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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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November 12, 2009

Massaging the Data for Neurontin?

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Posted by Derek

There's a disturbing article out at the New England Journal of Medicine on studies conducted on Neurontin (gabapentin) for various unapproved indications. Parke-Davis (and later Pfizer) looked at a wide range of possible indications for the drug - migraine, neuropathic pain, bipolar disorder, and more. That in itself isn't unusual, since CNS drugs often have rather broad and poorly defined mechanisms, and it's not like we understand any of them all that well.

What is unusual is the pattern found when comparing the internal reports with the published versions that showed up in the literature. The authors found that:

"More than half the clinical trials that we included in our analysis (11 of 20) were not published as full-length research articles. For 7 of the 9 trials that were published as full-length research articles, a statistically significant primary outcome was reported, and for more than half these trials, the outcome specified in the published report differed from the outcome originally described in the protocol. Three of the four trials with an unchanged primary outcome had statistically significant results for the protocol-specified primary outcome. Secondary outcomes also frequently differed between the protocol and the published report. Thus, trials with findings that were not statistically significant (P≥0.05) for the protocol-defined primary outcome, according to the internal documents, either were not published in full or were published with a changed primary outcome. . .all the changes that took place between what was specified in the protocol, what was known before publication (as presented in the internal company research reports), and what was reported to the public led to a more favorable presentation in the medical literature. . ."

The authors go on to point out that changing a primary outcome after you see the data is, in fact, a statistical sin (although that's not quite the phrase they use!) You really can't go around doing that, because you can end up chasing after random chance (and avoiding that is the whole point of running well-controlled trials). This does not cover Pfizer and Parke-Davis with glory, but it's worth noting that there's plenty of blame to go around when it comes to this practice:

"Our study is based on a relatively small number of trials undertaken to test a single drug manufactured by a single company and its successors. Furthermore, if a major purpose of the studies we examined was to promote off-label uses of gabapentin, the selective reporting we observed could be more extreme than that observed for studies conducted for other reasons. Previous studies in different settings have shown evidence of these same biases, however. Indeed, selective outcome reporting does not appear to be limited to studies funded by drug companies. Chan and colleagues examined published trials funded by the Canadian Institutes of Health Research and found that 40% of stated primary outcomes differed between the protocol and the published report. In addition, we cannot be certain that selective reporting was a decision made by employees of Pfizer and Parke-Davis, since the authors of the published reports included nonemployees. We did not systematically assess the methodologic quality of the included trials as described in the publications we examined. Previous research has indicated that quality scores are higher for trials conducted by the pharmaceutical industry than for trials conducted by not-for-profit entities, although reports from industry-sponsored trials have potentially distorted the scientific record because of other, less easily measured study factors."

That doesn't get the folks who conducted these gabapentin studies off the hook, although I should note that Pfizer disputes the conclusions of this article (as you'd certainly think that they would). And it's also worth noting that some of its authors have done work for the plaintiffs in suits against Pfizer over gabapentin (thus all the familiarity with the internal company documents, which came to light during discovery proceedings). But again, I don't see how that negates the paper's conclusions, and if Pfizer has any hard data that would do so, I think they should produce it with all speed.

And no, it's just a coincidence that this post involve Pfizer, after I've been going on about their merger business all week. Unfortunately, I think that they're probably not the only company that could be pointed at. But we in the industry shouldn't have things like this for others to uncover in the first place. Should we?

Comments (12) + TrackBacks (0) | Category: Clinical Trials | The Central Nervous System | The Dark Side | The Scientific Literature


COMMENTS

1. wei on November 12, 2009 1:52 PM writes...

I believe they did not change the primary endpoints for the study report. FDA has been very strict and consistent on this for their stat review.

I would rather understand this as the consequence of the fact/impression that reviewers for literature publication have a loose standard than reviews for FDA.

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2. Lucifer on November 12, 2009 3:03 PM writes...

love those pfizerites!

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3. An Onyx Moose on November 12, 2009 3:32 PM writes...

As someone who used to work in gabapentin manufacturing, and who therefore had an interest in sales volumes, I have to say that the success of Neurontin caught Warner-Lambert mostly off-guard. A lot of the off-label uses were discovered more or less by accident or anecdotally, and the studies followed up after the fact. The side effect profile was extremely mild, so there was little downside risk in evaluating additional indications (there were several incidents of attempted suicide by gabapentin overdose that resulted in no permanent injury.) The drug was surprisingly successful in treating neuropathic pain for which there were few treatment alternatives. I am confident that Parke-Davis & Pfizer were no paragons of ethical marketing practices, but that's not the whole story. And then there is the legitimate question of study design - sometimes you learn something you didn't expect to learn in a study. What do you do then? It's not an easy question to answer.

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4. Retread on November 12, 2009 4:43 PM writes...

Gamma amino butyric acid is the major inhibitory neurotransmitter in the brain. The name should allow you to draw the structure. To get gabapentin (Neurontin), take the two hydrogens off the beta carbon and put in 5 methylene groups forming a cyclohexane ring -- that's gabapentin. It was certainly reasonable to think that gabapentin's anticonvulsant activity had something to do with gamma amino butyric acid.

But it doesn't. The receptor for gabapentin is a large protein called alpha2delta1, originally found as a nonessential subunit of the L-type calcium channel. It has a mere 950 amino acids sitting outside the membrane. Mutate it so it doesn't bind gabapentin (or Lyrica), knock it into a mouse, and the two drugs lose their anticonvuslant effects.

At this point we have absolutely no clue as to why these drugs (which were rationally designed to mimic gamma amino acid) are anticonvulsants. It is unsurprising that they have other effects on various neurological problems.

The gabapentin receptor is also a receptor for thrombospondin, which is important in postnatal synapse formation [ Cell vol. 139 pp. 380 - 392 '09 ]

This fits with the humility we should have about our knowledge of what our drugs are actually doing -- and fits in with an earlier comment of mine on Derek's 5 November post "What Exactly does Resveratrol Do?"

November seems to be humility month, and the current post on Chemiotics II argues for more of it in another context.

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5. anon on November 12, 2009 4:50 PM writes...

Not to hijack things here, but I thought people in the chemistry community might want to know that Keith Fagnou from the University of Ottawa, who had earned quite a reputation in C-H activation and other areas of catalysis, passed away yesterday. Here’s the media release: http://www.media.uottawa.ca/mediaroom/news-details_1776.html

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6. Sili on November 12, 2009 5:53 PM writes...

The authors go on to point out that changing a primary outcome after you see the data is, in fact, a statistical sin (although that's not quite the phrase they use!
You're channelling Goldacre. (That's a compliment.)

I agree that this sounds like a failure of the publication branch. It really should be necessary to deposit all trials in a central register with their primary goal listed before the trial even starts. The register should of course be public (at least after a while) and it shouldn't be possible to publish articles on any data without them being deposited and reference made to them. We do it routinely with crystal structures - why should this be different (and it should really be mandatory for spectra and other analytical data too - damn, lazy journals).

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7. Don B. on November 12, 2009 6:27 PM writes...

I take 300 mg of gabapentin at bed time for the pain from two bad discs in my back. One on each side of L5.

It makes my life livable & I am greatful to Dr. Satzinger, the inventor.

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8. barry on November 12, 2009 8:12 PM writes...

If the drug company has done a sufficient Phase-II, they can (and should) turn the running of the Phase-III study over to a disinterested party. Let the company design the Phase-III, let the company pay for the Phase-III, but then let the data speak for themselves, pass or fail on the clinical endpoint defined in advance.

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9. Jose on November 12, 2009 8:28 PM writes...

"Publication bias" is a huge problem is meta-analyses. Who wants to publish negative non-sexy studies?

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10. cliffintokyo on November 13, 2009 4:06 AM writes...

Let's face it, publications on clinical trials are often (thinly/cleverly) disguised promotional tools.
I do think that the authors are justified in rewriting complicated explanations and discussions of clinical data analysis to make them easily digestible, otherwise what's the point?
However, the trial protocol requirements and original data should be immutable, and verifiably so. (CT databases, sure, but for ALL trials?)
I agree with others - who wants to waste time publishing papers on (any kind of) negative research results? And companies, naturally, and just like all other researchers, need to focus on pursuing what works and move it forward; what didn't work is history.

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11. Anonymous on November 14, 2009 11:08 PM writes...

the recent paper on predicting new targets for known drugs is also massaging data, but i am quite surprised it can be published in Nature--- probably due to its biological data. OK, NAture is a bio journal.

http://pubget.com/paper/19881490?title=Predicting%20new%20molecular%20targets%20for%20known%20drugs

Permalink to Comment

12. Anon on November 18, 2009 1:03 PM writes...

This story also doesn't help our industry's image http://www.nytimes.com/2009/11/15/us/politics/15health.html But you can also put blame on the politicians as well...

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