Last week’s article by New York Times reporter Gardiner Harris exposed Glaxo SmithKline’s (GSK) flagrant disregard for patient safety. For 11 years GSK suppressed internal studies showing that the world’s former best selling diabetes drug, Avandia, posed a much higher risk of heart attack than its main brand-name competitor, Actos.

Last Wednesday, an FDA advisory review panel concluded a two-day hearing by recommending 20 to 12 that Avandia remain on the market with label revisions and other restrictions. This deeply divided panel included 17 votes to add warnings or restrictions on the drug, and 12 votes to remove the drug from the market.

The members voting for Avandia’s removal said the drug “has no unique benefits and therefore the benefits of the drug do not outweigh the risks.” They also pointed out that Avandia’s primary competitor, Actos, is an acceptable alternative to Avandia and therefore there is no therapeutic necessity to keep Avandia on the market.

Even the use of Actos has been called into question. Harvard researchers based at the Independent Drug Information Service (, note that “in mid-2007 the FDA added black-box warnings cautioning that both rosiglitazone (Avandia) and pioglitazone (Actos) increase the risk of congestive heart failure. These safety concerns, along with an increased risk of fracture, have greatly dampened enthusiasm for use of both of these drugs.

The ultimate fate of Avandia now rests in the hands of the FDA. If the proposed additional warnings and restrictions are implemented, scientist Steve Nissen, who published the first study documenting the cardiac risks of Avandia in 2007, estimates that 95 percent of Avandia’s use will end. “Effectively, this drug is gone.”

Interestingly, the committee also recommended by a vote of 19-11 that the trial currently underway comparing Avandia to its rival Actos be continued, though at least one member questioned the ethics of this, given the potential risks.

The Phantom 1999 Study

We now know that GSK conducted a 1999 study comparing Avandia to its main competitor, Actos, that linked Avandia to a 43 percent increased risk of heart attacks. GSK never reported these findings to the FDA. An email from Dr. Martin I. Freed, a GSK executive at that time said:

Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK.
When another GSK official asked whether this trial and another negative study should be published, Freed responded: “Not a chance. These put Avandia in quite a negative light… [W]e would hope that these do not see the light of day.” Other company documents reveal that in the 1990s, GSK decided against doing another study to determine definitively whether Avandia caused heart attacks because it feared that the results might hurt sales.

Litigation yields access to studies, helps expose risks

GSK’s earlier suppression of studies showing risks associated with the anti-depressant drug Paxil led to litigation and settlements that required GSK to post information online about all their clinical trials. Using this and other information, researchers Nissen and Kathy Wolski of the Cleveland Clinic published in 2007 an analysis of over 40 studies showing that Avandia increased the risk of heart attack, stroke and death in comparison to rival drug Actos.

GSK responded to the Nissen study by publishing results from their own  six-year ‘RECORD’ study. At the time, GSK asserted the RECORD study proved that Avandia posed no increased risk of heart attack or death. But reviewers have found a dozen serious incidents were excluded in the total tally of adverse events from the RECORD study. According to one FDA reviewer, “deaths that occurred while taking Avandia were inexplicably dropped from the final analysis.” Now GSK’s possible role in manipulating the RECORD study to keep their drug on the market is in question.

New evidence, studies bring risks to light

Ongoing investigations by Senator Grassley and almost a dozen new studies documenting the risks of Avandia have kept the issue alive, prompting the FDA’s ongoing review, including last week’s hearing.

One comparative effectiveness study by David Graham of the FDA was published this past June. Graham worked with researchers at the Centers for Medicare and Medicaid Services to collect records from nearly a quarter million Medicare recipients.  Elderly diabetics, who used Avandia instead of its competitor Actos, had a 68 percent increase in the risk of heart attack, stroke, heart failure or death. Graham stated:

We estimate that about 48,000 excess cases of [heart attack], stroke, heart failure, or death were attributable to the use of [Avandia] rather than [Actos] from 1999-2009.
Graham additionally stated “the RECORD study would have been dismissed as ’garbage’ if it had been used to seek the drug’s original approval.”

What’s next?

Whether the FDA will allow Avandia will remain on the market is still in question.  Beyond that, what else can we do to stop such illegal and hazardous industry behavior – the same behavior that resulted in the Vioxx tragedy, which led to up to 60,000 deaths? Litigation and other sources have revealed the suppression of drug risks concerning Vioxx, Paxil, Celexa, Zyprexa, and many other drugs. The problem seems endemic.

To begin to address this problem, FDA needs the resources and authority to examine all relevant clinical studies for data-tampering. Government and private consumer lawsuits must continue, including possible criminal prosecution. Finally, we should all remember that what you read on your drug label or hear in a TV ad may not be the whole story. Skepticism is warranted and further regulation is critical to all of us – we need medical care we can trust.

— Emily Cutrell, Prescription Access Litigation