News outlets across the country dutifully reported a week ago that pharmaceutical giant GlaxoSmithKline had struck a deal with federal prosecutors, agreeing to pay $3 billion to settle criminal and civil charges related to its illegal promotion of various drugs.
Such deals have become sufficiently commonplace – Big Pharma has paid nearly $10 billion in the last 3 1/2 years to make federal authorities go away – that there may be a bit of fraud fatigue in reading such stories. But lawbreaking by pharmaceutical companies kills people and puts countless others at risk, so it’s worth revisiting the depth to which GlaxoSmithKline fell on its journey from respected pharmaceutical powerhouse to sophisticated criminal enterprise. And it’s equally worth noting that its crimes could not have been committed without the aiding and abetting of physicians and university scientists.
First, some background: When the Food and Drug Administration approves a drug, it permits a company to market the medicine for a specific indication and for a specific audience. While individual doctors are not constrained by those limitations and may in their judgment prescribe an approved drug for “off-label” use, it is illegal for a drug company to push a medicine for any such broader use – unless it goes back to the FDA with new evidence that the drug is safe and effective for a new indication.
Promoting drugs for off-label purposes has been enormously lucrative for drug companies willing to break the law, and it is that illegal behavior that ensnared GlaxoSmithKline, and many pharmaceutical firms before it. The crimes to which GlaxoSmithKline confessed are spelled out in a 32-page criminal complaint prepared by U.S. Attorney Carmen M. Ortiz of Massachusetts. Here’s what the federal investigation found, for the three drugs that led to GlaxoSmithKline’s prosecution – Paxil, Wellbutrin and Avandia:
After the Food and Drug Administration approved the sale of Paxil for adults suffering depression, GlaxoSmithKline conducted three placebo-controlled clinical trials to determine if the medication might also be effective in treating younger patients with depression. Before the studies began, scientists identified a number of primary and secondary endpoints – the criteria they would use to determine if Paxil performed better than a placebo pill in adolescents.
Paxil failed every pre-determined criteria in all three studies.
Nevertheless, after the failed tests, GlaxoSmithKline hired a freelance writer to ghostwrite a journal article suggesting that Paxil was shown to be effective in one of the trials. The article never mentioned that Paxil failed all of the endpoints created as part of the study protocol and never mentioned the other two studies that also showed that giving Paxil to depressed adolescents would not help them. Instead, the article declared: “The findings of this study provide evidence of the efficacy and safety of [Paxil] in the treatment of adolescent depression” – an assertion prosecutors said is patently false.
Initially, the ghostwriter did acknowledge that Paxil was more dangerous than the placebo pill and that study subjects given Paxil suffered more “adverse events,” including a worsening of their depression and more thoughts of suicide. But a GlaxoSmithKline employee changed that language to suggest that 90 percent of the adverse events suffered by Paxil users were unrelated to the drug. This was the first missed opportunity to alert the medical community that Paxil might lead to the death of the very people it was supposed to help.
Getting a medical journal to publish an article written by a hired freelancer would be a tall order. So the journal article bore the name of Dr. Martin Keller of Brown University, a once-respected scientist who was found to have accepted millions of dollars from drug companies to promote various medicines, often without acknowledging his financial conflicts of interest. Although it’s not clear that Keller fully analyzed the journal article for accuracy, he agreed to have it submitted under his name, and the article was published in July 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry.
GlaxoSmithKline did not submit the results of the drug trial to the FDA in hopes of receiving approval to market Paxil for adolescents. But it did send the journal article to its entire 1,900-member Paxil sales force, despite the fact that it would be illegal for the salespeople to push Paxil for pediatric use. In a memo to the sales force, company marketers claimed that the study showed Paxil had “REMARKABLE Efficacy and Safety in the treatment of adolescent depression,” even though that is not what the study found. Some sales reps then illegally used the study to persuade doctors to prescribe Paxil to children, without telling them the true risk to their patients.
The company also invited hundreds of psychiatrists – including psychiatrists who only treated children – to junkets in Puerto Rico, Hawaii and California in 2000 and 2001, paying all travel, lodging and meal expenses, as well as providing recreational activities including deep-see fishing, kayaking, snorkeling, sailing, horseback riding, balloon rides and golf. On top of that, the doctors were given $750 cash. A “leading child psychiatrist” – not identified nor charged by prosecutors – spoke at several of the outings, encouraging doctors to prescribe Paxil to young troubled patients, and falsely claiming that the Paxil drug trial had established that patients taking Paxil showed “significantly greater improvement” than patients who received the placebo. GlaxoSmithKline sales reps then used slides from the child psychiatrist’s paid talk to illegally promote Paxil for children during sales calls with other doctors.
GlaxoSmithKline monitored doctors’ prescribing habits after the free trips and concluded that they had a “significant impact” on Paxil sales. Paxil, in fact, became one of the ten best-selling drugs in the country, bringing in, according to the New York Times, $11.6 billion from 1999 to 2003.
It was not until 2003 – five years after a GlaxoSmithKline study first suggested that Paxil might actually deepen depression for adolescents – that the FDA understood how dangerous the drug could be for children. The agency issued a series of warnings on giving the drug to children, and by the end of 2004, ordered a “black-box warning” added to Paxil’s label, alerting doctors and parents that studies indicated the drug increased suicidal thinking and behavior in patients under 18. Subsequent studies suggested depressed adolescents taking Paxil were at least twice as likely to commit suicide as depressed adolescents taking no medication at all.
Wellbutrin, another psychiatric drug, was approved by the FDA solely for the treatment of major depressive disorder in adults. Despite that limitation, GlaxoSmithKline promoted Wellbutrin for weight loss, sexual dysfunction, attention deficit hyperactivity disorder, drug and gambling addiction, anxiety and bipolar disorder, and also pushed doctors to prescribe the drug to children and in unapproved doses. Sales reps called Wellbutrin the “happy, horny, skinny pill” as a shorthand during illegal promotional rounds with doctors.
The company also paid doctors to give frequent promotional talks for Wellbutrin and to recommend the drug for a variety of unapproved uses. The two most-frequently used doctors – who were neither identified nor charged by prosecutors – gave more than 800 promotional talks and were paid more than $1.5 million to persuade doctors to prescribe Wellbutrin for weight loss, sexual problems and even for patients with bulimia or who were abruptly discontinuing alcohol – both uses that Wellbutrin’s label specifcally warned against.
As with Paxil, GlaxoSmithKline treated prescribing doctors to lavish trips to Jamaica, Bermuda and elsewhere. The company also paid doctors to serve on advisory boards and as consultants – though the government concluded there was little advising or consulting, and that the arrangement was a guise to mask payments to doctors and to illegally boost sales of Wellbutrin for unapproved, off-label uses.
The company also arranged ostensibly independent Continuing Medical Education seminars for doctors – events that were actually controlled by the company and often featured the same paid physicians who spoke frequently at promotional events on behalf of the company. The illegal marketing helped Wellbutrin to become another of GlaxoSmithKline’s billion-dollar-a-year blockbusters.
After the FDA approved the diabetes drug Avandia in 1999, European regulators noticed a possible increase in heart problems among patients taking the medication, so they asked GlaxoSmithKline to conduct formal studies to determine if the drug were more dangerous than previously thought.
Drug companies are required by law to notify the FDA of any post-approval studies, so the agency has an early alert that there could be a problem with a medicine on the market. But in its 2001 report to the FDA, GlaxoSmithKline illegally left out any mention of the new studies, and kept the results secret after discovering that Avandia was indeed dangerous for heart patients. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” a GlaxoSmithKline executive wrote in an internal memo in 2001.
The company continued to break the law with respect to its annual reports in 2002, 2003, 2004, 2005, 2006 and 2007. With its cardiac risks obscured, Avandia became the best-selling diabetes drug in the world, with sales topping $3 billion in 2006. But the following year, the FDA finally obtained a clearer sense of the potential harm posed by Avandia, and ordered the company to add black-box warnings that the drug may increase the risk of heart attack and heart failure. Additional restrictions have severely limited sales around the world as doctors have switched to a safer diabetes drug. But for the years that physicians were kept in the dark about the risks of Avandia, GlaxoSmithKline rang up more than $10 billion in sales.
The $3 billion settlement — representing about 26 days’ worth of sales for the GlaxoSmithKline – is the only penalty the company will face in connection with criminal violations. No individual employees were indicted, so no one is going to prison.
Andrew Witty, CEO of GlaxoSmithKline, said the crimes committed by the company took place in “a different era” and that GlaxoSmithKline today operates under a new commitment to integrity, with new rules on how salespeople are compensated, and policies in place to claw back compensation from officials later found to have broken the rules.
“We are deeply committed to doing everything we can to live up to and exceed the expectations of those we work with and serve,” Witty said.
Some patient activists are skeptical, and say little will change in illegal pharmaceutical marketing until the punishment for getting caught exceeds the reward for breaking the law.
“Despite the seemingly large sums, the fines imposed on pharmaceutical companies for dangerous and illegal conduct pale in comparison to the profits generated from such activity,” said Sidney Wolfe, director of the Health Research Group at Public Citizen. “Until more meaningful penalties and the prospect of jail time for company heads who are responsible for such activity become commonplace, companies will continue defrauding the government and putting patients’ lives in danger.”