Avandia: Corruption, Bias, and Death

All drugs have side effects which can range from imperceptible to lethal. There is always a calculation that must be done to quantify the ratio of good effects of the drug to the bad effects of the drug. If the good sufficiently outweighs the bad, the drug might still be considered worthy of use. One assumes such decisions are to be made by an agency assigned the task of deciding what might be in the public good. The relevant agency in this case is the Food and Drug Administration (FDA). Unfortunately, the FDA does not itself produce the data needed to make decisions on safety. It has become common for a drug to be submitted for approval when the vast majority of the data available on its use comes directly from the drug companies themselves rather than from independent agencies. The opportunity for abuse in such an environment pertaining to such a critical mission is outrageous.

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deaths, Avandia was determined to significantly increase the probability of cardiovascular events and was essentially withdrawn from circulation.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.

Corruption

"The outlines of the Avandia case — in which the drug’s dangers had been recognized within the company long before the FDA pulled it from retail shelves — are well known."

"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.

"From nearly the beginning, Glaxo scientists confronted signs of potential heart dangers in Avandia. In 2000, about a year after the drug’s approval, a small internal study suggested that Avandia might raise "bad" cholesterol levels more than a competitor."

"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.

"....in 2005 and 2006, Glaxo conducted an examination of records from more than 14,000 patients and concluded that Avandia raised the risk of coronary blood flow problems by about 30 percent, the Senate investigators said."

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.

"As is common practice, the company arranged for a group of experts — mostly academics — to form a steering committee to guide and publish the experiment. Four of the 11 committee members were Glaxo employees. The other seven reported serving as paid consultants or had other financial connections to the company."

"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.

"To see whether his suspicions were warranted, [Steven E.] Nissen, with colleague Kathy Wolski, set out to assemble the data from every trial of Avandia that they could find. The more data they had, the more likely they could accurately gauge the risks. The drugmaker refused Nissen’s requests for data, but because of litigation brought by Eliot Spitzer, then New York’s attorney general, the company had been forced to make some of it public. In all, he discovered the summaries of 42 trials — 35 of them unpublished. Most of them had been sponsored by Glaxo."

"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.

"....scientists and statisticians at Glaxo largely agreed with Nissen’s calculations, the company e-mails released by the Senate show."

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?

Bias

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.

"Years ago, the government funded a larger share of such experiments. But since about the mid-1980s, research funding by pharmaceutical firms has exceeded what the National Institutes of Health spends. Last year, the industry spent $39 billion on research in the United States while NIH spent $31 billion."

"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,

"’Unfortunately, the entire evidence base has been perverted,’ said Joseph Ross, a professor at Yale Medical School who has studied the issue."

"....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.

"....medical science appears to have reached a crisis: Doctors have grown deeply skeptical of research funded by drug companies — which, as it happens, is most of the research regarding new drugs being published....."

"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."

Death

"A Food and Drug Administration scientist later estimated that the drug had been associated with 83,000 heart attacks and deaths."