These days Takeda Pharmaceuticals has gotten some bad press from a whistle blower suit which claims that TP deliberately withheld trial data for Actos, a drug which treats diabetes. The active ingredient is Pioglitazone, which improves the body's sensitivity to insulin and therefore your ability to metabolize glucose.
You remember one of my earlier blogs, in which I introduced you to the concept of "cherchez l'argent". The simple strategy of finding motives behind actions. Particularly within the health care environment. Which is why I want you to keep a few facts in mind before I tell you a little suspense story which plays out more often in the universe of medicine, than you and I would like to.
TP's Actos generates annually 2.6 Billion Dollars for TP.
It's patent expires in 2016.
GlaxoSmithKline's Avandia is, or was, Actos' competitor. Its active ingredient is Rosiglitazone, whose patent expires this year. Until 2005, Avandia saw yearly sales of 2.5 Billion dollars.
A few years back, the FDA became concerned with the entire class of drugs, the so called thiazolidinediones, because of serious side effects, such as an increased risk of heart disease, stroke and heart failure. Within it's 'adverse events reporting system', the FDA collects data on serious adverse events of drugs, which enables it to compare drugs based on benefits AND risk.
In 2007 the New England Journal of Medicine published the results of Dr. Nissen's meta-analysis of publicly available trial data on the cardiovascular effects of Avandia . In his analysis of 42 published studies he came to the conclusion that there was a significant increase in the risk of heart attacks in patients taking Avandia. Interestingly, Dr. Nissen also pointed out that he did not have access to the source data of these trials, which prevented him from conducting a "more statistically powerful time-to-event analysis". So his conclusion was, correctly, that "more comprehensive evaluations are required" to address these cardiovascular risks. Not an unreasonable demand, given that two thirds of diabetics die of such events. Which is why they are prescribed drugs like Avandia and Actos in the first place. Dr. Nissen expressed his hopes for the yet to be published results of the RECORD trial, which was under way at that time. Financed by GSK, mind you.
In a highly unethical move, one journal reviewer leaked the draft of the Nissen paper to GSK a few days after its submission. The source of the leak was no lesser than a professor of medicine at the University of Texas Health Sciences Center, Dr. Steve Haffner. Why would he do such a thing? Maybe, because he also happened to be a consultant to GSK? Your guess is as good as mine. Cherchez l'argent.
GSK's own scientists found Nissen's statistical methods beyond reproach. Not so GSK's marketing goons. They promptly showed up at Nissen's Cleveland Clinics in Ohio. But Nissen was prepared for the worst, as he expected GSK to apply some pressure tactics, as it had done in the past with Dr. John Buse, a professor of medicine at the University of North Carolina.
Buse had been at the receiving end of GSK's intimidation tactics for the same reason: openly voicing concerns about the cardiovascular risks associated with Avandia. The issue had gone to head, with the U.S. Senate Committee on Finance investigating the case and coming to the conclusion that "Had Dr. Buse been able to continue voicing his concerns, without being characterized as a “renegade” and without the need to sign a “retraction letter,” it appears that the public good would have been better served".
Buse had warned Nissen in a private email about GSK's corporate persuasion program. With this in mind Nissen secretly taped the entire conversation with the GSK representatives.
Anyway, Nissen was no push-over, and so his meta-analysis was published. Again, ethical considerations took a leave, this time from the RECORD trial, whose investigators were made to prematurely milk it for whatever results could be used to counter the Nissen paper. The manuscript submitted to the New England Journal of Medicine (NEJM) interpreted the results of the trial as contradicting the Nissen meta-analysis. Only the journal editors didn't think so. They simply couldn't reconcile the data with the authors' interpretation. That's why NEJM's reviewers and editors told GSK that "an explanation for the continued use of Avandia is needed in this manuscript". The paper was finally published on 5th July 2007 concluding that "The data do not allow a conclusion as to whether treatment with rosiglitazone results in a higher rate of myocardial infarction..." .
The FDA had somewhat different data. On July 30th 2007 their scientists concluded that Avandia had caused 83,000 excess heart attacks (in the U.S. only) since it had entered the market. But preventing heart attacks in diabetics is what these drugs are all about! So, what's the point of a drug, which controls your blood sugar but INCREASES your chance of a heart attack? The FDA wondered, too, and subsequently required the drug to be sold only under very strict conditions. Sales dwindled to a fraction of the 2.5 Billion US$ of 2006. But it continues to rake in over a Billion US$ worldwide.
Two years later the same authors who had glossed over Avandia's performance data conceded that those patients who took Avandia had a more than 2-fold risk of developing heart failure compared to those who didn't take that drug . Again the U.S. Senate Committee on Finance had to investigate the matter and came to the conclusion of misconduct on the part of GSK.
Guess who followed the GSK drama with delight? Correct, Takeda Pharmaceuticals. With Actos being beautified as the safer drug, and Avandia being seriously clobbered by stiff FDA restrictions and the senate committee's investigations, Actos had cornered the market. But the party mood is over.
Because now Takeda suddenly finds itself in the same hot seat which GSK has kept warm all the while. Dr. Ge's suit alleges that TP deliberately did not report heart failure cases, which, by right, should have been registered in the FDA's database. Dr. Ge claims that TP terminated her employment after she had complained to 3 superiors about the underreporting of events. Without the whistle blower suit Takeda would have stood another 4 years of market dominance (until its patent expires).
The Surprise Finale
Now here comes the twist: While Dr Ge does not name Dr. Nissen or Cleveland Clinics as a defendant, she insists that investigators of her claims should consider the financial connections between Takeda and Dr. Nissen's Cleveland Clinics.
And all the while you thought only John Grisham novels delivered suspense.
So, what else will we see and hear from the next senate committee report? Whatever it is, you'll see again that playing around with your health is big business. It wasn't if the old rule of the Hippocratic Oath would find its way back into the business of medicine: "Never do harm to anyone!"
Armed with our knowledge about these business ethics, we should suspect the degree of deception to correlate closely with the potential for profits. So, am I right with my 'cherchez l'argent' method? Before you answer, just keep one thing in mind: If successful with her suit, Dr Ge stands to get a sizeable chunk of the settlement. Enough for you AND me to comfortably retire for life. Very comfortably. So let's stay tuned to this unfolding opera.
In my next post I want to give you a glimpse at how deeply entrenched the ballgame with your health really is. And how you can safeguard yourself against being the unfortunate avoidable heart attack, also known as collateral damage.
1. Nissen, S.E. and K. Wolski, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine, 2007. 356(24): p. 2457-71.
2. Home, P.D., et al., Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis. New England Journal of Medicine, 2007. 357(1): p. 28-38.
3. Home, P.D., et al., Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet, 2009. 373(9681): p. 2125-35.
Nissen, S.E. (2007). Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes New England Journal of Medicine, 357 (1), 100-100 DOI: 10.1056/NEJMx070038
Home, P., Pocock, S., Beck-Nielsen, H., Gomis, R., Hanefeld, M., Jones, N., Komajda, M., & McMurray, J. (2007). Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis New England Journal of Medicine, 357 (1), 28-38 DOI: 10.1056/NEJMoa073394
Home, P., Pocock, S., Beck-Nielsen, H., Curtis, P., Gomis, R., Hanefeld, M., Jones, N., Komajda, M., & McMurray, J. (2009). Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial The Lancet, 373 (9681), 2125-2135 DOI: 10.1016/S0140-6736(09)60953-3PrintPDF