes junk science," and sent an email to an editor at the British medical journal The Lancet, questioning the "integrity" of Dr Graham's data.
Acting FDA commissioner, Dr Lester Crawford, accused Dr Graham of evading the agency's "long-established peer review and clearance process," and another agency official made calls to a Senate staffer, disparaging Dr Graham personally and professionally.
Before the testimony even began at the November 18 hearing, Senator Grassley responded to comments issued the night before by Dr Crawford against Dr Graham.
"News reports today," Senator Grassley noted, "say the FDA is calling Dr. Graham a "a maverick who did not follow Agency protocols."
Dr. Graham, he explained, completed an FDA sponsored three-year study under FDA guidance and with Drs. Campen, Levy, Shoor, Ray, Cheetham, Spence and Hui. Dr. Graham's immediate supervisor said the paper that formed the basis of the study was "... an excellent study and analysis of a complex topic."
"So the clarifications provided last night by Dr. Crawford," Senator Grassley said, "appear intended to intimidate a witness on the eve of hearing."
Dr Crawford knows there's a problem, he told the audience, "and would better serve the FDA by spending time on the problem rather than going after congressional witnesses who helped identify the problem in the first place."
Earlier in the year, on March 10, 2005, Senator Grassley gave a speech to the Consumer Federation of America and praised the FDA whistleblower and described how the FDA stonewalled concerns raised by Dr Graham after a study found an increased risk of heart attacks and strokes with Vioxx and said:
"Dr. Graham warned the FDA of the cardiovascular risks of Vioxx, the FDA approved the use of Vioxx for children. The director of FDA's office of new drugs suggested that Dr. Graham water down his Vioxx conclusions. Dr. Graham replied that in good conscience he could not. When Dr. Graham was asked to present his findings at my committee's Vioxx hearing, he was also undermined.
"Dr. Graham did testify before the advisory committee and his science was subjected to public scrutiny from his peers. ... In the end, the scientific process prevailed. But again, not before Dr. Graham's supervisors attempted to intercede."
In the speech, Senator Grassley said FDA whistleblowers are patriots.
"Think about the guts it takes to undermine your career," he said, "and to go against your supervisors at a huge federal agency, and in this case, the multi-billion-dollar drug companies."
"Whistleblowers are the rare birds who refuse to go along to get along," he told the audience. "The only thing they're guilty of is "committing truth," he said.
"Unfortunately," Grassley told the audience, "it appears that some drug companies are placing greed ahead of drug safety. In this fraudulent environment, the FDA's mission is more important than ever before. The FDA absolutely has to do a top-notch job on ensuring drug safety," he said.
The FDA "needs to demonstrate that it is unequivocally committed to the scientific process - and those who speak up on its behalf -- when it comes to drug safety and that nothing gets in the way of that, whether it's pressure from profit-oriented drug makers or institutional ego that doesn't want to admit a mistake," Grassley warned.
"The one and only client of the FDA must be John Q. Public," he declared.
Four months later, on July 18, 2005, Senator Grassley took to the floor of the Senate to explain why he would vote against the nomination of Dr Crawford to head the FDA, and gave a caustic speech about the FDA's relationship with drug companies as a whole, and Dr Crawford's conduct in the position of a temporary commissioner, and said in part:
"During the last 18 months, this country's confidence in the FDA has been shaken. It has been shaken not because of one isolated incident or one isolated whistleblower. It has been shaken because multiple drug safety concerns have been exposed by more than one courageous whistleblower.
"My oversight of the FDA leads me to the conclusion that there are cultural and systemic problems at the FDA. Unfortunately, Dr. Crawford has long been part of that same culture and system. The evidence is overwhelming that the FDA must change to better protect the American people. Dr. Crawford does not appear willing to be the man to change the FDA.
"During Dr. Crawford's tenure, I have witnessed the suppression of the scientific process and the muzzling of scientific dissent. First, with Dr. Mosholder finding a link between anti-depressants, children and suicide. And second with Dr. Graham's allegations regarding the FDA, Vioxx and post-marketing safety generally.
"Dr. Graham's testimony before the Finance Committee suggests that the problems are systemic. Oversight of the FDA exposed the cozy relationship that exists between the FDA and the drug industry. It revealed that the FDA negotiated for almost two years with Merck about how to change the Vioxx label so people would know about the risk of heart attacks."
In the end, Dr Crawford did become the FDA Commissioner in July 2005, but not for long. This Lester Crawford saga gives to new meaning to the phrase of "what goes around comes around."
After less than 3 months on the job, in a September 23, 2005 letter to President Bush, Crawford announced his resignation from the FDA and said it was "effective immediately."
In public, Crawford explained his departure by saying it was time for someone else to lead the agency. On September 28, 2005, Forbes.com reported that Crawford said he decided to leave the agency because he was tiring after three years at the agency. "He denies that financial conflicts of interest had anything to do with his decision to resign," Forbes noted.
However, Senators Mike Enzi (R-Wyo) and Edward Kennedy (D-Mass) disputed that claim and asked the HHS Inspector General to investigate Crawford's resignation to see whether he left due to an undisclosed financial conflict of interest.
Less than a month later, on October 26, 2005 the Wall Street Journal reported that as late as 2004, Crawford or his wife "owned stock in companies that make or distribute products regulated by the agency."
According to the Journal, Crawford or his wife held shares in several companies whose business is regulated by the FDA, as late as 2004, when Crawford was acting commissioner, quoting financial disclosure forms obtained by the Journal.
When Crawford began work at the FDA in 2002, the Journal said, he held stock in many companies, including Merck, Pfizer, and Johnson and Johnson. But he told ethics officials that he sold those stocks in 2002, along with stock he held in Kimberly-Clark, which makes medical devices.
Crawford also reported the sale of his stock in the company Teleflex Inc in 2002, which also makes medical devices, although "later forms show that he or his wife continued to own some shares," the Journal reports.
On the same day that the Journal's article was published, the Kaiser Daily Health Policy Report reported that the HHS Inspector General had confirmed that it had launched an investigation into Crawford's departure from the FDA.
About 3 months after that, on February 8, 2006, Crawford's new employer was revealed when the Washington Post reported that Crawford, "whose sudden resignation last fall after less than three months in office remains a mystery, has joined a lobbying firm that specializes in food and drug issues."
"Crawford is listed as "senior counsel" to the firm Policy Directions Inc." the Post said.
A few of the firm's clients listed in the article, include Merck, Altria Group Inc, formerly Philip Morris Companies, and the industry's trade group, the Pharmaceutical Research and Manufacturers of America.
According to the Post, "Crawford is barred from lobbying former colleagues at the FDA for a year, but he can give clients strategic advice about food and drug issues and can lobby members of Congress."
Less than a month later, on March 3, 2006, the Houston Chronicle reported that before he abruptly resigned, Crawford sold more than $50,000 in shares of Teleflex Inc, "a company that makes medical devices, according to financial disclosure forms" obtained by The Associated Press.
"As head of the FDA," the Chronicle noted, "Crawford oversaw the regulation of medical devices."
And on April 29, 2006, the Washington Post reported that the "former commissioner of the Food and Drug Administration is under federal investigation amid accusations of financial improprieties and making false statements to Congress."
The criminal investigation was disclosed at a hearing in a civil suit filed against the FDA over its handling of the emergency contraceptive Plan B, according to the Wall Street Journal on May 1, 2006. It seems Crawford was scheduled to be questioned under oath in the trial, but his attorney Barbara Van Gelder asked for a delay, saying she would instruct Crawford to invoke his Fifth Amendment rights.
Van Gelder said that Crawford is under criminal investigation and that the issue of his financial disclosures "is within the grand jury."
As for how things are going these days for Dr Graham, in April 2006, he was interviewed by Life Extension Magazine and described his life as "surreal" since the Vioxx scandal broke and discussed what its like to face the same people every day who tried to destroy him for simply telling the truth.
"It's very difficult," he said. "I periodically have to sit down with supervisors who I knew in November were lying to Congress about me, lying to The Lancet about me, and who tried to prevent my getting protection as a government whistleblower."
"They were doing hateful things," he explained, "and now they pretend nothing happened."
Dr Graham did say that the mistreatment comes only from senior management. "At the staff level," he said, "I'm very respected and supported."
"If anything, esteem for me has increased because they realize I told the truth," he told Life Extension. "They know the reality of what we're dealing with."
In April 2006, in what has to be one of Merck's worst nightmares, a federal judge ordered Dr Graham to testify at a deposition in the Vioxx multidistrict litigation. The MDL was created to consolidate pretrial proceedings for the thousands of lawsuits filed by users of Vioxx.
The FDA attempted to block Dr Graham's testimony by filing a motion to quash the Plaintiff's subpoena on grounds that his deposition would divert the agency's time and resources, and cripple its ability to fulfill its statutory mandate, and said there was no need to depose Dr Graham, given his public statements already made.
However, Judge Eldon Fallon denied the motion and said: "This court does not see how the deposition of one employee during nonworking hours would cripple the FDA's ability to function."
He also noted that none of the documents in the public record could "express Dr. Graham's opinion with the clarity and tone as he personally can in his deposition."