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.
The Villains
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.
The Beginning
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 [1]. 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.
The Assassination
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..." [2].
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 [3]. 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.
The Payback
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.
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)60953-3
nice post
ReplyDeleteThanks!
DeleteThe Actos patent has already expired this year.
ReplyDelete