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Articles Criticize Merck on Vioxx
Merck and Co., Inc. engaged in a series of deceitful actions that led to an underestimation of deaths caused by its blockbuster drug Vioxx during post-marketing research of the pain reliever, according to two articles in a medical journal that used documents released by Merck in lawsuits against the pharmaceutical giant.
The articles in the Journal of the American Medical Association, or JAMA, stated that Merck failed to disclose damaging information about death rates in Vioxx patients, and paid academic researchers to put their names on papers they did not write. In one case, the company probably should have stopped a trial because of a clear signal that patients on the drug were dying of heart attacks at higher rates, the authors said.
Merck reacted angrily to the articles. In a news release, Merck said that a careful analysis of the data at the time of the studies gave no indication the extra deaths were caused by the drug. It claimed the JAMA report’s conclusions are “false, misleading or lack context.” The company complained that it was unable to comment on the reports before their publication.
Noting that Merck has one of the best reputations in the drug industry, the authors suggested that such practices may be common among pharmaceutical companies. The disclosure of these actions point to the need for changes in the way that drug research is conducted and monitored by the Food and Drug Administration, they wrote. The articles come at a time when the FDA is regarded as critically short of manpower to carry out its regulatory functions.
In an editorial accompanying the articles, the JAMA editor-in-chief Catherine DeAngelis and her deputy, Phil Fontarosa, say the disclosures in the Vioxx case point to widespread problems that threaten to “erode the ethical foundation of medicine and medical research.”
“The profession of medicine, in every aspect—clinical, education and research– has been inundated with profound influence from the pharmaceutical and medical device industries,” the JAMA editors wrote. “Manipulation of studies by the pharmaceutical and medical device industry is either increasing or there has been more exposure of these practices. This has occurred because physicians have allowed it to happen, and this has to stop. Primum non nocere (“first do no harm”) does not hold true only for physicians directly treating patients.’’
Vioxx, one of three major COX-2 inhibitors, which are compounds that used a new biological pathway to fight pain, went on the market in 1999 and earned as much as $5.2 billion a year in sales. Merck pulled the drug off the market in 2004. FDA analysts estimate that the drug caused between 88,000 and 139,000 heart attacks, about a third of them fatal, in the five years it was on the market. Merck in November paid $5 billion to settle most of the tens of thousands of lawsuits.
Controversy has swirled over which company officials, FDA officials and journal authors and editors knew what, and when, about the severity of the drug’s problems. Both JAMA articles were the product of internal documents on drug studies conducted by Merck that it released in discovery for thousands of lawsuits.
In the first article, Bruce Psaty and Richard Kronmal of University of Washington found that in an April 2001 analysis of two trials of Vioxx for the prevention of Alzheimer’s disease, company officials found a three-fold risk of death in the patients who took the drug compared to those who took a sugar pill placebo. The three-fold risk was based on examining records of patients on the drug and those who had used it in the previous two years.
However, Merck did not provide this internal analysis to the FDA, according to the authors. In July 2001 it submitted a different analysis that reviewed only patients still on the drug. This number was believed to have underestimated the drug’s harm because it shortened the time patients were under observation, and missed those who dropped out of the trial after suffering side effects.
In that analysis, Merck reported 29 deaths (2.7 percent) out of the 1067 patients on Rofecoxib, the drug’s technical name, and 17 (1.6 percent) of the 1075 on placebo. Based on these numbers, Merck declared the drug “generally well-tolerated.” In December 2001, the FDA raised questions about the data, but Merck did not bring them to the study’s Institutional Review Board for examination, the authors wrote.
Some of the authors involved in the JAMA reports have worked as expert witnesses for plaintiffs in the Merck lawsuits. “We are disappointed that such false and misleading statements about Merck from trial lawyers have made their way into a medical journal,” said Peter Kim, president of Merck Research Laboratories.
In the second study, Joseph S. Ross of the Mount Sinai School of Medicine and his co-authors found in a review of Vioxx safety studies that Merck scientists often wrote the articles or hired one of two professional journal writing companies, then paid academics fees of up to $1,500 to review the work and be listed as senior authors. The journal-writing companies were never credited for their roles. The academics never disclosed the fee-for-service nature of their work, and sometimes didn’t even disclose any financial relationship with Merck.
Worse things may be going on at other drug companies, the authors wrote. “Access to industry documents through litigation presents a rare opportunity to explore the relationship between the medical profession and the pharmaceutical industry. Our case-study review suggests that inappropriately attributing authorship was common.”
The authors elaborated a list of 11 measures that would make publication of journal articles more transparent, with more disclosure about who actually did the work or wrote a paper, and requirements for outside statistical analysis in papers funded by industry.
CDC Aims to Appease Vaccine Critics
One autistic girl — a 9 year old from Atlanta whose illness is linked to an underlying medical condition — has suddenly shifted the debate on the possible link between vaccines and autism. It’s not that Hannah Poling’s case significantly alters the evidence. But it has introduced uncertainties that pose a logical stumbling block for officials defending vaccines.
This has created a defensive posture in the Dept. of Health and Human Services, which was already struggling to maintain parental confidence in vaccination amid a number of small measles outbreaks around the country.
Illustration by: Matt Mahurin
On Friday, the Centers for Disease Control’s Immunization Safety Office presented a five-year plan for expanding research into vaccine safety. The announcement, made at a regular meeting of a vaccine policy work group, the National Vaccine Advisory Committee, had been planned well in advance. But with the Poling case creating renewed anti-vaccine outcry, HHS took pains to invite vaccine critics. Improving vaccine safety “is a priority of the department, from the secretary on down,” said Dr. Bruce Gellin, head of the office that coordinates government responses to critical vaccine issues. Addressing a meeting attended by about 50 members of the public, many of them vocal critics, he added: “a crisis in confidence in vaccines could easily become a public health crisis.”
Since 1998, parents of autistic children have been blaming selected vaccines for their childrens’ illnesses. Several large epidemiological studies have demonstrated that neither the measles-mumps-rubella vaccine, nor exposure to the vaccine preservative thimerosal, has any link to autism. Still, parental refusal to vaccinate children seems to be growing. Four different measles outbreaks this year have been linked to unvaccinated youngsters.
Even as the evidence against the autism theories has grown, some parent groups have lumped autism with other childhood syndromes like attention deficit disorder, asthma, juvenile diabetes and severe allergies, blaming “over-vaccination” for all these problems. There is no evidence this is true, but the apparent increase in such conditions has led many parents to search for culprits in the common exposures of post-industrial society. Some of the increases are due to better diagnosis, while some have unknown causes. Because nearly all children are vaccinated, it is impossible to completely rule out such theories, though they have little biological plausibility.
The guardians of 4,900 autistic children have filed claims in a national vaccine court established in 1986 to compensate children who offer plausible arguments of injury from vaccines.The trials involving the autism claims are expected to last for years.
But in November, the government conceded one of the claims. The parents of Hannah Poling have shown that she suffered a high fever and eventually became autistic following the administration of five shots when she was about two years old. She was later diagnosed as having a mitochondrial disorder, a condition in which brain cells malfunction because they lack energy to deal with stresses like fever.
Parent groups who continue to insist that vaccines are to blame for autism have heralded the case as evidence for their position. A 2005 study in Portugal showed that 7 percent of autistic children in one patient group had mitochondrial dysfunction. Another study, discussed at a meeting of neuroscientists this week, showed that 23 of 37 autistic children referred to a clinic with muscle-tone problems had mitochondria defects as well. Might such an underlying condition predispose kids to vaccine damage?
Most experts, like Edwin Trevathan, director of the National Center on Birth Defects and Developmental Disabilities at the Centers for Disease Control and Prevention, have discounted the significance of the Poling case. No one has previously linked vaccines to mitochondrial disorders, he pointed out. However, doctors have often seen that fevers from vaccine-preventable diseases led to the onset of neurological disorders in kids with mitochondrial dysfunction.
But absolute certainty on the extent of vaccine damage in this subset of children is not available — partly because mitochondrial disorders are poorly understood. Last year, research into mitochondrial diseases got fewer than $12 million in NIH funding, according to Douglas C. Wallace, an expert on mitochondrial medicine at the University of California-Irvine. Questions as basic as the cause and the rates of mitochondrial disorders are unknown. Diagnostic methods are crude.
“This case raises a whole series of questions for which we have no answers,” said Wallace. The incidence of autism in mitochondrial patients, and the impact of infections or vaccinations on triggering the disease, are also unknown, he said. “Everything is this area is hypothetical.”
In an op-ed article in The Atlanta Journal-Constitution on Friday, Dr. Jon S. Poling, Hannah’s father and a neuroscientist, said that her case could help vaccine safety if it led to the use of a good diagnostic tool for mitochondrial disorder that would enable doctors to screen out babies for special treatment. But while such a tool might improve parental confidence, it isn’t clear how physicians would use it even if it existed. Kids with mitochondrial disorders are more prone to get sick following an infection, which in some ways would argue for more aggressive, earlier protection with vaccines.
Anti-vaccinists say the case argues for giving fewer vaccines in each visit. But scientists say there’s nothing about multiple vaccines, per se, that would harm children. Without scientific evidence, what’s the basis for deciding which vaccines should be delayed?
Terry Poling, Hannah’s mother, has said that something in the vaccines might have caused, rather than triggered, her daughter’s mitochondria to fail. If this were true, however, there would be no way to screen such children for special vulnerability to vaccines. Terry Poling testified at the hearing, and I asked her later about this inconsistency. “You’re right,” she said, “there would be no biomarkers if the vaccine itself caused the damage.”
At Friday’s meeting, CDC vaccine scientists presented a plan for studying vaccine reactions in children with underlying conditions like Hannah’s. They also stressed their willingness to allow the “public” a “place at the table.”
“I’m not a suit. I have a story too,” said John Iskander, the Immunization Safety Office’s acting director. Iskander noted that he had cases of vaccine-preventable deaths in his family, and also a nephew with autism. “Although I don’t expect you all to believe this, I enjoy the work when we do find a risk as much as I do when we don’t find one.”
Lou Cooper, the former president of the American Academy of Pediatrics and a venerable advocate for children, expressed optimism about the meeting. “I know a majority of the people in this room. I trust all of you, your integrity and your humanity,” he said. “What’s dividing us is the gaps in our knowledge. When we have all the facts we tend to come to the same conclusions.”
He was followed by Nadia Carrini, a young woman who said she was speaking on behalf of her 12 year-old brother. According to Carrini, children are being used as “human guinea pigs,” exposed to vaccines that “have created the sickest generation in the history of America.” The implacable conviction with which she spoke indicated that it will take more than good studies to convince some people.
The vaccine establishment needs public confidence in order to protect public health. But is its goal to empower opponents of vaccination, or to get them to stop spreading dangerous nonsense over the Internet? It might never bridge the gap between science-based informed opinion and those who demand changes in vaccine policy based on no evidence. A place at the table is fine. But people with knowledge have to be in charge.
Or, to paraphrase a line from the early 1960s musical, “The Unsinkable Molly Brown,” someone has to stand up and say: “The Lord has answered your prayers; the answer was no.”
Consumers’ Right to Sue Weakening
For more than a century, the regulation of U.S. food and drugs has seen its share of challenges — from the filthy slaughterhouses of Upton Sinclair’s Chicago to the tainted Chinese-made blood thinner that recently killed at least 19 people. The regulatory shortcomings on display in 1937, when ethylene glycol killed 105 antibiotic consumers, were still glaring six decades later, when Vioxx users started having heart attacks.
But throughout the history of the Food and Drug Administration, and its precursor agencies, U.S. consumers could always bring the manufacturer of a faulty product to court. Now, with the FDA woefully underfunded in its key role of assuring the safety and effectiveness of foods and drugs, and with political ideologues in the agency pushing industry prerogatives, the White House and the courts may be on the verge of stripping Americans of the right to sue. This would take away the last option for those seeking protection from –or recourse for — faulty products.
Illustration by: Matt Mahurin
Last month, in a 8-1 decision, the Supreme Court ruled that most people using medical devices do not have the right to sue manufacturers. In October, the court is expected to take up a more far-reaching case, Levine V. Wyeth, that could stop most lawsuits involving drugs. The court will examine the legality of a lawsuit preemption quietly written into an innocuous FDA labeling law in 2006. The author was Daniel E. Troy, then the FDA counsel, now an industry lobbyist. With major cuts in food and drug safety inspections, the take-home message, increasingly, is caveat emptor. Watch out for yourself, because the government won’t.
“Consumers are getting the worst of both worlds,” says David C. Vladeck, a Georgetown Law School professor. “They don’t get the protection the FDA promises because the agency is incapable these days of truly providing a safeguard for the drugs we get. And at the same time, the FDA is claiming that if we’re injured by a product falling through this quite penetrable safety net, all our rights to compensation are cut off by virtue of the FDA’s regulations—inadequate though they may be.”
Few of those who care about the FDA question that it is in deep trouble. A 180-member umbrella committee that includes academics, former government officials, business and consumer groups is pushing for more funding. At a Jan. 29 hearing of a House energy and commerce subcommittee, an expert panel reported that the FDA “cannot fulfill its mission” because of weaknesses in its staff, organization and information technology. “Science at the Food and Drug Administration today is in a precarious position,” said Peter Barton Hutt, a former FDA counsel who has chronicled the history of the agency. Hutt recommended a 50 percent increase in the FDA’s $2-billion budget over the next two years.
“In terms of both personnel and the money to support them, the agency is barely hanging on by its fingertips,” he said. “FDA has become the paradigmatic example of the hollow government syndrome; an agency with expanded responsibilities, stagnant resources and the consequent inability to implement or enforce its statutory mandates.” At the same hearing, FDA Commissioner Andrew C. von Eschenbach acknowledged, in general terms, that the agency was having problems meeting its responsibilities.
An FDA spokeswoman, asked to comment on this story, did not respond.
The FDA oversees about $1 trillion in products—25 cents on every dollar we spend. Yet despite an ever expanding mission, its budget has shrunk in real terms over the past three decades. The agency’s staff has fallen by 1,300 employees, to about 7,800, since 1994. Its competence, unsurprisngly, is also shrinking. “I’ve had telephone calls with FDA commissioners over the years in which they said, ‘Oh, we’re going to be leaner and meaner, we’ll do more with less,” said House Energy and Commerce chairman Rep. John D. Dingell (D-Mich.) “On the basis of my experience, they’re capable only of doing much less with the much less which they’ve been given.”
The Senate passed a budget resolution last week to give the FDA an additional $375 million—a 20 percent increase compared to the 3 percent proposed by the Bush administration.
When Sinclair wrote his novel “The Jungle,” about Chicago meatpacking plants, it provoked a wave of national disgust that helped lead to the creation of the first food regulatory agency in 1906. Sinclair was looking for bigger changes, though — he once said that he “aimed at the public’s heart and by accident hit its stomach.” The same is true today.
It’s often stomach-churning problems, like the slaughter of sick cows, which led to the recall of 143 million pounds of tainted beef from a California stockyard last month, that get public attention. And well they should. Since 2003, the FDA’s Center for Food Safety and Applied Nutrition, which oversees food and cosmetic inspections and the skimpy regulation of the ballooning, $20 billion dietary supplements industry, has seen a decline it its workforce from 950 to 771 full-time employees, according to Catherine E. Woteki, director of scientific affairs for Mars Inc., maker of candy and other foods. The center “no longer has the ability to generate the science needed to fulfill its human nutrition regulatory responsibilities,” she said.
But these may not even be the riskiest problems with a weakened FDA, especially now that manufacturers are getting new liability protection from the courts. “The food safety issue never really goes away, its roots are so deep,” says Donald Kennedy, the former FDA commissioner and editor of the journal “Science.” Perhaps more serious is the FDA’s inability to monitor the safety and efficacy of drugs it has approved, he said.
In 1992, under fire for failing to quickly license new drugs, the FDA instituted a user fee system, whereby drug manufacturers pay for the inspection of their products. By 2007, user fees made up about a fifth of the FDA’s budget. Yet the fees have only one purpose — to facilitate the licensing of new drugs. The safety profile of even the best-tested drug can’t be known until the drug has been on the market and is being used by millions, rather than the hundreds or a few thousand upon whom it was tested.
Yet the FDA relies mostly on passive reporting systems for drug adverse events, and it lacks the power to recall a drug unless it can show eminent peril.
“In retrospect, the user fees system was a bad step,” says Kennedy. “It didn’t do anything except make other people pay, and the funds FDA gets through user fees can’t be used for safety and efficacy monitoring or food safety or any of the other responsibilities that FDA has. We think Congress has to own up to its own responsibilities and not depend on user fees.”
Because it’s doubtful FDA could bolster its staff enough to take on this mission, some have proposed setting up a network of academic testing centers to handle the job—something similar to the way that NASA and the Pentagon use the Jet Propulsion Laboratory in California to test new industry technologies. Others, like Sen. Richard J. Durbin (D-Ill), have proposed breaking off the FDA and USDA food safety divisions and consolidating them in a single, food safety agency.
Meanwhile, in the real world, the drug industry continues to try to chip away at the authority of the FDA. In a move reported last month here, the FDA proposed allowing drug representatives to drop off copies of reprints from any peer-reviewed journals regarding off-label uses of drugs. Under current policy, the FDA has to approve such research before the drug reps distribute it. The obvious conflict is that “peer-review” is a poorly defined term, and small journals have an incentive to publish iffy research when they know that Merck, Wyeth and Co. are going to buy up hundreds of thousands of copies of the journal to pass out to doctors. It’s not a move that inspires confidence.
Important Bacteria Cultures Destroyed
Let’s say your 48-year-old husband has just been diagnosed with Legionnaire’s disease in a hospital intensive care unit. You learn that the bacteria causing this disease spread in water supplies, and you have a hot tub at home where your teen-age kids are currently splashing about. How do you find out whether the hot tub was the source of your husband’s infection?
Until recently, you sent water samples to the Special Pathogens Lab at the Veterans Administration hospital outside Pittsburgh. That’s what Lynn Winn, of Orange, Calif., did in July 2006. But she never got the results, because the VA closed down the lab without processing her samples.
Six months later, in what infectious disease specialists around the world are calling a tragic, inexplicable act of vandalism, the VA incinerated the lab’s library of 4,000 microbe cultures, including the world’s most important collection of legionella bacteria, collected over a period of nearly 30 years.
Illustration by: Matt Mahurin
No one seems to understand the point of this deliberate destruction. “My theory is that this was essentially a vindictive act,” sayd Dr. Victor L. Yu, who headed the lab. The VA has said the samples weren’t properly labeled. But Yu and his colleagues flatly deny that, and it seems hard to believe. VA spokesmen in Washington and Pittsburgh did not return several phone calls and emails seeking explanations.
A murky turf war seems to lie behind the closing of the pathogens lab, which was unusual because its influence extended well beyond the Veterans Administration health-care system. (For exhaustive details and background, go here). Yu has been at odds with the Centers for Disease Control in the proper way to detect and prevent legionella infections, but he doesn’t believe that scientific dispute had anything to do with the sacking of his collections.
Colleagues of Yu and his partner, Dr. Janet E. Stout, described the destruction of the collection as a calamity on a scale with the burning of a library of rare books or a museum full of prized artworks. They said it would damage research into Legionnaire’s and other illnesses; the collection also included strains of Pseuodomonas, Enterococcus, Klebsiella and many other pathogenic bacteria. Isolates of these bacteria could have been used to compare changes in virulence and antibiotic resistance, and to help fingerprint new outbreaks of disease.
“This was a tragic event, and it seems to me both stupid and egregious,” says Dr. William Bonnez, a physician and researcher at the University of Rochester Medical Center. “This was a collection that had taken years to collect and provided insight into all sorts of things—the evolution of bacteria and bacterial resistance, the genes that allow these germs to survive in the environment and in people.”
This story of destruction emerged in the April 1 edition of the journal Clinical Infectious Diseases, released on line last week, which included a petition signed by 250 infectious disease specialists. They demanded that the Veterans Administration convene an investigation of the Pittsburgh VA Healthcare System’s decision to close the lab and wreck its collection of microorganisms. “These isolates were accrued purely for the advancement of science,” the petitioners write, “And the beneficiaries of these studies were the patients.”
Kate Kelly, spokeswoman for Sen. Arlen J. Specter (R-Pa), said he has conducted an inquiry into the episode but, for the moment, had no further details.
Following the closure of the lab, Yu got into an ugly battle with the administration, which locked him out. The VA destroyed the microbe library in December 2006, without even notifying Yu or Stout. Both scholars had joint appointments at the University of Pittsburgh, and have moved their operations there.
Infectious disease doctors view Yu and Stout as the go-to experts on Legionnaire’s disease and the bacteria that causes it. Legionnaire’s bacteria sicken an estimated 20,000 Americans each year, mostly the old and immunocompromised, often in hospitals, according to the Centers for Disease Control. About a quarter of the patients die. Sending samples to Drs. Yu and Stout, hospitals around the world were able to determine whether the bacteria afflicting their patients existed in the microbiological record, providing hints as to the disease’s spread and the virulence of the particular strains they sent in.
“Many researchers depended upon them,” said David A. Relman of the Stanford VA Hospital and Stanford University. “Given the amount of time they put in, and the value of these collections it seems incredibly shortsighted to terminate it. Its value was immense, almost unmeasurable, and it’s very hard to replicate.”
David Cowgill, spokesman for the Pittsburgh VA, said in 2006 that the lab was closed because it had performed commercial testing, which he said wasn’t permitted in government buildings. In fact, the lab had for decades conducted tests for hospitals and for individuals, whom it did not charge. Its extensive links with doctors and hospitals around the world were part of what made the lab invaluable, supporters say. Cowgill did not respond to an email and two phone requests for comment on Friday.
Legionnaire’s bacteria are named for a 1976 outbreak that killed 34 people and sickened 221 others attending an American Legion convention in Philadelphia. Though first discovered during that outbreak, the germ seems to be common and growing health threat.
The Pittsburgh lab’s expertise was especially sought-after because legionella is a notoriously difficult bacteria to culture, and Legionnaire’s disease often difficult to diagnose. Yu and Stout proved that the disease frequently spreads through undetected contamination of tap water.
In 2005, after a mysterious outbreak of pneumonia at a Toronto nursing home killed 17 people, samples were sent to Yu’s laboratory, which confirmed legionella as the cause. Toronto doctors were unfamiliar with the intricacies of culturing the bacteria, and had failed to diagnose it.
Research by Yu, Stout and their colleagues has embroiled them in a scientific dispute with the Centers for Disease Control over the proper way to control legionella. Yu believes all hospitals should conduct routine examination of faucets and water coolers for legionella colonies. Most clusters of the disease, Yu and Stout believe, have broken out in hospitals that later turned out to have contaminated water.
The CDC’s guidelines, however, do not encourage proactive water testing. Many hospitals that are colonized with high counts of legionella do not have cases of the disease, while others have cases of the disease despite minimal contamination of water supplies, said Dr. Lauri A. Hicks, a CDC medical epidemiologist. Hicks maintains that decontamination of water supplies does not provide lasting protection against legionella contamination; Yu claims that such treatments do exist.
Most of Western European and some Asian countries now require hospitals to proactively check for legionella in their water, and Stout and Yu have attacked CDC for failing to follow suit. “We think this long-overdue approach should be adopted,” Stout told a Pittsburgh newspaper last year. “How much longer do we have to wait and how many more lives will be lost?”
In the study that reinforces this conviction most strongly, Stout and Yu’s team found high levels of legionella bacteria in six of 20 VA hospitals over a three-year period. Five of the six hospitals had cases of Legionnaire’s disease during the study; none of the 14 “clean” ones did.
A few years later, one of the “clean” VA hospitals, in Phoenix, found cases of Legionnaire’s disease. Yu’s lab processed water from that hospital and found that 65 percent of the samples contained legionella. That was the last piece of work his team did at the VA. Administrators sent in security guards to keep his employees from finishing samples sent in by other hospitals or individuals—including Winn’s hot tub waters.
“We were given 48 hours to shut down a lab that had been open for 25 years,” says Yu. “How could they shut this lab down? It was the legionella reference lab for the entire world.”
In response to the results Yu sent it, the Phoenix hospital installed a water treatment program, and since has been legionella-free.
“So,” said Yu, “we proved our point.”
Yu and Stout now operate a lab across town. Their library, and its precious volumes of killer bugs, is gone forever.
