The Bitter Pill

The Official Blog of UNITE – uniteforlife.org

MRI for Profit Scheme May Turn Deadly

Evelyn Pringle June 10, 2007

The FDA issued a press release on May 23, 2007, to announce that the agency was asking manufacturers to include a new black box warning on the labeling of all gadolinium-based contrast agents used to enhance the quality of magnetic resonance imaging (MRI).

The warning states that patients with severe kidney insufficiency who receive the agents are at risk for developing a debilitating and potentially fatal disease known as known as Nephrogenic Systemic Fibrosis or Nephrogenic Fibrosing Dermopathy (NSF/NFD).

In addition, the FDA warns that patients receiving the agents just before or just after liver transplantation, or patients with chronic liver disease, are also at risk for NSF if they are experiencing kidney insufficiency of any severity.

This NSF warning will likely shine a brighter spotlight on the MRI for profit scheme revealed on January 17, 2007, when Illinois Attorney General Lisa Madigan announced that her office had intervened in a whistleblower lawsuit filed by John Donaldson in 2006 against more than 10 Chicago-area MRI centers over their payment of kickbacks to doctors in exchange for referring patients to the centers.

According to the complaint, “Each participating MRI Service Center involved performs the subject MRI services and then engages in the making of illegal and unlawful kickbacks to the physicians from payments made by both Illinois citizen patients and their insurers.”

The kickbacks, the complaint alleges, provide a financial incentive for a physician to order unnecessary scan services, or excessive scan services, and thus bill insurers for unnecessary scans.

The schemes, the lawsuit alleges, make it impossible for legitimate providers to engage in legitimate practice of providing MRI services and remain in business if the scheme and unlawful practice of paying kickbacks for patients is not stopped.

According to Mr Donaldson, he has experienced a substantial drop in physician referrals over the past 24 month as more doctors referred patients to centers involved in the kickback scheme. In the complaint, he says, physicians have advised him that they would prefer to utilize his services, but only if his “business would pay kickback payments to physicians for referring MRI patients.”

Physicians were told the referrals could earn an annual revenue of $84,900 to $132,900, assuming the doctor had a referral rate of 40 scans per month, according to the May 10, 2007, Chicago Tribune, and although there are only 11 companies named in the complaint, the attorney general’s office thinks the scheme stretches across the country.

The FDA first notified the public and health care professionals about the MRI-related risks for NSF in June 2006 and updated the information in December. As of December 21, 2006, the FDA said it had received reports of 90 patients with moderate to end-stage kidney disease who developed NSF/NFD after they had an MRI or MRA with a gadolinium-based agent.

MRA is a special type of MRI used to study blood vessels to help in the detection of heart disorders, stroke and vascular diseases. The gadolinium-based agents are not FDA approved for MRA, but the FDA says, some radiologists believe that these agents help provide detailed images of blood vessels.

According to Doctors Guide on January 25, 2007, approximately 400 cases of NSF have been reported worldwide. “While gadolinium-based agents have not been definitively shown to cause NSF,” the article says, “as many as 90 percent of known NSF patients had previously received gadodiamide, and a recent survey of approximately 100 NSF patients revealed that more than 95 percent were exposed to a gadolinium agent within two to three months prior to disease onset.”

“Other evidence linking gadolinium with NSF,” Doctors said, “includes residual gadolinium in a skin biopsy of an NSF patient 11 months after the contrast agent was administered.”

The 5 agents approved for use in the US include: Magnevist (gadopentetate dimeglumine), Ominiscan (gadodiamide); OptiMARK (gadoversetamide); MultiHance; (gadobenate dimeglumine); and Prohance (gadoteridol).

Bayer Schering Pharma manufactures Magnevist; GE Healthcare is the maker of Omniscan; OptiMARK is manufactured by Mallinckrodt, Inc; and ProHance and MultiHance are made by Bracco Diagnostics Inc.

According to the EMEA (European Agency for the Evaluation of Medicinal Products), NSF develops over a period of days to several weeks. “The first symptoms are red or dark patches or papules that develop on the skin,” the EMEA states. “The skin of the limbs, and sometimes the trunk, thickens and feels ‘woody’.”

The skin surface can resemble an orange-peel texture, the EMEA says. “Patients may experience burning, itching, or severe sharp pains in the affected areas, and hands and feet might swell with blister-like lesions.”

“In many cases,” the agency notes, “skin thickening prevents joint movements and might result in contractures (an inability to straighten the joints) and immobility.”

Other organs that might be affected, include the lungs, liver, muscles and heart, and about 5% of patients have very rapid and progressive development, and some patients may die.

The FDA reports that, “there is no consistently effective treatment of this condition.”

Since NSF was first recognized in 1997, researchers had come up with several theories about the cause, but it was not until early 2006 that an association with gadolinium-based agents was made after a study found that several patients with end-stage renal failure developed NSF, 2 to 4 weeks after having an MRI.

The mechanism by which gadolinium-containing agents might trigger NSF is under investigation. However, kidney impairment is thought to be an important factor because NSF develops only in patients with advanced kidney dysfunction. Because the agent is excreted from the body via the kidneys, it may be that patients with kidney impairment clear the agent from the body at a much slower pace than patients with normal kidneys.

Experts say neonates and infants up to 1 year of age may also be at risk because their kidneys are not fully developed.

The UK Commission on Human Medicines (CHM) and one of its expert advisory groups reviewed the NSF issue in January 2007 and proposed a step-wise approach to restricting the use of the agents in patients with kidney disease, in liver-transplant patients and in neonates.

On the basis of the available evidence, the committee concluded, the balance of risks and benefits of gadodiamide in patients with severe kidney failure was negative, and that gadodiamide should not be used in these patients or in those who have had, or who are waiting for, a liver transplantation.

On a precautionary basis, the committee advised that a warning should be added to the product information about the use of gadodiamide in neonates because of their immature kidney function. They also recommended that strong warnings about NSF should be added to the product information for all other gadolinium-containing contrast agents.

According to the FDA, reports have identified the development of NSF following single and multiple administrations of the agents, but the reports have not always identified a specific agent. Omniscan was the most commonly reported agent, the FDA says, when a specific agent was identified, followed by Magnevist and OptiMARK.

NSF also has developed after the sequential administration of Omniscan and MultiHance and Omniscan and ProHance. Because reports incompletely describe exposure to gadolinium-based contrast agents, the FDA says, it is not possible to know if the extent of risks for developing NSF is the same for all agents.

The agency says all patients should be screened for kidney problems prior to receiving one of these agents, the recommended dose should not be exceeded, and before the agent is used again, enough time should elapse to ensure that a dose has been eliminated from the body.

Filed under: 2007, Fraud, MRI, whistleblower

Medtronic’s Medical Device Legal Troubles far from Over

Evelyn Pringle July 31, 2006

Minneapolis based Medtronic, Inc. is one of the nation’s largest medical device makers. In mid-July 2006, the company agreed to pay a $40 million fine to settle charges that its Sofamor Danek division paid kickbacks to doctors to get them to use the company’s spinal products, which accounted for 20% of the company’s $11.3 billion in sales in 2005.

On July 19, 2006 the US Department of Justice issued a press release announcing the settlement. The DOJ alleged that, between 1998 and 2003, Medtronic paid kickbacks in a number of ways, including sham consulting agreements, sham royalty agreements and lavish trips to desirable locations and that these kickbacks violated the Anti-Kickback Statute and the False Claims Act.

“Kickbacks to physicians are incompatible with a properly functioning health care system,” said Peter Keisler, Assistant Attorney General for the DOJ’s Civil Division. “They corrupt physicians’ medical judgment and they cause overutilization and misallocation of vital health care resources.”

“Today’s settlement,” he added, “reflects the progress we are making in the ongoing fight against abusive and illegal practices in the healthcare industry.”

The DOJ’s investigation was triggered by whistleblower qui tam lawsuits filed under the False Claims Act. The FCA allows private parties to file lawsuits on behalf of the US government and collect a share of any money recovered. The FCA prohibits any corporation or citizen from defrauding the government and the allegations against Medtronic in this instance involve the Medicare program.

“The settlement,” said David Kustoff, the US Attorney for the Western District of Tennessee in the press release, “demonstrates that schemes involving submissions of false or fraudulent claims by health care companies and health care providers to federal health care programs will be vigorously and energetically pursued.”

“This agreement,” he noted, “should serve as a deterrent to those entities that attempt to defraud or deceive the taxpayers.”

In addition to the fine, Medtronic entered into a 5-year corporate integrity agreement with the Office of the Inspector General of the US Department of Health and Human Services. The agreement requires the company to file regular reports with the Inspector General and track all non-sales related customer transactions.

The company must also set up an outside review organization, improve training and employee screening practices, and make a compliance officer a member of senior management, who reports directly to the chief executive and has access to the company’s board of directors

The two whistleblower lawsuits filed by former employees claim Medtronic paid millions of dollars in kickbacks. For instance, Dr Thomas Zdeblick, a Wisconsin surgeon who is listed as a defendant in one of the lawsuits, signed a 10-year consulting contract with the company in 1998, that only required him to consult with Medtronic for eight days a year for $400,000.

A Virginia physician received close to $700,000 in consulting fees for the first 9 months of 2005, and received $1.39 million between 2001 and May 2005, according to the lawsuit.

Internal Medtronic documents filed as part of the lawsuit in the US District Court in Memphis, reveal the details of the rigorous campaigns that Medtronic set up to influence doctors. The documents show the company made payments of at least $50 million to doctors over a four years period through June 2005.

In the lawsuit unsealed in January 2006, the plaintiff, Jacqueline Poteet, a former senior manager of travel services for Medtronic until 2003, says she handled the travel arrangements for doctors to attend medical conferences and is familiar with the company’s efforts to win the doctors’ favor.

She alleges that the company gave spine surgeons “excessive remuneration, unlawful perquisites and bribes in other forms for purchasing goods and medical devices.”

Spinal implants are used in a procedure known as spinal fusion, to make a patient’s spine more stable. The cost of a devices used in this type of surgery is about $13,000, according to Orthopedic Network News, an industry newsletter.

In a subsequent amended complaint, Ms Poteet, accuses the company of continuing the improper payments to doctors in 2004 and 2005, leading them to perform unnecessary spinal surgeries.

With billions of dollars up for grabs, in addition to consultant fees, Medtronic used other creative methods to induce physicians to use its products. According to the lawsuit, Medtronic hosted medical conferences where the “principal objective” was to “induce the physician, through any financial means necessary” to use its devices.

Company spreadsheets show that after a conference, Medtronic went to great lengths to track the use of its devices by each doctor who attended. A spreadsheet for a June 2003 conference in California, lists over 200 doctors and includes an estimate of the dollar amount of the devices each doctor uses in surgery. One surgeon is described as “a 100 percent compliant M.S.D. customer” (Medtronic Sofamor Danek), and other doctors are marked as needing “special attention.”

According to Ms Poteet, Medtronic zeroed in on surgeons while they were still in training, and the company paid for doctors to attend any of 200 professional meetings a year. If the doctors wanted to play golf or go snorkeling, she alleges, Medtronic paid for the outings. When doctors visited Memphis, she says, company employees would take them to the “Platinum Plus” strip club, and then write off the expense as an evening at the ballet.

In 2003, a company document reveals that Medtronic attorney, Todd Sheldon, questioned whether the company should be paying for all the excursions. “When we are sending scores of doctors to a nice resort like this under the guise of training and education on our products,” Mr Sheldon wrote in an email, “I think we need to be more careful and stick to the limits of our rules as best we can.”

Medtronic claims the company has scaled back payments to doctors, but not so, says Ms Poteet. Her amended complaint alleges that any changes made by Medtronic were merely temporary. Its “bribery program,” she alleges, “has not only failed to cease, but continues unabated with increased payments made to many physicians.”

She points out that while payments to some doctors were lowered in 2004, when the company first came under investigation, the payments went back up last year. For instance, Dr Hallett Mathews, of Virginia, was paid $300,000 in consulting fees in 2003, but only $75,000 in 2004. But then in 2005, he was paid nearly $700,000 in consulting fees in the first 9 months.

Had Medtronic not entered into a settlement agreement with the DOJ, the company could have been hit with a triple damages award if it lost in court, under a key provision of the FCA. As it is, the $40 million fine is the second financial penalty for Medtronic’s spinal division in a year. In 2005 the company paid $1.35 billion to settle a patent infringement lawsuit and cover the costs of additional patents from Los Angeles surgeon and inventor, Dr Gary Michelson.

Over the past couple years, the financial relationships between device makers and doctors have caught the attention of several law enforcement agencies. In 2005, US attorneys in Boston and Newark issued subpoenas to Medtronic, along with just about every other major medical device maker, as part of a far reaching investigation into the financial entanglements between physicians and the industry as a whole.

Therefore, legal experts say Medtronic is probably not breathing much easier these days. Three of the subpoenas issued last fall went to the top cardiac-rhythm-management companies, Medtronic, Guidant and St Jude Medical, and seek information on their marketing practices related to pacemakers and defibrillators.

And Medtronic already had plenty of legal problems with its defibrillator division. In February 2005, the company told 87,000 patients that their defibrillators might fail.

However, company documents filed in the California lawsuit, Randall v Medtronic, No C-05-3707-JW, in the US District Court for the North District of California, show the company knew about the flaw back in 2003, and continued to sell the faulty devices for two more years.

“Medtronic has been taking products they know are not quite right and putting them into people rather than take the loss,” according to Hunter Shkolnik, a New York attorney, who said in a February 13, 2006, interview with Bloomberg News, that he represents more than 200 people whose Medtronic devices were recalled.

“If you know there’s a problem with a component,” he said, “you don’t put it out and sell it to people.”

Since the recall, 19,000 people have had replacement surgery, Medtronic spokesman, Rob Clark, told Bloomberg News.

Critics say Medtronic refuses to acknowledge that undergoing replacement surgery is risky and constitutes an injury in itself. According to Bloomberg, based on Medtronic’s estimate of a 2 to 5% post-implantation infection rate, 380 to 950 patients may have developed infections after replacement of their devices.

Spokesman Clark told Bloomberg that Medtronic does not keep track of deaths, disabilities or extra medical costs resulting from such complications.

When announcing the recall last year, Medtronic said it would provide a new defibrillator to patients and up to $2,500 for out of pocket expenses. But the company expects taxpayers, through programs like Medicare, and insurance companies, to pick up the tab for the hospital and doctor bills incurred during the replacement surgery.

However, the company is now facing scores of lawsuits claiming that patients should not be expected to bear any of the costs for having the devices replaced. About 200 lawsuits from states all over the country are seeking class-action status and have been consolidated in US District Court in Minneapolis before Judge James Rosenbaum.

Last month, Medtronic asked the Judge to dismiss the lawsuits, arguing that FDA regulations for medical devices preempt lawsuits in state courts and that the FDA has special authority over lifesaving or life-sustaining medical devices, such as defibrillators. “Any warning has to be regulated by the FDA,” Medtronic attorney, Michael Brown, said.

But attorneys for the plaintiffs said Medtronic “glossed over” the problem in an October 2003, filing with the FDA that sought approval of a new defibrillator model, according to a July 11, 2006, article by the Associated Press.

Judge Rosenbaum is expected to issue a decision on Medtronic’s motion in early fall.

Six months after the first recall in 2005, the company was in hot water with the FDA again over another group of devices. In a June 9, 2005 letter, the FDA said that Medtronic failed to correct manufacturing problems and investigate its LifePak 12 external defibrillators and cited damaged cable connectors and failures to follow through with preventive action after inspections of the company’s Redmond, Washington plant.

The LifePak 12 external defibrillators, used in hospitals to shock the heart back to a normal rhythm, are similar to the LifePak 500 devices the company recalled. Medtronic’s cardiac rhythm management business, which also includes pacemakers and implantable defibrillators, accounted for 46% of its $2.78 billion in sales in its latest quarter, according to Bloomberg News on June 22, 2005.

At the time, about 60,000 LifePak 12 external defibrillators were in use worldwide, Mr Clark said.

In the warning letter, the FDA said Medtronic did not investigate all complaints about defibrillator malfunctions, including one involving a patient’s death. Problems were linked to broken or bent pins in the cable connectors, possibly because the company did not have adequate inspection procedures, the agency said. Failure to correct the problems may result in legal and civil penalties, the FDA warned.

Finally, in another turn of events that could have a negative impact on the financial future of the company, Medtronic is awaiting the final word on a Medicare proposal that would decrease reimbursement for procedures that are considered excessively profitable such as implanting heart devices.

Under the pending proposal, the Medicare reimbursement for implants would be cut from $31,833 to $23,755, or a loss of $8,078 for each procedure.

Filed under: 2006, MEDICAID, medical devices, MEDICARE, Medtronic, Poteet, prices, settlement, whistleblower

Merck Not Losing Sleep Over Vioxx Disaster

Evelyn Pringle June 16, 2006

Merck’s top management team reportedly remains unphased by Vioxx litigation woes. In fact, Prudential Equity Group analyst, Timothy Anderson, says Merck’s Chief Executive, Richard Clark, specifically told him that “Vioxx does not keep him up at night.”

According to Mr Anderson, “the company believes that lower court cases will be overturned on appeal, and it is even considering trying to reintroduce Vioxx.”

“A reintroduction might help Merck’s legal case,” Mr Anderson states, “as long as the FDA or its advisers do not decide that Merck’s risks really do outweigh its benefits,” he said in a June 21, 2006, article in Forbes.com.”

Critics say that’s not even a remote possibility because the FDA is still under fire for its own part in the Vioxx disaster and it wouldn’t dare pull a stunt like that.

When it comes to saving Merck in the Vioxx litigation, the FDA is at odds with some of the most powerful leaders in Congress. Senator Charles Grassley (R-Iowa), chairman of the Senate Finance Committee, is on record as saying the Vioxx debacle has shown that the FDA has gotten too cozy with drug companies to conduct proper oversight.

“The Vioxx example showed that the FDA and Merck were too close for comfort,” he said in a speech. “Testimony and documents at our Finance Committee hearing showed that the FDA allowed itself to be manipulated by Merck.”

Documents indeed reveal that the FDA knew about the problems with Vioxx very early on. A memo written by Shari Targum, MD, Project Manager for the Division of Anti-inflammatory Drug Products, clearly shows that as of November 18, 1999, the Data and Safety Monitoring Board of the VIGOR study, a committee independent from Merck, was concerned over the deaths from cardiovascular events in the Vioxx group, compared to the group taking another painkiller.

This memo documents a clear date of recognition by the FDA of when cardiovascular events were brought to the attention of Merck.

Admittedly, if it was up to the Bush administration, the FDA would allow Vioxx back on the market today. Bush does everything in his power to protect the profits of Big Pharma, the industry most responsible for his 8-year rent free lease of the White House.

Under Bush, the FDA has in fact become Big Pharma’s chief enabler when it comes to getting away with murder. A newly released report on June 26, 2006, titled, “Prescription for Harm: The Decline in FDA Enforcement Activity,” says that FDA enforcement actions have declined by 50% since Bush took office.

“The number of warning letters issued by the agency for violations of federal requirements,” the report said, “has fallen by over 50%, from 1,154 in 2000 to 535 in 2005, a 15-year low.”

“During the same period,” it noted, “the number of seizures of mislabeled, defective, and dangerous products has declined by 44%.”

Bush has never hesitated to utilize the FDA in the Big Pharma protection racket. For instance, on January 18, 2006, the FDA issued new regulations for labeling prescription drugs, supposedly aimed at providing doctors and patients with clearer information about their risks. But in the preamble to the regulations, the FDA inserted a claim that lawsuits alleging a failure to warn of known or reasonably knowable risks are preempted by federal law.

Also, amicus briefs filed by FDA attorneys appointed by Bush, on behalf of the drug companies, have tried to claim that because private lawsuits threaten to disrupt the nation’s system of drug regulation, federal standards preempt requirements established by state judges and lawmakers, and that if a state court finds that a drug is unsafe, it is in direct conflict with the conclusion reached by the FDA.

With Bush using the FDA to do the dirty work, Republicans lawmakers up for reelection this fall, don’t have to make a spectacle of themselves fighting for such blatant industry-friendly legislation during an election year.

A partner in the LA based Baum Hedlund law firm, attorney Karen Barth Menzies, has been litigating claims against drug companies for more than a decade and says “the Vioxx public health debacle has served to highlight deep-seeded problems within the FDA.”

“Drug companies are profit-driven,” she explains, “and are loath to issue warnings about risks associated with their drugs, even those that become quite clear.”

“Medicine is no longer about health,” Ms Menzies notes, “its about market share and profits.”

Since Bush took office, the FDA has sent out its legal squad to assert the preemption argument on behalf of drug companies in attempt to defeat private citizens in lawsuits numerous times. However, Ms Menzies’ team of Baum Hedlund attorneys has knocked the FDA briefs out of the ball park in a several cases, including Witczak v Pfizer and Motus v Pfizer.

But “the FDA’s legal arm has continued to intervene in private civil lawsuits on the side of drug companies,” she says, “arguing that FDA’s decisions should not be second-guessed by anyone, the federal preemption argument.”

In the past 15 plus years, Ms Menzies notes, the FDA has been worse than “comatose” as the New York Times recently described the agency. “It has sided with industry and become an adversary against consumers,” she points out.

“And it is precisely for this reason,” she says, “that the public is in such desperate need for an agency that advocates for them, rather than the drug industry.”

In light of recent disasters like Vioxx that have resulted in large part due to a lack of regulatory oversight, Ms Menzies contends that the “FDA’s decisions must be second-guessed for the safety of the public.”

Medical experts agree that the FDA must be second-guessed. “With an FDA that regularly displays incompetence and negligence in its deliberations about the efficacy and safety of medications,” says Dr Grace Jackson, author of, Rethinking Psychiatric Drugs: A Guide to Informed Consent, “it cannot possibly be the case that this federal agency possesses the institutional expertise to which courts or litigants should now defer.”

“Indeed,” she notes, “if the FDA is preempting anything, it is the sound practice of medicine, and the integrity of American health care.”

It will truly be a fatal day for the concept of separation of powers when a federal agency like the FDA can wield the power to enact federal law by filing legal briefs in private lawsuits, funded by tax dollars, to defeat American citizens who are already up against one of the most profitable industries on earth.

Moreover, if FDA attorneys are going waste tax dollars, the least they can to is come up with a few valid arguments. The argument that drug companies are not allowed to warn the public by adding a new warning to a label when dangers become known because it would violate FDA regulations, is ridiculous. There is not now, and there has never been, a law that prevents a drug maker from strengthening a warning or labeling consistent with the company’s specific regulatory ability to do so under 21 CFR 314.70(c)(6)(iii)(A).

The guy responsible for this silly argument is the FDA’s Chief Counsel, Daniel Troy, recruited straight off of Pfizer’s legal team, was Big Pharma’s inside man until he quit the FDA in the fall of 2004.

Instead of going after the drug companies for killing off citizens with lethal drugs in the name of profits, he devoted much of his time filing Joe Tax Payer funded briefs, on behalf of his former industry clients, and even invited drug company attorneys to submit their cases to him for amicus brief consideration.

On March 1, 2004, Jessica Rae Dart, an attorney involved in civil litigation against Pfizer, filed an affidavit in support of a plaintiff’s motion and described a lecture she attended by Mr Troy that clearly shows him offering the FDA’s services to trial lawyers representing drug companies.

On December 15, 2003, Ms Dart said, Daniel Troy, Chief Counsel of the FDA, headed a discussion for pharmaceutical firms and defense attorneys titled, “The Case for Preemption” at the 8th Annual Conference for the In house Counsel and Trial Attorneys, Drug and Medical Device Litigation” in New York City.

During Troy’s “Case for Preemption” talk, she said, Troy stated that he was the initiator behind all the FDA Amicus Briefs and/or Statement of Interest filed on behalf of manufacturers “since the new administration” took over. Specifically, he stated, “I am not the only one who decides,” but “I am the initial proposer.”

According to the affidavit, Troy made it clear that he wanted to file more amicus briefs on behalf of the drug companies and actually invited members of the defense attorney’s audience to approach him with requests for briefs, stating “we can’t afford to get involved in every case,” we have to “pick out shots,” so “make it sound like a Hollywood pitch.”

However, in an obvious effort to try and level the playing field for the little guy, in 2004, Representative, Maurice Hinchey (D-NY), chastised the administration for taking the FDA in a radical new direction, “seeking to protect drug companies instead of the public,” and persuaded the House to cut $500,000 from the budget of the chief counsel’s office as a penalty for the FDA’s aggressive opposition to citizen’s lawsuits.

Although the FDA’s current Chief Counsel, Sheldon Bradshaw, might not have the direct and visible financial links to Big Pharma of his predecessor, critics say, he certainly does not represent a changing-of-the-guard in political leadership at the FDA.

“In fact,” Attorney Menzies says, “following in his predecessor’s footsteps, Bradshaw submitted a legal brief in support of Pfizer’s federal preemption arguments.”

Judges across the nation have flat-out rejected the FDA’s argument. A Minnesota court said it declined “to treat statements from a single FDA legal brief as declarations afforded the preemptive force of law.”

A California court ordered the brief stricken from the record calling it “hearsay and irrelevant,” and an Illinois judge said it “contains nothing more than legal argument by [FDA] counsel.”

Most recently, in a June 6, 2005, Vioxx court hearing, the FDA’s position on preemption hit a major road block with New Jersey State Court Judge, Carol Higbee, who is handling the Vioxx cases, when she labeled the FDA’s Final Rule’s preamble “a political statement by the FDA.” She scoffed at the agency’s preemption claim and said:

“It is contrary to the U.S. Supreme Court’s decisions. It is contrary to all the law on preemption. … In addition to being contrary to the law of the land, it is also contrary to the Constitution of the United States.”

Judge Higbee ended her comments by throwing cold water on any planned attempt by Merck’s legal team to give the preemption argument a whirl, by telling them right-out in open court: “I am not going to allow you to use it.”

Speaking to the Consumer Federation of America in March 2005, Senator Grassley, basically said the FDA can’t be trusted to protect citizens against dangerous drugs like Vioxx because the agency is to “cozy” with companies like Merck.

Based on a clinical trial that took place in 2000, he told the audience, both the FDA and Merck were aware that heart attacks were 5 times more likely in patients taking Vioxx than among those taking a similar drug, but the FDA did nothing to change the labeling on the drug for nearly two years, while Merck aggressively marketed Vioxx on nightly TV.

Describing whistleblowers as “patriots” who risk their careers in the interest of public safety, Senator Grassley recounted the controversy over Vioxx that was fueled in large part by the efforts of FDA scientist, Dr David Graham, to shed light on the drug’s potential risks.

Senator Grassley described how the FDA “disregarded and stonewalled” concerns raised by its own scientist. “Dr. Graham completed a study that found an increased risk of heart attacks and strokes in patients taking Vioxx,” he told the Federation. “His immediate supervisor, however, dismissed this study as ‘scientific rumor.'”

“The very same month that Dr. Graham warned the FDA of the cardiovascular risks of Vioxx,” Senator Grassley continued, “the FDA approved the use of Vioxx for children.”

He told the audience how the director of FDA’s office of new drugs suggested that Dr. Graham water down his Vioxx conclusions and how 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,” the Senator said, “he was also undermined.”

News reports that day show that acting FDA Commissioner Lester Crawford called Dr Graham a “maverick who did not follow agency protocols.”

“This statement,” Senator Grassley told the Federation, “made on the eve of the hearing, could logically serve no purpose other than to intimidate Dr. Graham.”

The Vioxx matter became the focus of the Senate Finance Committee, basically because of the drug’s cost to public health care programs, and the Committee is responsible for oversight of the Medicaid and Medicare programs.

During a November 18, 2004, hearing, the ranking Democrat on the finance committee, Senator Max Baucus, discussed the tax dollars wasted on Vioxx: “In the 5 years that Vioxx was on the market, Medicaid spent more than $1 billion on the drug,” he said.

In addition, he complained about the fact that government programs are now paying the medical bills for patients harmed by Vioxx. “Medicaid bears the cost of any additional medical care necessary when drugs cause injury,” Senator Baucus said.

Merck’s last CEO, Raymond Gilmartin, resigned on May 5, 2005, the same day that another Congressional Committee, the House Committee on Government Reform, released more than 20,000 pages of documents showing how Merck continued to promote Vioxx long after it was aware of the safety problems.

Documents released that day at a Reform Committee hearing on Merck’s marketing practices, described in detail how Merck directed its 3,000-strong sales force to avoid discussions about the cardiovascular risks identified in the 2000 VIGOR study. During visits with doctors, sales reps were instructed to rely on a “Cardiovascular Card” that claimed Vioxx was actually protecting the heart rather than damaging it. The sales reps were specifically trained on how to speak, smile, and position themselves most effectively when talking to doctors.

If doctors asked about Vioxx increasing the risk, the sales reps were instructed to give them a pamphlet written by Merck’s marketing department that claimed Vioxx was eight times safer for heart patients than similar pain medications, and omitted Merck’s findings that Vioxx produced a 5-fold increase in the risk of heart attack and stroke compared with naproxen, the other painkiller used in the study.

The company’s training efforts were obviously successful because Vioxx was approved by the FDA in May 1999, and the drug reached $2 billion in sales in two years, faster than any drug in Merck’s history.

In 2000, the same year the VIGOR study was completed, Vioxx was the most heavily advertised drug in the US with $160.8 million spent on mass media promotion. And the blitz paid off well. In one year, retail sales of Vioxx rose from $329.5 million in 1999, to $1.5 billion in 2000, up 360%, according to a November 2001, report by the National Institute for Health Care Management.

For the same year, Pepsi only spent $125 million advertising its products. Vioxx also beat out Budweiser’s spending of $146 million, and matched Dell Computer’s ad expenditures of $160 million. And by far, the drug beat out Nike’s advertising budget of $78.2 million for shoes, and Campbell soup’s $58 million.

The increase in Vioxx sales from 1999 to 2000 accounted for 5.7% of the one-year increase in total prescription drug spending, more than any other single drug, the report said, and Vioxx was the 13th best selling drug in 2000.

In 2003, Merck upped the anti even more and spent 499.8 million on Vioxx promotion including the cost of sales reps detailing office and hospital-based physicians, advertising in medical journals and the retail value of samples passed out to doctors, according to IMS Health, Integrated Promotional Services in April, 2004. In return Vioxx saw growth of 24% and became the 6th best selling drug.

What’s that old saying about the bigger they are the harder they fall?

Nowadays, instead of spending hundreds of millions of dollars promoting Vioxx, shareholders are paying hundreds of millions a year for attorney fees. As of December 31, 2004, in its 2005 annual report, Merck said it had a reserve of $675 million solely for its future legal defense costs related to Vioxx. And in the fourth quarter of 2005, Merck said it recorded another charge of $295 million to increase the reserve.

“This reserve is based on certain assumptions,” the annual report said, “and is the best estimate of the amount that the Company believes, at this time, it can reasonably estimate will be spent through 2007.”

There is no money listed anywhere in Merck’s financial filings set aside to pay damages to any injured party, at least through 2007. The whole wad goes for Vioxx “legal defense costs.”

And to think, Republicans have the nerve to say that personal injury attorneys who go up against attorneys with a war chest of close to $700 million a year are financial gluttons.

However, thanks to a helpful group of plaintiff’s attorneys, going up against Merck in jury trials is getting bit easier. The group put together what they call a pre-made Vioxx trial package, complete with a guide to pursuing a claim against the corporate giant.

The package reportedly organizes and edits all of the information that shows Merck knew about the dangers of Vioxx but failed to inform consumers and includes the most damaging documents and evidence available against the drug maker. The package is offered on a small contingency fee basis and costs nothing until the lawsuit is won.

This month, Merck’s legal eagles were hit up once again when the New England Journal of Medicine issued a correction to a paper it published last year on Vioxx that mistakenly said that heart risks only became apparent after 18 months. The Journal editors deleted the 18 month statements saying a statistical error by Merck undermined the evidence for them.

All through litigation thus far, Merck’s main argument has been that the risk to patients from Vioxx did not begin until after 18 months of use, and with one sweep of the pen, the NEJM blew a hole in that defense.

But then juries are not buying into the 18 month defense in any event. In the first jury trial, in August 2005, the jury held Merck liable for the death of Vioxx victim, Robert Ernst, age 59, who died after only taking Vioxx for eight months.

Internal company documents introduced at the trial showed that Merck was aware of the problems with Vioxx as early as 1997. Attorney, Mark Lanier, showed jurors documents and e-mails to prove that Merck scientists knew about the cardiovascular risks (CVs), two years before the drug was approved.

For instance, one 1997 email written by Merck scientist Dr Alise Reicin, said: “The possibility of increased C.V. events is of great concern.”

“I just can’t wait to be the one to present those results to senior management,” he wrote.

As evidence to prove that physicians were deliberately misled, the jury was shown a 2001 Dear Doctor letter, in which Merck specifically stated that in the largest study ever of more than 4000 patients taking Vioxx, only 0.5%, or about 20 patients, had incurred CVs, when in fact, 14.6% of the patients, or 590, had cardiovascular problems, according to a Merck report submitted to the FDA.

It was also proven at trial that in April 2001, the doctor who prescribed Vioxx to Mr Ernst, had received the letter with the fraudulent statistics.

Mr Lanier played a video for the jury that showed sales reps were told that Vioxx did not increase heart attacks and were trained to view doctors concerns about CVs as “obstacles” to be avoided or dismissed. Another training document told sales reps to play “Dodgeball” if doctors raised questions about CVs.

In a more recent on-going trial, on July 5, 2006, more damaging testimony against Merck was given by Dr Lemuel Moye, a professor of biostatistics at the University of Texas, in a California case filed by a 71-year-old, Stewart Grossberg, who told the jury that Merck’s clinical trials conducted as far back as 1996, showed patients taking Vioxx were at risk for heart attacks and strokes, long before the drug went on the market, and that after reviewing the trials, he concluded that Vioxx carried more risks to patients than benefits.

But legal experts say that back in April 2006, Merck received the worst news possible when it lost an appeal to deny certification of a Vioxx-related class action lawsuit. They says the court’s decision to certify third-party payers, like health insurance companies, HMOs, and unions, has to be the most disturbing development for the company to date.

By ruling against Merck, the court gave the OK to apply New Jersey’s consumer fraud statutes to all members of the class, even to plaintiffs from states that have different laws. Experts predict that the consequences of this ruling will be profound and far-reaching, and the costs to Merck potentially staggering.

In light of the verdict in the April 2006, trial of Cona v Merck and McDarby v Merck, in which the jury said Merck violated New Jersey’s consumer fraud statute because it misled physicians about the cardiovascular risks of Vioxx and concealed information about those risks from doctors, experts say, the appeals court’s ruling might just turn out to be the nail in the coffin for Merck.

Christopher Seeger, the lead lawyer in the class action filed by HMOs, insurers, and unions, says that Judge Higbee, who is overseeing about 5,000 Vioxx cases, should apply the findings of this jury to the class action, which he said could be worth $10 billion.

Mr Seeger told Bloomberg News on April 5, 2006, that this was devastating for Merck: “This jury just said ‘Yes’ to consumer fraud, so I think we go right to damages.”

Mr Seeger is referring to collateral estoppel a situation in which the judgment in one case prevents, or estops, a party from litigating the same issue in future cases. Because of the consumer fraud verdict, Mr Seeger contends that Merck may now be permanently bound by the jury’s ruling.

Indeed, Bloomberg says, a judge could decide that the ruling that Merck failed to warn of Vioxx’s risks could be applied to thousands of future trials in New Jersey, leaving the jury to decide only whether Vioxx caused specific heart attacks.

Barry Turner is an academic lawyer in the UK who has taught medical ethics and for a number of years has been involved in litigation activities related to the pharmaceutical industry.

He has been advocating the use of federal and state false claims statutes against Big Pharma for years. “I take the view that because of the harsh penalties imposed when these actions are successful,” he explains, “that this is the legal strategy that will work against these people.”

“PI suits,” he says, “may very well be morally righteous but they will never make this industry change its ways.”

“What is at issue,” he continues, “is that companies factor litigation costs into ‘research and development’ and other costs of sales, so it does not hurt them to pay out in damages, what they already budgeted for.”

“The Federal and State False Claims Act actions are different,” he notes, “a drug company hit by a big one of these will have to pay out colossal amounts in fines and damages, hundreds of millions in most cases,” he says, “and these come out of profits.”

“Then the stock will go down,” he explains, “and they can be hit again under the Sarbanes Oxley Act.”

“And if anyone thinks that Sarbanes Oxley is feeble legislation,” he says, “they can always ask the Enron executives.”

“As well as defrauding the taxpayer,” Mr Turners notes, “the consequences of these deliberate and deceitful acts hurts shareholders when the litigation causes serious downturns in stock value.”

“This is a violation of Sarbanes Oxley,” he says, “and sooner of later there will be a major action here.”

In each of the cases Merck has lost, the juries have ordered the drug giant to pay large punitive damage awards, creating additional problems for the company. Punitive damages are awarded to punish a defendant and deter future misconduct. They are not covered by insurance because the conduct is an intentional act on the part of the insured; and the intent of punitive damages would be lost if a defendant could avoid payment simply by buying more insurance.

In the state of New Jersey, punitive damages are allowed to be as much as 5 times the amount of compensatory damages. The Texas $229 million punitive damage award against Merck, even when reduced, will still be about $26 million. Legal analysts say no company could avoid financial ruin if ordered to pay tens of thousands of $26 million punitive damage awards.

Punitive damages provide a basis for a derivative lawsuit seeking damages for conduct that compromised the value of the investments of shareholders. These types of lawsuits are being filed for much less than what Merck pulled with Vioxx.

For instance, in March 2005, a class action lawsuit was filed in the US District Court for the District of Massachusetts, on behalf of shareholders in Elan Corp PLC, after the company’s withdrawal of the multiple sclerosis drug Tysabri, with many of the same allegations that can be made against Merck.

The complaint alleges that Elan failed to disclose and misrepresented material adverse facts in connection with Tysabri including serious immune-system side effects and that the information was concealed in order to fast track Tysabri for FDA approval.

In any event, notwithstanding that Merck continues to contend that it will try every single case, legal analysts say, state courts will never be able to handle the trials for the lawsuits already filed, much less the additional cases still being filed on a regular basis.

“At some point courts are going to be clogged with these cases and judges will start to put pressure on Merck and the plaintiffs to settle these cases,” according to John Leubsdorf, professor of law at Rutgers Law School, on CNN Moneyline on April 26, 2006.

“The only scenario in which they won’t settle,” he says, “is if they win so much that all the plaintiffs go away.”

But experts say that is definitely not going to happen.

Filed under: 2006, FDA, FDA Crawford, Graham, Merck, Preemption, stroke, Troy, Vioxx, whistleblower

Big Pharma Research Racket Is Killing People

Evelyn Pringle June 23, 2006

Over the past six years, ten FDA approved drugs have been withdrawn from the market due to deaths and injuries, leading lawmakers to accuse the FDA of not doing its job in protecting the public from unsafe drugs and to call for measures of improvement.

On June 20, 2006, the New York Times reported that “two influential senators are expected within weeks to introduce a legislative proposal that could drastically change how drugs are tested and approved in the United States.”

The Senators behind the proposal are Michael Enzi (R-Wy), chairman of the Health, Education, Labor and Pensions Committee, and Ted Kennedy (D-MA), the ranking Democrat on the committee.

“In broad terms,” the Times article by Gardner Harris explains, “the bill would require that drug makers disclose the results of all large human tests of their drugs, known as Phase 3 and Phase 4 trials; create a detailed risk management plan to uncover and control any safety problems that arise after a drug is approved; and pay penalties if they fail to follow through with this plan, according to four experts who were briefed on the proposals.”

However, while lawmakers search for ways to ensure that Big Pharma does not continue to conceal adverse reactions that surface during drug trials and to sever the ties between the nation’s public health officials and Big Pharma, the Bush administration continues to promote their cozy relationships and help drug companies escape accountability for misconduct.

The best example of the administration’s efforts to protect Big Pharma was revealed recently when the FDA announced a preemption rule that would disallow lawsuits in state court against drug makers if a drug has been approved by the FDA.

“We think that if your company complies with the FDA processes, if you bring forward the benefits and risks of your drug, and let your information be judged through a process with highly trained scientists, you should not be second-guessed by state courts that don’t have the same scientific knowledge,” said FDA deputy commissioner on medical and scientific affairs, Scott Gottlieb.

But in all fairness, the FDA is certainly not the only public health agency in bed with Big Pharma. Nobody can deny the fact that Big Pharma is an equal opportunity corrupter. Its obvious that drug companies have infiltrated every Federal regulatory agency in the US.

For instance, on June 14, 2006, a National Institute of Health Alzheimer’s researcher, Dr Trey Sunderland, asserted his Fifth Amendment rights, and refused to testify before the House Energy and Commerce Committee about accusations that he has profited from giving Pfizer access to spinal fluid and plasma samples collected by the NIH.

Documents presented at the hearing revealed that between 1996 an 2004, Dr Sunderland accepted consulting, speaking and advisory fees totaling about $612,000 and committee staff members estimate that about $285,000, was related to 3,245 samples taken from 538 patients who participated as volunteers at the NIH.

At a price of about $12,000 per patient, the committee estimates the cost of collecting the samples that Dr Sunderland handed to Pfizer is close to $6.5 million.

The committee also noted that he did not seek prior approval to work for Pfizer, and did not report any of the income to the agency as required by NIH rules.

In fact, at one point, when asked, Dr Sunderland said he had no outside deals. According to the December 22, 2004 LA Times, while reviewing financial disclosure reports from scientists at the NIH, in March 2000, ethics officer Olga Boikess noticed that Dr Sunderland had not declared any jobs with the industry so she sent him an e-mail that said: “You did not list any outside positions.”

To which, Dr Sunderland replied: “I do not have any outside positions to note.”

This case had been dragging on for years but the doctor has probably not been too worried because history shows that any time a Republican lawmaker get too pesky about the money trails leading to the NIH, Big Pharma simply offers enough money to induce him to jump ship.

A couple years ago, two Republicans on powerful committees switched sides shortly after they launched investigations into conflicts of interest between drug companies and employees at the NIH.

Representative, WJ “Billy” Tauzin (R-La), was chairman of the House Energy and Commerce Committee, and had cited “secret consulting fees and stock options from drug companies” as reasons to request documentation of all payments from Big Pharma to NIH scientists.

But next thing you know, Tauzin announces that he is not running for reelection, and leaves Congress to become President of the Pharmaceutical Research and Manufacturers of America, the giant trade group that represents Big Pharma, with a reported $2 million a year in salary, benefits and perks.

Next up to bat, was Representative James Greenwood (R-Pa), who led 3 hearings on NIH conflicts of interest and criticized the agency for allowing scientists to use “a swivel chair” to make decisions while taking drug company money.

But low and behold, shortly thereafter, in July 2004, Rep Greenwood announced that he was giving up his post as chairman of the Energy and Commerce subcommittee to retire, only to become President of the Biotechnology Industry Organization, a group that in the same year, urged lawmakers not to bar NIH scientists from entering into paid consulting deals.

A report by the Office of Government Ethics, released the same month that Rep Greenwood announced his “retirement,” said the NIH was beset by a “permissive culture,” and revealed that 40% of the 155 randomly selected sample payments to agency employees reviewed had not been approved or accounted for within the NIH.

The FDA remains at the top of the list for corruption simply because the FDA evaluates the safety and effectiveness of drugs and decides which drugs can be marketed in the US.

Typically, as a first step toward the approval process, a drug company will initiate laboratory testing to assess the effectiveness and safety of a drug and if the laboratory testing is successful, the company will begin testing the drug on animals. The FDA does not become involved until the drug maker seeks permission to test the drug on humans.

When the drug reaches that point, the FDA’s Center for Drug Evaluation and Research, evaluates the results of laboratory and animal testing prior to allowing any study on humans.

Once a drug is approved for testing on humans an Institutional Review Board (IRB) is appointed to review and monitor the research. An IRB is generally made up of outside scientists, doctors and other medical professionals and has the authority to approve or disapprove a study or to require modifications to secure approval of the research.

The purpose of an IRB is to assure that appropriate steps are taken to protect the rights and welfare of human subjects. To that end, an IRB uses a group process to review research protocols and materials such as informed consent documents and investigator brochures related to the research.

In recent years, serious questions have been raised regarding the impartiality of the review process due to the fact that many of the FDA advisors recommending approval of a product are at the same time employed by the drug company that developed the drug or hold some other financial interest link to the company.

Due to these conflicts of interests, critics say dangerous drugs are winning approval. For instance, nearly a third of the members of the advisory panel that reviewed the data on Vioxx, Celebrex and Bextra, and voted to allow the drugs to remain on the market, even after Vioxx had been pulled off the market, had financial ties to the makers of the drugs and had their votes not been counted, they would never have received a vote of approval.

In addition, problems continue to surface in the private research industry. Contract Research Organizations (CRO), are now hired by the industry to perform research.

Critics says the competing CROs are skewing research in favor of approval in order to win more contracts. The funding up for grabs is enormous. According to a March 24, 2006, MSNBC commentary by Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, “Private companies running studies for pharmaceutical and device companies are now a $14 billion industry in the United States alone.”

According to John Abramson, a clinical instructor at Harvard Medical School, and author of, “Overdosed America”, “When the institutional review boards were created, most medical research was conducted by universities and nonprofit institutions.”

“Similarly,” Mr Abramson says, “oversight of the safety of human volunteers in most U.S. studies is no longer done by nonprofit IRBs, but by for-profit review companies, hired directly by the for-profit research companies.”

In his opinion, he says the system lacks the appropriate checks and balances to protect human volunteers.

In the April 6, 2006 LA Times, Mr Abramson made a shocking revelation when he said, “the FDA recently approved “phase 0 studies” in which human beings can be given minuscule doses of experimental drugs even before animal studies are completed.”

A recent case in the UK demonstrates the dangers that could occur in such a study. In March 2006, six otherwise healthy men ended up in a London hospital in critical condition after participating in the trial of a new an anti-inflammatory drug, called TGN1412, to treat conditions involving the immune system, such as leukemia, multiple sclerosis and rheumatoid arthritis, conducted by the US based company, Parexel International Corp, on behalf of the German drug maker TeGenero.

The worst affected of the six men, Mohamed ‘Nino’ Abdelhady, called the Elephant Man because of the extreme swelling of his head, on April 5th, told the Daily Mail that he is plagued by nightmares.

Still recovering in the hospital at the time, he explained what he remembered. “I started to feel ill,” he said, “almost as soon as they had finished injecting me.”

“I felt as if I had rocks on my head,” he recalled, “and I must have started hallucinating.”

“Help me,” he told the newspaper that he screamed, “I’m dying.”

Ryan Wilson, the most critically ill man, begged doctors to put him to sleep because he was in such agony. His family was warned that his heart, lungs and kidneys failed.

His sister-in-law Jo Brown, recalled the horrific moment when they saw Mr Wilson in intensive care. She told reporters that his head had swollen to nearly three times its normal size, and that his neck was the same or wider than his head and that his skin had turned a dark purple.

Mr Wilson remained in a coma for three weeks, and upon awakening, learned that he may lose parts of his fingers and toes, which had turned black because of his reaction to the drug.

“I’m told it’s like frostbite and my fingers will just fall off,” he told the UK’s News of the World recently.

In addition, Mr Wilson also suffered from heart, liver and kidney failure, septicemia, pneumonia and dry gangrene and is considered very luck to be alive, according to News Target on May 20, 2006.

The Parexel research was at the Phase I stage, where a drug is tested for safety with a small number of people who are given a tiny dose under careful supervision, not to determine whether the drug works, but to check for side effects, according to Q&A Drug trials by BBC News on March 16, 2006.

Experts say the recruitment of subjects for the Parexel trial left much to be desired. The web site that announced the recruitment hardly mentioned the potential risks, but elaborated at great length about the good pay, free food and “plenty of time to read or study or just relax, with digital TV, pool table, video games, DVD player and free Internet access.”

Parexel also recruits by placing ads online or in local papers, where critics say, they draw the attention of the young and poor. Once on the books, recruits often get automatic offers. “The offers keep rolling in via text message,” Tom de Castella, a former Parexel volunteer said in the March 19, 2006 Times Online. “$650 for three days here, $1,000 for a week there,” he said.

Ethicists shown the Parexel consent form, which is supposed to describe the experiment and its risks, told Bloomberg News, “the document didn’t sufficiently inform participants of the therapy’s possible dangers or properly depict the treatment as a novel drug that can disrupt the body’s immune system.”

The 13-page form also exploited the subjects’ need for money, they said, by threatening to withhold the 2,000 pound ($3,500) payment if the men left the test early.

Highly questionable research recruitment techniques are also occurring in the US. On November 29, 2005, in Texas, CBS News channel 42 reporter, Nanci Wilson, revealed records showing that staff at state mental hospitals in Texas help recruit patients into studies of experimental drugs not approved by the FDA.

At a state hospital in San Antonio, CBS News found 16 beds set aside to allow drug companies to conduct studies on mental patients under the state’s care. CBS 42 asked Austin psychiatrist, Deborah Peel, to review some of the records they obtained.

Dr Peel said the situation raised serious questions as to whether this is moral and ethical treatment. “They are essentially turning the state hospital population into research subjects,” she noted.

Texas hospital officials claim the mentally ill patients give informed consent by signing a detailed form describing the risks and benefits of participating in the study. But Dr Peel says, “I think there are real questions how informed their consent would be under those situations, because these are not people who have the means to choose to go elsewhere for treatment, and so, there’s a powerful element of pressure, of coercion that they have to feel.”

“Once again,” Dr Peel points out, “we have people who have no means, who are dependent on the state system, and the state system is working hand-in-glove with private corporations.”

In many studies, CBS news investigators determined that patients had been taken off drugs that were working and in the new study, some patients were given the experimental drug while others received a placebo.

Critics point out that for patients taking a new drug, there is no guarantee it will work, and the risks and long-term effects are not known. “To take people off medication when they have just been admitted for an inability to function and might have even been a harm to themselves or others, that raises real questions for me,” Dr Peel told CBC News.

What’s worse, she says, is that patients are not told whether they are taking a placebo or a drug even when they are discharged from the hospital during the study. They could get suicidal, she said, or could harm others.

The FDA has ignored atrocities in research involving mentally ill subjects for years. Back in 1998, a review of the data on atypical antipsychotic drugs submitted to the FDA, obtained with FOIA requests by Robert Whitaker, revealed numerous safety problems for subjects who participated in the trials.

Mr Whitaker found that among 12,176 patients from the US and abroad at the time the data was submitted, there were 88 deaths, including 38 suicides, meaning there was an overall death rate of 1 out of every 138 patients, according to his article in the November 17, 1998 Boston Globe.

The suicide rate in trials was found to be 2 to five times higher than the norm. In the medical literature, Mr Whitaker reported, suicide rates for schizophrenics ranged from two to five deaths per 1,000 per year, while the rate in trials was close to 10 per 1,000.

In addition, he found that for the three approved drugs in the study – Zyprexa, Risperdal, and Seroquel – 60% of the 7,269 patients who received the drugs dropped out before the end of the study, which typically lasted six to 8 weeks.

In the 1990s the prospect of antipsychotic drugs gaining FDA approval, promised a major market for Big Pharma and therefore, drug companies needed to recruit trial subjects quickly. And drug companies were willing to pay top dollars to researchers for each patient recruited.

In the Boston Globe article, Mr Whitaker discusses a criminal case in Georgia that reveals just how far researcher are willing to go to meet recruitment goals.

Dr Richard Borison, chairman of the psychiatry department at the Medical College of Georgia, and Bruce Diamond, a pharmacologist on the school’s faculty, were favorites for schizophrenia drugs and demonstrated a knack for rounding up psychotic patients quickly for trials funded Eli Lilly, Janssen, Zeneca, and Novartis.

As faculty members, Borison and Diamond were supposed to get approval for research and payments for trials were supposed to go the school. But according to Georgia authorities, who indicted the duo in early 1997, in 1989 they started having the drug makers send payments directly to them.

They simply opened an office across from the school, hired a commercial service to do ethical reviews of their studies, and placed their staff on the school’s payroll but kept all the money for themselves.

As unbelievable as it may seem, the scheme worked for about 7 years. From 1989 to 1996, Borison and Diamond made over $10 million including more than $4 million from schizophrenia drugs, according to the indictment and testimony during an investigation by the Augusta Veterans Affairs Hospital, where Borison was chief of psychiatry.

And these guys were slick. To recruit the mostly male patients, they hired good-looking young women, who testified that they were paid bonuses that ran into the thousands, and one staffer was even given a Honda Accord.

To find their recruits, workers looked for mentally ill patients who were stable and living in the community and offered them $150 to check into the VA so they could be in a study. Patients already in locked wards were offered cigarettes to participate.

Study coordinators, many with no medical training, determined whether a patient belonged in a study. According to an FDA investigation, untrained staff drew blood samples and adjusted doses of the drugs, and Borison and Diamond hardly ever saw the patients at all.

But the two researchers lived high off the hog, according to Georgia authorities. They socked away more than $5 million in cash and securities, spent nearly a half a million on antiques and drove Mercedes-Benz vehicles.

But as the old saying goes, all good things must end. In December, 1997, Diamond pleaded guilty to theft and bribery charges and was fined, $125,000, sentenced to 5 years in prison, and ordered to pay $1.1 million to the college.

Borison pleaded guilty to theft and racketeering charges, was sentenced to 15 years in prison, fined $125,000, and ordered to pay $4.26 million to the college.

To cover all bases, over the years, Big Pharma has also become adept at corrupting the judicial process.

For instance, Dr Bruce Levine, PhD, Clinical Psychologist and author of, World Gone Crazy, tells a story about Eli Lilly corrupting the judicial process in a case that began in 1989 when Joseph Wesbecker opened fire at his former place of employment, killing 8 people and wounding 12 more, before committing suicide, a month after he began taking Prozac. The victims of the shooting sued Eli Lilly, claiming that Prozac had pushed the guy over the edge.

It has long been known that Prozac induces violence in some patients but the FDA never required Lilly to list violence on the drug’s label. But as it turns out, five of the 9 members on the 1991 FDA advisory panel investigating the association between Prozac and violence that voted against requiring a warning label for violence, had ties to Big Pharma and two of the members had served as lead investigators for Lilly-funded Prozac studies.

The Wesbecker trial did not take place until 1994, but in the meantime, according to Dr Levine, “Eli Lilly had been settling many Prozac violence cases behind closed doors.”

In fact, he says, more than 150 Prozac lawsuits had been filed by the end of 1994, so “it was looking for a showcase trial that it could win.”

A crucial component of the victims’ legal strategy in the Wesbecker case was for the jury to hear about Lilly’s history of reckless disregard toward consumers, especially about the drug Oraflex, introduced in 1982 but taken off the market 3 months later.

“A US Justice Department investigation linked Oraflex to the deaths of more than 100 patients,” Dr Levine notes, “and concluded that Lilly had misled the FDA.”

In the end, Lilly was charged with 25 counts related to mislabeling side effects and pled guilty.

At the Wesbecker trial, Lilly attorneys argued that the Oraflex information would be too prejudicial for the jury to hear and the Judge initially agreed. However, when Lilly attorneys used witnesses to testify about it’s superb system of collecting and analyzing side effects, the Judge said that Lilly had opened the door to evidence to the contrary and so the Oraflex information would also be allowed in.

However, to Judge’s amazement,” Dr Levine says, “victims’ attorneys never presented the Oraflex evidence and Eli Lilly won the case. “

It was later learned that Lilly was successful in corrupting the judicial process in the case by cutting a secret deal with victims’ attorneys to pay them and their clients not to introduce the damaging Oraflex evidence.

However, Dr Levine says, the Judge “smelled a rat” and fought for an investigation, and in 1997, Lilly quietly agreed to the verdict being changed from a victory to “dismissed as settled.”

Legal experts are finding ways to expose and punish Big Pharma for conducting fraudulent research that requires no involvement by the nation’s compromised regulatory agencies. Barry Turner, Lecturer in Law at Leeds Law School in the UK, is a great fan of the False Claims Act legislation in the US.

As an academic lawyer, he has for a number of years been involved in litigation regarding the activities of the pharmaceutical industry and for the past two years, he has been involved in Qui tam litigation preparation.

“Tying Qui tam into human rights and civil liberties issues is easy,” Mr Turner says. “When President Lincoln initiated this law in 1863 it was because Union soldiers were going into battle in shoddy boots and uniforms equipped with guns and ammunition that were third rate,” he explains. “All because ‘businessmen’ saw the war as a gravy train.”

“Qui tam,” Mr Turner explains, “protects taxpayers and since tax revenue is the lifeblood of any state, any evasion of liability or deliberate defrauding of a taxpayers is an attack on all taxpayers and consequently all citizens.”

Qui tam in its long history, he says, has brought to book many crooks who stole from the US taxpayer and is based on the individual citizen being able to blow the whistle for the benefit of fellow citizens and the country.

The more recent Sarbanes-Oxley Act of 2002 (SOX), was enacted in the wake of the Enron and WorldCom scandals, and was designed to restore investor confidence in the nation’s financial markets by improving corporate responsibility through changes in corporate governance and accounting practices and by providing whistleblower protection to employees of publicly traded companies who report fraud.

SOX contains a civil and a criminal whistleblower provision. Section 806, creates a civil cause of action for employees who have been subject to retaliation for whistleblowing, and Section 1107, makes it a felony for anyone to knowingly retaliate against or take any action harmful to any person, including interfering with employment, for providing truthful information relating to the commission or possible commission of a federal offense.

According to Mr Turner, SOX is not limited to shareholders of a company. “What needs to be understood,” he says, “is that many millions of people who own no stock at all get defrauded in scams all the time.”

“Those who pay into pension funds are vulnerable to the financial shenanigans not only of fund managers but of boards of companies,” he explains, “and CEO’s that fail to police the companies activities or in some cases actively encourage fraud and reckless business practices.”

SOX came into being to prevent those financial shenanigans, he says. “The fat cats may lose a small amount of their stake in any scam,” he points out, “but the little man as ever stands to lose all.”

One of the features of SOX, he says, is the ability to bring an action against those who recklessly and fraudulently deal with stockholders money. Big Pharma, and its handmaiden psychiatry, he notes, is built on fraud.

For example, Mr Turner explains, Ritalin fraud consists of labeling millions of children as basket cases based on fraudulent research and a consensus of the vested interest.

“SSRI fraud,” he advises, “extends depression into the world of normal human experience to ever-extend the peddling of the often useless and frequently dangerous treatments.”

In other instances, he says, many poor and elderly people are starved of life saving drugs because the budgets of Medicare and Medicaid are bled dry by claims from drug companies for ‘me too’ drugs that in many cases are superfluous.

“Even where there is some justification for the use of these drugs,” he explains, “there is a drive to constantly increase the dose above the minimum effective one because a ‘minimum effective dose’ to the drug company means minimum effective profit.”

“Where money is diverted from real healthcare provisions, to a profit greedy industry that manufactures an illness to fit the drug,” he notes, “rather than provide drugs for real illnesses, then the most fundamental of constitutional rights ‘Life, Liberty and the Pursuit of Happiness’ is most at risk.”

Every unnecessary dose of Ritalin, Prozac, Paxil, and other psychiatric drugs prescribed and paid for with US tax dollars, he says, deprives patients dependant on state healthcare programs of drugs they need for cancer, diabetes, heart disease and other serious conditions.

In addition, Mr Turner points out that, “the marketing of these drugs and the ever expanding definition of psychiatric disorder that is part of this marketing strategy labels, discriminates against, and stigmatizes hundreds of thousands of American Citizens.”

“It is indeed a dramatic irony,” he says, “that in very many of these cases the US taxpayer gets to fund an industry that acts in a manner so alien to the American Constitutional ideals.”

For purposes of the litigation, “knowingly” is defined as: (1) Actual knowledge of the false information; (2) Acts in deliberate ignorance of the truth or falsity of the information; or (3) Acts in reckless disregard of the truth or falsity of the information.

Therefore, according to Mr Turner, “inducing people to invest in companies that engage in illegal and reckless activity is a violation of SOX.”

“Inducing people to take vast amounts of drugs that are known to be harmful and deliberately hiding the known dangers is a violation of SOX,” he contends.

“One day this edifice will come tumbling down,” he says, “and what will the investors in Big Pharma say then?”

In light of the Vioxx disaster, Mr Turner says, we should perhaps ask people who invested in Merck.

“Those at the top of this company,” he notes, “gambled with the lives of patients and the money of stockholders in equal bad faith when they engaged in fraudulent and dishonest behavior that allowed a dangerous drug to be marketed.”

“Those who today peddle drugs for fictitious illnesses and push dangerous and useless medications on the children,” he warns, “in our societies are doing just this.”

Merck acted with reckless disregard for the truth because it had prior knowledge of the adverse effects of Vioxx. The same goes for Eli Lilly and its prior knowledge of the lack of efficacy of Prozac and GlaxoSmithKline’s knowledge of Paxil’s suicide ideation

While suppressing negative studies, these companies placed drugs on the market that were known to be faulty in one way or another. All of these drugs have cost taxpayers dearly, not to mention the personal suffering they have inflicted in other ways

In considering other acts of fraud, Mr Turner looked at the Pharma backed charities that are based on fraudulent research to see what Federal laws they may be violating.

“Since a number of imaginative illnesses are based on this fabricated research and since a number of charities are based on the ‘imaginative illnesses’ that arose out of the imaginative research,” he says, “its just a matter of connecting the dots.”

Because charities receive tax breaks, he says, fraudulent charities defraud US taxpayers.

“The fraud in this industry is not divided into that which injures by over drugging and that which cheats taxpayers and stockholders out of their money,” he explains. “They are two sides of the same counterfeit coin.”

Mr Turner says we must tackle them together, and that lawyers in the US should be actively seeking clients who have lost money by these frauds and getting the matter before the Security and Exchange Commission now.

Filed under: 2006, antipsychotics, Eli Lilly, NIH, NIMH, Parexel, Prozac, SOX, SSRIs, whistleblower

Merck Litigation Strategy – Destroy Expert Witnesses

May 22, 2006

Evelyn Pringle

Former Vioxx users could be at risk of developing strokes for years, a prominent scientist said this week after evaluating new data from a 107-page report on patients who were followed for a year after they stopped the drug

“It may be that Vioxx is causing permanent damage to the cardiovascular system, accelerating atherosclerosis or a sustained increase in blood pressure,” said Dr Curt Furberg, a professor of public health at Wake Forest University, and a member of the FDA Safety and Risk Management Advisory Committee, according to a report by Reuter’s news on May 18, 2006.

During his examination of the report, Dr Furberg determined that within the one-year follow-up of the APPROVE study, 7 Vioxx users had strokes, and 2 others had mini-strokes, compared with no strokes in patients taking a placebo.

“These data raise some very important questions because for a while we assumed Vioxx caused temporary problems, and here it is more than that,” Dr Furberg told Reuters. “It could be causing permanent damage.”

“In the past we weren’t quite sure of the stroke risk,” he added, “so stroke is now back on the agenda in a bigger way.”

Also this week the Wall Street Journal reported that heart attack risks for Vioxx users increase long before the 18 month period claimed by Merck. The new report is the 1-year follow-up to the APPROVE trial and includes a graph tracking “confirmed thrombotic cardiovascular events,” that shows that at four months of use, the number of CV events among Vioxx users began to outnumber those in patients who were given a placebo.

On May 18, 2006, CNN’s Moneyline reported that: “Merck is denying news reports that suggest new data from the drug maker indicates Vioxx increased heart attack risks earlier than previously reported and that the risk for stroke persisted long after the patient stopped taking the drug.”

But then when has it ever done anything but deny its wrongdoings?

This appears to be a month of reckoning for Merck because another study published earlier this month in the online edition of the Canadian Medical Journal, Queen’s University researcher Linda L’vesque, along with James Brophy and Bin Zhangat at McGill University in Montreal Canada, found that 25% of Vioxx users who suffered a heart attack did so within 14 days of taking the first dose.

What this all means to Merck’s legal team is that the stakes are getting higher and the company’s SEC filings indicate the drug giant knows it.

Last year, Merck had listed a reserve of $675 million for legal defense expenses related to Vioxx; but in January 2006, the company announced that it had increased the fund by $295 million to cover legal costs through 2007.

According to Merck’s SEC filings, in 2005, the company had worldwide sales of $22 billion, compared to $22.9 billion for 2004. Total sales decreased 4% for the year, which Merck says, reflects a decrease of 7% related to the VIOXX withdrawal, offset by revenue growth in all other products of 3%.

Included in marketing and administrative expenses, the company noted reserves solely for future legal defense costs for Vioxx litigation recorded in the 4th quarter of 2005 and 2004, of $295 million and $604 million, respectively, as well as $141 million associated with the withdrawal of Vioxx recorded in 2004.

According to a January 31, 2006 Merck press release, there are “9,650 lawsuits, which include approximately 19,100 plaintiff groups alleging personal injuries resulting from the use of VIOXX.”

In addition, another 3800 plaintiffs have signed tolling agreements, meaning they have cut a deal with Merck to forego suing in the short term; but should Merck start losing Vioxx lawsuits in marginal cases, attorneys say, those thousands are likely to multiply.

There are also numerous lawsuits filed against Merck for claims other than personal injuries. For instance, the Attorney General of Texas, Greg Abbott, has filed a lawsuit seeking $250 million, accusing Merck of defrauding Texas citizens by representing Vioxx as safe when applying for the drug’s approval to be included on the state’s list of drugs approved to be covered for patients on Medicaid.

According to the lawsuit’s complaint, Merck’s failure to disclose the harmful effects of Vioxx, while offering it to the state’s Medicaid program as a safe painkiller, violates the Texas Medicaid Fraud Prevention Act and the Texas Medicaid program reimbursed pharmacists $56 million for Vioxx prescriptions over a five-year period.

In another case, on March 31, 2006, a New Jersey court of appeals upheld a class action lawsuit against Merck filed by private insurers and HMOs, as third-party payors, under the New Jersey Consumer Fraud Act, to recover losses incurred in purchasing Vioxx for their health plans.

The appellate court ruled that Judge Carol Higbee of New Jersey Supreme Court properly exercised her discretion in certifying a nationwide class. “New Jersey’s contacts with this dispute are both extensive and weighty,” the appeals court said, noting the fact that Merck was a New Jersey corporation and that most of Vioxx-related research and marketing efforts took place in the state.

“Given the confluence of New Jersey contacts and interest,” the court stated, “choosing New Jersey as the site for this nationwide class action is not unconstitutionally ‘arbitrary or unfair'”.

On July 29, 2005, Judge Higbee had granted a motion by the International Union of Operating Engineers Local #68 Welfare Fund, a labor union health plan, to allow the lawsuit to proceed as a nationwide class action, based on allegations that Merck engaged in widespread and systematic concealment of data concerning the safety and health risks of Vioxx.

“This Court,” the judge wrote, “sees no reason why the duty to be honest about the safety and usefulness of a drug when marketing it as a product for sale should not extend to the third party payors who actually pay for the purchase of drugs for members.”

Chris Seeger, the lead attorney for the union health plan, states that “the decision applies to all non-governmental third-party payors in the country, including health insurers, unions, and large employers, who paid for Vioxx prescriptions for their plan members.”

“The decision,” he says, “also allows for all such third-party payors in the country to prosecute their allegations of being misled by Merck’s misrepresentations and concealments concerning Vioxx in one class action, rather than in a multitude of individual actions.”

The plaintiffs contend that had they been properly informed of the facts, they would not have included Vioxx on their lists of approved drugs or reimbursed their members for its high cost. In this type of case, the plaintiffs do not have to prove Vioxx caused any injuries or deaths. All they have to prove is that Merck continued to push the sale of the drug after it knew of the increased risks it posed.

Besides recouping costs of purchasing Vioxx for their plan members, if successful, the third-party payors would be entitled to triple damages under the New Jersey Consumer Fraud Act.

That said, Merck must have a lot confidence in its legal team because it reportedly has not reserved any money for liability. Which means it probably plans on using the same trial strategy that has proven somewhat effective so far.

Search out and destroy the credibility of the expert witnesses who might testify for the plaintiffs.

Several of the most feared witnesses provided a preview of their testimony at a November 18, 2004, hearing before the Senate Finance Committee, where the topic was focused on whether the FDA and Merck had failed to protect the public against Vioxx.

In his opening statement, the chairman of the committee, Senator Charles Grassley (R-Iowa), set the parameters for what he called the biggest drug disaster in US history.

“Merck acknowledged that Vioxx carried with it serious cardiovascular risk,” he told the audience, “when it withdrew the drug from the market.”

However, he explained, during “today’s hearing we will hear about the red flags that were raised about those risks in the years before and the years after Vioxx was approved by the Food & Drug Administration.”

The star of the hearing was FDA whistleblower, Dr David Graham, who told the panel that his superiors at the FDA tried to suppress the results of a recent study that determined that Vioxx at low doses was associated with a 50% increase in the risk; and doses of greater than 25 mg a day showed a 370% increase in the risk of heart attacks.

In reviewing the documents on the Vioxx-related studies, a strange coincidence appeared. As it turns out, the report for the above study, authored by Dr Graham, has the exact same date, September 30, 2004, that Merck supposedly “voluntarily” took Vioxx off the market and it says it was sent to Paul Seligman, MD, then acting director of the FDA’s Office of Drug Safety.

“Disturbingly,” Dr Graham wrote in the report, “while evidence of increased cardiovascular risk with rofecoxib continued to accrue following VIGOR in 2000, the only study to examine the gastrointestinal benefits of rofecoxib compared to celecoxib found that the risk of hospitalization for gastrointestinal bleeding was significantly increased in patients treated with rofecoxib.”

“Additionally,” he continued, “this reviewer was unable to identify articles demonstrating a substantial benefit with the high-dose strength of rofecoxib that would counter-balance the level of cardiovascular risk shown in VIGOR or any subsequent observational study, including this one,” he wrote.

Dr Graham’s report and testimony at the hearing led many doctors and scientists, at home and abroad, to conclude that the FDA was in large part responsible for the deaths of tens of thousands of Americans, because it allowed Vioxx to remain on the market for years while Merck made billions of dollars off the sale of the drug.

Critics liken the rise and fall of Vioxx to a masterful public relations coup of aggressive marketing and ineffective regulation. In the months following the hearing, Merck and the FDA, came under attack from experts all over the world. Two months after Vioxx was pulled off the market, Dr Richard Horton, editor in chief of the British medical journal Lancet, wrote: “With Vioxx, Merck and the F.D.A. acted out of ruthless, short-sighted, and irresponsible self-interest.”

Other experts demanded an explanation. A team of scientists from the University of Berne, Switzerland, expressed distain in the December 2004 Lancet saying: “Our findings indicate that Vioxx should have been withdrawn several years earlier.”

“The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified,” they said.

In the weeks following the hearing, Dr Graham was interviewed on a series of TV news programs and was also featured in articles in USA Today, Newsweek, the Wall Street Journal, and the Washington Post, leaving a trail of ammunition for attorneys to use in court as far as Dr Graham’s opinions.

However, federal judge Eldon Fallon dealt Merck a major blow in April 2006, when he ordered Dr Graham to testify in a deposition for the Vioxx multidistrict litigation proceedings in response to subpoena issued by attorneys for the plaintiffs.

In addition to Dr Graham, the equally forthright expert witness, Dr Gurkirpal Singh, MD, Adjunct Clinical Professor of Medicine at Stanford University School of Medicine also testified at the November 18, 2004, hearing through a video conference due to health problems.

Dr Singh is a rheumatologist by training with research expertise in drug safety and epidemiology. For the hearing, Dr Singh was asked to review internal company documents and emails between Merck scientists and executives that had been subpoenaed by Congress.

Dr Singh began his testimony by pointing out that as far back as 1996, Merck was already considering the possibility that a clinical trial of Vioxx versus a non-selective NSAID, would find that patients treated with Vioxx would have an increased risk of cardiovascular complications.

“We now know that by November of 1996,” Dr Singh told the panel, “Merck scientists were seriously discussing a potential risk of Vioxx – association with heart attacks.”

At that time, he said, it was not known that Vioxx could cause heart attacks, but the discussion focused on the issue that by inhibiting platelets, other painkillers may protect against heart attacks. Vioxx has no effect on platelets, and thus may seem to increase the risk of heart attacks in studies comparing it to other painkillers, he said.

“This was a serious concern because the entire reason for the development of Vioxx was safety,” he explained. “If the improved stomach safety of the drug was negated by a risk of heart attacks,” Dr Singh said, “patients may not be willing to make this trade-off.”

“Merck scientists,” he told the committee, “were among the first to recognize this.”

“At this point in time,” he said, “scientists should have started a public discussion about this potential trade-off, and designed studies that would more carefully evaluate the risk-benefit ratio of the drug.”

“It appears from the internal Merck e-mails provided to me,” he advised, “that in early 1997, Merck scientists were exploring study designs that would exclude people who may have a weak heart so that the heart attack problem would not be evident.”

“Clinical trials should be designed to test a drug under “real world” circumstances – on patients who are most likely to use the drug,” Dr Singh told the panel.

“Clinical trials should not be designed,” he said, “to selectively favor one outcome over another by excluding people similar to those who would take the drug after its approval.”

“Certainly,” he continued, “clinical trials should not be designed to put marketing needs in front of patient safety – we need to know how a drug behaves in people who are going to take it, even if it “kills the drug”.

Referring to documents provided to him by the Committee, Dr Singh said, “there were many other internal discussions within Merck on these concerns of heart attack-stomach bleed trade-offs, although the practicing physician did not learn of any of this till many years later,” he added.

For instance, one document in 1998 authored by Merck scientist, Dr Doug Watson, presented an analysis of serious heart problems with Vioxx compared to patients enrolled in studies of other Merck drugs and concluded that in women, the risk of heart problems was more than double compared to people not taking any drug in other studies.

“To the best of my knowledge,” Dr Singh said, “these data were never made public.”

“This is when a public scientific discussion of the pros and cons of the medication should have started,” he told the committee.

By 1999, he said, more serious problems were emerging. “By the time Merck had filed for the approval of Vioxx,” he informed the panel, “there were several small studies evaluating the efficacy and safety of Vioxx in patients with pain and arthritis.”

“None of these studies were large enough to study the risk-benefit trade offs of stomach bleeds versus heart attacks,” he explained.

But in a careful review of Merck’s FDA drug application for Vioxx, he told the panel, “Dr. Villalba noticed that “thomboembolic events are more frequent in patients receiving VIOXX than placebo…”.

The review showed that among 412 patients taking a placebo, only one had a cardiovascular event; but among the 1631 patients receiving 12.5 mg or more of Vioxx, 12 had a cardiovascular event.

This meant that not only did Vioxx not inhibit the platelets, Dr Singh said, but for some reason, it was likely to promote heart attacks. “Many scientists would consider this three-fold difference as an early warning sign,” he explained.

“It is my opinion,” he told the panel, “that at this point in time, larger and more definitive studies should have been done before the drug was approved.”

Dr Singh noted that Vioxx was no more effective than any other available pain-killer and at the time, there were nearly 30 such drugs on the market in the US. Celebrex, he said, had no such risk and had been available for 6 months prior to Vioxx.

“There was certainly no emergent need to approve Vioxx without further studies if there were lingering safety concerns,” he said. “The trade-off of heart attacks for the rare instances of stomach bleeds,” he advised, “is not a reasonable one.”

But instead, he reminded the panel, “the drug was approved by the FDA in a priority review within 6 months – with no discussion on the heart attack trade-off.”

“The prescribing physicians,” he noted, “remained unaware of any of these data or discussions, till much later – with the new label change in April, 2002.”

Dr Singh explained, that the VIGOR study was the first public release of information about the heart attack-stomach bleed trade-off. The 500% increase in the risk of heart attacks found in VIGOR stunned him, he said.

At the time that the results were announced, Dr Singh said he was involved in teaching and some of his educational lectures were sponsored by Merck. “I was strongly in favor of this new class of drugs,” he explained, “and before the VIGOR trial, was unaware of any significant heart attack issues.”

Merck’s press release on the study, with a brief mention of the heart attack risk was not enough for him to continue to educate doctors in his lectures Dr Singh said, so he asked Merck for more detailed data, and when he was unable to obtain the information after multiple requests, he added a slide to his presentation that showed a man – representing the missing data – hiding under a blanket.

Up until this time, Dr Singh said, Merck had responded to all of his requests promptly. But when he persisted in his enquiries, he told the committee, “I was warned that if I continued in this fashion, there would be serious consequences for me.”

“I was told that Dr. Louis Sherwood, a Merck senior vice-president, and a former Chief of Medicine at a medical school, had extensive contacts within the academia and could make life “very difficult” for me at Stanford and outside,” he testified.

And as it turns out, Dr Sherwood did call Dr Singh’s superiors at Stanford University to complain.

However, documents that have surfaced in litigation over the past couple of years, reveal that Dr Singh had no idea how important he had become in the minds of Merck officials.

The documents show that for most of June 2000, Merck officials had their heads together trying to come up with a plan to rein in Dr Singh. He presented a major problem because he was widely respected at the FDA and also had connections with large institutional buyers that were vital to Merck sales.

On June 5, 2000, Merck senior business director, Terry Strombom, sent an email that shows Merck found itself caught between a rock and a hard place. “The one thing I am pretty sure of is that Dr. Singh could impact us negatively if he chose to do so,” he wrote. “I would recommend we handle this very carefully… I just don’t think canceling all the programs and walking away completely will serve us well in the long term,” he said.

Another email shows one official acknowledging that Dr Singh’s criticisms about Vioxx were valid. On June 5, 2000, Heather Robertson, a coordinator of health education projects, reported a conversation with Dr Singh’s contact at Merck, (who had since left the company) in an email that said:

“I spoke to Kirsten directly for the first time this past week to learn that Dr. Singh makes a balanced presentation (he must since he is an FDA advisor) but reports product information that is not favorable to Merck… Kirsten feels that no amount of work would change Dr. Singh’s position, and although we may not like to hear about it, his information is scientifically accurate.”

On June 19, 2000, a marketing manager, Susan Baumgartner, wrote an email saying: “Dr. Singh continues to play up the cardiovascular adverse events associated with Vioxx… I think there are many other speakers who deliver good messages, and we should not risk supporting the negative messages that he continues to deliver.”

Merck also had a high-tech surveillance system in place in the medical community where doctors, many with financial ties to Merck, would contact the company whenever they heard criticism. A July 21, 2000, memo reads: “Communication from advocate regarding a program given by Dr. Singh… It was hyper-inflammatory.”

A July 2000 document shows that Merck even knew about the cartoon he used in his lectures and reads: “Received reports that Dr. Singh showed a cartoon of a character hiding under a blanket and asked the audience to speculate about what it is that Merck is trying to hide.”

Other documents show sales reps were gathering information as they made their rounds to doctors’ offices and would use voicemail to relay the data to Merck’s National Service Center. A July 26, 2000 memo reads: “NSC report that at nine meetings in the L.A. area over the last three days, Singh presented sessions that were very unfavorable to Vioxx.”

Around this same time, Dr Singh made his concerns about Vioxx known to one of Merck’s largest Vioxx buyers, the Department of Veterans Affairs. Reportedly it was at this point that Dr Sherwood elevated himself to the director of damage control and a detailed report began to be compiled on Dr Singh’s activities, with nearly a dozen Merck executives involved.

An October 4, 2000 memo, by a senior regional executive states: “I have in excess of 80 e-mails pertaining to interactions with Dr. Singh from March 1999 to present. The following is my best recollection of what has happened. Because of the sensitive nature of the following, I strongly encourage you not to share with anyone unless they clearly have a need to know.”

Less than a month later, Dr Sherwood called Dr Singh’s boss at Stanford University, Dr James Fries.

“I don’t usually receive phone calls on a Saturday at home from representatives of drug companies,” Dr Fries said during an interview with National Public Radio, of a call he received from Dr Sherwood on October 28, 2000. “So it was definitely unusual,” he said.

Dr Fries told NPR he received a call “stating that someone on my staff had been making wild and irresponsible public statements about the cardiovascular side effects of Vioxx.”

According to Dr Fries, Dr Sherwood hinted there would be repercussions for Stanford if Dr Singh did not stop making negative statements about Vioxx and he was left with the impression that Merck’s financial support to Stanford University was at risk.

Back at Merck, on November 17, 2000, apparently believing his efforts were successful, Dr Sherwood wrote an email to the marketing department that said: “Fries and I discussed getting Singh to stop making the outrageous comments he has in the past few months… I will keep the pressure on and get others at Stanford to help.”

In another email, he specifically directed one Merck executive to pressure Dr Singh himself. “Tell Singh that we’ve told his boss about his Merck-bashing,” he wrote. And tell him, “should it continue, further actions will be necessary (don’t define it.),” he said.

However, after speaking to Dr Sherwood, Dr Fries told NPR he started making calls of his own and learned that Dr Sherwood had called 7 other institutions, including the University of Minnesota, the University of Texas Southwestern and a Harvard teaching hospital, where researchers had raised concerns about the safety of Vioxx.

After Dr Fries learned about those calls, he wrote a letter to Merck CEO, Raymond Gilmartin, and questioned the propriety of Dr Sherwood’s calls in what Dr Fries referred to as, “a consistent pattern of intimidation of investigators by Merck.”

The letter included the warning: “There is a line that you can’t go across. … It had gone over that line.”

In response to questions from his boss, on January 23, 2001, Dr Sherwood wrote a memo saying there was no “orchestrated campaign or specific program” to deal with “problem individuals.”

But then he went on to discuss how he only gets involved if other Merck department heads are unsuccessful in their attempts to “balance” critics. “I will only get involved when our representatives… regional medical directors, Merck research lab physicians… or key individuals in the therapeutic business group have felt frustrated by their inability to reach out or to ‘balance’ selected individuals,” he wrote.

And he boasted about his own importance in dealing with officials at Universities. “Without trying to appear immodest,” Dr Sherwood wrote, “I believe I am the most respected physician in the pharmaceutical industry among academic chairs and deans…”

“Therefore,” he continued, “when I call them on a matter of urgent concern, they generally take it seriously… This has been a source of strength… as I have been able to exert balanced leverage in some difficult situations.”

This slew of internal documents have become a real problem for Merck’s legal team. In fact, in the first Vioxx jury trial decided on August 19, 2005, where a Texas jury awarded the widow of a Vioxx user $253.5 million, the plaintiff’s attorney, Mark Lanier, used many of them to show jurors how hard Merck worked to silence doctors like Dr Singh and the back and forth letters between Merck’s CEO and Dr Fries were very effective in accomplishing that task.

Prior to the trial, in June 2005, Merck’s legal team filed a motion with the court in a feeble attempt to suppress the leaked documents claiming a story in the “national media” had revealed a privileged attorney-client communication that could prejudice a jury against Merck after the Associated Press reported that Merck scientists had contacted company lawyers in 2000 about reformulating Vioxx over concerns it could cause cardiovascular problems.

So anyways, on November 18, 2004, when Dr Singh told the Senate committee, “I learnt that this was a persistent pattern of intimidation by Dr. Sherwood,” he obviously did not yet know the half of it.

But he did say that the harassment stopped after Dr Fries wrote to Merck’s CEO.

Dr Singh told the committee that he had objected to the way Merck published the results of the VIGOR study in the New England Journal of Medicine, because it minimized the significance of heart attacks, but prominently discussed the reduction of stomach bleeds in patients taking Vioxx.

He pointed out how Merck did not mention that patients on Vioxx had more serious adverse events, and more hospitalizations than patients on Naproxen.

But Merck’s misdeeds included more than omissions. Company documents obtained during the congressional investigation, show that in April 2000 Merck developed a “Cardiovascular Card,” and Merck’s sales reps were instructed to refer doctors who raised questions about cardiovascular risks to the card, which claimed that Vioxx was eight to 11 times safer than other similar painkillers.

The card made no reference to the VIGOR study and even though an FDA advisory committee had voted that doctors should be informed of the finding of the VIGOR study in 2001, Merck subsequently sent a memo to sales reps that stated, “Do not initiate discussions of the FDA arthritis committee… or the results of the… VIGOR study.”

In addition, sales reps were told to respond to doctors’ questions about the study by saying, “I cannot discuss the study with you”

In closing his testimony, Dr Singh said, he was especially annoyed when a few weeks before the November 18, hearing, “Merck announced that the published VIGOR data was “preliminary” and that the “final” data was presented to the FDA.”

“To the best of my knowledge,” he said, “the VIGOR paper did not indicate anywhere that the data were preliminary or incomplete.”

“Nor, did I ever see a correction or erratum indicating this fact,” he advised the panel, “up until a few weeks ago, almost 4 years later.”

He also criticized the fact that it took the FDA 2 years to add the heart attack risks to the Vioxx label, and noted that even then, the change supported mostly Merck’s position, not the one advanced by FDA’s own reviewers in public hearings.

“The FDA should regulate the drug companies,” he advised the panel, “not collaborate or negotiate with them if there is any question of public safety.”

Dr Singh also told the committee that it was important to recognize that the APPROVE study that led to the Vioxx withdrawal from the market, was not a safety study, it was an efficacy study, designed to add another indication for Vioxx treatment.

It was not a large enough study to detect a heart attack risk, he explained, “that it did find a risk was a lucky break for patients,” he said, “but this is not what it was designed to do.”

In addition, he told the panel that the FDA approval process needs to be open and subject to public scrutiny and that once a drug is approved, all the data supporting its approval should be put in the public domain.

And since an FDA reviewer had concerns about heart attacks before its approval, Dr Singh said, the FDA could have provided a conditional approval that would have required Merck to complete large safety studies within a certain time frame.

“The failure to conduct large long-term safety studies,” he told the committee, “subjected millions of patients over 4 years to a drug whose safety had been questioned by the FDA even before its approval.”

“This is not the proudest chapter in drug approval in the US,” he concluded.

A group of 12 attorneys, who were appointed by Federal District Judge Eldon Fallon to manage pretrial discovery for all federal lawsuits, has developed a Vioxx trial package that includes a guide for pursing a lawsuit against Merck and contains all the damaging documents and evidence available against the drug giant.

The package also includes parts of video statements made by top Merck officials, and courtroom slides with text and visuals.

It also includes the videotaped deposition testimony of expert cardiologist Dr Eric Topol, one of the first experts to raise questions about the safety of Vioxx and the first expert witness to experience the power of Merck’s wrath.

Shortly after learning that Vioxx had been recalled, in October 2004, Dr Topol, wrote an oped for the New York Times, and posted a column on the New England Journal of Medicine’s web site, and called for a congressional review of what he called the Vioxx “catastrophe.”

“The senior executives at Merck and the leadership at the FDA,” he wrote, “share responsibility for not having taken appropriate action and not recognizing that they are accountable for the public health.”

A little over a year later, Dr Topol, testified in a videotaped deposition, first played at a Houston jury trial on December 3, 2005, and said that Vioxx posed an “extraordinary risk,” and that he had urged Merck to conduct more trials.

Dr Topol said that after the 2000 VIGOR study showed patients using Vioxx faced an increased risk of a heart attack, he began his own evaluations after finding “discrepancies” between Merck’s studies and the data submitted to the FDA.

After analyzing 3 Vioxx studies, Dr Topol said he found patients began experiencing higher rates of heart problems “four to six weeks after the start of taking Vioxx.”

“There was not any question about” the link between Vioxx and heart ailments, he told the jury.

Dr Topol, testified that 3 years before the drug was pulled off the market, he and two colleagues published a paper in the Journal of the American Medical Association that raised the issue of whether Vioxx caused heart problems.

Dr Topol pointed out that although they published clear warnings about the cardiovascular risk in 2001, the FDA never ordered a trial to determine the extent of the problem and said Merck countered the JAMA article with a “relentless series of publications” and numerous papers in peer-reviewed medical literature written by Merck employees and consultants.

During his testimony, Dr Topol told the jury how a colleague at the Cleveland Clinic, Richard Rudick, had informed him that Raymond Gilmartin, the former CEO of Merck, had called the Cleveland Clinic board of trustees and complained about Dr Topol in mid-October 2004, after he criticized Merck’s handling of the Vioxx situation in the New York Times and New England Journal of Medicine.

He described how Mr Gilmartin called the chairman of the board, and said “what has Merck ever done to the Cleveland Clinic to warrant this?’

Dr Topol told the jury that Mr Gilmartin’s approach “appalled” him.

Two days after his deposition was played in court, Dr Topol found himself removed as provost and chief academic officer at the Cleveland Clinic medical school.

According to Dr Topol, he was told early in the morning not to attend a meeting of the clinic’s board of governors, because the position of chief academic officer had been abolished.

Dr Tope was somewhat vindicated later in December 2005, with the publication of an “Expression of Concern” by the editors of the New England Journal of Medicine, that charged that the VIGOR, published in the journal in 2000, was submitted to the journal after data on 3 heart attacks and other cardiovascular events among trial participants was deleted by Merck.

According to an article by Amanda Gardner in Health Day Reporter, right after Vioxx was removed from the market, the editors opened a computer diskette that had been submitted with the study and found a blank table with no data – lines had been drawn but not filled in.

“They did not know what should have been in there,” Sandra Jacobs, a spokeswoman for the NEJM said. “It raised some concern, but we didn’t know enough to act on it,” Jacobs added.

On November 21, 2005, Ms Garner says, NEJM’s executive editor, Dr Gregory Curfman, was deposed for a Vioxx trial and during the process, a July 5, 2000 memorandum came to light that indicated that at least 2 of the VIGOR authors knew of the problems 2 weeks before submitting the first of two revisions, and four-and-a-half months before the study was actually published.

Dr Curfman told HealthDay that electronic records showed “a pre-submission version of the study from which data, including the number of heart attacks and deaths, were deleted by a Merck editor two days before submission.”

As a dedicated scientist and health practitioner with nothing to gain, in hindsight, it appears that Dr Topol certainly paid a high price for committing the simple act of truth-telling to protect the public from a dangerous drug and its pusher.

As a small law firm practitioner turned legal reform activist, Attorney Zena Crenshaw is highly critical of Merk’s debilitating cross examinations of experts who essentially claim the company recognized Vioxx’s potential cardiac risks before it went on the market.

Ms Crenshaw is the Executive Director for National Judicial Conduct and Disability Law Project, Inc, a legal reform organization combating abuses of the American legal system that are facilitated by judicial misconduct.

She explains that such is a signature tactic of “mega-corporations” that it seems only “mega-lawfirms” and governmental agencies can neutralize.

Ms Crenshaw says, “the grueling questions help liken American courts to the playgrounds of bullies.”

“Some prescription drug manufacturers,” she says, “clearly bully scientists who challenge their products and ethics.”

“To survive the ordeal emotionally and with credibility intact,” Ms Crenshaw advises, “witnesses for alleged victims need to become smooth courtroom actors, as well as experts in their fields.”

“If the process is not appropriately bridled by judges,” she notes, “the “search for truth” will have much less to do with American jurisprudence than the “quest to win”.”

Merck’s SEC filings on April 27, 2006, list the following upcoming Vioxx trial dates:

Doherty New Jersey Superior Court, Atlantic County June 5, 2006

CA Coordinated California Superior Court, Los Angeles County June 21, 2006

Barnett Eastern District of Louisiana (MDL) July 24, 2006

Kozic Florida Circuit Court, Hillsborough County July 31 – August 25, 2006

Anderson Tribal Court of the Mississippi Band of Choctaw Indians August 7, 2006

Hatch / McFarland New Jersey Superior Court, Atlantic County September 11, 2006

Smith Eastern District of Louisiana (MDL) September 11, 2006

Crook Alabama Circuit Court, Jefferson County, October 26, 2006

Mason Eastern District of Louisiana (MDL) October 30, 2006

Miller or Rigby Texas District Court, Harris County, November 8, 2006

Dedrick Eastern District of Louisiana, (MDL) November 27, 2006

Filed under: 2006, FDA, FDA hearing, Graham, MEDICAID, Merck, NSAIDs, stroke, Vioxx, whistleblower

Merck Caught Misrepresenting Vioxx Risks Again

May 17, 2006

Evelyn Pringle

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.”

Filed under: 2006, FDA, FDA Crawford, FDA hearing, GAO, Graham, Judge Fallon, Merck, NSAIDs, Vioxx, whistleblower

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Status: 76% AGAINST S. 324 The MOTHERS Act. Vote & Comment.

UNITE ARCHIVES – Join the Coalition Against The MOTHERS Act on Facebook!

3,271 Facebook Members and Counting!

UNITE ARCHIVES – Stop The Dangerous and Invasive MOTHERS Act!

13,500 Signatures and Counting!

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