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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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February 24, 2010

Steve Nissen's Meeting with GSK

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Posted by Derek

Well, this is interesting. Back when Steve Nissen was about to publish his meta-analysis on the safety of Avandia (rosigiltazone), he met with several GlaxoSmithKline executives before the paper came out. At the time, GSK was waiting on data from the RECORD study, which was trying to address the same problem (unconvincingly, for most observers, in the end). Nissen had not, of course, shown his manuscript to anyone at GSK, and for their part, the execs had not seen the RECORD data, since it hadn't been worked up yet.

Well, not quite, perhaps on both counts. As it happens, a reviewer had (most inappropriately) faxed a copy of Nissen's paper-in-progress to the company. And GSK's chief medical officer managed to refer to the RECORD study in such a way that it sounds as if he knew how it was coming out. How do we know this? Because Nissen secretly taped the meeting - legal in Ohio, as long as one party knows the taping is going on. At no point does anyone from GSK give any hint that they knew exactly what was in Nissen's paper. Here's some of it:

Dr. Krall asked Dr. Nissen if his opinion of Avandia would change if the Record trial — a large study then under way to assess Avandia’s risks to the heart — showed little risk. Dr. Krall said he did not know the results of Record.

“Let’s suppose Record was done tomorrow and the hazard ratio was 1.12. What does...?” Dr. Krall said.

“I’d pull the drug,” Dr. Nissen answered quickly.

The interim results of Record were hastily published in The New England Journal of Medicine two months later and showed that patients given Avandia experienced 11 percent more heart problems than those given other treatments, for a hazard ratio of 1.11. But the trial was so poorly designed and conducted that investigators could not rule out the possibility that the differences between the groups were a result of chance.

Somehow, I don't think that many pharma executives are going to agree to meetings with Nissen in his office in Cleveland after this. But I certainly don't blame him for making the tape, either.

Comments (24) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology


COMMENTS

1. anchor on February 24, 2010 10:19 AM writes...

More than science, it seems that the story line (taping, subterfuge, senate investigation etc.) is begging for a Hollywood movie! Can any one suggest lead characters to play these roles? Hm..at the outset it seems to me that everyone in this story are shenanigans.

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2. Bill Graney on February 24, 2010 10:33 AM writes...

I disagree that Nissen's taping the meeting was justified. Even if legal, clandestine taping violates social norms, and is, frankly, creepy. If he was somehow afraid of the consequences of the meeting, he should not have attended, or simply had a colleague attend with him as a witness. Or he could have been honest and put the recorder on the meeting table. No one's life or well being depended directly on the outcome of the meeting, and in my view, his behavior was somewhere between a low budget cinema spy and a self-righteous vigilante.

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3. All in Keeping on February 24, 2010 10:35 AM writes...

This tells a lot about Nissan, his motives, and his integrity.

GSK management may not have done everything perfectly, but Nissan (from his own recording) comes arcoss as very arrogant, uncooperative, ego driven. He does not want to let the data tell the story, but rather insists his own conclusions to be the end-game.

Another piece to this untasty pie, the Cleveland Clinic had received substantial funding from Takeda, the maker of the competitor to Avandia Actos, creating a huge conflict of interest. Why does this never make part of the story line? Maybe Congress should be investigatng the ethics of Dr. Nissan & the Cleveland Clinic......

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4. Vader on February 24, 2010 11:37 AM writes...

Risk ratio of 1.11? Forget random errors; at that level, subtle confounders make the result meaningless.

No, I don't have any stock in Big Pharma or any other reason to shill for them. Except the general desire to see them stay in business long enough to keep developing better drugs.

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5. DavidQ on February 24, 2010 12:55 PM writes...

@Bill: does knowingly marketing a drug that is more likely to kill people than an existing alternative break any social norms?

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6. Doug on February 24, 2010 1:03 PM writes...

OK, you guys in pharma are starting to scare me...

I am certain in my heart that there are a ton of people working every day to find and market drugs that benefit humans. The chemists, the clinical trials people, heck even marketing and sales folks.

But floating along on top of this layer of tasty goodness is a thin stripe of shit that just doesn't care about anything but the next bonus. Unfortunately, all that goodness is borked by the line-o-shit on top meaning good drugs may not make it out (low profit margins) and bad drugs may if they have sufficient profit.

Crap! Guess I'm turning Christian Scientist.

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7. darwin on February 24, 2010 1:08 PM writes...

How about "No Pharma for Old Men"

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8. John on February 24, 2010 1:31 PM writes...

So
I'm always questioning meta studies. We all know that they themselves can be massaged very easily and many different conclusions drawn from the same data. We could look at the recent review of monsanto data on their GM corn (at least I think it's corn) by european scientists who came to exact opposite conclusion.
Now I don't know Dr. Nissen and in no way wish to imply anything about his motivations. His actions (audio taping the converstation), as reported by the times, makes me wonder about his overall feelings towards pharma, and his motivation in carrying out the meta study. If I go to court over this I get at least 3 statisticians to tear apart his analysis (and I bet it'd be easy to attack his methods as any meta study is open to this kind of attack) and then paint him as an anti pharma hippy with an agenda.
While we need to protect our own butts, academics need to stay above reproach in these types of situations. Academic freedom and protection are one thing, but they just don't exist in the courts of law or public opinion.

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9. Philip on February 24, 2010 2:05 PM writes...

I suggest Fred Melamed to play Dr. Nissen in the movie.

As for Dr. Nissen's meta study, he left out some studies that did not show an increased risk from his analysis. I do not understand Dr. Nissen's reasoning for not including all studies. I am not a statistician or a cardiologist, so I may not see the valid reasons for leaving out some studies.

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10. Jose on February 24, 2010 3:06 PM writes...

Philip- generally papers with low data quality or shoddy design are excluded from meta-analytics. Other authors include everything, but use a weighing function to offset "bad" studies. Lastly, some are built using a pooled dataset to recalculate everything from all the studies (if authors will share), while others just use the pooled risk ratio from the collected studies. It's statistical voodoo, and as Vader says, a RR/OR of 1.1 can be due to an array of factors.

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11. Jose on February 24, 2010 3:06 PM writes...

Philip- generally papers with low data quality or shoddy design are excluded from meta-analytics. Other authors include everything, but use a weighing function to give offset "bad" studies. Lastly, some are built using a pooled dataset to recalcualte everything from all the studies (if authors will share), while others just use the pooled risk ratio from the collected studies. It's statistical voodoo, and as Vader says, a RR/OR of 1.1 can be due to an array of factors.

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12. Jose on February 24, 2010 3:16 PM writes...

Philip- generally papers with low data quality or shoddy design are excluded from meta-analytics. Other authors include everything, but use a weighing function to offset "bad" studies. Lastly, some are built using a pooled dataset to recalculate everything from all the studies (if authors will share), while others just use the pooled risk ratio from the collected studies. It's statistical voodoo, and as Vader says, a RR/OR of 1.1 can be due to an array of factors.

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13. SteveM on February 24, 2010 4:34 PM writes...

"Lies, Damned Lies and Statistics"

Of course Big Pharma uses every statistical sleight of hand possible to shade the results of clinical studies.

If there were an award for stochastic machinations, the in-house number crunchers who game psychotropic drug outputs would win hands down.

That said, it's hard to generate sympathy for GSK's position in any context.

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14. bob on February 24, 2010 6:23 PM writes...

I generally don't even consider meta analyses evidence, quite frankly. In certain specific cases where there are a number of high quality RCTs to pool and reach a consensus, fine. 90% of the time, though, I have no doubt you could get whatever answer you wanted by playing around with the inputs and outputs.

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15. Anonymous on February 24, 2010 6:28 PM writes...

I mean really? if you look at the data tables in Nissen's NEJM paper you see we're talking about 39 Heart Attack related deaths among a 15,000+ Avandia patient pool v. 22 heart attack related deaths in a 15,000+ control pool. I mean forget the advanced statistics...the raw numbers show you that this isn't a big issue.

And Nissen who's made a career out of imagining heart attack-related side effects for useful drugs, wants this thing pulled over this?

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16. Anonymous2 on February 24, 2010 6:41 PM writes...

Would the GSK employees please raise their hands?

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17. CMCguy on February 24, 2010 6:52 PM writes...

#13 SteveM I am not a (bio)statistician but I think you are off base. I have worked with a few biostatisticans and a consistent trait observed is highest integrity: data is data and although may "game" to attempt to make sense out of the noise they typically are aware of the limitations and possible biases and fight to overcome these. They are asked to provide precise answers to specific questions with complex data sets and by comparison chemical synthesis is just grunt work (as recently accused).

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18. cliffintokyo on February 24, 2010 7:48 PM writes...

#15
Whatever *pharma* says, even one drug-related [please differentiate the data] heart attack death is really, really seriously bad news as far as public opinion (and the patient's family) is concerned.
Knee-jerk reaction scenario: *After all the progress in lowering the death-rate from heart disease, big pharma is jacking it up again!*
How many more patients might be suffering from non-lethal side effects on their heart? How would you feel if you were taking this drug? Its not about statistics. We are the big, bad $wolf.
Perception is all; i.e. we are responsible. And the court's favor public opinion in the US.
IMO, FDA probably should have made the decision back in 2007, and made it *easy* for GSK management.

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19. metaphysician on February 24, 2010 7:55 PM writes...

OTOH, a 10% higher risk of heart attack versus the comparison treatment might well be worthwhile, if there's a segment of the market who don't respond well to the comparison treatment. After all, if Actos doesn't *help* you, then the fact you'd run lower risk using it doesn't matter.

Admittedly, I don't know how much patient variability of this type actually occurs with diabetes drugs ( as opposed to, say, anything nervous system ).

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20. Jose on February 24, 2010 8:08 PM writes...

The real issue with the DREAM trial is that diabetes is a significant risk factor for CVD (one of the biggest reason to keep glucose well controlled), and then we see an *increased* risk for very serious CVD events in the treatment arm. Even a small number are therefor doubly bad news!

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21. cliff on February 24, 2010 9:38 PM writes...

#23
Subjectively, I prefer the actual numbers to the percentage (its more than 10% vs comparator?)
So, would you tell diabetic patients that they have a higher risk of CVD events because of their disease, and that it is increased by taking this drug? Can the average patient *understand* this logic?

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22. SteveM on February 24, 2010 9:41 PM writes...

Re: CMCguy

See some statistical book cooking here:

http://clinpsyc.blogspot.com/search?updated-min=2009-01-01T00%3A00%3A00-08%3A00&updated-max=2010-01-01T00%3A00%3A00-08%3A00&max-results=33

Anything for a buck...

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23. MedChem on February 25, 2010 10:46 AM writes...

" mean really? if you look at the data tables in Nissen's NEJM paper you see we're talking about 39 Heart Attack related deaths among a 15,000+ Avandia patient pool v. 22 heart attack related deaths in a 15,000+ control pool. I mean forget the advanced statistics...the raw numbers show you that this isn't a big issue."

The hysteria over safety has gone from rational to insane! I bet if you pool 15000 people who consume 1 small order of french fry once a week, the heart attack rate would likely be higher than both of these two groups (0.15 to 0.26% rate). Wait, forget about that, looking at the general population heart attack rate statistics below one would conclude that Avandia LOWERS heart attack rate!!!

****************************
The estimated age-adjusted prevalence of angina in women age 20 and older was 4.5 percent for non-Hispanic white women, 5.4 percent for non-Hispanic black women and 4.8 percent for Mexican-American women. Rates for men in these three groups were 4.7, 4.0 and 2.9 percent, respectively.*
Among adults in the United States age 20 and older, the estimated age-adjusted prevalence of coronary heart disease for non-Hispanic whites is 9.4 percent for men and 6.9 percent for women; for non-Hispanic blacks, 7.8 percent for men and 7.8 percent for women; and for Mexican-Americans, 5.3 percent for men and 6.6 percent for women.*
*Based on the National Health and Nutrition Examination Survey (NHANES, 2003–06), National Center for Health Statistics and NHLBI.

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24. cliff on February 25, 2010 7:48 PM writes...

#23 Good thoughtful post.
If the data from post #15 that you have quoted is correct (I have not verified vs source):
You have highlighted the important risk/benefit issue of which is more important:
1. The fact that Avandia does lower the incidence of CVD events relative to the general population (and presumably even more so relative to the relevant untreated diabetic population, i.e. patients for whom Avandia would be a suitable treatment) and is therefore effective;
2. The fact that there is a safety signal in the CT data; 0.26% vs 0.15% translates as 73% increased risk, if I am interpreting the data correctly......?

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