Peter Whoriskey has produced an excellent series of articles for the Washington Post covering the less-well-known practices of the drug industry. Here we will discuss his article titled As drug industry’s influence over research grows, so does the potential for bias.
Avandia was a drug produced by GlaxoSmithKline (Glaxo) for the treatment of diabetes. The data provided to the FDA indicated that Avandia was safe to use and was more effective than competing drugs. Several years later, after numerous heart attacks and deaths, Avandia was determined to significantly increase the probability of cardiovascular events and was essentially withdrawn from circulation. How this came to pass is the focus of Whoriskey’s article.
"But the way that company officials employed academics — and the prestige of the nation’s top journal — to promote the idea that the drug was safe has received little public scrutiny, and a full account offers a window into the corporate decisions underlying today’s drug research."
"Interviews, FDA documents and e-mails released by a Senate investigation indicate that GlaxoSmithKline withheld key information from the academic researchers it had selected to do the work; decided against conducting a proposed trial, because it might have shown unflattering side effects; and published the results of an unfinished trial even though they were inconclusive and served to do little but obscure the signs of danger that had arisen."
Glaxo knew at an early stage that there was reason to be suspicious about side effects from Avandia. They chose to ignore the possibility and decided to avoid gathering any potentially damaging data.
"The company considered sponsoring a full-blown trial to weigh the issue, but before it did, scientists conducted a "risk/benefit" analysis — not to calculate the risks and benefits of the drug to patients but to see whether a full-blown trial could harm the drug’s reputation."
"When that analysis showed a sign of danger — Avandia raised bad cholesterol levels more than the competitor — the company decided to drop the subject."
’Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,’ said an internal e-mail that was widely reported after it turned up in the Senate investigation."
Warnings came in from an international monitoring agency suggesting that drugs such as Avandia might be associated with heart trouble in 2003.
When asked by the FDA to conduct a safety trial and include cardiovascular effects, Glaxo devised a clinical test that excluded people who were considered at risk for heart trouble and failed to tell the investigators (so the investigators claim) that cardiovascular issues should be a point of focus.
"But as the FDA later noted, the.... trial was not really designed to assess heart risks. For one thing, it excluded people most at risk of heart trouble, making it harder to spot a problem. Moreover, investigators did not have a group of doctors validate reports of heart attacks, as is customary because they can be difficult to detect. Finally, about 40 percent of patients dropped out of the trial."
"Why would the academics have set up a trial like that? One reason is that Glaxo apparently did not tell its own academic researchers that the FDA had requested that the....trial look at possible heart troubles."
How did Glaxo finally get caught? Independent researchers were disturbed enough to force the release of data so that an unbiased evaluation could be performed.
"After analysis, the results were stark: Avandia raised the risks of heart attack by 43 percent and of death from heart problems by 64 percent."
Glaxo continued to fight back and deny the validity of these results even though its own scientists agreed with the conclusions.
It would be another three years until Glaxo’s defenses collapsed and the use of the drug was restricted in the US and banned in Europe. Meanwhile people who were prescribed the drug continued to die.
When does corporate death-causing malfeasance become manslaughter, a punishable crime?
There are disturbing trends in the testing and marketing of drugs that lead one to suspect that the entire system needs to be rethought and put under an independent agency that better represents the welfare of consumers.
"The billions that the drug companies invest in such experiments help fund the world’s quest for cures. But their aim is not just public health. That money is also part of a high-risk quest for profits, and over the past decade corporate interference has repeatedly muddled the nation’s drug science, sometimes with potentially lethal consequences."
The many billions the drug companies spend on research have resulted in a tremendous growth in for-profit drug testing entities that compete with academic sites. Business is business, so these outfits know that receiving continued funds from a given company depends on how happy the drug company is with the results delivered. Yet another system that is ripe for abuse.
The drug companies have also used their funds to feed fees, research dollars, and investment opportunities to doctors and researchers who study and/or promote drug products. The result is that it has become difficult to assemble experts, on any subject, that do not have financial ties to one or more drug companies. One might argue that this money has no effect, but the evidence that bias, inadvertent or purposeful, is nearly inevitable in medical science is overwhelming. For example,
"....Ross notes that corporate bias can be particularly strong. The odds of coming to a conclusion favorable to the industry are 3.6 times greater in research sponsored by the industry than in research sponsored by government and nonprofit groups, according to a published analysis by Justin Bekelman, a professor at the University of Pennsylvania, and colleagues."
Other studies have arrived at similar conclusions.
If there is a positive note in this tale it is the suggestion by Whoriskey that doctors are beginning to take note of the drug company activities.
"According to a survey published this fall in NEJM [New England Journal of Medicine], doctors are about half as willing to prescribe a drug described in an industry-funded trial. That’s unfortunate, doctors say, because a good portion of the industry-funded research is done well."