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Some clinical trials found to be biased
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Photo source: FDA website
During the past two decades, the pharmaceutical industry has gained unprecedented control over the evaluation of its own products as less money has been available from academic and governmental sources for clinical research. Today drug companies finance most clinical studies of prescription drugs, spending $84 billion yearly on drug development in an attempt to capture as much of the annual $162 billion prescription market as possible.
Recently there have been numerous reports suggesting that in the rush to get these drugs to the public, clinical trials may not only be poorly executed, but actually manipulated deliberately to reflect only positive results.
In the case of one recent scandal, journal articles concerning Merck's drug rofecoxib (Vioxx) attributed to academic investigators were later discovered to have been written by Merck employees or medical publishing companies hired by Merck. The company’s own internal analysis of data pooled from two studies testing the drug for Alzheimer's disease showed three times the risk of death in patients on Vioxx compared to those who had taken a placebo in 2001 -- three years before Merck pulled Vioxx from markets worldwide in the biggest drug recall in history.
Bias in how industry-sponsored research is conducted and reported is not unusual and by no means limited to Merck. South Korean researcher Hwang Woo-Suk faked evidence of human cloning and Jon Sudbø of the Norwegian Radium Hospital and the University of Oslo fabricated mouth cancer trials . These incidents demonstrate that fraudulent research is very easy to publish, even in the most prestigious journals.
A new analysis of multiple reported surveys and studies by Danielle Fanelli of the University of Edinburgh published online in May attempts to quantify how many scientists fabricate and falsify research. On average, across the surveys, around 2% of scientists admitted they had "fabricated" (made up), "falsified" or "altered" data to "improve the outcome" at least once, and up to 34% admitted to other questionable research practices including "failing to present data that contradict one's own previous research" and "dropping observations or data points from analyses based on a gut feeling that they were inaccurate."
In surveys that asked about the behavior of colleagues, 14% knew someone who had fabricated, falsified or altered data, and up to 72% knew someone who had committed other questionable research practices. In both kinds of surveys, medical and pharmacological researchers reported misconduct most frequently. This suggests that either the latter are more open and honest in their answers, or that frauds and bias are more frequent in their fields. The latter interpretation would support growing fears that industrial sponsorship is severely distorting scientific evidence to promote commercial treatments and drugs.
As in all surveys asking sensitive questions, it is probable that some respondents did not answer honestly, especially when asked about their own behavior. Therefore, a frequency of 2% is probably a conservative estimate, while it remains unclear how the figure of 14% should be interpreted.
What can happen if a drug is released to the public based on distorted studies or insufficient feedback about all the possible side effects?
Statins may be a good example. These are drugs that physicians prescribe to lower cholesterol in an attempt to prevent heart disease. $25 billion worth of statins are sold every year and with increasing numbers potential patients, the drug industry is racing to create new, ostensibly improved products.
“Every statin company is trying to make people believe their statin is better than another one," Dr. Wolfe Director of the Public Citizen's Health Research Group,said.
After astronaut and flight surgeon. Duane Graveline’s cholesterol increased from 230 to 270, NASA doctors put him on Lipitor. Not long after that, he began experiencing transient global amnesia, the sudden inability to formulate new memory (known as anterograde amnesia), combined with varying degrees of retrograde memory loss--sometimes for decades into the past.
Because no alerts had been sent to his doctors about this as a possible side effect of the drug, his doctors assumed that Lipitor was not the cause. However, Graveline, an MD with an MPH himself, found studies not widely reported, indicating that in fact, statins can impact cholesterol in the brain and affect memory. He also discovered about 400 cases of amnesia reported to the FDA by individual between 11/97 and 4/07s. Yet none of these had ever been reported back to the medical community. He writes about this on his website and in his book .
Erick Turner, Senior Scholar at the Center for Ethics and Health Care at Oregon Health and Science University in Portland is a physician who reviewed trials for the better part of his career. However, after becoming a reviewer for the FDA he was shocked by how many negative trials he was seeing. "I had been clueless,” he told an Ivanhoe reporter. “These were studies that simply weren’t getting published, or perhaps they were being presented in a way that made them look positive."
A 2003 British Medical Journal study found that “systematic bias favors products which are made by the company funding the research.” A 2006 JAMA study found industry-sponsored research was positive 87 percent of the time compared with 65 percent of non-industry-sponsored research.
Such data has led come to conclude that many medical journals are becoming marketing instruments for the drug companies. "The financial success of medical journals, particularly the major journals, is intimately tied to meeting the needs of the companies that sponsor these big studies," said Dr. Hoffman of Public Citizen's Health Research Group.
There is a move to demand more disclosure. This year the New England Journal of Medicine, JAMA and other journals have started to require authors to disclose any patents or royalties related to their research and it publishes the information with the studies. Many believe this is the first step to fixing the problem. “No study is perfect," Dr. Hoffman said. "The large majority come to conclusions that can be questioned."
Those inaccuracies and misrepresentations can end up costing lives. Some researchers believe the only way to completely fix the problem is to take private funds out of research. That can only happen if the federal government allocates the kind of resources needed for cutting edge clinical research. Other healthcare experts are pushing for a drug trial registry that would allow the public to see if any trials ended with negative results.
One example of the dangers of no registry is the infamous Study 15, a long term trial of the antipsychotic drug Seroquel whose results contradicted common wisdom that newer, expensive psychiatric drugs are better than the reliable, older ones. Newly unearthed documents show that negative results were buried for 8 years until a taxpayer-funded study rediscovered what Study 15 had found -- and raised serious concerns about an entire new class of expensive drugs.
Study 15 results were squelced in 1997, the same year Seroquel was approved by the FDA to treat schizophrenia. The drug went on to be prescribed to hundreds of thousands of patients around the world and has earned billions for London-based AstraZeneca International -- including nearly $12 billion in the past three years. The results of Study 15 were never published or shared with doctors, even as less rigorous studies that came up with positive results for Seroquel were published and used in marketing campaigns aimed at physicians and in television ads aimed at consumers. The results of Study 15 were provided only to the FDA which maintains that it does not have the authority to place such studies in the public domain.
Bottom line, consumers need to be more proactive about understanding what medications they are taking (both prescription and over-the-counter) and try, as best as possible, to learn about potential harmful side effects as well as when alternative treatments might actually be safer (for example, an older generic medication rather than a brand new brand name drug in some cases). Keeping informed is ultimately the best medicine.
Some sources for more information:
Worst pills, best pills
Side effects of drugs
FDA website
FDA drug safety newsletter
Implications for vaccine efficacy studies
NOTE: My new novel, Dead Air by Deborah Shlian & Linda Reid, is a medical mystery that delves into the issue of industry funded clinical research conducted on a college campus. Look for it in December.
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