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About this Author
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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July 7, 2014

That Retracted Stressed Stem Cell Work

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Posted by Derek

This article from David Cyranoski at Nature News is an excellent behind-the-scenes look at all the problems with the "STAP" stem-cell work, now retracted and apparently without any foundation at all. There were indeed problems with all of it from the start, and one of the key questions is whether these things could have been caught:

The committee was more vexed by instances of manipulated and duplicated images in the STAP papers. Obokata had spliced together gel lanes from different experiments to appear as one. And she had used an image of cells in a teratoma — a tumorous growth that includes multiple types of tissue — that had also appeared in her PhD dissertation. The captions indicated that the image was being used to represent different types of cell in each case. The committee judged that in both instances, although she might not have intended to mislead, she should have been “aware of the danger” and therefore found her guilty of misconduct. Obokata claimed that they were mistakes and has denied wrongdoing. . .

. . .Philip Campbell, editor-in-chief of Nature, says: “We have concluded that we and the referees could not have detected the problems that fatally undermined the papers.” But scientists and publishers say that catching even the less egregious mistakes raises alarm bells that, on further investigation, can lead to more serious problems being discovered.

Many say that the tests should be carried out on all papers. Christopher says that it takes about one-third of her working week to check all accepted manuscripts for the four journals published by EMBO Press. At Nature and the Nature research journals, papers are subjected to random spot-checking of images during the production process. Alice Henchley, a spokeswoman for Nature, says that the journal does not check the images in all papers because of limitations in resources, and that the STAP papers were not checked. But she adds that as one outcome of this episode, editors “have decided to increase the number of checks that we undertake on Nature’s papers. The exact number or proportion of papers that will be checked is still being decided.”

A complication is that some of the common image manipulations (splicing gel lanes, for example) are done in honest attempts to present the data more clearly, or just to save space in a figure. My guess is that admitting this up front, along with submitting copies of the original figures to the editors (and for inclusion in the Supplementary Material?) would help to clear that up. The article raises another good point - that editors are actually worried about confronting every example of image manipulation that they see, for fear of raising the competence of the average image manipulator. There's an evolutionary-arms-race aspect to all this that can't be ignored.

In the end, one gets the impression that Nature's editorial staff (a separate organization from the News people) very much regret ever having accepted the work, as well they might. Opinion seems divided about whether they could have caught the problems with the papers themselves - this was one of those cases where a number of reputable co-authors, at reputable institutions, all screwed up simultaneously when it came to cross-checking and verification. What remains is a portrait of how eager people can be to send in groundbreaking results for publication, and how eager editors can be to publish it. Neither of those are going to change any time soon, are they?

Update: from the comments, see also this timeline of events for a look at the whole story.

Comments (13) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 30, 2014

The GSK-China Situation Gets Even Weirder

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Posted by Derek

OK, the GlaxoSmithKline/China business has officially crossed over into new territory. Over the weekend, the company confirmed reports that Mark Reilly, the GSK executive in the country who's been in the middle of this affair from the beginning, was the object of a blackmail attempt by unknown parties. (The story was broken by the Sunday Times, and it's behind a paywall, but it's been picked up by every major news outlet).

Someone shot extensive footage of Reilly alone with his Chinese girlfriend, and mailed the resulting file to higher-ups at the company. The connection between all this and the corruption allegations has not been made clear, but the footage apparently accompanied some of the emails accusing the company of bribery. We may never know quite what's going on here, but I'll bet it's very interesting indeed. More on surveillance in China here.

Update: an excellent overview from the BBC.

Comments (36) + TrackBacks (0) | Category: Business and Markets | The Dark Side

June 27, 2014

Varieties of Scientific Deception

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Posted by Derek

Some may remember a paper from 2011 on the "reverse click" reaction, an interesting one where triazoles were pulled apart with mechanical force. This was an interesting system, because we really know surprisingly little, down on the molecular level, about what happens when bonds are physically stressed in this way. What do molecular orbitals look like when you grab both ends of the molecule and tug hard? Which bonds break first, and why? Do you get the reverse of the forward reaction, or do different mechanisms kick in (free radical intermediates, etc.)? (Note that the principle of microscopic reversibility doesn't necessarily apply when the conditions change like this).

Unfortunately, there seems to be trouble associated with this example. Science has an editorial "expression of concern" on the paper now, and it appears that much of it is not, in fact, reproducible (see this report in C&E News).

The paper was from the Bielawski lab at UT-Austin, and Bielawski is reported as saying that a former group member has confessed to manipulating data. But he also says that the conclusions of the paper are unchanged, which is interesting. My guess is that the "unclick" does happen, then, but nowhere as smoothly as reported. Someone may have sweetened things to make it all look better. At any rate, a correction is coming soon in Science, so we should get more information at that point.

This reminds me of the scheme I use to rate political and economic corruption. Stage I is paying someone off to do something they wouldn't normally do (or aren't authorized to do) for you. This happens everywhere, to some extent. Stage II is when you're bribing them just to do the job they're supposed to be doing in the first place. Many countries suffer from institutional cases of this, and it's supremely annoying, and a terrible drag on the economy. And Stage III, the worst, is when you're paying them not to harm you - a protection racket with the force of law behind it. Cynics may adduce examples from the US, but I'm thinking about countries (Russia, among others) where the problem is far worse.

Similar levels apply to fakery in the scientific literature. Here's how I break it down:

Stage I is what we may have in this case: actual conclusions and effects are made to look cleaner and better than reality. Zapping solvent peaks in the NMR is a perfect small-scale example of this - for organic chemists, solvent peaks are sometimes the training wheels of fakery. The problem is, once you're used to altering data, at what point do you find it convenient to stop? It's far better not to take that first step into matters-of-degree territory.

Stage II is unfortunately common as well, and there's a nice slippery path from Stage I that can land you here. This is when you're convinced that your results are correct, but you're having such a hard time getting things to work that you decide to "fake it until you make it". That's a stupendously bad idea, of course, because a lot of great results were never real in the first place, which leaves you hung out to dry, and even the ones that can be finally filled in don't have to do so in the way that you were faking them to happen. So now a real result is tainted by deception, which will call the whole thing into doubt when the inconsistencies become clear. And faked results are faked results, even if they're done in what you might think is a good cause. Many big cases of scientific fraud have started off this way, with someone just trying to fill in that one little gap, just for now.

Stage III, the bottom, is when something is faked from beginning to end. There was no question of it even working in the first place - it never did. Someone's just trying to get a paper, or a degree, or tenure, or fame, or something, and they're taking the shortcut. I think that there are two main classes of fakery in this category. In one group (IIIa?), you have people whipping up bogus results in low-profile cases where no one may notice for years, if ever, because no one cares. And you have IIIb, the famous high-profile cases (see Jan-Hendrik Schön, among too many others) where impressive, splashy, look-at-that stuff turns out to have been totally faked as well. Those cases are a study in human psychology. If you report a big result in superconductors, stem cells, cancer therapy or any other field where a lot of smart, competent people are paying very close attention, you will be found out at some point. How can you not be? We're in Bernie Madoff territory here, where someone comes into work every day of every week knowing that their whole reputation is a spray-painted scrim of deception that could have a hole punched through it any minute. How people can possibly live this way I don't really know, but people do. The self-confidence displayed by this sort of personality is a wonder of nature, in its way. IIIa cases are initiated by the desperate, stupid, and/or venal. IIIb cases, though, are brought on by people born to their task.

Update: as pointed out by several good comments, there are plenty of not-quite-fraud sins that neighbor these. Those are worth a separate post, partly because they're even more common than straight-up fraud.

Comments (53) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 2, 2014

No More Acid Stem Cells

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Posted by Derek

In case you hadn't seen it, the "acid-washed stem cells" business has gone as far into the dumper as it can possibly go. It now appears that the whole thing was a fraud, from start to finish - if that's not the case, I'll be quite surprised, anyway. The most senior author of the (now retracted) second paper, Teruhiko Wakayama, has said that he doesn't believe its results:

The trigger, he told Bioscience, was his discovery—which he reported to Riken a few weeks ago--that two key photos in the second paper were wrong. Obokata, lead author on both papers, had in April been found by Riken guilty of misconduct on the first paper: the falsification of a gel electrophoresis image proving her starting cells were mature cells, and the fabrication of images proving resulting STAP stem cells could form the three major tissue types of the body.

But Riken had not yet announced serious problems with the second paper.

Last week, however, there was a flurry of activity in the Japanese press, as papers reported that two photos—supposed to show placenta made from STAP cells, next to placenta made from embryonic stem (ES) cells—were actually photos of the same mouse placenta.

As with so many cases before this one, we now move on (as one of Doris Lessing's characters once put it) to having interesting thoughts about the psychology of lying. How and why someone does this sort of thing is, I'm relieved to say, apparently beyond me. The only way I can remotely see it is if these results were something that a person thought were really correct, but just needed a bit more work, which would be filled in in time to salvage everything. But how many times have people thought that? And how does it always seem to work out? I'm back to being baffled. The stem cell field has attracted its share of mentally unstable people, and more.

Comments (11) + TrackBacks (0) | Category: Biological News | The Dark Side | The Scientific Literature

May 14, 2014

China Raises the Stakes in the GSK Scandal

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Posted by Derek

GSK's troubles in China have just gotten even more serious. The government has formally charged Mark Reilly, former head of the company's operations in China, of organizing and participating in a bribery scheme. This seems to have been a stronger step than people were expecting - we'll see what happens. Reilly's whereabouts do not seem to be clear to anyone - I would assume that he left China some time ago, but if he hasn't, then he's not leaving for some time to come.

Comments (11) + TrackBacks (0) | Category: Business and Markets | The Dark Side

April 22, 2014

J. Appl. Drivel or Gibberish Lett.? Choices, Choices.

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Posted by Derek

People keep hoaxing the predatory "scholarly" publishers out there, and the publishers keep falling for whatever drivel is slung at them. Here's the latest example from a reporter at the Ottawa Citizen, Tom Spears. He molded a pile of steaming gibberish into the rough shape of a manuscript, and that was more than enough:

I have just written the world’s worst science research paper: More than incompetent, it’s a mess of plagiarism and meaningless garble. . .

. . .I copied and pasted one phrase [in the title] from a geology paper online, and the rest from a medical one, on hematology.

I wrote the whole paper that way, copying and pasting from soil, then blood, then soil again, and so on. There are a couple of graphs from a paper about Mars. They had squiggly lines and looked cool, so I threw them in.

Footnotes came largely from a paper on wine chemistry. The finished product is completely meaningless.

The university where I claim to work doesn’t exist. Nor do the Nepean Desert or my co-author. Software that catches plagiarism identified 67 per cent of my paper as stolen (and that’s missing some). And geology and blood work don’t mix, even with my invention of seismic platelets.

And you guessed it - the acceptances came rolling in, and pretty damned quickly, too. Peer-reviewed, refereed, and edited within 24 hours - where are you going to find an honest journal with service like that? 16 of the 18 bottom-feeding "journals" accepted it, and one of the rejections suggested that it just needed a bit of tweaking to be accepted. And one of the publishers has asked Spears to serve on an editorial advisory board, so he's clearly got what it takes.

Of course, as yesterday's post shows, even a peer-reviewed journal with a recognizable name can publish gibberish. But I assume that Drug Discovery Today and Elsevier didn't charge the author $1000 to do it. On the other hand, they might have taken more than 18 hours to review the manuscript. Or not.

Comments (14) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature | The Scientific Literature

April 16, 2014

Professor Fukuyama's Solvent Peaks

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Posted by Derek

See Arr Oh expresses some doubts about all the NMR spectral corrections we've been seeing lately. He's specifically referring to Bethany Halford's interview piece, and he has this to say after reading it:

If your group focuses on "clean up your spectra" more than "purify your compounds better," that's a communications issue. If a professor with a large group sees nothing but perfect spectra all day, two thoughts should crop up:

1. "I must have the smartest, most efficient students in the world," or...
2. "Something's fishy here."

Perfect-looking data should always be a cause for concern in any experiment. My guess is that Prof. Fukuyama was closer to Option One, though, possibly in the variant of "My group has such high standards!" But high standards or not, a series of perfect, flat, NMR spectra with no solvent and no impurities is rather hard to achieve in total synthesis, considering the quantities that are being used. Load up the tube with 50mg of material and you can make a lot of stuff look good, but you don't have fifty mgs at step thirty-four, do you? I remember putting everything I had into one NMR tube (or worse, one polarimeter tube) in my own total synthesis days, and I carried the thing down to the machine like it was a bag of gold.

But there's no doubt that in a big group, there will be people who try to slip things past the boss. I've seen it myself; I'm sure that a lot of you have. And if you're giving the boss exactly what the boss wants to see - perfection - then it's going to be a lot easier. These spectral problems look like a collaborative effort to me - expectations from above, willingness from below. And there are a lot of other groups that have done (and, I feel sure, still do) the same thing. Zapping the solvent peaks in the NMR is the least of it, in some cases.

Update: added a direct link to the Fukuyama/Yokoshima interview.

Comments (19) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

March 28, 2014

More on the UT-Austin Retraction Case

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Posted by Derek

I mentioned an unusual retraction from Organic Letters here last year, and here's some follow-up to the story:

Nearly six years after Suvi Orr received a Ph.D. in chemistry from the University of Texas, the university told her it has decided to do something that institutions of higher learning almost never do: revoke
the degree. Orr, in turn, has sued UT in an effort to hold onto the doctorate that launched her career in the pharmaceutical industry.

Her lawsuit in state district court in Travis County contends that revocation is unwarranted and that the university violated her rights by not letting her defend herself before the dissertation committee that condemned her research long after she graduated. In addition, she says, the committee relied heavily on her former professor, who, she claims, was motivated to “cast the blame elsewhere.”

What a mess. More details as things develop. . .

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

February 26, 2014

The Instructive Case of Galena Biopharma

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Posted by Derek

If you're in the mood for another reason why you should always be cautious about your biopharma investments, look no further than Galena Biopharma (GALE to its many clueless fans). I've been following this story over the last couple of weeks, and what a mess it is. Galena is a small company in Oregon with a few assets, including a cancer vaccine candidate. Its stock hovers in the low single digits, as is appropriate. But in December and January, it began to trade up, and up. From $2/share to $4. Then to $6, and then higher. And this on no particular news or change in the company's prospects, which for a stock like this is often a sign of "momentum" players getting involved. "Momentum" investing is a fancy name for "I'm buying this because it's going up", and the people who do this sort of thing are understandably anxious for you to buy some, too. They're also very, very unwilling to hear about anything that might cause the stock to go back down, because the proper direction for stocks, we must remember, is up. They only go down because of evil short bashers; everyone knows this.

Adam Feuerstein of TheStreet.com delivered a great big dose of that evil stuff (known to the rest of us as "reality") on February 12 with this article, which showed why the stock had been rising. The company was paying a PR firm to beat the drums for it, said drum-beating going as far as having people post multiple supposedly-independent articles on sites like Seeking Alpha under a list of pseudonyms.

An outfit called the "DreamTeam Group" was hired for the promotion. They run a stable of stock-touting web sites, full of wonderful tales about the companies that are paying them to say these wonderful things. And they spread the word on other sites (as above), and on Twitter, by e-mail and whatever means come to hand. If carrier pigeons come back into fashion, you can count on one fluttering down with a hot stock tip for you. And if you're greedy and stupid, you could see all this hype and convince yourself that a Great Opportunity is spawning right in front of you - why, all these people are buzzing about this hot little company, and money is right there for the taking. The only reason not to get in on a deal like this would be a lack of vision.

Galena's insiders do not lack vision. Indeed, they have proven beyond any doubt that money was in fact there for the taking. GALE peaked at nearly $8/share, but its directors and officers were unloading millions of dollars worth of shares into that market. And who could blame them? These are legal financial transactions between consenting adults, and if one set of those adults know what's going on and the other set doesn't, well, it's that kind of world, isn't it? A look at any jungle will show the larger predators eating the smaller ones, and God knows the Street isn't any different.

Yesterday GALE closed at about $4, and many of its "investors" are hopping mad about that, as a look at Feuerstein's mailbag will show. But here are some cynical people who figure that the company is actually worth about seventy-two cents a share. Reasonable observers can disagree about that figure. But if you want to argue that the company is cruelly undervalued at $4, you are probably not a reasonable observer. Or you bought at $7. Same thing.

Update: if you'd like to know why people are so skeptical of the prospects for Galena's vaccine, look no further than this comment. It's right on target.

Comments (65) + TrackBacks (0) | Category: Business and Markets | The Dark Side

February 14, 2014

"It Is Not Hard to Peddle Incoherent Math to Biologists"

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Posted by Derek

Here's a nasty fight going on in molecular biology/bioinformatics. Lior Pachter of Berkeley describes some severe objections he has to published work from the lab of Manolis Kellis at MIT. (His two previous posts on these issues are here and here). I'm going to use a phrase that Pachter hears too often and say that I don't have the math to address those two earlier posts. But the latest one wraps things up in a form that everyone can understand. After describing what does look like a severe error in one of the Manolis group's conference presentations, which Pachter included in a review of the work, he says that:

. . .(they) spun the bad news they had received as “resulting from combinatorial connectivity patterns prevalent in larger network structures.” They then added that “…this combinatorial clustering effect brings into question the current definition of network motif” and proposed that “additional statistics…might well be suited to identify larger meaningful networks.” This is a lot like someone claiming to discover a bacteria whose DNA is arsenic-based and upon being told by others that the “discovery” is incorrect – in fact, that very bacteria seeks out phosphorous – responding that this is “really helpful” and that it “raises lots of new interesting open questions” about how arsenate gets into cells. Chutzpah. When you discover your work is flawed, the correct response is to retract it.

I don’t think people read papers very carefully. . .

He goes on to say:

I have to admit that after the Grochow-Kellis paper I was a bit skeptical of Kellis’ work. Not because of the paper itself (everyone makes mistakes), but because of the way he responded to my review. So a year and a half ago, when Manolis Kellis published a paper in an area I care about and am involved in, I may have had a negative prior. The paper was Luke Ward and Manolis Kellis “Evidence for Abundant and Purifying Selection in Humans for Recently Acquired Regulatory Functions”, Science 337 (2012) . Having been involved with the ENCODE pilot, where I contributed to the multiple alignment sub-project, I was curious what comparative genomics insights the full-scale $130 million dollar project revealed. The press releases accompanying the Ward-Kellis paper (e.g. The Nature of Man, The Economist) were suggesting that Ward and Kellis had figured out what makes a human a human; my curiosity was understandably piqued.

But a closer look at the paper, Pachter says, especially a dig into the supplementary material (always a recommended move) shows that the conclusions of the paper were based on what he terms "blatant statistically invalid cherry picking". See, I told you this was a fight. He also accuses Kellis of several other totally unacceptable actions in his published work, the sorts of things that cannot be brushed off as differences in interpretations or methods. He's talking fraud. And he has a larger point about how something like this might persist in the computational biology field (emphasis added):

Manolis Kellis’ behavior is part of a systemic problem in computational biology. The cross-fertilization of ideas between mathematics, statistics, computer science and biology is both an opportunity and a danger. It is not hard to peddle incoherent math to biologists, many of whom are literally math phobic. For example, a number of responses I’ve received to the Feizi et al. blog post have started with comments such as

“I don’t have the expertise to judge the math, …”

Similarly, it isn’t hard to fool mathematicians into believing biological fables. Many mathematicians throughout the country were recently convinced by Jonathan Rothberg to donate samples of their DNA so that they might find out “what makes them a genius”. Such mathematicians, and their colleagues in computer science and statistics, take at face value statements such as “we have figured out what makes a human human”. In the midst of such confusion, it is easy for an enterprising “computational person” to take advantage of the situation, and Kellis has.

You can peddle incoherent math to medicinal chemists, too, if you feel the urge. We don't use much of it day-to-day, although we've internalized more than we tend to realize. But if someone really wants to sell me on some bogus graph theory or topology, they'll almost certainly be able to manage it. I'd at least give them the benefit of the doubt, because I don't have the expertise to call them on it. Were I so minded, I could probably sell them some pretty shaky organic chemistry and pharmacokinetics.

But I am not so minded. Science is large, and we have to be able to trust each other. I could sit down and get myself up to speed on topology (say), if I had to, but the effort required would probably be better spent doing something else. (I'm not ruling out doing math recreationally, just for work). None of us can simultaneously be experts across all our specialities. So if this really is a case of publishing junk because, hey, who'll catch on, right, then it really needs to be dealt with.

If Pachter is off base, though, then he's in for a rough ride of his own. Looking over his posts, my money's on him and not Kellis, but we'll all have a chance to find out. After this very public calling out, there's no other outcome.

Comments (32) + TrackBacks (0) | Category: Biological News | In Silico | The Dark Side | The Scientific Literature

January 31, 2014

Beelzebub Pharma, Inc.

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Posted by Derek

I wanted to note my latest column for the RSC's Chemistry World, because I thought many readers here would be able to relate to it. I have a series of proposals for running the worst drug discovery organization I can think of - a set of simple rules that I think would bring things to a frantic, juddering halt while seeming to aim at enhancing everyone's productivity. A sample:

Appearances matter. And if it comes to a contest between surface and substance, then the glossiest surface wins. Woe to anyone whose presentations are not smooth and slick, with as many colorful charts as possible. Woe, similarly, to those who fail to tell anyone who asks (and many who don’t) how cleanly and tightly their current project is running. The first step to making problems disappear is to get them out of everyone’s sight. Right?

There will be many, many meetings to show off those beautiful slides. Multiple overlapping layers of meetings: it’s the only way to keep things running smoothly. Your worth as a manager, and as a human being, is tied to how many people you can cause to assemble in a room on a regular basis and how frequently you can get them to stand up in front of you.

I'm coming up (this fall) on twenty-five years of industrial research, and I found this column alarmingly easy to write. I was reminded of C. S. Lewis' experience in composing The Screwtape Letters, and his reluctance to write any more in that style. It really does just come out like opening up a water line once you get started, which says something about human nature.

Comments (43) + TrackBacks (0) | Category: Life in the Drug Labs | The Dark Side

January 20, 2014

A Long Fight Over Allegations of Fraud

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Posted by Derek

Here's a long article from the Raleigh News and Observer (part one and part two) on the Eaton/Feldheim/Franzen dispute in nanoparticles, which some readers may already be familiar with (I haven't covered it on the blog myself). The articles are clearly driven by Franzen's continued belief that research fraud has been committed, and the paper makes the most of it.

The original 2004 publication in Science claimed that RNA solutions could influence the crystal form of palladium nanoparticles, which opened up the possibility of applying the tools of molecular biology to catalysts and other inorganic chemistry applications. Two more papers in JACS extended this to platinum and looked at in vitro evolutionary experiments. But even by 2005, Franzen's lab (who had been asked to join the collaboration between Eaton and Feldheim, who were now at Colorado and a startup company) was generating disturbing data: the original hexagonal crystals (a very strange and interesting form for palladium) weren't pure palladium at all - on an elemental basis, they were mostly carbon. (Later work showed that they were unstable crystals of (roughly) Pd(dba)3, with solvated THF. And they were produced just as well in the negative control experiments, with no RNA added at all.

N. C. State investigated the matter, and the committee agreed that the results were spurious. But they found Feldheim guilty of sloppy work, rather than fraud, saying he should have checked things out more thoroughly. Franzen continued to feel as if justice hadn't been done, though:

In fall 2009, he spent $1,334 of his own money to hire Mike Tadych, a Raleigh lawyer who specializes in public records law and who has represented The News & Observer. In 2010, the university relented and allowed Franzen into the room where the investigation records were locked away.

Franzen found the lab notebooks, which track experiments and results. As he turned the pages, he recognized that Gugliotti kept a thorough and well-organized record.

“I found an open-and-shut case of research fraud,” Franzen said.

The aqueous solution mentioned in the Science article? The experiments routinely used 50 percent solvent. The experiments only produced the hexagonal crystals when there was a high level of solvent, typically 50 percent or more. It was the solvent creating the hexagonal crystals, not the RNA.

On Page 43 of notebook 3, Franzen found what he called a “smoking gun.”

(Graduate student Lina) Gugliotti had pasted four images of hexagonal crystals, ragged around the edges. The particles were degrading at room temperature. The same degradation was present in other samples, she noted.

The Science paper claimed the RNA-templated crystals were formed in aqueous solution with 5% THF and were stable. NC State apparently offered to revoke Gugliotti's doctorate (and another from the group), but the article says that the chemistry faculty objected, saying that the professors involved should be penalized, not the students. The university isn't commenting, saying that an investigation by the NSF is still ongoing, but Franzen points out that it's been going on for five years now, a delay that has probably set a record. He's published several papers characterizing the palladium "nanocrystals", though, including this recent one with one of Eaton and Feldheim's former collaborators and co-authors. And there the matter stands.

It's interesting that Franzen pursued this all the way to the newspaper (known when I Iived in North Carolina by its traditional nickname of the Nuisance and Disturber). He's clearly upset at having joined what looked like an important and fruitful avenue of research, only to find out - rather quickly - that it was based on sloppy, poorly-characterized results. And I think what really has him furious is that the originators of the idea (Feldheim and Eaton) have tried, all these years, to carry on as if nothing was wrong.

I think, though, that Franzen is having his revenge whether he realizes it or not. It's coming up on ten years now since the original RNA nanocrystal paper. If this work were going to lead somewhere, you'd think that it would have led somewhere by now. But it doesn't seem to be. The whole point of the molecular-biology-meets-materials-science aspect of this idea was that it would allow a wide variety of new materials to be made quickly, and from the looks of things, that just hasn't happened. I'll bet that if you went back and looked up the 2005 grant application for the Keck foundation that Eaton, Feldheim (and at the time, Franzen) wrote up, it would read like an alternate-history science fiction story by now.

Comments (14) + TrackBacks (0) | Category: Chemical News | Press Coverage | The Dark Side | The Scientific Literature

January 2, 2014

It Just So Happens That I Have A Conference Right Here

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Posted by Derek

Here's a good addition to the "bogus conferences" file. The folks at Retraction Watch have the story of Navin Kabra, an Indian engineer who's blowing the whistle on a racket peculiar to that country.

There are apparently many universities in India that have a requirement that everyone attaining a certain degree has to have their work accepted at an "international conference". So. . .a number of "international conference" organizers have stepped up to fill that market niche, with hefty registration fees and talk of rigorous peer review and high standards. They do nothing of the kind, of course. People pay their cash, pay their own way to the conference, and get to present to a scattered audience of other people who've done the same thing. No one else shows up - why would anyone?

So Kabra sent them a manuscript full of gibberish and stretches of dialog from "My Cousin Vinny", and (you guessed it), the thing passed the brutal review process as soon as the cash appeared. After revealing his hoax, the paper seems to have been taken down from the conference web site, but up until then, it was available for interested scholars, or people interested in Joe Pesci and/or Marisa Tomei. As long as the universities pretend that everyone coming through their programs has done work that's fit to present, there will be people there who will pretend to hold conferences for them. The real losers are the students, many of whom apparently think that these are real meetings. How do you recognize the real thing if all you've ever been exposed to are the scams?

Comments (7) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

December 18, 2013

Press Release Fraud - The Verdict Stands

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Posted by Derek

The Harkonen/Intermune case (blogged about here) seems to have come to a resolution (or no resolution, depending on your viewing angle): the Supreme Court has declined to hear W. Scott Harkonen's appeal. So the original verdict (and the rejection of its appeal) stand, and the argument that the disputed press release was merely a scientific argument fails. I agree with that, because this case seemed pretty egregious, but it might have been nice to see what the Supreme Court thought about the issue. The problem is, when you invite that, you get to, well, find out what the Supreme Court thinks about the issue. And like the old Fleetwood Mac song, "Oh, Well", they might not give the answer that you want them to.

I wanted to mention, since I linked to the Pharmalot article on this, that it appears that the whole PharmaLive/Med Ad News/Pharmalot operation is being shut down as of the end of this year. As soon as I hear what Ed Silverman, Pharmalot's longtime author, is up to after this, I'll make a note of it on the blog.

Comments (6) + TrackBacks (0) | Category: The Dark Side

December 6, 2013

Shop Up Some Gels For the Paper

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Posted by Derek

There have been many accusations over the years of people duplicating and fudging gels in biology papers. The Science-Fraud.org site made quite an impression with some of these, and there are others. But as in so many other fields, manual labor is giving way to software and automation.

Nature News has the story of an Italian company that has come up with an automated way of searching images in scientific papers for duplication. The first scalp has already been claimed, but how bad is the problem?

Now midway through the analysis, he estimates that around one-quarter of the thousands of papers featuring gels that he has analysed so far potentially breached widely accepted guidelines on reproducing gel images. And around 10% seem to include very obvious breaches, such as cutting and pasting of gel bands. Some journals were more affected than others, he says. Those with a high impact factor tended to be slightly less affected. He plans to publish his results.

I'll be happy to see the paper, and glad to see this sort of technique applied more broadly. I wonder if it can be adapted to published NMR spectra?

Comments (21) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

December 3, 2013

What You Can Publish After a Shamectomy

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Posted by Derek

The sleazy scientific publishing racket continues to plumb new depths in its well-provisioned submarine. Now comes word of "Stringer Open" - nope, not Springer Open, that one's a real publisher of real journals. This outfit is Stringer, which is a bit like finding a list of journals published by the American Comical Society. The ScholarlyOA blog noticed that the same person appears on multiple editorial boards across their various journals. When contacted, she turned out to be a secretary who's never heard of "Stringer". Class all the way. The journals themselves will be populated by the work of dupes and/or con artists - maybe some of those Chinese papers-for-rent can be stuffed in there to make a real lasagna of larceny out of the whole effort.

Comments (12) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

December 2, 2013

Authorship For Sale. Papers For Sale. Everything For Sale.

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Posted by Derek

Academic publishing fraud in China has come up here before, but Science has an in-depth look at the problem. And a big problem it is:

"There are some authors who don't have much use for their papers after they're published, and they can be transferred to you," a sales agent for a company called Wanfang Huizhi told a Science reporter posing as a scientist. Wanfang Huizhi, the agent explained, acts as an intermediary between researchers with forthcoming papers in good journals and scientists needing to snag publications. The company would sell the title of co–first author on the cancer paper for 90,000 yuan ($14,800). Adding two names—co–first author and co–corresponding author—would run $26,300, with a deposit due upon acceptance and the rest on publication. A purported sales document from Wanfang Huizhi obtained by Science touts the convenience of this kind of arrangement: "You only need to pay attention to your academic research. The heavy labor can be left to us. Our service can help you make progress in your academic path!"

For anyone who cares about science and research, this is revolting. If you care a lot more about climbing that slippery ladder up to a lucrative position, though, it might be just the thing, right? There are all sorts of people ready to help you realize your dreams, too:

The options include not just paying for an author's slot on a paper written by other scientists but also self-plagiarizing by translating a paper already published in Chinese and resubmitting it in English; hiring a ghostwriter to compose a paper from faked or independently gathered data; or simply buying a paper from an online catalog of manuscripts—often with a guarantee of publication.

Offering these services are brokers who hawk titles and SCI paper abstracts from their perches in China; individuals such as a Chinese graduate student who keeps a blog listing unpublished papers for sale; fly-by-night operations that advertise online; and established companies like Wanfang Huizhi that also offer an array of above-board services, such as arranging conferences and producing tailor-made coins and commemorative stamps. Agencies boast at conferences that they can write papers for scientists who lack data. They cold-call journal editors. They troll for customers in chat programs. . .

The journal contacted 27 agencies in China, with reporters posing as graduate students or other scientists, and asked about paying to get on a list of authors or paying to have a paper written up from scratch. 22 of them were ready to help with either or both. Many of these were to be placed in Chinese-language journals, but for a higher fee you could get into more international titles as well. Because of Chinese institutional insistence on high-impact-factor journal publications, people who can deliver that kind of publication can charge as much as a young professor's salary. (Since some institutions turn around and pay a bonus for such publications, though, it can still be feasible).

Some agencies claim they not only prepare and submit papers for a client: They furnish the data as well. "IT'S UNBELIEVABLE: YOU CAN PUBLISH SCI PAPERS WITHOUT DOING EXPERIMENTS," boasts a flashing banner on Sciedit's website.

One timesaver: a ready stock of abstracts at hand for clients who need to get published fast. Jiecheng Editing and Translation entices clients on its website with titles of papers that only lack authors. An agency representative told an undercover Science reporter that the company buys data from a national laboratory in Hunan province.

The article goes on to show that there are many Chinese scientists that are trying to do something about all this. I hope that they succeed, but it's going to take a lot of work to realign the incentives. Unless this happens, though, the Chinese-language scientific literature risks finding itself devolving into a bad joke, and papers from Chinese institutions risk having to go through extra levels of scrutiny when submitted abroad.

Comments (29) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

November 22, 2013

A Place to Go For Scientific Whistleblowing

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Posted by Derek

You've seen those "Call for papers" notices, from journals or conferences? Over at Synthetic Remarks, there's a call for whistleblowers. Reacting to the recent reports of scientific fraud, Fredrik von Kieseritzky is asking those who want to get the details of such things out safely to contact him. Swedish law is very protective of sources, and he's basically making that jurisdiction available to anyone for whom it would be in a position to help. He also has some sound advice on how to communicate such things (Tor, PGP, TrueCrypt), which are the sorts of tools that, apparently, the modern world is trying to make sure that everyone stays current with whether they felt like doing so or not.

This is a sincere offer, and may well draw some sincere responses. We'll see. . .

Comments (1) + TrackBacks (0) | Category: The Dark Side

November 4, 2013

The Herbal Supplement Industry Is Not A Very Funny Joke

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Posted by Derek

The regulatory system we have in the US for selling herbal supplements is screwed up. I've thought so for many years, and we're not the only country that fits that description, either. The system is screwed up in so many important ways that it's hard to know where to start, but how about back at the very basics - quality control?

Try this paper from BMC Medicine out (open access) and see what you think. The authors, from the DNA barcoding initiative at Guelph, tested 44 different brands of various herbal supplements, purchased in both the US and Canada. They found ridiculous levels of contamination. In fact, contamination is not the right word: one-third of the samples had no detectable amounts of the herb on the label. Instead, there were invasive weeds, ornamental plants from China, ground rice, soybeans, what have you. 10 of the 12 companies whose products were tested had at least one in this lovely category; 4 of them had nothing but.

This brings up several interesting questions: for one, how come this garbage continues to sell? Could it be that many of these preparations are of no benefit other than the placebo effect, which means that lawnmower scrapings will indeed work just as well? Second, who's ripping off whom? I would assume that some of these companies are buying from middlemen and repackaging, in which case, they're getting hosed (and passing the hosing along to you!) Doesn't anyone have even a passing interest in seeing if they've been sold the right material, or do they just not care, since it sells anyway?

When drug companies sell products of poor quality, the roof should come down on them, and I'm glad when it does. But these sleazeballs - is there even a roof to bring down? Now, I realize that some people will look at my background, and say, sure, this is someone who works in the pharma industry, of course he's going to put down these safe, natural, effective herbal medicines. Why, those would put his kind out of business if people just realized how wonderful they were! But I'm not denying that some herbal preparations can be used as medicines. If they can, though, they should have to prove it (the way we do in the drug industry), and they should have to actually sell what it says on the label, the way we do. Selling people a bunch of ditch clippings from a Chengdu compost pile is not acceptable, and if you're a big proponent of herbal remedies, you should be even more upset about this crap than I am.

More: Here's the New York Times on this story.

Comments (59) + TrackBacks (0) | Category: Snake Oil | The Dark Side

October 22, 2013

ACSNano on Problematic Papers

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Posted by Derek

The editorial board at ACSNano has come out with a statement on how they'd like problematic papers to be handled. This, the article most pointedly does not say, is surely a response to the controversy over a recent (ridiculously Photoshopped) paper that appeared in the journal. That one didn't make anyone look good, and I can see why the editors felt that they had to make an effort.

The piece is superficially reasonable. They're asking that if someone sees a paper with questionable content, that they should contact the journal first, which I think is good practice in any case. But then we have this:

In the end, a decision will be made, ranging from notification that no cause was found to support the accusations made, corrections to a published article, retraction of the article, and/or to notifying the authors’ institutions of such actions. At ACS Nano, we take scientific fraud seriously and, as needed, retract articles and place sanctions on authors for set numbers of years, including bans on further submissions. The difference between this formalized accusation investigation and reports in blogs or on Twitter is that, during the investigation, the authors of the article under dispute have a fair chance to explain, and the decisions are made by known experts in the field. After we have made our decision, all are welcome to comment on it in any blog, even if they have different opinions; this is their privilege. We strongly suggest that such comments be made without the cloak of anonymity, using real names and affiliations, so that direct and open discussion of the work can be understood by others.

While we appreciate readers being critical and thus helping to weed out incorrect or fraudulent manuscripts, we still should not consider each publication from a competitor as being potentially wrong. A climate of mistrust will not help anyone and will only hamper honest scientists, which are the great majority of our community. Researchers make their reputations by publishing excellent data, not by being whistleblowers with mixed records of accuracy. It is easy to criticize the work of others, but it is substantially harder to achieve something by oneself. In other words, be critical, but never forget to be fair. One can be competitive, but still friends with colleagues, who naturally are also in some ways competitors. We are all humans, and we should never forget the human touches in our work.

So no one is supposed to comment until the editors have made a decision, no matter how long that might take? Desirable or not, I don't see that happening. Look, a scientific paper, once published out on the flippin' internet, is open to comment from whoever wishes to read it. That's what it's there for, to be made use of as its readers find appropriate. I tend to think that a more wide-open discussion of the merits of articles (or their lack of same) is actually good for the field. It should spur people on to write better papers, and put a bit more fear into those who might be tempted to fake things up.

I realize that people are afraid of libel, of character assassination, and so on. But arguing over the details of scientific publications does not lend itself to those activities very easily, although it's certainly true that there are plenty of folks out there who would not above that sort of thing if they thought they could get away with it. But these misdeeds are rather transparent, for the most part, and can just end up making the accusers themselves look foolish. They get the same kind of scrutiny as everyone else. (And besides, don't the sorts of people who really get into that stuff have a significant overlap with the sorts who would fake their papers?) I don't see this as mistrust - I see it as science. If your results are firm, they should be able to stand up to some shaking. If they can't, well, everyone should know about it. If you accuse someone mistakenly, well, you yourself should be ready to take the consequences of that, too. On the other hand, assuming (as the ACSNano piece seems to assume) that anyone with complaints about a paper must be a disgruntled competitor seems be a rather mistrustful way to look at things, too.

That second paragaph above, with its "play nice" advice, should be read while glancing at the "nanorod" photos from that recent paper. Try to reconcile the high-minded tone with what you see, and see if you have any better luck than I did.

Comments (62) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

October 16, 2013

Holding Back Experimental Details, With Reason

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Posted by Derek

There's a lot of worry these days about the reproducibility of scientific papers (a topic that's come up here many times). And there's reason to believe that the sharing of data, protocols, and materials is not going so well, either.

. . . authors seem less willing to share these additional details about their study protocols than they have been in the past, according to a survey of 389 authors who published studies in the Annals of Internal Medicine. The findings, presented on 9 September at the International Congress on Peer Review and Biomedical Publication in Chicago, found that over the five years studied the percentage saying they would be willing to do so has dropped from almost 80% to only 60%.

A lack of incentives for sharing might be partly to blame. “There's no recognition, no promotion and no profit for scientists who share more information,” says Steven Goodman, a clinical research expert at Stanford University School of Medicine in California, who was part of the team that evaluated the survey results.

But there are two new papers out that deliberately does not share all the details, and it's not hard to see why. This NPR report has the background, but the abstract from the first paper will be enough for anyone in the field:

Clostridium botulinum strain IBCA10-7060, isolated from a patient with infant botulism, produced botulinum neurotoxin type B (BoNT/B) and another BoNT that, by use of the standard mouse bioassay, could not be neutralized by any of the Centers for Disease Control and Prevention–provided monovalent polyclonal botulinum antitoxins raised against BoNT types A–G.

That's not good. Until an antitoxin is available, the sequence of this new neurotoxin will not be published, although the fact of its existence is certainly worth knowing. The Journal of Infectious Diseases has two editorial articles on the issues that this work raises:

(The) identification of a novel, eighth botulinum neurotoxin (BoNT) from a patient with botulism expands our understanding of Clostridium botulinum and BoNT diversity, C. botulinum evolution, and the pathogenesis of botulism, but it also reveals a significant public health vulnerability. This new toxin, BoNT/H, cannot be neutralized by any of the currently available antibotulinum antisera, which means that we have no effective treatment for this form of botulism. Until anti-BoNT/H antitoxin can be created, shown to be effective, and deployed, both the strain itself and the sequence of this toxin (with which recombinant protein can be easily made) pose serious risks to public health because of the unusually severe, widespread harm that could result from misuse of either [3]. Thus, the dilemma faced by these authors, and by society, revolves around the question, should all of the information from this and similar studies be fully disseminated, motivated by the desire to realize all possible benefits from the discovery, or should dissemination of some or all of the information be restricted, with the goal of diminishing the probability of misuse?

I think they've made the right call here. (Last year's disputes about publishing work on a new strain of influenza are in just the same category.) Those studying botulin toxins need to know about this discovery, but given the molecular biology tools available to people, publishing the sequence (or making samples of the organism available) would be asking for potentially major trouble. This, unfortunately, seems to me to be an accurate reading of the world that we find ourselves in. There is a point where the value of having the knowledge out there is outweighed by the danger of. . .having the knowledge out there. This is going to be a case-by-case thing, but we should all be ready for some things to land on this side of the line.

Comments (14) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side | The Scientific Literature

October 10, 2013

A Leak at Lilly

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Posted by Derek

The Indianapolis Business Journal has reported that two ex-Lilly employees have been indicted on charges of stealing trade secrets:

The indictment charges two Carmel residents, Guoqing Cao and Shuyu Li, with seven counts of theft and conspiracy to commit theft. It also describes the actions of a third man, referred to only as Individual #1, who also played a part in the alleged crime.

According to the indictment, Cao and Li, both of whom are scientists with doctoral degrees, e-mailed sensitive information about nine experimental drug research programs at Lilly to Individual #1, who is employed by Jiangsu Hengrui Medicine Co. Ltd., based in China.

The story is puzzling in its details. These were apparently all "early stage" results across several therapeutic areas, which is hard to figure. If the information was from too early a stage, one wonders what the Jiangsu Hengrui Medicine Company would be able to make out of them, without spending a big pile of its own money, which I presume was not the plan. The article attaches a figure of $55 million to what was stolen, but I have absolutely no idea of how that was calculated. That must be a rough estimate of how much Lilly has spent on whatever it was; future value of these things is, naturally, a complete coin toss. We may also be looking at someone else's understanding of drug development, where everything short of picking the package color is considered early and/or brief. At any rate, Lilly's general counsel has said that the theft "does not significantly jeopardize our overall research and development pipeline", which makes you wonder why it was worth stealing in the first place. More on this as details come out. . .


Comments (11) + TrackBacks (0) | Category: The Dark Side

October 4, 2013

An Open Access Trash Heap

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Posted by Derek

Science magazine and writer John Bohannon have done us all a favor. There's a long article out in the latest issue that details how he wrote up a terrible, ridiculous scientific manuscript, attached a made-up name to it under the aegis of a nonexistent institution, and sent this farrago off to over three hundred open-access journals. The result?

On 4 July, good news arrived in the inbox of Ocorrafoo Cobange, a biologist at the Wassee Institute of Medicine in Asmara. It was the official letter of acceptance for a paper he had submitted 2 months earlier to the Journal of Natural Pharmaceuticals, describing the anticancer properties of a chemical that Cobange had extracted from a lichen.

In fact, it should have been promptly rejected. Any reviewer with more than a high-school knowledge of chemistry and the ability to understand a basic data plot should have spotted the paper's short-comings immediately. Its experiments are so hopelessly flawed that the results are meaningless.

I know because I wrote the paper. Ocorrafoo Cobange does not exist, nor does the Wassee Institute of Medicine. Over the past 10 months, I have submitted 304 versions of the wonder drug paper to open-access journals. More than half of the journals accepted the paper, failing to notice its fatal flaws. Beyond that headline result, the data from this sting operation reveal the contours of an emerging Wild West in academic publishing.

Well, sure, you're saying. Given the sorts of lowlife publishers out there, of course they took it, as long as the check cleared. But it's even worse than it appears:

Acceptance was the norm, not the exception. The paper was accepted by journals hosted by industry titans Sage and Elsevier. The paper was accepted by journals published by prestigious academic institutions such as Kobe University in Japan. It was accepted by scholarly society journals. It was even accepted by journals for which the paper's topic was utterly inappropriate, such as the Journal of Experimental & Clinical Assisted Reproduction.

Here's all the documentation, and it documents a sorry state indeed. You'll note from the world map in that link that India glows like a fireplace in this business. Nigeria has a prominence that it does not attain in the legitimate science publishing world, and there are exotic destinations like Oman and the Seychelles to be had as well. The editors of these "journals" tend to be people you've never heard of from universities that you didn't even know existed. And the editorial boards and lists of reviewers have plenty of those folks, mixed in with people who reviewed one paper before they didn't know better, and with people who didn't realize that their names were on the mastheads at all.

Bohannon didn't actually submit the exact same manuscript to all 304. He generated mix-and-match versions using an underlying template, giving him variations of the same crap and taking great care that the resulting papers should be obviously flawed:

he papers describe a simple test of whether cancer cells grow more slowly in a test tube when treated with increasing concentrations of a molecule. In a second experiment, the cells were also treated with increasing doses of radiation to simulate cancer radiotherapy. The data are the same across papers, and so are the conclusions: The molecule is a powerful inhibitor of cancer cell growth, and it increases the sensitivity of cancer cells to radiotherapy.

There are numerous red flags in the papers, with the most obvious in the first data plot. The graph's caption claims that it shows a "dose-dependent" effect on cell growth—the paper's linchpin result—but the data clearly show the opposite. The molecule is tested across a staggering five orders of magnitude of concentrations, all the way down to picomolar levels. And yet, the effect on the cells is modest and identical at every concentration.

One glance at the paper's Materials & Methods section reveals the obvious explanation for this outlandish result. The molecule was dissolved in a buffer containing an unusually large amount of ethanol. The control group of cells should have been treated with the same buffer, but they were not. Thus, the molecule's observed "effect" on cell growth is nothing more than the well-known cytotoxic effect of alcohol.

The second experiment is more outrageous. The control cells were not exposed to any radiation at all. So the observed "interactive effect" is nothing more than the standard inhibition of cell growth by radiation. Indeed, it would be impossible to conclude anything from this experiment.

I like this - the paper looks superficially presentable, but if you actually read it, then it's worthless. And yes, I realize that I've described a reasonable fraction of the ones that actually get published, but this is a more egregious example. I hope. The protocol was that Bohannon submitted the paper, and if it was rejected outright, that was that. If any reply came back addressing the paper's flaws in any way, he had a version ready to send back with more stuff in it, but without fixing any of the underlying problems. And if the paper was accepted, at any point in the process, he sent the journal a note that they'd discovered a serious flaw in their work and had to withdraw the manuscript.

157 journals accepted the paper, and 98 rejected it. He'd submitted it to a further 49 journals from his original list, but at least 29 of those appeared to be out of the business entirely, and the other 20 still had the paper "under review". So of those 255 decisions, 149 of them looked as if they'd occurred with little or no review. For a rejection, that's not so bad - this is a perfect example of manuscript that should not even be sent out for review. But the acceptances, well. . .

The other 106 editorial decisions made with some review are problematic, too. 70% of these were acceptances. Even in the few cases (36 times out of 304) where the paper was actually reviewed, and the reviewers realized that something was wrong with it (as they should have), the paper was accepted by 16 journals anyway.

The Elsevier journal that took this heap of junk was Drug Invention Today, in case you're wondering. I've never heard of it, and now I know why. The Sage journal was the Journal of International Medical Research, so you can strike that one off your list, too, assuming that the name wasn't enough all by itself. Another big open-access publisher, Hindawi (they advertise on the back cover of Chemistry World in the UK) rejected the paper from two of its journals, much to their relief. Jeffrey Beall's list of predatory publishers came as as pretty accurate, as well it might.

The problems with all this are obvious. These people are ripping off their authors for whatever publication fees they can scam, and some of these authors are not in a position to afford the treatment they're getting. No doubt some subset of the people who send manuscripts to these places are cynically padding their publication lists. The "editors" of these things get to reap a little unearned prestige for their "efforts" as well, so the whole enterprise just adds to the number of self-inflated jackasses with padded reputations, and the world is infested with too many of those people already. But I'm sure that there's another subset of authors who don't realize that they're submitting their results into a compost pile, and being asked to pay for the privilege. The first group are contemptible; the second group is sad. None of it's good.

Comments (57) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

September 30, 2013

They'll Fake the Journal if You'll Fake the Papers

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Posted by Derek

The Economist has a disturbing article on the extent of academic publishing fraud in China. It's disturbing that it goes on so much, and should be disturbing that it's in The Economist:

DISGUISED as employees of a gas company, a team of policemen burst into a flat in Beijing on September 1st. Two suspects inside panicked and tossed a plastic bag full of money out of a 15th-floor window. Red hundred-yuan notes worth as much as $50,000 fluttered to the pavement below.

Money raining down on pedestrians was not as bizarre, however, as the racket behind it. China is known for its pirated DVDs and fake designer gear, but these criminals were producing something more intellectual: fake scholarly articles which they sold to academics, and counterfeit versions of existing medical journals in which they sold publication slots.

As China tries to take its seat at the top table of global academia, the criminal underworld has seized on a feature in its research system: the fact that research grants and promotions are awarded on the basis of the number of articles published, not on the quality of the original research. . .

If there's one thing that economists are sure of, it's that you get what you subsidize (even if you might not have realized up front just what it was you were paying for). And if the Chinese establishment has decided that long publications lists are necessary, then long publication lists they shall have. The same thing happens in a drug research department when management is so foolish as to reward people for sheer number of compounds submitted - you get a deluge of amides, sulfonamides, and methyl-ethyl-butyl-futile coupling reactions. One half of the stockroom gets mixed with the other half, in the presence of HATU and/or palladiu, and voila, productivity on a shingle.

At least those are real componds. Apparently, many of the papers being generated under the Chinese onslaught are not just repetitious, bite-sized chunklets of stretched-out lab results, but flat-out fantasies:

The pirated medical-journal racket broken up in Beijing shows that there is a well-developed market for publication beyond the authentic SCI journals. The cost of placing an article in one of the counterfeit journals was up to $650, police said. Purchasing a fake article cost up to $250. Police said the racket had earned several million yuan ($500,000 or more) since 2009. Customers were typically medical researchers angling for promotion.

And this makes you wonder how many of the people doing the evaluating also knew, or suspected, that these journals were fakes, but had reasons of their own to pretend otherwise. Something needs to be done about all this, clearly, but that's not going to be possible without a lot of disruption. The longer it goes on, though, the worse that disruption might be. . .

Comments (21) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

September 26, 2013

An Unknown Author With Someone Else's Work. Why?

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Posted by Derek

Here's a bizarre one: someone apparently faked up a bunch of author names and contact information, and published results (in Biochemical and Biophysical Research Communications) that they're heard Bruce Spiegelman of Harvard talk about. The motive? Well. . .the only thing that makes sense is sheer vituperativeness, and even that doesn't make much. Here's the story - see if you can make sense of it!

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

September 19, 2013

File Under "Nerve, Lots Of"

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Posted by Derek

From an editorial in Science written by the president and the vice-president of the European Research Council:

Imagine sitting over a pile of applications submitted to one of the most prestigious funding agencies. Suddenly, what you read appears familiar—not only the idea, but its terminology and the methods proposed. You recognize entire sentences because you wrote them. This scenario must have been an utter surprise for one of the European Research Council’s (ERC’s) evaluation panel members who, last year, stumbled across the most bizarre case of scientific misconduct that the organization has witnessed so far.

Yep, the application had been copied from one of the reviewer's own grant applications, submitted a few years before on a different continent. It was just bad luck for the plagiarist that their copy-paste job landed up on the desk of the scientist who wrote it in the first place. But as the editorial goes on to say, the ERC ended up being unable to take any actions against this person (except, one assumes, denying the opportunity to fund them). Another case is mentioned from 2011, where an applicant from a "respected European university" forged a document in a grant application. The ERC notified the university, but that institution took no action until the person had applied for another grant while forging yet another document. Reading between the lines, you can see the whole editorial as (perhaps) a plea for being given powers to actually do something about these situations, or at the very least, a plea for those who can do something to actually do it once in a while.

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September 9, 2013

Exposing Faked Scientific Papers

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Posted by Derek

Chemistry World has a good article on the problem of shaky data in journal article, and the intersecting problem of what to do about it in the chemistry blogging world. Paul Bracher's ChemBark is, naturally, a big focus of the piece, since he's been highlighting some particularly egregious examples in the last couple of months (which I've linked to from here).

The phrase "witch hunt" has been thrown around by some observers, but I don't think that's fair or appropriate. In great contrast to the number of witches around (and their effectiveness), faked information in published scientific articles is very much a real thing, and can have real consequences. Time spent looking for it and exposing it is not time wasted, not when it's at its current levels. But who should be doing the looking and the exposing?

The standard answer is "Why, journal editors and reviewers, who shouldn't be letting this stuff past in the first place". Quite true. But in many cases, they are letting it past, so what should be done once it's published? A quiet, gentlemanly note to the editorial staff? Or a big blazing row in a public forum, such as a widely-read blog? Even though I don't start many of these myself, I come down more on the side of the latter. There are problems with that stance, of course - you have to be pretty sure that there's something wrong before you go making a big deal out of it, for one thing. Hurting someone else's reputation for no reason would be a bad thing, as would damaging your own credibility by making baseless accusations.

But in some of these recent cases, there's been little doubt about the problem. Take that nanorod paper: the most common result when I showed to to people was "Oh, come on." (And the most common result when I showed the famous "Just make up an elemental" paper to people was "Oh, (expletive)", with several common words all filling in appropriately). So if there's clearly trouble with a published paper, why is it such a good thing to make a big public spectacle out of it?

Deterrence. I really think that there will be less of this if people think that there's a reasonable chance that fake science will be exposed widely and embarrassingly. Covering up half your NMR spectrum with a box of digital white-out is fraud and people committing fraud have given up their opportunity to be treated with respect. And don't forget, the whole deterrence argument applies to editors and reviewers, too. I can guarantee that many chemists looked at these recent examples and wondered if they would have let these papers go through the review process, through carelessness or lack of time, and resolved to do better the next time. I certainly did.

That said, I do not intend to make this blog the full-time scourge of the chemical literature by patrolling the literature myself. If I see something suspicious, I'll speak up about it, and if other chemistry blogs (or readers) pick up on something, I'm very glad to hear about it or link to it. But finding these examples is a perfect example of something that I think is best left to the crowd. The person best equipped to discover a fraudulent paper is the person who is interested in its subject and would like to build on its results - in other words, the person who would be most harmed by it. And if someone fakes a paper, but no one ever reads it or refers to it, well, that's the author's own reward, and I hope that they enjoy it.

Comments (24) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

August 14, 2013

Now It's Novartis's Turn in China

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Posted by Derek

So reports FiercePharma, quoting a story in the 21st Century Business Herald and the Shanghai Daily. A former Novartis sales rep says that she was "ordered" to bribe doctors to meet sales quotas. As Tracy Staton at Fierce puts it:

With Chinese authorities actively looking for any suggestion of corruption or bribery, we're likely to see more whistleblowers come forward and officials investigations follow. Though no one wants to admit it, payments to doctors and hospitals have been commonplace in China for years. The BBC reported this week that bribes are "routinely paid" by big drugmakers in China, citing 5 pharma reps working in China. One of those reps, however, said such payments are "rare," and "only very few people" get money from pharma.

The government previously tolerated the practice--or encouraged it, even, by putting doctors on paltry salaries. Now, officials are targeting foreign drugmakers for it, perhaps to make examples of them, perhaps to twist their arms for lower prices. Probably both.

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August 13, 2013

Sanofi in China

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Posted by Derek

Now Sanofi is tangled up in trouble in China. The last few days have brought news of a wide-ranging investigation into payments to hospitals and medical workers, similar to what GlaxoSmithKline has been accused of.

And I don't have much reason to doubt either story, because (as this BBC story details) payments of this sort are rife. I would also note that, according to the AP, the Chinese government "is investigating production costs at 60 Chinese and foreign pharmaceutical manufacturers, according to state media, possible as a prelude to revising state-imposed price caps on key medications."

A system where everyone is in violation of the law has a lot of advantages - if you're the government. Retribution, when it's needed, is always at hand, because all you have to do is threaten to enforce what's already on the books. And lest someone think that I'm just beating away at the Chinese situation, the same applies to the US (on what I hope is a lower level). Here's economist Tyler Cowen, from the Marginal Revolution blog, on that very subject:

Faced with the evidence of an non-intentional crime, most prosecutors, of course, would use their discretion and not threaten imprisonment. Evidence and discretion, however, are precisely the point. Today, no one is innocent and thus our freedom is maintained only by the high cost of evidence and the prosecutor’s discretion.

The GSK and Sanofi allegations are, of course, all about intentional acts. But prosecuting them is very much up to the discretion of the Chinese authorities. If they're trying to root out corruption in their health care system, more power to them, because that's a worthy cause. But if they're just putting the squeeze on people long enough to bargain with them, only to let things return to the status quo ante after concessions have been extracted, then I have another opinion. Cynically, that's just what I expect to happen. After all, one might need to charge these companies with bribery again at some point. The Chinese authorities - authorities in general, all over the world - are not in the habit of putting down useful weapons and walking away from them.

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August 9, 2013

An Interview With A GSK Shanghai Scientist

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Posted by Derek

Here's an interview with Liu Xeubin, formerly of GlaxoSmithKline in China. That prospect should perk up the ears of anyone who's been following the company's various problems and scandals in that country.

Liu Xuebin recalls working 12-hour shifts and most weekends for months, under pressure to announce research results that would distinguish his GlaxoSmithKline Plc (GSK) lab in China as a force in multiple sclerosis research.
It paid off -- for a while. Nature Medicine published findings about a potential new MS treatment approach in January 2010 and months later Liu was promoted to associate director of Glaxo’s global center for neuro-inflammation research in Shanghai. Two months ago, his career unraveled. An internal review found data in the paper was misrepresented. Liu, 45, who stands by the study, was suspended from duty on June 8 and quit two days later.

Liu was the first author on the disputed paper, but he says that he stands by it, and opposed a retraction (only he and one other author, out of 18, did so). He had been at the NIH for several years before being hired back to Shanghai by Glaxo, which turned out to be something of a change:

“This was my first job in industry and there was a very different culture,” Liu said behind thick, rimless glasses and dressed in a short-sleeve checked shirt tucked neatly into his belted trousers. “I was also not experienced with compliance back then, and we didn’t pay enough attention to things such as recording of reports from our collaborators.”

There was also a culture in which Glaxo scientists were grouped into competitive teams, known as discovery performance units, which vied internally for funds every three years, he said. Those who failed to meet certain targets risked being disbanded.

What I find odd is Liu's emphasis on publishing, and publishing first. That seems like a very academic mindset - I have to tell you, over my time in industry, rarely have I ever felt a sense of urgency to publish my results in a journal. And even those exceptions have been for other reasons, usually the "If we're going to write this stuff up, now's the time" sort. Never have I felt that we were racing to get something into, say, Nature Medicine before someone else did. Getting something patented before someone else, into the clinic before someone else? Oh, yes indeed. But not into some journal.

But neither have I been part of a far-flung research site, on which a lot of money had been spent, trying to show that it was all worthwhile. Maybe that's the difference. Even so, if the results that the Shanghai group got were really important for an approach to multiple sclerosis therapy, that's all the more reason why the findings should have spoken for themselves inside the company (and been the subject of immediate further development, too). We don't have to get Nature Medicine (or whoever) to validate things for us: "Oh, wow, that stuff must be real, the journal accepted our paper". A company doesn't demonstrate that it finds something valuable by sending it out to a big-name journal, at least not at first: it does that by spending more time and money on the idea.

But Liu doesn't talk the way that I would expect in this article, and I feel sure that the Bloomberg reporter on this piece didn't pick up on it. There's no "We delivered a new MS program, we validated a whole new group of drug targets, we identified a high-profile clinical candidate that went immediately into development". That's how someone in drug R&D would put it. Not "We were racing to publish our results". It's all quite odd.

Comments (18) + TrackBacks (0) | Category: Drug Development | The Dark Side

August 8, 2013

Make Up the Elemental Analysis: An Update

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Posted by Derek

Chemistry Blog has more on the incident picked up first at ChemBark and noted here yesterday. This rapidly-becoming-famous case has the Supporting Information file of a paper published at Organometallics seemingly instructing a co-author to "make up" an elemental analysis to put in the manuscript.

Now the editor of the journal (John Gladysz of Texas A&M) has responded to Chemistry Blog as follows:

Wednesday 07 August
Dear Friends of Organometallics,

Chemical Abstracts alerted us to the statement you mention,which was overlooked during the peer review process, on Monday 05 August. At that time, the manuscript was pulled from the print publication queue. The author has explained to us that the statement pertains to a compound that was ”downgraded” from something being isolated to a proposed intermediate. Hence, we have left the ASAP manuscript on the web for now. We are requiring that the author submit originals of the microanalysis data before putting the manuscript back in the print publication queue. Many readers have commented that the statement reflects poorly on the moral or ethical character of the author, but the broad “retribution” that some would seek is not our purview. As Editors, our “powers” are limited to appropriate precautionary measures involving future submissions by such authors to Organometallics, the details of which would be confidential (ACS Ethical Guidelines, http://pubs.acs.org/page/policy/ethics/index.html). Our decision to keep the supporting information on the web, at least for the time being, is one of transparency and honesty toward the chemical community. Other stakeholders can contemplate a fuller range of responses. Some unedited opinions from the community are available in the comments section of a blog posting: http://blog.chembark.com/2013/08/06/a-disturbing-note-in-a-recent-si-file/#comments

If you have any criticisms of the actions described above, please do not hesitate to share them with me. Thanks much for being a reader of Organometallics, and best wishes. . .

This is the first report of the corresponding author, Reto Dorta, responding about this issue (several other people have tried to contact him, with no apparent success). So much for the theory, advanced by several people in the comments section at ChemBark, that "make up" was being used in the British-English sense of "prepare". Gladysz's letter gets across his feelings about the matter pretty clearly, I'd say.

Comments (31) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

August 6, 2013

Academic Kickbacks in China?

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Posted by Derek

Here's a provocative post over at Chemjobber's blog, taking off from a letter to C&E News. James Collmann (emeritus at Stanford) wrote in about a recent article on Chinese scientists returning to that country to take academic positions. He mentions, as a "widely known but seldom discussed" problem, that large research grants in China require an illegal kickback, in cash, to someone at the granting agency.

Having never applied for a grant in China, I have no testimony to offer here. Some readers may, though, be able to shed some light on this from their own experiences. I will say, however, that I do not find this unbelievable at all.

And for anyone who wants to pop up in the comments section and accuse me of blind anti-Chinese bias, the reason I find this plausible is because of the way politics worked back where I grew up in Arkansas. We had a number of officials in my part of the state whose career trajectories ended up with an encounter with federal prosecutors because of this same attitude. No substantial sum of money could change hands, these folks seemed to think, without some of it sticking to theirs along the way. Road and construction projects were particularly favored for this kind of thing, but it certainly didn't, and doesn't, stop there.

And lest someone pop up in the comments to accuse me of blind anti-Arkansas bias (which hasn't happened yet, although you never know), I adduce a long list of politicians and officials from other US states, with ex-governor Rod Blagojevich of Illinois coming to mind immediately. But one could just as easily reel off names from Rhode Island, Louisiana, Connecticut, Ohio, New York, Arizona, Massachusetts and many another state beside. The only differences between them, and between them and China (or between China and dozens and dozens of other countries) is how common this behavior might be, on what scale it is practiced, and how likely it is to be uncovered or punished. Differences in degree, in other words, not in kind.

And Chemjobber's commenters waste no time in mentioning the "overhead" system built into academic grants in the US. Universities have a standard rake that they take off the top of every grant that comes in, as most of you will know. Lest you think that it's the smaller and hungrier schools that do this the most, the overhead percentage is famously highest at some of the most prestigious places. This goes for administration (a roomy category), paying the salaries of faculty who have tenure but bring in no grants themselves, paying that salaries of entire departments who bring in precious little grant money themselves (because there's precious little to be given in their subjects), and so on. Not all of these are illegitimate uses, by any means, but I think a lot of people outside of academia might still be struck by how much money changes hands, and by what percentage of each hundred thousand that Professor X pulls in for research actually ends up going to Professor X's research. In their defense, though, I will say that these overhead arrangements in the US are made explicit, although they're not exactly advertised, and are used by the universities themselves, rather than quietly lining the pockets of someone at a granting agency.

At any rate, if anyone knows more about these accusations concerning China, please let us know in the comments. And if anyone finds them unbelievable prima facie, let us know about that, too. That would be nearly as interesting.

Update: it's been pointed out to me that there are very specific regulations in the US about using overhead funds for salaries (and many other restrictions, besides). I take the point; I've never had to wade through that paperwork. But I wonder - if this money is going into some other (approved) pile at the University, does that not somehow, some way, follow on through the various budgetary piles to free up money for those other uses?

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July 24, 2013

GSK Scandal Info

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Posted by Derek

Several comments to the posts on the GSK China problems seem quite. . .knowledgable. This has inspired a journalist to get in touch with me, but I've told her that (since these comments are anonymous) that I have no way of verifying their contents or getting in touch with the people who left them. She is, however, interested in hearing from people with knowledge of the situation, and has left a comment to that effect on the most recent post. I'm standing out of the way on this one; I merely note that the request is out there. Readers and commenters are free to use their own best judgment about what, if anything, to do about it.

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July 23, 2013

One GSK China Scandal Blends Into Another

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Posted by Derek

According to the New York Times, the problems with GSK's China operations have been going on for a while. It's worth distinguishing two types of trouble, though: there's the bribery scandal, where the company's representatives have been paying off people up and down the Chinese health system, and there's the scientific scandal at the Shanghai R&D site, which has led to a very public retraction and dismissal of employees. I make this distinction because the research end and the commercial end of a given drug company are usually quite far apart from each other; you have to go very high up the chain to find someone who's in charge of both.

What the Times has bears on the R&D problems, and it's not good. THey've obtained a confidential document dated November 2011:

Executives at the British drug maker GlaxoSmithKline were warned nearly two years ago about critical problems with the way the company conducted research at its drug development center in China, exposing it to potential financial risk and regulatory action, an internal audit found. . .

Auditors found that researchers did not report the results of animal studies in a drug that was already being tested in humans, a breach that one medical ethicist described as a “mortal sin” in the world of drug research. They also concluded that workers at the research center did not properly monitor clinical trials and paid hospitals in ways that could be seen as bribery.

That last part refers to a practice of paying clinical trial coordinators a flat fee for their services, regardless of how many people were enrolled at their site. This could be a way of paying someone for supposedly doing a full-time job when they're actually doing nothing of the kind. And that, I have to say, sort of mixes the paint together for all these stories: if even the clinical development group was paying people off, where does it end? Now we have a scientific scandal, a bribery scandal, and a scientific bribery scandal - if this goes on, I'm going to have to make a chart to keep it all straight.

I've been saying unkind and cynical things about the Chinese government while writing about the bribery scandal, and I don't plan on taking any of that back. But there are unkind things to say about GlaxoSmithKline, too. With all the information that's coming out, you have to wonder how well GSK was keeping an eye on things. The Chinese market is so huge, and so potentially lucrative, that some companies might just be tempted to say "OK, you folks are the XYZ Corporation's Chinese branch. Do what you need to do to stay competitive over here, but don't tell us about it, OK?" But I don't think that's something you can get away with, not forever. It catches up with you, especially when dealing with a government like China's that has no problem pitching high and inside when they feel the need.

GSK is a big company, full of people who understand how the world works. The Times document shows that they were aware of what was going on, and what could happen. And here it is, happening. Anyone on the inside who was sounding the alarm probably isn't getting much satisfaction about saying "I told you so", though.

Comments (31) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

July 18, 2013

China's GlaxoSmithKline Crackdown

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Posted by Derek

Keeping up with the GlaxoSmithKline/China story has been hard - every day or two there's a new twist. But here's what's going on so far:

Four GSK executives have been arrested on charges of bribery. Hospitals, doctors, officials of all kinds - the accusations are the the GSK people jacked up prices and sales figures by greasing people everywhere they thought necessary. Report have it that travel agencies (to inflate the costs of meetings and trips as a form of payment), high-priced consultation deals, and good ol' sexual favors were involved. In addition to the four executives who've been arrested, China has told GSK's financial director for that unit that he's not allowed to leave the country.

A mess indeed, and pretty much the last thing that GSK was in the market for, I'll bet. I am, sadly, not amazed at the idea of large organized bribery in the Chinese market. Nor, I'm sure, are the Chinese authorities. The country has a well-publicized problem with corruption, with high-level officials regularly being removed from their positions amid accusations of all sorts of malfeasance. Even if you mark some of that up to political maneuvering and score-settling (which I'm sure are factors, too), the country's current system of authoritarian capitalism is an invitation to such behavior on every level. Every country in the world has this sort of thing to some degree - who you know, who you're related to, who owes you favors, who you've paid off - but the combination of China's one-party system and its huge business boom of the last decades combine to make it a particular problem there.

It also combines to breed conspiracy theories. You might wonder if GSK is in trouble because their behavior was particularly noticeable or on a large scale, of if there's some other reason that we're not seeing. It's impossible to say, and not very fruitful to speculate on, but it's not a line of thought that can be dismissed easily, either. Perhaps the idea was pour encourager les autres. This article is along those lines:

A Chinese bribery investigation into British drugmaker GlaxoSmithKline (GSK.L) has sent tremors through multinational pharmaceutical firms in China, prompting at least one to review how they do business in the country.

Experts said foreign companies across the spectrum were watching closely to see what happened to GSK and its four detained Chinese executives given bribery and business go hand-in-hand in the world's second biggest economy. . .

Pharmaceutical companies are at the mercy of Chinese regulators in getting products licensed for import or manufacture in China, or to get them listed on the national drug registry. They typically rely on hired distributors to get their drugs to market and into hospitals. . .

. . .According to sources with knowledge of the industry, China's sophisticated and thriving market for fake documents also allows local employees to provide forged paperwork to more senior or global managers.

Efforts made by drug firms at compliance training can even backfire, as some employees learn how to avoid detection.

That Reuters piece also mentions speculation that the Chinese government is leaning hard on drug companies for better pricing, as it faces mounting health care costs, and you can't rule that one out, either. That's the problem - you can't rule much of anything out at all.

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July 16, 2013

Touching Up the Spectra

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Posted by Derek

Organic chemists have been taking NMR spectra for quite a while now. Routine use came on in the 1960s, and higher-field instruments went from exotic big-ticket items in the 1970s to ordinary equipment in the 1980s. But NMR can tell you more about your sample than you wanted to know (good analytical techniques are annoying that way). So what to do when you have those little peaks showing up where no peaks should be?

The correct answer is "Live with 'em or clean up your sample", but wouldn't it be so much easier and faster to just clean up the spectrum? After all, that's all that most people are ever going to see - right? This little line of thought has occurred to countless chemists over the years. Back In The Day, the technology needed to remove solvent peaks, evidence of isomers, and other pesky impurities was little more than a bottle of white-out and a pen (to redraw the lovely flat baseline once the extra peaks were daubed away). Making a photocopy of the altered spectrum gave you publication-ready purity in one easy step.

NMR spectra are probably the most-doctored of the bunch, but LC/MS and HPLC traces are very capable of showing you peaks you didn't want to see, either. These days there are all sorts of digital means to accomplish this deception, although I've no doubt that the white-out bottle is still deployed. In case anyone had any doubt about that, last month Amos Smith, well-known synthetic organic chemist and editor of Organic Letters, had this to say in a special editorial comment in the journal:

Recently, with the addition of a Data Analyst to our staff, Organic Letters has begun checking the submitted Supporting Information more closely. As a result of this increased scrutiny, we have discovered several instances where reported spectra had been edited to remove evidence of impurities.

Such acts of data manipulation are unacceptable. Even if the experimental yields and conclusions of a study are not affected, ANY manipulation of research data casts doubts on the overall integrity and validity of the work reported.

That it does. He went on to serve notice on authors that the journal will be checking, and will be enforcing and penalizing. And you can tell that Smith and the Org Lett staff have followed up on some of these already, because they've already had a chance to hear the default excuse:

In some of the cases that we have investigated further, the Corresponding Author asserted that a student had edited the spectra without the Corresponding Author’s knowledge. This is not an acceptable excuse! The Corresponding Author (who is typically also the research supervisor of the work performed) is ultimately responsible for warranting the integrity of the content of the submitted manuscript. . .

As the editorial goes on the say, and quite rightly, if a student did indeed alter the spectrum before showing it to the boss, it's very likely because the boss was running a group whose unspoken rule was that only perfection was acceptable. And that's an invitation to fraud, large and small. I'm glad to see statements like Smith's - the only ways to keep down this sort of data manipulation are to make the rewards for it small, increase the chances of it being found out, and make the consequences for it real.

As for those, the editorial speaks only of "significant penalties". But I have some ideas for those that might help people think twice about the data clean-up process. How about a special correction in the journal, showing the altered spectra, with red circles around the parts that had been flattened out? And a copy of the same to the relevant granting agencies and department heads? That might help get the message out, you think?

As an aside, I wanted to mention that I have seen someone stand right up and take responsibility for extra peaks in an NMR. Sort of. I saw a person once presenting what was supposed to be the final product's spectrum, only there were several other singlet peaks scattered around. "What are those?" came the inevitable question. "Water" was the answer. "Umm. . .how many water peaks, exactly?" "Oh, this one is water in solution. And this one is water complexed with the compound. And this one is water adsorbed to the inside of the NMR tube. And this one is water adsorbed to the outside of the. . ." It took a little while for order to be restored at that point. . .

Comments (38) + TrackBacks (0) | Category: Analytical Chemistry | The Dark Side | The Scientific Literature

July 15, 2013

An Update on the Wisconsin Lab Theft Case

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Posted by Derek

Back in April I mentioned this story, about a researcher at the Medical College of Wisconsin who'd been charged with economic espionage. The accusation was that Hua-jun Zhao had stolen an investigational oncology compound from the lab of Prof. Marshall Anderson, apparently to set up a research program with it back in China.

Now comes word that Zhao has pleaded guilty to a lesser charge, breaking into a university computer. But this is still not a good outcome for him:

Zhao, 41, initially pleaded not guilty to tampering with a private computer and lying to a federal agent. An additional charge of economic espionage was dropped but prosecutors maintained the right to renew it with a future indictment.

Instead, as part of a plea deal, Zhao pleaded guilty to a reduced charge of accessing a computer without authorization, thereby obtaining information worth at least $5,000. He faces up to five years in prison and a $250,000 fine and will be sentenced next month.

If this is what things got bargained down to, the situation must have been grim. The medical school says that it has no objection to the plea. The missing vials of compound have not been recovered, but it doesn't look like Zhao (update: fixed the name!) is going to be working on the stuff any time soon.

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July 12, 2013

Clinical Trial Fraud Uncovered

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Posted by Derek

Hmmm. This article from Bloomberg says that the BMS/Pfizer anticoagulant Eliquis (apixaban), a Factor Xa inhibitor approved late last year by the FDA, was delayed for months because of misconduct in its Chinese clinical trials. (Its clinical trials had not been without incident even before this). Documents posted by the FDA have the details. Says the article:

In the Eliquis trial, Bristol-Myers hired Pharmaceutical Product Development Inc., a closely held, Wilmington, North Carolina, company known as PPD, to help oversee it.

The Eliquis trial was questioned on two issues, according to the FDA documents first cited by the journal Pharmaceutical Approvals Monthly. One was the improper manipulation of records at a study site for 35 patients at the Shanghai 9th Peoples Hospital in China. The second involved the high percentage of the 9,000 patients who were supposed to be getting Eliquis, and instead were either given the wrong drug, or the wrong dose.

There was a broad list of issues at the Shanghai hospital, according to FDA documents. They included failure to report four potential adverse medical events, late reports on three others and three medical outcomes that weren’t included in the data. Additionally, some patient names and dates were wrong, and Chinese and English records didn’t match in some cases. The FDA also reported that some patient records disappeared just ahead of a site visit by agency inspectors.

I wonder if the Bloomberg reporter was tipped off to this himself, because you have to dig into this PDF (which is one of many) to find the goods (do a search for the words "Shanghai" and "fraud"). Here are some quotes from the document itself:

Although BMS contracted with a Contract Research Organization, PPD, to provide site monitoring for ARISTOTLE, PPD did not have a presence in the People’s Republic of China when the trial was initiated in PRC; BMS initially used its own employees for monitoring. One BMS employee along with at least one other individual altered subject records after being notified the site would be inspected by OSI. OSI inspected eight clinical sites worldwide after becoming aware of this action. Additionally, after errors in dispensing study drug became an issue, BMS and PPD, a CRO involved in conducting and monitoring ARISTOTLE, were inspected specifically to review the issue of trial oversight and monitoring. OSI concludes that the study appears to have been conducted and monitored adequately. They did recommend that data from sites in China be excluded because the employee who committed the GCP violation in China was involved in the conduct of the trial at all Chinese sites.

This came to light because a contract worker went to his or her supervisors with a problem: this person had been asked to change data and documentation on a hard drive before an FDA inspection, and the supervisor making the request (who was later fired) had worked at 18 other trial locations in China. This led the FDA, naturally enough, to say that it was worried about what else might have been going on, and to complain about broad problems with oversight.

As shown in the FDA documents, the agency went on to run the data with that specific site excluded, and then with all the other Chinese site data excluded, and the analysis still came out in favor of apixaban (although not as robustly in some categories). So the approval of the drug seems to have been the right call; the conclusions of the trial don't seem to have been switched by the misconduct. Still, you don't want this sort of thing.

Elliot Levy of BMS is quoted several times in the Bloomberg article, generally playing down the problems mentioned by the FDA: "not exceptional", "appropriately documented and reported", and so on. But if everything was normal, why did things stall for nine months? The lead outside investigator on the trial, Christopher Granger of Duke, has a different perspective:

“There is a greater likelihood of some of this impropriety in certain regions,” Granger said in a telephone interview. “We’ve had experiences in India and China where we’ve had more than we would have expected.”

Unfortunately, I think that's a fair assessment. But it doesn't have to be that way. There are vast numbers of ethical, hard-working scientists and staff in both India and China; it's not like these entire countries are full of cheaters and corner-cutters. But international companies go to these countries to get work done for lower cost, so the incentives are there to keep those costs down by whatever means come to hand. There are underhanded shortcutters in every country in the world, but some business environments give these people more scope to exercise their talents.

I'm actually glad when this sort of thing comes to light. Although it's not like Bristol-Myers Squibb or Lilly were rushing to do that, were they? I think that the only way to clean up this kind of behavior is to make it public, so that it has as many consequences as possible. If a country's reputation for doing fast, cost-effective clinical trials is compromised by a reputation for regulatory trouble and unreliable data, well, that's another set of incentives at work, but this time in the right direction. Throwing a towel over these incidents does no one any good in the long run. Make it public; make it sting.

Comments (10) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | The Dark Side

July 9, 2013

Non-Reproducible Science: A Survey

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Posted by Derek

The topic of scientific reproducibility has come up around here before, as it deserves to. The literature is not always reliable, and it's unreliable for a lot of different reasons. Here's a new paper in PLOS ONE surveying academic scientists for their own experiences:

To examine a microcosm of the academic experience with data reproducibility, we surveyed the faculty and trainees at MD Anderson Cancer Center using an anonymous computerized questionnaire; we sought to ascertain the frequency and potential causes of non-reproducible data. We found that ~50% of respondents had experienced at least one episode of the inability to reproduce published data; many who pursued this issue with the original authors were never able to identify the reason for the lack of reproducibility; some were even met with a less than “collegial” interaction.

Yeah, I'll bet they were. It turns out that about half the authors who had been contacted about problems with a published paper responded "negatively or indifferently", according to the survey respondents. As to how these things make it into the literature in the first place, I don't think that anyone will be surprised by this part:

Our survey also provides insight regarding the pressure to publish in order to maintain a current position or to promote ones scientific career. Almost one third of all trainees felt pressure to prove a mentor's hypothesis even when data did not support it. This is an unfortunate dilemma, as not proving a hypothesis could be misinterpreted by the mentor as not knowing how to perform scientific experiments. Furthermore, many of these trainees are visiting scientists from outside the US who rely on their trainee positions to maintain visa status that affect themselves and their families in our country.

And some of these visiting scientists, it should be noted, come from backgrounds in authority-centered and/or shame-based cultures, where going to the boss with the news that his or her big idea didn't work is not a very appealing option. It's not for anyone, naturally, but it's especially hard if you feel that you're contradicting the head of the lab and bringing shame on yourself in the process.

As for what to do about all this, the various calls for more details in papers and better reviewing are hard to complain about. But while I think that those would help, I don't see them completely solving the problem. This is a problem of human nature; as long as science is done by humans, we're going to have sloppy work all the way up to outright cheating. What we need to do is find ways to make it harder to cheat, and less rewarding - that will at least slow it down a bit.

There will always be car thieves, too, but we don't have to make it easy for them, either. Some of our publishing practices, though, are the equivalent of habitually walking away with the doors unlocked and the keys in the ignition. Rewarding academic scientists (at all levels) so directly for the number of their publications is one of the big ones. Letting big exciting results through without good statistical foundations is another.

In this vein, a reader sends along the news that the Reproducibility Initiative is now offering grants for attempts to check big results in the literature. That's the way to get it done, and I'm glad to see some money forthcoming. This effort is concentrating on experimental psychology, which is appropriate, given that the field has had some recent scandals (follow-up here) and is now in a big dispute over the reproducibility of even its honestly-meant data. They need all the help they can get over there - but I'll be glad to see some of this done over here in the biomedical field, too.

Comments (16) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

July 8, 2013

19 Years to a Retraction. Bonus Midnight Camera Footage Included.

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Posted by Derek

This Retraction Watch post details the longest correction/retraction saga I've heard of yet. A 1994 paper in Nature has finally been pulled back, after years and years of wrangling. And by "wrangling" I mean multiple attempted repeats, blinded samples, fraught exchanges over scientific ethics with one of the most high-profile professors in the Czech Republic and hidden camera footage from the lab freezer. Yep, it got to that point - midnight break-ins to alter the stored samples. Read the post for more; it's really something.

Comments (4) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 11, 2013

More on the GSK Shanghai Scandal

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Posted by Derek

The accusations of data fabrication at GlaxoSmithKline's China research site are quite real. That's what we get from the latest developments in the case, as reported by BioCentury, Pharmalot, and the news section at Nature Medicine. Jingwu Zang, lead author on the disputed paper and former head of the Shanghai research site, has been dismissed from the company. Other employees are on administrative leave while an investigation proceeds, and GSK has said it has begun the process of retracting the paper itself.

As for what's wrong with the paper in question, BioCentury Extra has this:

GSK said data in a paper published in January 2010 in Nature Medicine on the role of interleukin-7 (IL-7) in autoimmune disease characterized data as the results of experiments conducted with blood cells of multiple sclerosis (MS) patients "when, in fact, the data reported were either the results of experiments conducted at R&D China with normal (healthy donor) samples or cannot be documented at all, suggesting that they well may have been fabricated."

Pharmalot and others also report that GSK is asking all the authors of the paper to sign documents to agree that it be retracted, which is standard procedure at the Nature Publishing Group. If there's disagreement among them, the situation gets trickier, but we'll see what happens.

The biggest questions are unanswered, though, and we're not likely to hear about them except in rumors and leaks. How, for one thing, did this happen in the first place? On whose initiative were results faked? Who was supposed to check up on these results, and was there anything that could have been done to catch this problem earlier? Even more worrying - and you can bet that plenty of people inside GSK are thinking this, too - how many more things have been faked as well? You'd hope that this was an isolated incident, but if someone is willing to whip up a batch of lies like this, they might well be willing to do much more besides.

The involvement of the head of the entire operation (Jingwu Zang) is particularly troubling. Sometimes, in such cases, it turns out that the person at the top just had their name on the paper, but didn't really participate much or even know what was going on. But he's the only person so far in this mess who's been outright fired, which suggests that something larger has happened. We're not going to hear much about it, but you can bet there are some rather worried and upset people digging through this inside GlaxoSmithKline. There had better be.

Comments (30) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 7, 2013

Mutato Nomine De Te Fabula Narratur

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Posted by Derek

Reader may remember the sudden demise of science-fraud.org, under threats of legal action. Its author, Paul Brookes, had a steady stream of material pointing out what very much seemed to be altered and duplicated figures in many scientific publications.

Now comes word that the Brazilian researcher (Rai Curi) whose legal threats led to that shutdown has corrected yet another one of his publications. That Retraction Watch link has the details, but I wanted to highlight the corrections involved:

After the publication of this manuscript we observed mistakes in Figures 3A, 4A, and 6A. The representative images related to pAkt (Figure 3A), mTOR total (Figure 4A), and MuRF-1 total (Figure 6A) have been revised. Please note the original raw blots are now provided with the revised Figures as part of this Correction.
In Figure 3A, pAkt panel, the C and CS bands had been duplicated.
In Figure 4A, the bands were re-arranged compared to the original blot.
In Figure 6A, the band for group D was incorrect.

The remaining Figures, results and conclusions are the same as originally reported in the article. The authors apologize for these errors and refer readers to the corrected Figures 3A, 4A, and 6A provided in this Correction.

So I'm certainly glad that Prof. Curi went after a web site that looks for rearranged blots and altered gels. We wouldn't want any of that around. Would we, now.

Comments (32) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 6, 2013

Research Fraud at GSK Shanghai?

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Posted by Derek

Update: the story continues to develop. The scientist mentioned below, Jingwu Zang has been dismissed from GSK, and others are under investigation. The paper itself is in the process of being retracted. More here.

This is quite bad. Reports have been circulating that GlaxoSmithKline is investigating the scientists (and the results) behind this 2010 paper in Nature Medicine.

That first link from Pharmalot mentions this thread at the Chinese mitbbs.com site, and similar stuff has been showing up elsewhere. The online speculation is about Jingwu Zang (sometimes appearing as Zhang, the more common transliteration of the name), who was the lead author on the paper. Various postings (from the same person?) claim that Zang has been let go from GSK, and the Biocentury link in the first paragraph says that mail to his corresponding address bounces back.

The paper is (was?) on IL-7's role in autoimmune disease, a perfectly good topic for a drug company research group to be investigating, of course. But now we're going to have to watch to see if any retraction comes out of this - GSK doesn't have to comment on their hiring (and firing) decisions, but I hope that they wouldn't let a fraudulent Nature Medicine paper stand. That's the really disturbing thing about this situation; I'll see if I can explain what I mean.

A critic from outside the drug industry might say "So what? You people publish shady junk all the time? What's another truth-stretching paper, more or less?" Now, I resent implications like that, but at the same time, there have indeed been instances of nasty publication behavior (ghostwriting, etc.), which I deplore. But those things have been driving by the desire to increase sales of approved drugs. They come from overzealous marketing departments clawing for share, trying to get physicians to write for the company's drug over the other choices.

But the further back you go from the elbow-throwing front lines of the market, the less of that stuff you should see. The paper under scrutiny is early-stage research; it could have come from any good lab (academic or industrial) studying T-cell behavior, multiple sclerosis, or autoimmune mechanisms. Frankly, most of the shady stuff (and retractions) in this kind of work come from academia: the viciously competitive front lines of their market are publications in prestigious journals (like Nature Medicine), which directly bear on funding and tenure decisions. Drug companies have an incentive to stretch the truth about how wonderful their current drug is, not about what their scientists have discovered about biochemistry and cell biology. That doesn't bring in any money.

But what a publication like that does bring in, perhaps, is internal prestige. If you're trying to show what a big deal your particular branch of the company is, and what high-quality work they do, this would be one good way to do it. Keep in mind, publications like this are not the primary goal of people in the drug business; it's not like academia. The job of a drug company research group is to increase the number of drugs the company finds, and publishing in a good journal really doesn't have much to do with that. This publication, though, is a way of telling everyone else - other drug companies, other academic and industrial scientists, other departments and higher-ups at GSK, who may or may not know much about immunology per se, that GSK's Shanghai labs do good enough work to get it into Nature Medicine.

And while we're talking about this, let's talk about another widely-held belief about pharma research branches in China. There have, of course, been a number of these opened over the last five or ten years. And there are a lot of good scientists in China, and there are a lot of research topics that are relevant to the needs of a big drug company, so why not? But it's also widely assumed - although this is certainly not written down anywhere - that the Chinese government very much encourages big foreign companies to start such operations in China itself. If you lend your company's internationally known name to an operation in Shanghai (or wherever), if you invest in getting that site going, if you hire a big group of Chinese nationals to work there and manage things. . .well, the Chinese authorities are just going to like you more. Aren't they? And while being liked by the authorities is never a bad thing in any country in the world, particularly in a heavily regulated industry like pharmaceuticals, it is a particularly good thing in some of them.

This is an unfortunate situation. I believe very strongly in a government of laws, not of men - appropriately enough for where I work, that phrase was written by John Adams into the Constitution of Massachusetts. It's an ideal very difficult to realize, particularly since both Massachusetts and the rest of the world are stocked with human beings, but ideals are supposed to be difficult to realize. I understand that personal connections matter all over the world, and that this is by no means always a bad thing. But the bigger and broader the issues, the more important should be the rule of law.

The particular problem of multinational Chinese research institutes, which this current scandal can only worsen, is that too many people can assume that they've been built mainly to satisfy the Chinese government. They suffer, in other words, from the curse of affirmative action (and other such preference programs): the ever-present suspicion that once merit and ability are made secondary, that all bets are off. (This online debate at The Economist does a good job of airing out such concerns). In other words, the government of China could well end up accomplishing the exact reverse of what it's presumably trying to do: instead of elevating Chinese research (and researchers), it could be damaging the reputations of both.

Comments (58) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

May 17, 2013

A Little Ranbaxy Example

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Posted by Derek

Compare and contrast. Here we have Krishnan Ramalingam, from Ranbaxy's Corporate Communications department, in 2006:

Being a global pharmaceutical major, Ranbaxy took a deliberate decision to pool its resources to fight neglected disease segments. . .Ranbaxy strongly felt that generic antiretrovirals are essential in fighting the world-wide struggle against HIV/AIDS, and therefore took a conscious decision to embark upon providing high quality affordable generics for patients around the world, specifically for the benefit of Least Developed Countries. . .Since 2001, Ranbaxy has been providing antiretroviral medicines of high quality at affordable prices for HIV/AIDS affected countries for patients who might not otherwise be able to gain access to this therapy.

And here we have them in an advertorial section of the South African Mail and Guardian newspaper, earlier this year:

Ranbaxy has a long standing relationship with Africa. It was the first Indian pharmaceutical company to set up a manufacturing facility in Nigeria, in the late 1970s. Since then, the company has established a strong presence in 44 of the 54 African countries with the aim of providing quality medicines and improving access. . .Ranbaxy is a prominent supplier of Antiretroviral (ARV) products in South Africa through its subsidiary Sonke Pharmaceuticals. It is the second largest supplier of high quality affordable ARV products in South Africa which are also extensively used in government programs providing access to ARV medicine to millions.

Yes, as Ranbaxy says on its own web site: "At Ranbaxy, we believe that Anti-retroviral (ARV) therapy is an essential tool in waging the war against HIV/AIDS. . .We estimate currently close to a million patients worldwide use our ARV products for their daily treatment needs. We have been associated with this cause since 2001 and were among the first generic companies to offer ARVs to various National AIDS treatment programmes in Africa. We were also responsible for making these drugs affordable in order to improve access. . ."

And now we descend from the heights. Here, in a vivid example of revealed preference versus stated preference, is what was really going on, from that Fortune article I linked to yesterday:

. . .as the company prepared to resubmit its ARV data to WHO, the company's HIV project manager reiterated the point of the company's new strategy in an e-mail, cc'ed to CEO Tempest. "We have been reasonably successful in keeping WHO from looking closely at the stability data in the past," the manager wrote, adding, "The last thing we want is to have another inspection at Dewas until we fix all the process and validation issues once and for all."

. . .(Dinesh) Thakur knew the drugs weren't good. They had high impurities, degraded easily, and would be useless at best in hot, humid conditions. They would be taken by the world's poorest patients in sub-Saharan Africa, who had almost no medical infrastructure and no recourse for complaints. The injustice made him livid.

Ranbaxy executives didn't care, says Kathy Spreen, and made little effort to conceal it. In a conference call with a dozen company executives, one brushed aside her fears about the quality of the AIDS medicine Ranbaxy was supplying for Africa. "Who cares?" he said, according to Spreen. "It's just blacks dying."

I have said many vituperative things about HIV hucksters like Matthias Rath, who have told patient in South Africa to throw away their antiviral medications and take his vitamin supplements instead. What, then, can I say about people like this, who callously and intentionally provided junk, labeled as what were supposed to be effective drugs, to people with no other choice and no recourse? If this is not criminal conduct, I'd very much like to know what is.

And why is no one going to jail? I'm suggesting jail as a civilized alternative to a barbaric, but more appealingly direct form of justice: shipping the people who did this off to live in a shack somewhere in southern Africa, infected with HIV, and having them subsist as best they can on the drugs that Ranbaxy found fit for their sort.

Comments (43) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

May 16, 2013

Ranbaxy: Looking Under the Rock

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Posted by Derek

Here's an excellent, detailed look from Fortune at how things went off the rails at Ranbaxy and their generic atorvastatin (Lipitor). The company has been hit by a huge fine, and no wonder. This will give you the idea:

On May 13, Ranbaxy pleaded guilty to seven federal criminal counts of selling adulterated drugs with intent to defraud, failing to report that its drugs didn't meet specifications, and making intentionally false statements to the government. Ranbaxy agreed to pay $500 million in fines, forfeitures, and penalties -- the most ever levied against a generic-drug company. (No current or former Ranbaxy executives were charged with crimes.) Thakur's confidential whistleblower complaint, which he filed in 2007 and which describes how the company fabricated and falsified data to win FDA approvals, was also unsealed. Under federal whistleblower law, Thakur will receive more than $48 million as part of the resolution of the case. . .

. . .(he says that) they stumbled onto Ranbaxy's open secret: The company manipulated almost every aspect of its manufacturing process to quickly produce impressive-looking data that would bolster its bottom line. "This was not something that was concealed," Thakur says. It was "common knowledge among senior managers of the company, heads of research and development, people responsible for formulation to the clinical people.

Lying to regulators and backdating and forgery were commonplace, he says. The company even forged its own standard operating procedures, which FDA inspectors rely on to assess whether a company is following its own policies. Thakur's team was told of one instance in which company officials forged and backdated a standard operating procedure related to how patient data are stored, then aged the document in a "steam room" overnight to fool regulators.

Company scientists told Thakur's staff that they were directed to substitute cheaper, lower-quality ingredients in place of better ingredients, to manipulate test parameters to accommodate higher impurities, and even to substitute brand-name drugs in lieu of their own generics in bioequivalence tests to produce better results."

You name it, it's probably there. Good thing the resulting generic drugs were cheap, eh? And I suppose these details render inoperative, as the Nixon staff used to say, the explanations that the company used to have about talk of such problems, that it was all the efforts of their big pharma competitors and some unscrupulous stock market types. (Whenever you see a company's CEO going on about a conspiracy to depress his company's share price, you should worry).

The whole article is well worth reading - your eyebrows are guaranteed to go up a few times. This whole affair has been a damaging blow to the whole offshore generics business, India's in particular, and does not help them wear their "Low cost drugs for the poor" halo any better. Not when your pills have glass particles in them along with (or instead of) the active ingredient. . .

Comments (26) + TrackBacks (0) | Category: The Dark Side

May 7, 2013

One Case of Plagiarism Down. Two Zillion to Go.

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Posted by Derek

You may remember this case from Chemistry - A European Journal earlier this year, where a paper appeared whose text was largely copy-pasted from a previous JACS paper from another lab. This one has finally been pulled; Retraction Watch has the details.

The most interesting part is that statement "The authors regret this approach", which I don't recall ever seeing in a situation like this. The comments at Retraction Watch build on this, and are quite interesting. There are many countries (and cultures) where it's considered acceptable (or at least a venial sin) to lift passages verbatim from other English-language papers when you're publishing in that language. I can see the attraction - I would hate to have to deliver a scientific manuscript in German, for example, which is the closest thing I have to a second language.

But I still wouldn't do it by copying and pasting big hunks of text, either. Reasons for resorting to that range from wanting to be absolutely sure that things are being expressed correctly in ones third or fourth language, all the way to "Isn't that how it's supposed to be done?" The latter situation obtains in parts of Asia, where apparently there's an emphasis in some schools on verbatim transcription of authoritative sources. There's an interesting cite to Yu Hua's China in Ten Words, where one of those ten words is "copycat" (shanzhai):

As a product of China’s uneven development, the copycat phenomenon has as many negative implications as it has positive aspects. The moral bankruptcy and confusion of right and wrong in China today, for example, and vivid expression in copycatting. As the copycat concept has gained acceptance, plagiarism, piracy, burlesque, parody, slander, and other actions originally seen as vulgar or illegal have been given a reason to exist; and in social psychology and public opinion they have gradually acquired respectability. No wonder that “copycat” has become one of the words most commonly used in China today. All of this serves to demonstrate the truth of the old Chinese saying: “The soil decides the crop, and the vine shapes the gourd.”

Four years ago I saw a pirated edition of [my novel] Brothers for sale on the pedestrian bridge that crosses the street outside my apartment; it was lying there in a stack of other pirated books. When the vendor noticed me running my eyes over his stock, he handed me a copy of my novel, recommending it as a good read. A quick flip through and I could tell at once that it was pirated. “No, it’s not a pirated edition,” he corrected me earnestly. “It’s a copycat.”

This tendency isn't a good fit with a lot of things, but it especially doesn't work out so well with scientific publication. I haven't seen it stated in so many words, but a key assumption is that every scientific paper is supposed to be different. If you take the time to read a new paper, you should learn something new and you should see something that you haven't seen before. It might be trivial, it might well be useless, but it should be at least slightly different from any other paper you've read or could find.

Now, as the Retraction Watch comments mention, some of these plagiarism cases are examples of "templating", where original (or sort of original) work was done, but the presentation of it was borrowed from an existing paper. That's not as bad as faking up results completely, of course, but you still have to wonder about the value of your work if you can lift big swaths of someone else's paper to describe it. Even when the manuscript itself has been written fresh from the ground up, there's plenty of stuff out in the literature like this. Someone gets an interesting reaction with a biphenyl and a zinc catalyst, and before you know it, there are all these quickie communications where someone else says "Hey, we got that with a napthyl", or "Hey, we got that with a boron halide catalyst". Technically, yes, these are different, but we're in the land of least publishable units now, where the salami is sliced so thinly that you can read a newspaper through it.

So the authors regret this approach, do they? So does everyone else.

Comments (9) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

April 26, 2013

Research Fraud, From A Master Fraud Artist

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Posted by Derek

A couple of years back, I wrote about the egregious research fraud case of Diederick Stapel. Here's an extraordinary follow-up in the New York Times Magazine, which will give you the shivers. Here, try this part out:

In one experiment conducted with undergraduates recruited from his class, Stapel asked subjects to rate their individual attractiveness after they were flashed an image of either an attractive female face or a very unattractive one. The hypothesis was that subjects exposed to the attractive image would — through an automatic comparison — rate themselves as less attractive than subjects exposed to the other image.

The experiment — and others like it — didn’t give Stapel the desired results, he said. He had the choice of abandoning the work or redoing the experiment. But he had already spent a lot of time on the research and was convinced his hypothesis was valid. “I said — you know what, I am going to create the data set,” he told me. . .

. . .Doing the analysis, Stapel at first ended up getting a bigger difference between the two conditions than was ideal. He went back and tweaked the numbers again. It took a few hours of trial and error, spread out over a few days, to get the data just right.

He said he felt both terrible and relieved. The results were published in The Journal of Personality and Social Psychology in 2004. “I realized — hey, we can do this,” he told me.

And that's just what he did, for the next several years, leading to scores of publications and presentations on things he had just made up. In light of that Nature editorial statement I mentioned yesterday, this part seems worth thinking on:

. . . The field of psychology was indicted, too, with a finding that Stapel’s fraud went undetected for so long because of “a general culture of careless, selective and uncritical handling of research and data.” If Stapel was solely to blame for making stuff up, the report stated, his peers, journal editors and reviewers of the field’s top journals were to blame for letting him get away with it. The committees identified several practices as “sloppy science” — misuse of statistics, ignoring of data that do not conform to a desired hypothesis and the pursuit of a compelling story no matter how scientifically unsupported it may be.

The adjective “sloppy” seems charitable. . .

It may well be. The temptation of spicing up the results is always there, in any branch of science, and it's our responsibility to resist it. That means not only resisting the opportunities to fool others, it means resisting fooling ourselves, too, because who would know better what we'd really like to hear? Reporting only the time that the idea worked, not the other times when it didn't. Finding ways to explain away the data that would invalidate your hypothesis, but giving the shaky stuff in your favor the benefit of the doubt. N-of-1 experiments taken as facts. No, not many people will go as far as Diederick Stapel (or could, even if they wanted to - he was quite talented at fakery). Unfortunately, things go on all the time that might differ from him in degree, but not in kind.

Comments (27) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

April 2, 2013

Stealing A Compound, To Set Up in China

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Posted by Derek

Here's a strange case worth keeping an eye on. Via Deborah Blum's Twitter feed we have this report of a researcher in Wisconsin being charged with economic espionage - specifically, investigational oncology.

Huajun Zhao, 42, faces a single count of economic espionage, according to a federal criminal complaint, an offense punishable by up to 15 years in prison and a $500,000 fine. . .

. . .According to the complaint, Zhao worked as an associate researcher at the college, assisting professor Marshall Anderson by conducting experiments in pharmacology.

On Feb. 22, Anderson set down three pill bottle-size containers of a cancer research compound called C-25, and later noticed they were missing from his desk. After searching extensively for the bottles, he reported them lost or stolen on Feb. 26.

The next day, security video showed Zhao entering Anderson's office on Feb. 22, and leaving shortly after. No one else was seen entering the office on the videos. Security officials questioned Zhao, who didn't admit or deny taking the compound, but said he couldn't understand the questions, and that, regardless, everything would be resolved in 10 days.

The public safety manager of the college, Jessica Luedtke, contacted the FBI. She said Zhao had been disciplined months earlier for putting lab data on his personal computer. The college staff also discovered that on a professional researcher's website, Zhao claimed to have discovered a cancer-fighting compound that he wanted to bring back to China, where he had been from December till mid-February.

Since his return, his résumé lists him as an assistant professor at Zhejiang University in China.

There's more evidence presented in the article. The professor involved works on mitochondrial apoptosis and on Nf-kappaB inhibitors, but I've been unable to find any publications on the "C-25" compound itself. None of Prof. Anderson's recent papers seem to have an "H. Zhou" or anything similar in the list of co-authors, so that doesn't narrow things down, either.

This is quite odd. People do indeed steal compounds by a variety of means, but it doesn't always work out very well. But those examples involve taking things from industrial labs - stealing an academic compound like this is presumably being done to advance one's own career, rather than being a path to direct wealth. According to the report, a grant application was found on Zhou's computer, claiming that he had discovered this compound and proposing funding for more studies. It does make you wonder what it is, and what sort of tenure-achieving, publication-spinning, grant-renewing powers it has. Or perhaps it really does have promising oncology activity, and Zhou pictured himself getting into the business? More details as they become available. . .

Comments (41) + TrackBacks (0) | Category: Cancer | The Dark Side

April 1, 2013

Fake Journals - But They'd Like Real Money

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Posted by Derek

I wish that this were an April Fool's entry - and a number of scientists would like for that to have been the case, too. Nature reports that at least two journals (Archives des Sciences from Geneva and Wulfenia, a botany journal from Austria) have had their names hijacked by scam artists. Neither journal really had a web presence, so some enterprising sleazeball(s) decided to give each of them a convincing one. They were convincing enough to fool Thomson Reuters for months, and enough to get an unnamed number of authors to think that they'd published papers - after, I should add, sending publication fees to banks in Armenia. That last detail might (or should) have caused some worry, but who would have imagined a top-to-bottom counterfeit journal operation?

The journal "sites" even include editorial board members, some of whom seem to be fictitious, and some of whom are very much not (and were very much not aware that their names were being used). So if you're looking for evidence of how profitable scientific publishing can be, look no further: it's valuable enough to fake.

Comments (8) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

March 26, 2013

The Wyeth/Elan Insider Trading Case Resolves

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Posted by Derek

You may remember this insider trading scandal from last year, involving a lead investigator for Wyeth/Elan's trials of bapineuzumab for Alzheimer's.

Here's the sequel. The hedge fund involved has agreed to pay $600 million dollars to settle the charges, although this does not get the manager himself off the hook (litigation in his case continues). Dr. Sidney Gilman, the investigator who leaked the information, has already been required to give back all his own gains, with interest and penalties.

Comments (6) + TrackBacks (0) | Category: Business and Markets | Clinical Trials | The Dark Side

March 14, 2013

Thallium Poisoning, Again

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Posted by Derek

I agree with something Chemjobber said about this case - there's clearly a lot more to it than we know. Last fall, a student at the University of Southampton in the UK was poisoned with arsenic and thallium. According to this article in Chemistry World, it was more than the usual lethal dose, and both accidental exposure and suicide have been ruled out. The student himself is making a slow recovery; I wish him the best, and hope to eventually report good news.

So, not an accident, and not suicide. . .well, that doesn't leave much but intentional poisoning, does it? As this post details, though, thallium is the murder weapon of idiots who think that they're being high-tech. The Dunning-Kruger effect in action, in other words.

Comments (15) + TrackBacks (0) | Category: The Dark Side | Toxicology

March 6, 2013

Anonymity, Fakery, et al.

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Posted by Derek

I wanted to link to this piece at C&E News on the whole question of anonymity when it comes to comments on the chemical literature. This was brought on by the advent of Blog Syn, but it applied before that, and will continue to apply to other situations.

Its author, Fredrik von Kieseritzky, also calls for synthetic details to make it back into the body of papers, rathe than being relegated to the Supporting Information (which is never as carefully refereed as the manuscript itself). That would be a good thing, but I despair of it happening, at least until the major journals break down and admit that their page count restrictions for submissions are, in large part, relics of the days when everyone read them in print. (They serve another useful function, thought, which is getting people to tighten up their writing. "There wasn't enough time to make it shorter" is a real phenomenon).

But the rest of the commentary grew out of this piece by Rich Apodaca, whose morning it is around here. He wonders about the use of pseudonyms in science, where author recognition has long been a big motivating factor. von Kieseritzky's take is that he can see why people go anonymous (and Rich lists some very plausible reasons, too), but that he's never regretted using his own name online.

That goes for me, too. The topic of anonymity has come up here several times over the years: in chem-blogging, and in peer review of publications and grants. I'm glad that I've used my real name over the years on this blog (although it hasn't always been a smooth ride), but I also think that anonymity is a necessary option, although it certainly can be abused.

That opinion is not shared by the (pseudonymous) author of this piece in the Journal of Cell Science. It's a bit of dystopian what-if, an agitated response to the (now taken down) Science Fraud site. "Mole VIII" relates how some people (an extremely small percentage) did indeed fake scientific papers, and how this embittered other people who had been unable to make the careers in science that they wished to. So they started web sites where they cried "Fake!" about papers of all kinds, which forced the authors to spend all their time defending themselves. Many of them were driven out of doing science, whereupon they turned to exposing their former colleagues as the next best thing. And then, in one generation, science was done - stopped forever, in a hurricane of finger-pointing and snide remarks.

What a load. For one thing, I think that fakery, while not rampant, is more widespread than many people think. And even if it isn't, I think that legitimate results stand up to challenges of this sort, while the shady ones collapse at a push. Furthermore, I find the whole cycle-of-bitterness conceit ridiculous. A look back at the history of science will show that accusations of fakery and bad faith have been with us forever, and often in much more vitriolic form than today.

One problem might be that the author is a bit too academic. Try this part:

Soon, there were very few scientists left. And then fewer. Public confidence for publicly funded research disappeared. The only research that was done any more was kept secret and in the corporations. And while this gave us many new package designs for the sale of established drugs, the actual idea of ‘doing science’, of making discoveries to share with a community of interested and devoted researchers, dwindled, and finally, vanished.

Yep, that's about the size of it - package designs. I try to stay alert to threats to the scientific endeavor, and I try not to take it for granted. But I'm willing to put my real name on the opinion that the author of this stuff is being foolish.

Comments (14) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

February 19, 2013

The Wages of Copy-Pasting

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Posted by Derek

A few weeks ago I mentioned this situation regarding work by Prof. Xi Yan. Two recent papers seem to have been substantially copy-pasted from earlier work published by completely different groups. Now See Arr Oh has some details on what happens to you when you have the nerve to do that in a journal of the Royal Society of Chemistry: why, you have to publish a note regretting that you didn't cite the paper you copied from, that's what. "The authors apologize for this oversight."

There, that should square things up. Right? See Arr Oh is not very happy about this response, and I don't blame him for a minute. The RSC editors seem to be ignoring the word-for-word aspect of a substantial part of the new paper; it really is a paste job, and you're not supposed to do that. And the only problem they have is that the paper being stolen from wasn't cited? Oversight, my various body parts.

Comments (20) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

February 7, 2013

How To Enhance Your Online Reputation. Sure.

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Posted by Derek

We will file this one under N, for Nerve, Lots Of. Readers will probably remember the cancer research scandal at Duke a couple of years ago, where Anil Potti turned out to have faked a wide range of results in the clinic. This led to his leaving Duke rather abruptly, with a trail of retracted papers, all sorts of unpleasant complications with the funding agencies and so on. Retraction Watch covered this business extensively, as well they might have, since it's just the sort of thing that site helps to spotlight.

The campus newspaper (the Duke Chronicle) noted at the time that Potti had hired some sort of online reputation management firm. (I should mention in passing that I owe a debt to that newspaper, whose crossword puzzle got me through an electron spin resonance course while I was a grad student in the 1980s. Without it I would have been forced to listen to the lecture material, and who knows what would have become of me then?) It looks like these reputation-polishers are still in business. That's why that link to Retraction Watch goes to their front page instead of one of their posts on the scandal itself.

Those posts have been taken down, you see. Oh, yes. Copyright problems, don't you know - why, one of the most famous news sites in the world, one "Newsbulet.in" turns out to have published all that stuff on its own, and has filed a DMCA takedown notice with Wordpress to have the posts removed.

It must be bovine waste products week around here at In the Pipeline. because that's another big steaming load of the stuff. Here, take a look at the request itself:

Myself Narendra Chatwal Senior editor in NewsBulet.In, a famous news firm in India. All the news we publish are individually researched by our reporters from all over India and then we publish them on our site and our news channel. Recently we found that some one had copied our material from the category Medical Reviews and published them on their site. So we request you to help us in protecting our content and copy right.

Ah, but if you take a look at that domain, you find that it didn't even exist until October 2012, well after all but one of the posts that they're complaining about. And as the commenters to the Ars Technica post on this noticed, the address given in the WhoIs records corresponds to a nightclub in London. Peachy. So not only is this a spurious copyright complaint, it's a stupid, incompetent spurious copyright complaint. Whoever is providing this sort of service to Anil Potti is ripping him off - not that that bothers me much after reading the facts in the Duke case.

And the thing is, this sort of effort is futile. It's the very definition of futile, because getting the internet off of you is impossible. That Duke Chronicle story says (at the time of its writing) that the first page of Google results about Potti contained no mention of the scandal, just social media sites and glowing statements. That sure didn't last long, though - now the front page contains lots of details about the Duke imbroglio, and (as of this morning) several discussions of this current ridiculous DMCA effort.

After reviewing the facts of the earlier case, and these new attempts at reputation-burnishing being done on his behalf, I'm sticking with my earlier statements about Dr. Potti: I would not hire him to mow my lawn. Has Newsbulet.in published that before?

Comments (16) + TrackBacks (0) | Category: The Dark Side

January 23, 2013

Coincidence, No Doubt. Well, Some Doubt.

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Posted by Derek

Has anyone happened to read this paper, from 2009, or this one, from this year? Well, Shawn Burdette of WPI has, and he noticed that (to a significant extent) they're the same paper. Prof. Valerie Pierre of Minnesota, author of the first paper, is reportedly not too amused, and I don't blame her. But hey, the 2013 authors did at least cite her paper. . .in reference 14d. So at least there's that.

Update: but wait, there's more!

Comments (12) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

January 21, 2013

Dr. Das Sues U Conn. Good Luck With That.

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Posted by Derek

About this time last year, I mentioned Prof. Dipak Das at the University of Connecticut, who was the involved in a large accusation of research fraud. That second link has some quotes from a press release put out by Resveratrol Partners defending Prof. Das and his work, and I've just received another one. So if you're wondering how these things work here in these days of modern times, this is how:

Noted red wine molecule heart researcher Dipak Das PhD has filed a $35 million defamation claim against the University of Connecticut (U CONN) Health Center for wrongful termination, violation of the university’s by-laws, and lack of due process as protected by the 14th Amendment to the United States Constitution.

I don't see a copy of the press release out on the web yet (I'll put up a link when one shows up). One of its claims is that Das's work on resveratrol and heart attacks has not been shown to be invalid:

Specifically, U CONN Health Center authorities claimed Dr. Das had altered images showing the production of gene-derived proteins (called a western blot image). But alteration of these images would only change understanding of the underlying genetic mechanisms involved in Dr. Das’ experiments, not the conclusions of his studies which showed unequivocal ability of resveratrol to protect the heart prior to and during a heart attack.

I believe that this effort is going to be an uphill fight, because those alterations, if they occurred (which they most certainly seem to have) would be enough grounds for dismissal by themselves. The press release also makes much of the university's accusation that Das was the only person with a key to the office where the images were manipulated, saying that this was not the case, that students went in and out all the time. I don't care. Das was the lead author on all those papers, and if he couldn't keep up with his own lab's work enough to catch any of these things, he wan't doing his job. Das was fired from U Conn last year, and (via Retraction Watch, which has him at 19 retractions so far), I see that the university's board of trustees unanimously affirmed that decision.

Comments (8) + TrackBacks (0) | Category: The Dark Side

January 4, 2013

Science Fraud and Legal Action

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Posted by Derek

There have been occasional links here in the comments to Science-Fraud.org, although I'm not sure if I ever linked them directly or not. Note the use of the past tense: as detailed here at Retraction Watch, the site has suddenly gone (mostly) dark under threats of legal action. Nothing appears on the Wayback Machine at archive.org, either.

I'm not all that surprised. I've said unkind things about people and organizations on this blog, but Science Fraud seemed to have that pedal pushed down to the floor the entire time. And while I've had threats of legal action, I think that I've managed to stay just this side of defamation, although with some people that's hard to do. (I mean for that to be interpreted both ways - both that it's hard to avoid saying nasty things about some people, but also that in such cases, it's hard to think of things that are nasty enough to be defamatory). But which side of that line Paul Brookes, the now-public U. Rochester scientist behind the Science Fraud site, has landed on is still up for debate. More as this story develops. . .

Comments (4) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

December 21, 2012

The Last Thing a Professor Wants to Hear

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Posted by Derek

This can't be good. A retraction in PNAS on some RNA-driven cell death research from a lab at Caltech:

Anomalous experimental results observed by multiple members of the Pierce lab during follow-on studies raised concerns of possible research misconduct. An investigation committee of faculty at the California Institute of Technology indicated in its final report on this matter that the preponderance of the evidence and the reasons detailed in the report established that the first author falsified and misrepresented data published in this paper. An investigation at the United States Office of Research Integrity is ongoing.

As that link from Retraction Watch notes, the first author himself was not one of the signees of that retraction statement - as one might well think - and he now appears to be living in London. He appears to have left quite a mess behind in Pasadena.

Comments (14) + TrackBacks (0) | Category: Biological News | The Dark Side | The Scientific Literature

December 17, 2012

Dr. Gilman's Turn Toward the Inside

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Posted by Derek

Remember that story last month about insider trading on the Wyeth bapineuzumab Alzheimer's results? Dr. Sidney Gilman of Michigan is accused of passing on the data and profiting from it. Now the New York Times has some very interesting background:

What is clear is that Dr. Gilman made a sharp shift in his late 60s, from a life dedicated to academic research to one in which he accumulated a growing list of financial firms willing to pay him $1,000 an hour for his medical expertise, while he was overseeing drug trials for various pharmaceutical makers. Among the firms he was advising was another hedge fund that was also buying and selling Wyeth and Elan stock, though the authorities have given no sign they have questioned those trades.

His conversion to Wall Street consultant was not readily apparent in his lifestyle in Michigan and was a well-kept secret from colleagues. Public records show no second home, and no indication of financial distress. Nevertheless, he was willing to share a glimpse of his lifestyle with a 17-year-old student whom he sat next to on a flight from New York to Michigan a few months ago, telling her how his Alzheimer’s research allowed him to enjoy fine hotels in New York and limousine rides to the airport.

This is hard. Experts have real value, and should be able to share the expertise that they've built up. But when these amounts of money are involved, there seems no way to do that without walking through a minefield. I get the impression that Prof. Gilman may have found out the truth of Screwtape's assertion:

"Indeed the safest road to Hell is the gradual one--the gentle slope, soft underfoot, without sudden turnings, without milestones, without signposts. . ."

Comments (11) + TrackBacks (0) | Category: The Dark Side

November 20, 2012

And Since We're Talking About Insider Trading

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Posted by Derek

Here's something from just this morning, a whopping large case on illegal trading in Wyeth and Elan stock. This one involves a hedge fund manager, Mathew Martoma, and (quite disturbingly), Dr. Sidney Gilman of the University of Michigan, who was the lead investigator on a very large bapineuzumab trial for Alzheimer's. His conduct appears, from the text of the complaint, to be completely inexcusable, just a total, raw tipoff of confidential information.

I blogged at the time about the trial results, not knowing, of course, that someone had been pre-warned and was trading 20 per cent of Elan's stock volume on the news (and at least ten per cent of Wyeth's). So I take back anything I said about insider trading cases becoming more small-time over the years; this case has jerked the average right back up.

Update: Adam Feuerstein on Twitter: "Gilman's presentation of bapi data at 2008 ICAD meeting was so poorly done. It was shockingly bad. Now we know why."

Comments (18) + TrackBacks (0) | Category: Alzheimer's Disease | Business and Markets | Clinical Trials | The Dark Side

Easy Money, Right?

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Posted by Derek

Public biopharma companies have to put in a lot of effort to safeguard sensitive information. Since we have so many big, important binary events in our business (clinical trial results, sales figures for individual drugs, and so on), you really have to keep that stuff from getting out and around.

Which means that there's also a strong incentive for such things to leak. One could do very well for one's self, if one were not so concerned with being forced to disgorge all of one's profits, and even spending one's time in the slammer. And those factors completely neglect one's sense of ethics, assuming that one has any. These concerns are brushed aside strictly on a risk basis, one understands:

John Lazorchak, 42, director of financial reporting at Celgene, regularly tipped others to nonpublic information on acquisitions, quarterly earnings results and regulatory news, according to a Federal Bureau of Investigation complaint filed yesterday in federal court in Newark, New Jersey.
Mark Cupo, 51, the director of accounting and reporting at Sanofi-Aventis, now known as Sanofi; and Mark Foldy, 42, a marketing executive at Stryker Corp., also were charged. Prosecutors said most of the profit went to Lawrence Grum, 48, and Michael Castelli, 48, who also tipped friends and family. The case involves two sets of high school friends and at least one witness who secretly recorded Grum for the FBI.

Oh, dear. The total profit, in this instance, is about $1.5 million, and standards vary, but even if I had ethical problems I wouldn't run such risks for a share of that amount. Or the full amount, either. But as this Bloomberg story details, insider trading seems to have become a rather more democratic activity over the years, and the amounts of money involved have changed accordingly. Perhaps the people involved are thinking that these sums are too small to be noticed, by the standards of Wall Street and the SEC, and that they'll have a better chance of getting away with the trades.

Not so. I knew someone once who was having a dispute with the IRS, and was (by my standards) insufficiently concerned about his situation. "I'm just a little guy", was the response, "they don't care about someone like me". What I told him was "Whales eat plankton, you know". In that spirit, that second link gives the grim details of a case involving an employee at Seattle Genetics, and it could serve as the template for many others like it. It's a sad story. Most of them are.

Comments (14) + TrackBacks (0) | Category: Business and Markets | The Dark Side

November 6, 2012

How Much Fraud, As Opposed to Plain Old Error?

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Posted by Derek

How many retracted papers, would you say, are due to honest error rather than fraud and other misconduct? We now can put a number on that, thanks to this paper. The authors have looked over all 2,047 paper listed on PubMed from the life sciences as "retracted" (better them than me), with the earliest going back to 1977. The authors are careful to point out that this is absolutely an underestimate, though, with several examples of papers which are known to be fraudulent but have never been officially retracted. But they find that:

. . .only 21.3% of retractions were attributable to error. In contrast, 67.4% of retractions were attributable to misconduct, including fraud or suspected fraud (43.4%), duplicate publication (14.2%), and plagiarism (9.8%).

They blame incomplete and outright misleading retraction notices for confusing the issue about these numbers. (I've always liked, in a teeth-gritting way, the idea of a dubious retraction notice - it gives these things the full surround-sound sensory experience). Many published retractions that blame things like "flaws in the data analysis" turn out, on follow-up, to have been the subject of investigations that strongly suggested fraud.

Other trends: the US, Germany, Japan, and China accounted for the majority of papers pulled because of fraud, but China and India each stand out a bit in a crowded plagiarism field (China also stand out in the "duplicate publication" category). Higher-impact journals were significantly more likely to have papers retracted because of outright fraud rather than plagiarism (a result that makes sense, and squares with my own experience as a reader). And retractions have definitely been increasing over time, probably with several factors operating at once (greater incentives to fraud, coupled with increased detection). The paper sums up this way:

Given that most scientific work is publicly funded and that retractions because of misconduct undermine science and its impact on society, the surge of retractions suggests a need to reevaluate the incentives driving this phenomenon. We have previously argued that increased retractions and ethical breaches may result, at least in part, from the incentive system of science, which is based on a winner-takes-all economics that confers disproportionate rewards to winners in the form of grants, jobs, and prizes at a time of research funding scarcity.

Fixing this, though, will not be easy. There are recommendations for an increased focus on ethics training (which will do nothing at all, I think, to stop the sort of person who would do these sorts of things). But they also call for some standardization of retraction notices, with minimum standards of disclosure, which sounds like a good idea, and also for trying to find some way to reward scientists that doesn't involve publishing a ton of papers. I like that idea, too, although the implementation will be tricky. . .

Comments (10) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

November 1, 2012

Hype, Malpractice, and Scientific Misconduct in Organic Synthesis

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Posted by Derek

That's the word-for-word title of a provocative article by Rolf Carlson and Tomas Hudlicky in Helvetica Chimica Acta. That journal's usually not quite this exciting, but it is proud of its reputation for compound characterization and experimental accuracy. That probably helped this manuscript find a home there, where it's part of a Festschrift issue in honor of Dieter Seebach's 75th birthday.

The authors don't hold back much (and Hudlicky has not been shyabout these issues, either, as some readers will know). So, for the three categories of malfeasance described in the title, the first (hype) includes the overblown titling of many papers:

As long as the foolish use of various metrics continues there is little hope of return to integrity. Young scientists entering academia and competing for resources and recognition are easily infected with the mantra of importance of
publishing in 'high-impact journals' and, therefore, strive to make their work as noticeable as possible by employing excess hype.

It is the reader, not the author, of papers describing synthetic method who should evaluate its merits. Therefore, self-promoting words like 'novel', 'new', 'efficient', 'simple', 'high-yielding', 'versatile', 'optimum' should not be used in the title of the paper if such qualities are not covered by the actual content of the paper.

It also includes the inflation of reaction yields (see that link in the second paragraph above for more on that topic). This is another one that's going to be hard to fix:

Unfortunately, the community has chosen and continues to choose the yield values in submitted manuscripts as a measure of overall quality and/or utility of the report. This, of course, encourages the 􏰛'adjustment' in the values in order to avoid critique. An additional problem in the reported values is the fact that synthesis is performed on small scales, thanks to advances in NMR and other techniques available for structure determination. On milligram scales it is extremely difficult to accurately determine weight and content of a sample, given the equipment available in typical academic laboratory.

The second category, malpractice, is sloppy work, but not outright fraud:

Malpractice, as explained above, is usually not deliberate and derives primarily from ignorance or professional incompetence. The most frequent cases involve improper experimental protocols, improper methods used in characterization of compounds, and the lack of correct citations to previous work.

For example, the authors point out that very, very rarely are any new synthetic methods given a proper optimization. One-variable one-at-a-time changes are worthwhile, but they're not sufficient to explore a reaction manifold, not when these changes can interact with each other. As process chemists in industry know, the only way to explore such landscapes is with techniques such as Design of Experiments (DoE), which try to find out what factors in a multivariate system produce the greatest change in results. Here's an example; the process chemistry literature furnishes many more.

And finally, you have outright scientific misconduct - fraud, poaching of ideas from grant applications and the like, plagiarism in publications, etc. It's hard to get a handle on these - they seem to be increasing, but the techniques to find and expose them are also getting better. Over time, thought, these techniques might just have the effect of making fraud more sophisticated; that would be in line with human behavior as I understand it, and with selection pressure as well. The motives for such acts are with us still, and do not seem to be abating much, so I tend to think that determined miscreants will find ways to do what they want to do.

Thoughts? Some of this paper's points could be put in the "grumblings about the good old days" category, but I think that a lot of it is accurate. I'm not sure how good the old days were, myself, since they were also filled with human beings, but the pressures found today do seem to be bringing on a lot of behaviors we could do without.

Comments (71) + TrackBacks (0) | Category: Chemical News | The Dark Side | The Scientific Literature

October 22, 2012

The Absolute Bottom of the Publishing Barrel

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Posted by Derek

Every so often, you come across scientific journals that you've absolutely, completely never heard of. Back in graduate school (mid-1980s for me), I used to keep track of the weirdest references that came up - Journal of the Siberian Oil Chemist's Society, or Bulletin of the Kentucky Academy of Sciences (1954), which I think you'd have a hard time laying your hands on even in Kentucky. Then there are all the obscure "flag carrier" journals. One that shows up fairly often in searches for odd heterocyclic systems in the Egyptian Journal of Chemistry, but there are others that I have never seen a reference to in nearly 30 years of looking at the chemical literature, such as the Revista Colombiana de Quimica. Europe used to be covered with national chemistry titles, most of which have ceased publication or were merged into Chem. Eur. J. or the like. But some of the newly independent countries were glad to start up their own literature, so you have (for example) the Journal of the Serbian Chemical Society.

Now, I have no wish to offend any Serbian readership I may have, but I will not be bringing any unexpected news if I point out that JSCS is not the most prestigious venue available. In the old days, such a title would be full of local papers, and to be sure, there are plenty of manuscripts from Belgrade. But there are also plenty from places like Brazil, Iran, Egypt, Pakistan, and (naturally) the further corners of India and China. I suspect that some authors from these countries get to count such papers as having been published in a European scientific journal, as opposed to the less-impactful venues closer to home. There is, for example, an Iranian Journal of Chemistry and Chemical Engineering, as there is a Journal of the Brazilian Chemical Society.

But these days, there's a much larger and fuzzier category of obscure journal, and we have the internet and the idea of open access to thank for them. Well, those and greed. If I had to pick, I'd say that greed is the main factor. I'm talking about scam publishing, the dozens upon dozens of "open access" journals that have sprung up that (1) accept everything, and (2) charge a significant publication fee. That money is supposed to cover the costs of editorial work and open access on publication - and such fees can be completely legitimate, of course. But in the case of these publishers, it's a scam, since there are very, very few costs involved. No one edits these papers to any significant degree, and to a good approximation, no one ever accesses the papers, either. Bandwidth charges are thus held down to manageable levels.

Here's a good resource on these outfits, Beall's List of Predatory Open-Access Publishers. Jeffrey Beall of the University of Colorado-Denver has compiled a list of shady operations, most of which are characterized by suspiciously vast lists of titles and hefty publication charges. The one publisher on the list that you might have heard of is Bentham Open, the "open-access" arm of Bentham Publishing. I've always considered their regular list of journals to be pretty borderline stuff, although they have published some useful reviews. But Beall characterizes Bentham Open as "a scholarly vanity press", and that seems pretty accurate.

Take, for example, their Open Medicinal Chemistry Journal. It appears to have published two papers so far this year. Last year, it put out a special issue on "Medicinal Chemistry of Novel Anti-Diabetic Drugs", which sounds interesting until you note that there are three papers therein: a leadoff editorial (from an author at the University of the United Arab Emirates), a paper from that editorial writer and several collaborators (four authors, four countries), and still another paper from him and one of the authors of the first paper. Hmm.

Now, the scholarly worth of such things can be debated. They're of little immediate interest, but if the results contained are real, then they are, presumably, tiny bricks in the great edifice of scientific knowledge, and might conceivably be useful to someone, someday. From that standpoint, I don't have much room to criticize them. But since I've said many unkind things about the established scientific publishing houses and their business models, it's only fair that I point out that some of the untraditional ones are just as rapacious. The sorts of "journals" on Beall's list are not even pretending to add anything to the store of human knowledge: they're publication mills, turning anything you want to pay for into a "scientific paper". Some (not all) of the authors may deserve sympathy, by virtue of their obscure, unfunded origins (although they must have enough funds to pay for these papers), but the publishers deserve none at all for taking advantage of them. And when they're not taking advantage of ignorance and/or desperation, then the transaction is a cynical one indeed, reminding me of the old joke from the Soviet Union that went "As long as they pretend to pay me, I'll pretend to work".

Will they really publish anything? Why, yes, they will, as a mathematician proved by submitting a paper full of incoherent gibberish and getting it accepted. He used MathGen, a modified version of the random-paper generator SciGen that I've written about here. You'd think that the institutional address of "University of Southern North Dakota at Hoople" would tip someone off, but there are no P.D.Q. Bach fans in that audience.

Comments (27) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

September 17, 2012

Pharma Sales Corruption in India. And How.

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Posted by Derek

I work in research. Early research, pulling-stuff-out-of-thin-air type early drug research. I'm about as far from the commercial end of the companies I've worked at as I can be, but it's the commercial end that pays my salary and keeps the labs running.

But that does not mean that everything that drug companies do to sell drugs is therefore justified. Far, far from it. Unfortunately, I have another entry today that will go into my category tag marked "The Dark Side". It's on drug sales tactics in India, which are explored by Frederik Joelving in this article at Reuters. It is not pretty:

The Abbott guide -- reps say the company produces them regularly -- is evidence of a larger problem in India. In interviews with Reuters, dozens of doctors, drug reps and other healthcare insiders said domestic and multinational drug makers routinely shower Indian doctors with gifts, posh junkets abroad, and cash payments disguised as consultancy or other types of fees.

"Indian CRM," or customer-relationship management, is what industry insiders call this system of inducements. None of the doctors or reps who described their participation in this trade would speak on the record. Under Indian law, doctors are prohibited from accepting cash, gifts or travel from drug companies. Still, enforcement is rare, and drug makers may lavish gifts on doctors with impunity, though their home countries may punish the practice.

In a country where doctors often make less than $10,000 a year, it can be an effective strategy.

The drug reps apparently have entire catalogs, with the incentive gifts laid out - a coffeemaker for this drug at this prescription level, a new vacuum cleaner over here, cookware, an invitation to a "conference" in Thailand, what have you. And the indications are that even these gifts are being replaced by more direct inducements, such as sheer cash. That's paid out for being part of a "postmarketing study" that no one controls, whose numbers no one pays attention to, and whose only purpose is to provide cover to pay people off:

Doctors and reps say that often, companies use these studies as cover for paying doctors to prescribe the drugs under study. According to one Abbott rep, the company doesn't pay doctors if sales at nearby pharmacies don't increase.

A doctor who has done post-marketing studies in India says the companies rarely monitor the studies or check the data. "We all understand that post-marketing studies are not really true studies," says the doctor, a diabetes specialist at a Calcutta hospital. They're "just a way to offer an honorarium. So we also don't take them seriously."

Several companies are named in the article - Abbott, Ranbaxy, local Indian drug makers - but the strong impression one gets is that this is how everyone is doing business there, and has for a long time. And that's a major problem. The sales and marketing people in such situations take this as normal, and no one's shocked or upset. They should be, though. Treating this sort of thing as no big deal is bad for the culture of a company, and it's obviously not saying anything good about Indian business culture, either.

I think that there are three levels of corruption. These are distinctions I worked out a while back; see if they make sense. Level 1 is paying people to do something that they wouldn't normally do. Get me good tickets, bump me to the front of the line, that sort of thing. Level 2 is paying people just to do what was supposed to be their job in the first place (but which they won't actually perform unless the honorarium is coming). And Level 3 is the worst - that's when you're paying them not to harm you. A protection racket, in other words, whether it's run by the mob or some Russian regulatory agency that might just enforce some little-known tax laws on you if you don't play ball.

This Indian drug-rep stuff is Level 1 for sure, and probably some Level 2 as well. It wouldn't surprise me at all if there weren't some doctors who wouldn't bother to prescribe a given medicine at all - medical judgement be damned - if the sales reps hadn't provided the goods. That's what I mean when I say that no one comes out the better for this - not the companies, not the doctors, not the patients, not the country. India is full of people who realize that the country is being held back by this sort of corruption, that it's a deadweight loss compared to not having to bribe everyone all the time.

But drug companies are supposed to be full of people who realize that this sort of thing is wrong. That's a culture of corruption for you, though: paying people off with toasters and trips to Thailand is how you make your numbers, and if you don't make your numbers, well, they'll find someone who will. Don't feel like lugging around a sack of kitchen gadgets and consumer electronics? Don't be a drug rep in India - simple.

No, this whole thing is disturbing and disgusting. As I said, I spend my time back in early research, thinking up ideas that might turn into a drug one day. It would not make me happy, to put it mildly, to think of a drug that I'd had a part in discovered being flogged via sleazy vacation offers and sets of cookware dumped on a doctor's office floor. It's my hope that articles like the Reuters one will bring enough attention (and be the source of enough controversy and shame) to start making a difference.

Comments (29) + TrackBacks (0) | Category: The Dark Side

July 25, 2012

When Is A Company Shading the Truth About Its Clinical Trials?

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Posted by Derek

I wanted to point out this fine piece by Adam Feuerstein, "How to Tell When a Drug Company Fibs About Clinical Trial Results". The points he makes apply especially to small companies trying to stay afloat, but they can show up anywhere.

You need to look at when the trial started (and thus how long it took, relative to how long it should have taken), what the stated endpoints were before the trial, the time points at which these benefits (real and otherwise) occurred, and how the current trial results match up with previous ones. One general rule that I have, which Feuerstein also notes, is that when a company makes a big deal out of their investigational drug being safe/well-tolerated in a Phase II trial, that's a red flag. It's certainly a good thing that the drug was tolerated, but finding that out is not the point of Phase II.

But as the article details, clinical endpoints are where a lot of the hand-waving goes on. If a trial is designed well at all, it's run to look for the most clinically relevant signs that the investigators can think up - the ones that are going to make the patients, the physicians, the regulatory agencies, and the investors pay attention. And if a trial concludes and the company starts talking instead about various other benefits and trends that were seen in the data, while not making as big a deal out of the previously stated endpoints, well. . .there's a reason for that. It's not a good reason, and may not even be a very honorable one, but believe it, there is a reason.

Comments (15) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

July 3, 2012

The Papers In This Journal Are Just So Darn Relevant

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Posted by Derek

Thomson Reuters is out with their lists of impact factors for journals, and these come with the usual cautions: too much is made of the impact factor in general, and the very fact that the tiniest variations are seized on gleefully by journal publishers should be enough to set off alarms.

This time a record number of journals were taken off the list for excessive self-citation. And as that Nature News article notes, somewhat gleefully, one of the journals had recently been profiled by Thomson Reuters as a "Rising Star". (All that profiling and interviewing has made me wonder in the past, and I'm not surprised at all that this has happened. The company measures the impact factors, promotes them as meaningful, interviews journal editors who have found ways to raise theirs, which makes that important news because the people who sell impact factors say that it's important, and they have the press releases to prove it. I'm standing by my earlier comparison to the Franklin Mint. (And in case you're wondering, the fact that I'm citing my own blog on the topic of self-referentiality has not escaped me).

At any rate, I don't believe that any chemistry journals were on the banned list. The most interesting case was a group of journals that were deliberately citing each other, but I'll freely admit that I'd never heard of any of them, despite their best efforts to rise in the world. If anyone does have any evidence of citation oddities in the chemistry world, though, I'd be happy to help publicize them. . .

Comments (13) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

The GlaxoSmithKline Settlement

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Posted by Derek

You'll have heard that GlaxoSmithKline has paid out three billion dollars in a settlement on illegal marketing practices, misreporting of safety data, and other violations. Needless to say, GSK does not have a spare three billion lying around that's not being used for anything; they'd be a lot better off if they hadn't put themselves in this position.

What's hard to figure, though, is how much money the company made through these actions. There's a lot of talk, understandably, about how drug companies (and their executives) could be warned off such behavior, but if GSK realized, say, an extra $4 billion in the process of incurring their $3 billion dollar fine, it's going to be hard to make the case to some of those people. The settlement actually appears to be a bit less than some investors were expecting, and there may, in the end, be no way to have the magnitude of the potential fines do all the work of a deterrent.

Matthew Herper at Forbes notes that the company's current CEO, Andrew Witty, has issued an unusually forthright statement (by CEO standards) on the whole matter:

All of the actions predated the tenure of current GlaxoSmithKline chief executive Andrew Witty, who has been trying to improve the company’s reputation. He has pushed forward with efforts to develop medicines for poor nations, including a malaria vaccine that Glaxo is developing with the Bill & Melinda Gates Foundation. He has also taken steps to remove incentives that made pharma salespeople so overzealous, no longer tying compensation to how much of a drug they can sell. In a statement, he said that employees have been removed from positions as a result of the changes and that new provisions will allow the company to take back compensation from executives if they don’t adhere to the company’s standards.

Glaxo has done something else right, too: Witty actually managed, in the press release disclosing this settlement, something close to a full-throated apology. He said:

“Whilst these originate in a different era for the company, they cannot and will not be ignored. On behalf of GSK, I want to express our regret and reiterate that we have learnt from the mistakes that were made.”

That may not sound like much, but in the context of an industry that has almost never seen fit to apologize for anything it is a step in the right direction.

But I also wanted to mention by name two of the people who set this entire thing in motion. One of them is Blair Hamrick, and another is Greg Thorpe. These were GSK sales reps who grew concerned about illegal activity over ten years ago:

“Regardless of what company policy may be, my letters to human resources and my previous complaints of misconduct have been quashed. My 23-plus year career with this company has been trashed, and it is obvious I can no longer work with my district manager and friends/counterparts just because I have come forward with the truth, which could save the reputation of GSK and millions of dollars in fines,” wrote Thorpe, one of the whistleblowers on whose claims the feds based their allegations, in a January 2002 note to Glaxo officials. . .instead, though, Glaxo officials issued their own warnings to Thorpe about his willingness to be a team player and refused to address various violations of the False Claims Act, which he referred to specifically and repeatedly in numerous communications.

"Team player" is one of those phrases that should put a person on their guard. It can be used completely innocuously, but it can also be used to justify pretty much any behavior that the rest of a group is doing, and on no more basis than, well, the rest of the group is doing it. I reserve my admiration for those who need more justification than that for their actions.

There are some effects that I hope this GSK news will have: making someone think twice about getting caught when they're planning something that goes over the line, or (on the other side) shoring up the resolve of a person who's deciding not to go along with something that they've realized is wrong. The world tends to run short of both of those.

Comments (32) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

June 5, 2012

Merck Finds Its Phase II Candidates For Sale on the Internet

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Posted by Derek

Via Pharmalot, it appears that a former WuXi employee helped himself to samples of two Merck Phase II clinical candidates that were under evaluation. The samples were then offered for sale.

Here's a link to a Google Translate version of a Chinese news report. It looks like gram quantities were involved, along with NMR spectra, with the compounds being provided to a middleman. It's not clear who bought them from him, but the article gives the impression that someone did, was satisfied with the transaction, and wanted more. But in the meantime, Merck did pick up on an offer made by this middleman to sell one of the compounds online, and immediately went after him, which unraveled the whole scheme. (The machine translation is pretty rocky, but I did appreciate that an idiom came through: it mentions that having these valuable samples in an unlocked cabinet was like putting fish in front of a cat).

I would think that this kind of thing is just the nightmare that WuXi's management fears - and if it isn't, it should be. The cost advantage to doing business with them (and other offshore contract houses) is still real, but not as large as it used to be. Stories like this can close that price gap pretty quickly.

Comments (45) + TrackBacks (0) | Category: Business and Markets | Drug Development | The Dark Side

May 8, 2012

Laboratory Crime, Not Paying

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Posted by Derek

You'll remember the Sanofi chemist who was caught selling proprietary compounds through her own Chinese outsourcing company. Now, via Pharmalot, comes word that Yuan Li has been sentenced to 18 months in prison, along with paying $131,000 in restitution. This foolproof business plan has turned out not to perform up to expectations. Perhaps this example will keep another fool from trying it?

Comments (14) + TrackBacks (0) | Category: The Dark Side

March 7, 2012

Eight Billion Dollars Apparently Isn't Enough

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Posted by Derek

You'd think that 8 billion dollars would be enough to get some attention. But that's how much drugmakers have paid in fines in recent years, and the regulatory agencies are wondering if anything's changing. This USA Today article has the details.

The fines, as many readers here will know, are for a range of offenses - Medicare reimbursements, off-label marketing, kickbacks from the sales force, and so on. And as things stand now, the government has really only two options when it comes time to lower the boom: fines, and the threat to remove the company from eligibility to sell via Medicare. But that second one is really sort of an empty threat, since most large companies are (for now!) selling drugs that are quite valuable to the Medicare patient population. So new techniques are being sought:

To try to change that trend, the government announced in 2010 that, rather than exclude an entire company, investigators would go after individuals within a company. [Gregory Demske at HHS] said his organization, the Justice Department and the Food and Drug Administration have come up with some ideas to use within the scope of the rules — such as taking away a company's patent rights as a condition of a settlement. That could begin with cases being investigated now, he said.

Now, that might get some attention, for sure. We'll see if it happens, because you can expect the industry to fight this as hard as possible. To that end, the article notes that $200 million was spent on lobbying last year by the drug and medical device industries. One first thought might be "Two hundred million! That's a lot of money!", but mine was "Two hundred million! Why, that's nothing compared to the issues involved. . ." Marginal Revolution has had some posts about lobbying and money in politics, mostly wondering why there isn't more of it than there is. With that kind of bang-for-the-buck, I wonder the same thing.

Comments (16) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

March 2, 2012

Stem Cells in Texas: Quite the Business

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Posted by Derek

I (and many of the readers here) have long thought that stem cells are perhaps the most overhyped medical technology out there - at least for now. I definitely agree that the possibilities for their use are staggering, and I very much hope that some of these pan out, but the gap between those possibilities and the current reality is just as huge. And it's a gap that really shows how hard medical progress is compared to how hard it is in the public imagination.

Nature has an article that bears on this, and on some other important topics. They've found that stem cell treatments are being sold to patients in Texas.

(The investigation) suggests that (Celltex Therapeutics) has supplied adult stem cells to Texas doctors who offer unproven treatments to patients, and that the company is involved in these treatments. One doctor claims that the treatments are part of a clinical study run by Celltex and that the company pays him US$500 a time to inject the cells into patients, who are charged up to $25,000 for a course. The US Food and Drug Administration (FDA) considers it to be a crime to inject unapproved adult stem cells into patients. David Eller, chief executive of Celltex, denies that the company is involved in treatment procedures, but would not comment on Nature's findings about how its cells are used or answer questions about them.

This makes me wonder about what is going on down there in Texas (and I can tell you, as an Arkansan, I'm willing to believe just about anything in that department). This latest business reminds me of the Burzynski cancer treatment stuff, in the way that definitions of "clinical trial" are stretched like rubber bands. Personally, I think that clinical trials are supposed to follow something very much like Yog's Law in publishing ("Money flows towards the writer"). If you're being asked to put up all kinds of money to get your book edited and published, you're very likely being scammed. And if you're being asked to pay thousands of dollars to be in a "clinical trial", well. . .you're being sold something. Real clinical trials reimburse their patients for time and effort, with money and/or medical care. They do not bill them for 25 long ones at the end of the dosing schedule

I should mention here that Slate also had an article up on Celltex, but there have been some problems. They've taken the piece down, citing editorial problems, but (as you'd figure), the cherchez le lawsuit rule applies here. Nature, though, doesn't seem to be getting sued for what they've written.

Now, back to the stem cell treatments. Among other things, Nature mentions a blog by a woman in Texas, who's written about her experiences being treated with adult stem cells from Celltex. It appears that she's receiving these treatments for multiple sclerosis, and was told that "This method has been successful with auto immune diseases such as Parkinson’s, arthritis, Multiple Sclerosis as well as others." She had apparently had a similar procedure done earlier in Mexico, but then:

". . .a friend told Larry about a doctor in Houston who went to South Korea two years ago for a stem cell transplant to treat the debilitating effects of psoriatic arthritis. He is now able to continue his medical practice, perform surgeries, and live without pain. Because our friends had noticed progress from my first stem cell transplant, they wanted us to know that Dr. Jones was now licensed to perform the procedure in Houston. To say the least, we were both excited about the possibilities and timing."

As that extract illustrates, at no point (that I have found) does this patient mention the phrase "clinical trial". One gets the strong impression, actually, that she believes that she is paying to undergo a new medical procedure, the latest thing, rather than participating in any kind of investigational study for a therapy that has not yet been reviewed by the FDA. The Nature writer, David Cyranoski, was able to speak with the physician involved, who says he's treated a number of people with cells from Celltex:

Lotfi says that most of his patients claim to get better after the treatment, but he admits that there is no scientific evidence that the cells are effective. “The scientific mind is not convinced by anecdotal evidence,” he acknowledges. “You need a controlled, double-blind study. But for many treatments, that's not possible. It would take years, and some patients don't have years.”

“The worst-case scenario is that it won't work,” he adds. “But it could be a panacea, from cosmetics to cancer.” He says that Celltex is conducting a trial in which patients “will be their own control”. “If you can compare before and after and show improvement, there's no need for a placebo,” he explains. “How can you charge people, and then give them a placebo?”

Indeed! Maybe you could try not charging them, and not making them spend their own money to find out whether your treatment is any good. Maybe you could get a large, statistically significant number of people together, who've been given thorough diagnostic workups, and give half of them the best standard of care for multiple sclerosis and half of them the stem cell treatment - at your expense - and see if they get better. How about that? (Oh, and just a little note - the worst case is not that nothing happens at all. It might be good for the people involved to think about that a bit).

This gets back to the discussions we've had around here about rethinking clinical trials. One of the things I'll say for the FDA is that they do force people to be rigorous, and to put new medical ideas to well-controlled tests. My worry about the "sell, then test" ideas was summed up in the first link in this paragraph: "I fear that there are any number of entrepreneurial types who would gladly stretch things out, as long as someone else is paying, in the hopes of finally seeing something useful. No one will - or should - pay for extending fishing expeditions." Read that Celltex article and see if that sounds familiar.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side

February 29, 2012

Bias in Industry-Funded Trials in Rheumatoid Arthritis?

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Posted by Derek

The title of this one says it all: "Association of industry funding with the outcome and quality of randomized controlled trials of drug therapy for rheumatoid arthritis". Any number of critics of the drug business will tell you what that association is: we publish the good stuff and bury the bad news, right?

Well, not so much in arthritis, apparently. The authors identified 103 recent clinical trials in the area, over half of them industry-funded. But when it came to outcomes, things were pretty much the same. Trials from the three largest classes of funding (industry, nonprofit, and "unspecified") all tended to strongly favor the tested drug, although the small number (six) of mixed-funding trials ended up with two favoring and four against. The industry-run trials tended to have more subjects, while the nonprofit ones tended to run longer. The industrial trials also tended to have a more complete description of their intent-to-treat and workflow. As you'd figure, the industrial trials tended to be on newer agents, while the others tended to investigate different combinations or treatment regimens with older ones. But the take-home is this:

No association between funding source and the study outcome was found after adjustment for the type of study drug used, number of study center, study phase, number of study subject, or journal impact factor. . .

. . .Though preponderance of data in medical literature shows that industry funding leads to higher chances of pro-industry results and conclusions, we did not find any association between the funding source and the study outcome of "published" (randomized clinical trials) of RA drug therapies.

The one worrying thing they did find was a trend towards publication bias - the industry-sponsored studies showed up less often in the literature. The authors speculate as to whether these were trials with less favorable outcomes, but didn't have enough data to say one way or another. . .

Comments (5) + TrackBacks (0) | Category: Clinical Trials | The Dark Side | The Scientific Literature

February 7, 2012

More Industrial Espionage

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Posted by Derek

Well, we last got into arguments about industrial espionage here in December, so it's what? February already? Then here we go: from C&E News, we have this:

Federal prosecutors charged last week that Chinese government officials played a role in the theft from Dupont of technology to manufacture the paint pigment titanium dioxide.

According to a document filed on Jan. 31 in U.S. District Court for the Northern District of California, Federal Bureau of Investigation officials obtained letters in a search of the home of Walter Liew. The letters show that Liew “was tasked by representatives of the People’s Republic of China government to obtain technology used to build chloride-route titanium dioxide factories,” prosecutors say.

Here are more details from Reuters. More on this as it develops. . .

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January 18, 2012

Selling Sanofi's Compounds on the Side

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Posted by Derek

Now here is an amazingly stupid move: a medicinal chemist at Sanofi (Yuan Li) downloaded a large set of proprietary compounds from the company's files, and founded another company on the side to sell them.

Strangely enough, someone at Sanofi noticed that their in-house compounds were appearing for sale at Abby Pharmtech, of Newark, Delaware. (Better take a look at that web site while you can). It is supposedly the US subsidiary of Xiamon KAK, of Xiamen, China. According to this criminal complaint (thanks to Pharmalot for the link), Sanofi found (in May and June of last year) 6,000 of their internal compounds showing up on SciFinder as available from Abby. A search of Li's computer at Sanofi showed all sorts of useful stuff - a listing of 144,000 compounds in a file called "Abby Pharmtech" (complete with internal Sanofi registration codes), tax forms showing her as a partner and co-founder of Abby (confirmed by IRS records), and so on.

The penalty? There's been a plea agreement (again, thanks Pharmalot), and sentencing is scheduled for April 23. There's a maximum potential prison term of 10 years, and a maximum fine of at least $250,000 - all that is up to the judge. This is in addition to restitution to Sanofi ($131,000) and a very high likelihood of immigration proceedings. It is safe to say that this master plan has not worked out too well.

What, just what, was this person thinking? How lucrative could this idea have possibly been, compared to the risks? And how could they have imagined that this would fly at all - that no one at Sanofi would ever notice that stuff from their own files and lab notebooks was now for sale? You just never know what people can get up to.

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January 16, 2012

Defending Das' Resvertrol Research. Oh, Come On.

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Posted by Derek

I'm getting all the press releases from Bill Sardi, of Resveratrol Partners, as he does damage control from the Das scandal at UConn. And I have to say, he's putting in the hours getting these together. Problem is, on some key points, he doesn't know what his biggest problems are.

The latest one is titled "World Without Resveratrol: Researcher Falsely Accused", and claims that this may all be a plan to "send a message" to any academic who collaborates with the makers of resveratrol pills. The release goes on about how these are old accusations, which Das has refuted since then, and asks why these ancient concerns are coming up now, eh? The phrase "orchestrated hit job" is used. But that glosses over the times of the whole investigation, which has been a very detailed and involved one, and glosses over the amount of due process involved as well. There are a lot of problems with the publications from the Das lab, as detailed in the report that I linked to the other day, and tying them together has involved a lot of work.

But here comes my favorite part of the latest Sardi release:

". . .I asked Dr. Das directly, did he altered (sic) western blot images, or directed others in his lab to do so. While his initial answer was no, meaning he had not fabricated or altered any scientific finding, altering western blot images are a common practice in laboratories for reasons other than deception. The university chose to present their findings in a derogatory manner. Dr. Das explains that editors at scientific publications commonly request researchers enhance faded images of western blot tests so they can be duplicated in their publications. Western blot tests are frequently altered to remove backgrounds, enhance contrast and increase dots-per-inch resolution so they are suitable for publication. This had been fully explained to university officials long before. . .

No, no, no. The problems with the Das papers have nothing to do with enhancing the contrast on Western blots. They have to do with cutting and pasting sections of them, rearranging them, reusing them, and creating them out of pieces of other experiments. Look at that report. These people appear to have spent a ridiculous amount of time assembling "Western blots" out of miscellaneous digitized chunks. The resulting figures purport, in many cases, to represent particular experiments, but they do no such thing. They represent a bunch of previous bands from other experiments entirely, sliced and diced in a way that would seem to have no other possible motive than to deceive. Come on.

Oh, but there's more. Here, according to the press release, is how a cutting-edge academic lab works these days:

"As I drilled Dr. Das’ former students with questions, I found that lead researchers like Dr. Das do not do any lab bench experiments. Students do all the work and submit their results to him via e-mail or by directly downloading data into his computer. Dr. Das says when he is not traveling his office is open and students can enter and download data directly onto his computer. I had previously visited Dr. Das at the University of Connecticut and noticed his office door was left open and anyone could have access to his computer.

One former student told me that typically lead researchers like Dr. Das write the introduction and conclusion of experiments and the students enter all the data, before publication in scientific journals. Dr. Das, who is busy lecturing all over the globe because of his groundbreaking studies, does not directly oversee tests that are performed, and neither do most other lead researchers. The University of Connecticut report says the university holds Dr. Das responsible for all of the data. Probably most lead researchers in scientific laboratories around the globe are vulnerable to errors or even fabrication of data by their students."

Where to start? What the heck is this "download data directly into his computer" stuff? And what about all the doctored files found on other machines in the group? And yes, while lead authors are indeed vulnerable to errors and fabrication, this sort of thing typically does not involved years of work spread out across dozens of papers in multiple journals. Even the busiest and most distracted principal investigator might be expected to take the time to notice, eventually, that his group's work is a tower of fraud. And yes, the University should hold Dr. Das responsible for the data in his papers. His name is on the grants, his name is on the office door, he's the one with a high-paying tenured position while the students are cranking away under low salaries and stipends, and it's his name with an asterisk next to it on all those papers, as the contact person for any questions about them. Damn right he's responsible. He's responsible for making sure that anything going out into the literature with his name on it is something that he can stand behind.

Ah, but not to worry. It's all being taken care of:

"Dr. Das says many editors at scientific journals don’t believe the University of Connecticut report. They full-well know that editing of western blot tests is common practice and that the tests in question in no way invalidate his work and were only one part of the evidence provided in his papers from which Dr. Das drew conclusions. This is the case of scientific fraud that wasn’t."

That would explain why Dr. Das has been pulled from the co-editor job he had at one of those journals. They must believe him. And that would also shore up all those allegations of prejudice against East Indian researchers, since the editor of that journal is. . .well, he's Indian too, but you know what I mean. (Personally, if I were from India myself, I'd be furious at Das for helping to drag the reputation of my country's scientists through the mudhole, but maybe that's just me.)

No, I hope these press releases keep on coming. So far, we have lots of elaborate reasons why Dr. Das had nothing to do with all these fabricated Western blots, but who cares, right, since they're only a tiny part of his papers, which are great and important work even though he really doesn't write them anyway, and no, he has almost no connection with Longevinex and Resveratrol Partners, which is why the head of the company is spending all this time defending him in this case of minor stuff he never did, all 600 pages of summary and 60,000 pages of investigation material, and that explains why the journals that believe him are ditching him from their mastheads and publishing retractions of those great papers. Because it's all a conspiracy. Yeah. That's it.

Comments (28) + TrackBacks (0) | Category: Aging and Lifespan | The Dark Side | The Scientific Literature

January 13, 2012

Dealing With Dishonesty

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Posted by Derek

So, we've been talking here since yesterday about what looks like large-scale fraud, but there's small-scale stuff that goes on inside various labs (often in academia, which is where people like this are supposed to wash out). Many readers will have encountered, in their grad school days, the person whose reactions won't quite reproduce, who comes in while you're not around and "borrows" your reagents, and who can't quite locate that key procedure when it's time to look at it closely. (And yes, I've had dealings with members of this tribe before, and they're no fun at all).

Here's a reminiscence from a professor at Nebraska of how he dealt with someone like this, and his technique may be something that others have tried (or been tempted to). It worked, though. This is the flip side of the laboratory sabotage discussed here and here, used for good instead of for evil. Are such methods justified? Used carefully, and in extreme cases, I'd say yes. Thoughts?

Comments (32) + TrackBacks (0) | Category: Graduate School | The Dark Side

January 12, 2012

A Resveratrol Research Scandal. Oh, Joy.

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Posted by Derek

My inbox has exploded with the story that many reports on the effects of resveratrol appear to be fraudulent. Prof. Dipak Das of Connecticut is at the center of what looks like a huge research stink bomb, which is being well covered by Retraction Watch (here and here), among others. The Chronicle of Higher Education has a lot of good info as well.

Here's what's known so far: UConn has a press release saying that Das has been under investigation for the last three years, and that the university (along with the Office of Research Integrity) has uncovered substantial evidence of fraud and misconduct.

An extensive research misconduct investigation has led the University of Connecticut Health Center to send letters of notification to 11 scientific journals that had published studies conducted by a member of its faculty. Dipak K. Das, Ph.D., a professor in the Department of Surgery and director of the Cardiovascular Research Center, was at the center of a far reaching, three-year investigation process that examined more than seven years of activity in Das’ lab. . .

. . .The investigation was sparked by an anonymous allegation of research irregularities in 2008. The comprehensive report, which totals approximately 60,000 pages, concludes that Das is guilty of 145 counts of fabrication and falsification of data. Inquiries are currently underway involving former members of Das’ lab; no findings have been issued to date.

Here are the details, in a long PDF, if you want them. What that report shows are a lot of manipulated Western blots, with obvious copy-and-paste artifacts. Well, they're obvious once you're alerted to them, at any rate - the first thing you think of when you see a gel isn't "Hmmm. . .I wonder if that's been Photoshopped?" At any rate, examination of presentation slides on various hard drives also showed Westerns with various regions - in some cases, every single damn band on the whole thing - which had been moved around with the "Group" and "Ungroup" tools, starting from separate unrelated files. And they've even tracked down the original images which formed the basis for the figures in so many other papers, once they'd been sliced and diced. Classy stuff. Dr. Das, for his part, told the investigators that he had no idea who had prepared any of these figures, a position that (since he's the lead flippin' author on them), strains belief. "Dr. Das has been of no help in this matter", states the report, and I'd say that still overstates his contributions.

UConn has notified the editors of 11 journals where Das and his group had published suspect results - and on three of these journals, according to Retraction Watch, he had editorial or advisory responsibilities. Looking over the list, it's not exactly the most high-profile publication record that you could imagine. Das's papers do seem to have picked up a number of citations, in many cases, but I don't really get the sense that he was driving the field. (That Chronicle link above quotes David Sinclair, of sirtuin fame, as saying that he'd never even heard of Das at all, and for what it's worth, I hadn't either).

Meanwhile, Retraction Watch has received a press release from Das' lawyer, and it looks like he's not going down without firing all his ammo. To wit, Das claims that:

. . .the charges against him involve prejudice within the university against Indian researchers. Six other East Indian researchers were also named as “potential respondents” to charges of scientific fraud, but no researchers of other ethnicities. . .

. . .Another party, a university internal investigator whom Dr. Das accuses of long-standing prejudice against foreign-born researchers, reportedly broke the lock on Dr. Das’ office door, removed computer files and personal items such as bank records and a passport, and could have manipulated data in his computer files. Dr. Das says this university investigator has had a long-standing vendetta against him going back to 1984. . .

There's a lot more in the same vein (and great big steaming heaps of it in Das' official response to the investigation) and it all points to a long, ugly process. The lawyers involved will have plenty to keep themselves occupied.

There's one last big issue: Das appears to have had a business relationship with Longevinex, a well-known supplier of resveratrol supplements. I note that Bill Sardi, the managing partner of the firm that runs Longevinex, has showed up on this site in the comments section before, as have many fans of the product itself. (I know that David Sinclair has heard of those guys, because they were throwing around his name for a while, which seems to have led to talk of possible legal action). And it's worth noting as well that Dr. Das had published work suggesting that Longevinex was superior to garden-variety resveratrol. That paper (and that journal) does not appear to be one of the ones named specifically in the fraud investigation. But one of the authors on it (other than Das) figures prominently in the UConn report. Who feels inclined to trust it?

Now for the last big issue: what does this do to the whole resveratrol/sirtuin field? Not as much as you might think. As mentioned above, Das really doesn't seem to have been that big a figure in it, despite cranking out the publications, and a lot of interesting (although often confusing) work has come from a variety of other labs. The people who did this study in humans, for example, are (to the best of my knowledge) above reproach. But (as that post shows in its various links), there's a lot of conflicting data about resveratrol in animal models. The whole topic is deeply confusing. But this UConn/Das business does not help clear anything up, not at all - it's a big bucket of mud and slop dumped into the tank, which is just what we didn't need.

And as for sirtuins, well, I don't think anyone would disagree with the statement I made here, that resveratrol has so many off-target effects that it's completely unsuitable as a tool to understand sirtuin biology, which is quite difficult enough to understand already, thanks very much. Sirtuins have their own wild complications and (seeming) contradictions, separate from resveratrol - this latest scandal is off to the side of that topic completely, or should be.

But I don't mean to minimize Das' apparent misconduct here, not at all. He's not at the center of his field, but he looks to be at or near the center of something very dishonorable, very dishonest, and very wrong.

Comments (30) + TrackBacks (0) | Category: Aging and Lifespan | The Dark Side

December 15, 2011

More on Chinese Pharma Espionage

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Posted by Derek

Well, a lot of comments have come in about the last post on Chinese industrial espionage - some temperate, some not. I wanted to fill out another post responding to some of these, so, in no particular order:

1. "Everyone does this all the time". Indeed. Espionage is a constant fact of international relations; the "gentlemen do not read each other's mail" comment was wildly out of sync with reality even in its own time. I don't mean to suggest that I'm shocked by the fact of Chinese intelligence-gathering, although its scope and thoroughness is impressive. But I think that everyone should be aware that it goes on - and that pointing out that it's going on is also a move in the same game. We're not hearing so much about this from the US government now for no reason; someone thinks that there's an advantage in making these accusations public in such detail.

2. "More to the point, the US does this too, and thus has no room to talk". This is merely a tu quoque argument, and as such doesn't address any underlying issues. Of course the US engages in espionage, and I hope that we're good at it. But for the most part, we're doing it for a different purpose than some of the Chinese activity that's been revealed. I tend to think that more of ours is national-security related, and less pure economics - more "How can we figure out what these guys are up to?" and less "How can we jump-start our aerospace industry?"

Now, one big reason for that is that the US is not as far behind anyone else in the world as China feels itself to be behind in some key industries. They have more to gain. I'm sure that China does plenty of national-security spying, but for a country whose economy is as export-driven as China's, economic reasons and national security reasons are even more tangled together than usual. And yes, other countries have done just this sort of thing in the past. See the story of how the British got rubber-tree seeds to plant in Malaysia. Or earlier, how they learned the details of tea production and got that going in India, and that's not even mentioning their strategy of smoothing out the trade imbalance with opium sales. We shouldn't allow ourselves, though, to think that this stuff is just for the history books.

3. "OK then, what's more, the US did just this kind of economic/industrial snooping back when it was an up-and-coming nation".. This is another tu quoque, but the facts are as stated. In the 19th century, the US was generally a backwater compared to the European powers, and we did indeed have a reputation as the Kings of Shoddy Unauthorized Knockoffs (even of our own inventions). Charles Dickens was enraged when he visited to find how many pirated versions of his works were for sale, and this tradition took a long time to die out. (See, for example, the saga of how Donald Wollheim unilaterally decided in the 1960s that Tolkein's publishers had not properly secured the US copyright for The Lord of the Rings).

But while we were at our peak as intellectual property buccaneers, we were not simultaneously considered both a world power and a huge financial market. China is not to the rest of the world as the US of the 1850s was. Our big exports were agricultural products; we did not have huge factories on which many of the world's largest corporations were depending. China, in catch-up mode though it may be, is not a technological backwater. It has nuclear weapons and a manned space program - mind you, both of those were developed partly through just the sort of short-cutting we're talking about.

4. OK, that means that every Chinese post-doc is a spy. Or a potential spy, right? Here's where I flip over to the other side. Now, there surely has been intelligence gathering by such routes. But it appears that a lot of work is being done from back home, by large groups associated with the People's Liberation Army and various Chinese intelligence agencies. And when you consider what a lot of postdocs end up working on, you can see that most of it isn't going to confer much of an advantage on anyone - what are they going to do, steal K. C. Nicolau's strategy for an 89-step synthesis? I think it would be a lot more useful for US institutions to spend their time hardening their security against wholesale data-scooping than giving their foreign postdocs the fish-eye. Most of them are just trying to make better lives for themselves.

So where does this leave us? I think that China's position is unique. They're an enormous country of huge economic and political importance. And their economy is a mixture that might be called "authoritarian capitalist", no matter what they call it themselves. So for a country like the US, they're simultaneously a vital trading partner, and a potential political adversary and rival. (And the US is the same thing to China, naturally). It's a tricky balance, and there are a lot of conflicts of interest.

We're seeing one in the drug industry. No major company can afford to ignore the Chinese market. The financial advantages of pharma outsourcing have been hard to ignore, too (leaving aside the question of its effectiveness, which varies). But no company can afford to ignore the possibility that Chinese industry (or the Chinese government itself) might rip them off. These things exist simultaneously, and it's very much worth the effort keeping both of them in mind.

Comments (57) + TrackBacks (0) | Category: Business and Markets | Current Events | The Dark Side

Chinese Pharma Espionage?

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Posted by Derek

That's a pretty blunt headline, but this is a pretty blunt article in Businessweek. It will do nothing to allay the concerns people have about all the pharma collaborations being done in China. The article claims that hundreds of US corporations have had data stolen in what appears to be a deliberate program:

China has made industrial espionage an integral part of its economic policy, stealing company secrets to help it leapfrog over U.S. and other foreign competitors to further its goal of becoming the world's largest economy, U.S. intelligence officials have concluded in a report released last month. . .Intelligence documents obtained by Bloomberg News show that China-based hackers have hunted technology and information across dozens of economic sectors and in some of the most obscure corners of the economy, beginning in 2001 and accelerating over the last three years.

Here's a report (PDF) from McAfee on cyber-intrusions. It doesn't mention China by name, but the author confirmed to the Bloomberg people that that's who he's talking about (not that it took any great powers of deduction). And this is not just about defense and electronics:

In the biotechnology sector, their victims include Boston Scientific, the medical device maker, as well as Abbott Laboratories and Wyeth, the drug maker that is now part of Pfizer Inc.

The hackers also rifled networks of the Parkland Computer Center in Rockville, Maryland, according to documents provided to Bloomberg News by a person involved in government tracking of the cyberspies, who declined to be identified because the matter isn't public. Parkland is the computing center for the Food and Drug Administration, which has access to drug trial information, chemical formulas and other data for almost every important drug sold in the U.S.

Now that's worth thinking about. By the time a drug gets to the FDA, everyone knows what its structure is, and can figure out how to make it. But there's a lot of clinical information in the system that doesn't necessarily get disclosed in detail, and that certainly has value. It should go without saying, though, that the files from inside a drug company could be quite valuable indeed.

And this does put the recent pharma emphasis on the Chinese market in an interesting light, doesn't it? As I say, I hate to be so direct about it, but you can't get much more direct than hacking into someone's files and ransacking them, either. Right?

Comments (54) + TrackBacks (0) | Category: Business and Markets | The Dark Side

November 30, 2011

The XMRV Story Is Not Getting Any Saner

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Posted by Derek

Dismissals, accusations, possible data theft, and now an arrest - when a scientific hypothesis (and a scientific career) unravels, it unravels all the way. . .

Comments (6) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

November 2, 2011

Faking Two Papers A Month. For Seven Years.

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Posted by Derek

There's a big research scandal that's been coming on for a while in the Netherlands. I haven't covered it, since it's in academic psychology, and thus pretty far out of my field, but some of the behavior in it is well worth noting. Here's a rundown from Science on Diederik Stapel, who appears to have forged scores of studies over the years. It seems that he rarely bothered to collect actual data, preferring to just condense it out of thin air to save time and effort:

Many of Stapel's students graduated without having ever run an experiment, the report says. Stapel told them that their time was better spent analyzing data and writing. The commission writes that Stapel was "lord of the data" in his collaborations. It says colleagues or students who asked to see raw data were given excuses or even threatened and insulted.

Here's more from Nature, via Scientific American. At least two earlier groups of whistleblowers had raised questions about Stapel's work, the commission found. No one followed up on their concerns, however. . .His colleagues, when they failed to replicate the results, tended to blame themselves, the report says. Among Stapel's colleagues, the description of data as too good to be true "was a heartfelt compliment to his skill and creativity," the report says.

Well, he did have skill and creativity - I mean, we're talking about someone who's published over 150 papers in the last seven years. And that means that he wasn't lazy, either, because keeping that many balls in the air is no small job. No, what we have here is an industrious, committed, fraud with a real talent for his chosen line of work: fakery. I'd like to think that it's somewhat easier to get away with this (for this long) in a social science field, but then, there's Jan-Hendrik Schön to think about. So I'm not sure that my high ground is all that high.

The same old lessons apply (". . .And the Gods of the Copybook Headings / limped up to explain it once more"): if something looks too good to be true, it probably is. If multiple people can't reproduce what's supposed to be a scientific result, then there may well be something wrong with it. And if someone that you're working for or with won't show you raw data, then head for the door, because nothing but trouble can ensue. The alarm bells have at that point gone off, whether you can hear them or not.

Comments (19) + TrackBacks (0) | Category: The Dark Side

October 31, 2011

A Note About Identity Spoofing

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Posted by Derek

Over the weekend, it became clear to me that there had been a case of identity spoofing in the comments to this post. A person had left comments while claiming to be a Merck HR employee, but this same Merck employee contacted me, in understandable confusion, when colleagues asked him about this. That's because he'd never posted anything here at all.

I'd wondered at the time about what was going on - neither of the comments were posted from a Merck IP address, but that wasn't necessarily surprising either way. But hearing from the person himself, most definitely from Merck this time, made up my mind very quickly.

There have been occasional games played around here in the comments section, and most of it's harmless. I'll let jokes through that claim to be from various Nobel Prize candidates - that's just the Internet doing one of the things it's good at. But deliberate assumption of identity like this is another thing altogether. The original comments have been deleted, and the responses to them are now "inoperative", as they used to say in Nixon's day.

Comments (37) + TrackBacks (0) | Category: Business and Markets | The Dark Side

September 27, 2011

So, How Come You're So Darn Lucky, Eh?

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Posted by Derek

Now here is a fascinating piece of work for anyone who's invested in the small pharma/biotech sector. The authors looked over the stocks of companies developing cancer therapies, ones that have had critical Phase III results or regulatory decisions announced over the past ten years. And they looked at the trading in their stocks, for 120 days before and after the announcements. What, do you suppose, did they discover in this exercise?

Uh-huh. You have surely guessed correctly:

The mean stock price for the 120 trading days before a phase III clinical trial announcement increased by 13.7% for companies that reported positive trials and decreased by 0.7% for companies that reported negative trials. . .Trends in company stock prices before the first public announcement differ for companies that report positive vs negative trials. This finding has important legal and ethical implications for investigators, drug companies, and the investment industry.

Indeed it does. Interestingly, the authors did not find such a split around announcements of FDA regulatory decisions, suggesting that insider trading there is not as big a problem compared to what goes on from inside the industry.

But wait - there's more, as they say in the infomercials. In a follow-up commentary on the article, Mark Ratain of Chicago and Adam Feuerstein of TheStreet.com (who certainly has seen his share of market shenanigans) find another striking disparity in the data:

This analysis demonstrated a remarkable difference between companies that had positive and negative announcements. Specifically, the median market capitalization was approximately 80-fold greater for the companies with positive trials vs companies with negative trials. . .Furthermore, there were no positive trials among the 21 micro-cap companies (ie, companies with less than $300 million market capitalization, whereas 21 of 27 studies reported by the larger companies analyzed (greater than $1 billion capitalization) were positive.

That makes sense, as they point out: these small-cap stocks had such low valuations for a reason: because investors thought that the drugs weren't going to work, and in most cases, no larger companies had been willing to put up money on them, either. The oncology Phase III success rate for larger companies is comparable to therapeutics areas in the rest of the industry; the Phase III success rate for micro-cap oncology companies is catastrophic.

Comments (7) + TrackBacks (0) | Category: Business and Markets | Cancer | The Dark Side

September 20, 2011

Honest Research in China

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Posted by Derek

Continuing a sort of informal series here on China's research environment, a reader sent along this editorial from China Daily. That, of course, is an organ of the Chinese government, and its title is a rather pointed one: "Honest Research Needed":

An investigation by the Chinese Association of Scientists has revealed that only about 40 percent of the funds allocated for scientific research is used on the projects they are meant for. The rest is usually spent on things that have nothing to do with research. . .Besides, the degree of earnestness most scientists show in their research projects nowadays is questionable. Engaging in scientific research projects funded by the State has turned out to be an opportunity for some scientists to make money. There are examples of some scientists getting research funds because of their connections with officials rather than their innovation capacity.

This would seem to be part of a broader anticorruption movement on the part of the government, which (from all reports) is finding plenty of material to work with. But I still have to wonder how effective that's going to be. As long as it's the state that is the main source of funding, the source of all permissions, and the final judge on what's worthwhile, then corruption has both a strong incentive to exist and a clear leverage point from which to work.

If you subsidize something, you're going to get it. It may be that the Chinese government has subsidized, in too many cases, something that was billed as "research", without realizing that it was going to have those quotation marks around it.

Comments (25) + TrackBacks (0) | Category: The Dark Side

September 6, 2011

Chronic Fatigue: Enough Energy Left for Death Threats, Anyway

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Posted by Derek

I've written a bit about the struggles to find the biological causes of chronic fatigue syndrome - but perhaps I should shut up? That seems to be the wiser course, given what's reported in this piece from the UK:

The full extent of the campaign of intimidation, attacks and death threats made against scientists by activists who claim researchers are suppressing the real cause of chronic fatigue syndrome is revealed today by the Observer. According to the police, the militants are now considered to be as dangerous and uncompromising as animal rights extremists.

One researcher told the Observer that a woman protester who had turned up at one of his lectures was found to be carrying a knife. Another scientist had to abandon a collaboration with American doctors after being told she risked being shot, while another was punched in the street. All said they had received death threats and vitriolic abuse.

The crime these people have committed, according to the various unhinged activists, is that they're suggesting that there could perhaps be a psychological component to the condition, or even just that the various proposals put forth for a viral cause don't seem to be holding up well. And we jump from that to death threats, harassment, calls for defunding, and accusations of dark deeds underwritten by Evil Pharmaceutical Companies.

That last one is especially weird, as one of the interviewees in the article makes clear. If there were a definite viral cause for chronic fatigue and allied syndromes, we Evil Pharma Scientists would do what we've done so evilly for HIV, hepatitis, and other diseases: come up with drugs to treat people or (better yet) vaccines to try to keep anyone from ever getting the disease again. Dark stuff indeed.

Comments (38) + TrackBacks (0) | Category: Infectious Diseases | The Dark Side

August 31, 2011

The Finest Retraction Notice Ever?

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Posted by Derek

RetractionWatch has this gem from the Journal of Clinical Microbiology. My favorite part is midway through: "Moreover, we realized after our article had been published that major parts of the text had been plagiarized almost verbatim. . .".

Oh, yeah. There is that. But there's more at the link. The RetractionWatch people are trying to get more details, but I wish them luck. This looks like one of those things that no one is going to be very happy to talk about. . .

Comments (12) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

August 11, 2011

Scientific Retractions: A Growth Industry?

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Posted by Derek

The Wall Street Journal has an interesting article based on data from Thomson Reuters on the frequency of retracted papers. It seems to be increasing dramatically:

Since 2001, while the number of papers published in research journals has risen 44%, the number retracted has leapt more than 15-fold, data compiled for The Wall Street Journal by Thomson Reuters reveal.

Just 22 retraction notices appeared in 2001, but 139 in 2006 and 339 last year. Through seven months of this year, there have been 210, according to Thomson Reuters Web of Science, an index of 11,600 peer-reviewed journals world-wide.

They mention Retraction Watch, as well they should. But ten years ago, would there have been enough new material to keep that blog running? Pharmalot has some more from its founder about what might be going on. There are, of course, more journals than ever these days, and many of them are junk. But it's not the bottom-tier journals that are driving this trend, I'd think, since honestly, when does anyone ever retract a paper in one of them? Consistent with that view, this bar chart of PubMed retractions by journal is heavily weighted towards the big dogs. A lousy or nonreproducible paper in one of the top journals is more likely to be of enough interest to attract attention, but one in J. Whatever will just sit there.

No, when you look at this chart, it appears that retractions-per-papers-published have been climbing, so the answer must be some combination of more mistakes, more fraud, or better policing. Retractions due to fraud seem to be where most of the growth is, according to this study, so that takes us down to the latter two explanations.

Software has definitely made the lazier sorts of fraud easier to detect, automatically flagging copy-and-paste hack jobs. But those aren't the kinds of things that show up in the better journals, are they? We may be seeing a mix of greater incentive to commit fraud and a rise in skepticism among readers. There have been enough cases, enough highly-publicized retractions and scandals, that more people may be willing to wonder if some exciting new result is true at all.

That's not a bad thing. The rise in fraud is a bad thing, but a corresponding rise in scrutiny is the only thing that's going to cure it. There are always a few pathological types out there that kind of know that they're going to get caught and kind of don't care. Those we shall always have with us, and not much is going to discourage them. But as for the rest of the fraudsters, the thought that they have a better chance of being found out and punished should give them something to think about.

Comments (15) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

August 9, 2011

What An Offer

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Posted by Derek

The glamorous side of blogging is that you get chances like this, delivered right to your e-mail queue:

". . .I am working with a couple of small-cap biotech companies who have good fundamental technologies, but are not on the radar screen of a lot of investors. We are looking for some influential bloggers to put some spotlight on these companies, so more people can be exposed to the value proposition and opportunities available. In the past we have worked with some bloggers who have written both paid as well as unpaid articles on these companies. I would like to explore your interest and to discuss this further. . .

I explained to this person just what my level of interest was, in terms that I don't think were misinterpretable, and pointed out that if their operation was not, in fact, a pump-and-dump penny stock scheme, then they should take more care not to make it sound exactly like one. But I thought I would at least get some use of of this sleazy offer by getting a few things on the record.

I write paid columns for Contract Pharma and Chemistry World, and I occasionally do paid pieces for other (respectable!) outlets. But in none of those do I tout stocks, companies, or products. As for the material on this blog, it's produced for free, which (by no coincidence) is what I charge for reading it. The only money that changes hands around here is if someone buys something through an Amazon link, and I try to keep those down to things that people could actually find useful and relevant - no links to plasma TV sales, for example, although if you want to buy one through Amazon, please do feel free.

And of course, I stay away from anything that might involve (or be thought to involve) material information concerning my place of work. But there are no commercial considerations involved in my choice of topics or my expressed opinions on them. If I have a stock position in a company - a rare event, these days, since my kids and my mortgage have seen to it that I don't have a vast fund of free-floating investment capital - then I say so. (A careful look though the archives would show that depending on me for investment advice is not necessarily a winning plan, although it would at least be full of excitement).

So there you have it. No pay-for-play around here. But if you across someone going on about what a great thing this tiny biotech you've never heard of is, well, exercise the usual amount of caution.

Comments (10) + TrackBacks (0) | Category: Blog Housekeeping | The Dark Side

August 3, 2011

What the Bottom of the Barrel Looks Like

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Posted by Derek

Want some evil pharma/biotech executives to hate? Don't waste your time on the usual suspects. Go to Immunosyn and Argyll Biotechnologies; they're worth your while. Never heard of them, you say? Well, many of the people that have wish that they hadn't:

"These executives routinely authorized public filings that told investors a story about the status of the company's prized drug that was far different from the behind-the-scenes reality," said Merri Jo Gillette, Regional Director of the SEC's Chicago regional office. "Three of these executives went one step further to illegally profit from their tall tales by selling their company stock and reaping more than $20 million while repeatedly misleading investors about the drug.

Misleading, as in telling people that the lead drug was beginning clinical trials when it wasn't, was in the regulatory process in Europe when it wasn't, and neglecting to mention that its IND actually been placed on hold twice by the FDA and was basically going nowhere. And we haven't even gotten to the $300,000 worth of (undelivered) shares that were flogged to the hapless (and in some cases terminally ill) patients at a Texas "holistic clinic". Oh, these are some fine, fine specimens of humanity we're talking about

Comments (16) + TrackBacks (0) | Category: The Dark Side

July 28, 2011

Massive Piles of Faked Data - But Right On Time

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Posted by Derek

Here's every outsourcing manager's nightmare: you contract out for research, and your CRO turns around the studies you want right on schedule. They send back the complete data package, and everything's in place. But they faked it.

Gives you the shivers, doesn't it? Well, unfortunately, it seems to be the case with an outfit called Cetero Research out of Houston. The FDA has been investigating them, and has found enough warning signs to believe that none of the data generated there can be relied on. The companies that used their services now have to decide if they need to re-run these studies themselves, which I'm sure excites them no end.

FDA is taking this action as a result of two inspections of Cetero's bioanalytical facility in Houston, Texas conducted in 2010, as well as the company's own investigation and third party audit. The inspections and audit identified significant instances of misconduct and violations of federal regulations, including falsification of documents and manipulation of samples.

The pattern of misconduct was serious enough to raise concerns about the integrity of the data Cetero generated during the five-year time frame. FDA concurs with the assessment of Cetero's independent auditor who stated, "This misconduct appears to be significant enough to cast doubt on the data generated...If the foundation of the laboratory is corrupt, then the data generated will be also."

The investigation appears to have started with an internal whistleblower, according to this letter from the FDA. The company conducted its own investigation, but the agency is slamming them both for the violations and for the inadequacy of that internal review:

According to your internal investigation, electronic records of key card building entry times demonstrated approximately 1900 instances of blood/plasma samples allegedly extracted on weekends and holidays between April 15, 2005, and June 30, 2009, where the arrival times of laboratory chemists were greater than one hour after the documented start time of the sample extraction. In addition, there were approximately 875 instances where the laboratory chemists were not present in the facility at the documented sample extraction date.

The company's original theory was that its scientists were falsifying the weekend hours in order to get paid more, but that the numbers themselves were OK. But as the FDA notes, they didn't go on to see if times were being faked during the working week (where there was no overtime incentive), and it turns out that they were. Falsus in uno, falsus in omnibus, as the lawyers say, and that appears to be the case here. A third-party investigation found many other irregularities - faked standard concentration curves and back-filling of internal standards, for example. One of the worst was the use of not-yet-analyzed samples as preliminary runs, apparently as a quick look to see if the numbers were going to come out looking good or not. That's not quite how you want to be conducting your research, and most especially if you're going to follow that up by "fixing" the numbers that you don't like. The whistleblower alleged just that. The FDA letter says that the company's conduct makes that a real possibility, and that the documention that's available sure isn't sufficient to rule it out.

You hear a lot of talk (in the comments on this blog and in other venues) about the alleged unreliability of offshore CRO work. But you don't have to go to China to get shaky data. Houston is far enough.

Update: Here's Cetero's response to the FDA.

Comments (35) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

July 19, 2011

Sezen / Sames: What Does it Say About Grad School?

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Posted by Derek

If you haven't seen it, Chembark has Part III of the series on the Sezen/Sames research scandal. And it's another good one, focusing this time on Prof. Sames and his responsibilities in the whole affair. Everyone who's interested should go over to Paul's blog to read what he has to say about things. He's not keeping things bottled up:

Apparently, there is a double standard when it comes to judging students and professors. I guess that shouldn’t surprise anyone. Apparently, students should be fired for failure to replicate fictitious results, but professors are to be rewarded with tenure for being so grossly negligent as to oversee the greatest case of scientific misconduct in the history of organic chemistry.

But that quote shouldn't give you the idea that his post is all invective - there's a lot to back up those statements as well. I'll add that I'm not surprised by a double standard, either - after all, tenured professors are around for years. They bring in grant money (and overhead), while students. . .well, they're transient, and there are always more of them where the last bunch came from.

And while I think it would be a good thing if some of that were to change, I'm not optimistic about that happening. Unstacking that deck would be very, very hard. What would help a bit, though, would be for graduate students (and prospective graduate students) to realize that the deck is stacked, or in some of the more extreme cases of cluelessness, to realize that the deck exists in the first place. Forewarned is forearmed. You are in a very unequal and potentially precarious position as a graduate student, which is one the reasons my standard grad-school advice is to get a PhD as quickly as is consistent with honor and propriety. Don't hang around one day longer than you have to. My own university educated me in that regard: whenever it was more advantageous for them to consider us students, well, that's what we were. Did it then, five minutes later, cost them less money and trouble with respect to some other issue to consider us staff? Then we were staff. Whatever put the university in a better relative position or allowed them to save a nickel.

That's not to say the world beyond graduate school is fair, because it isn't, of course. Wide-ranging hopes in that line will not serve you well. Fred Schwed put it well, quoting what he called "the falsest text in the language" (from Sterne), to the effect that the Lord tempereth the wind to the shorn lamb. "He doesn't, you know,, said Schwed. "Look around you". But at least in some other spheres there are usually more options, more means of redress, than are available to any graduate student. Those problems with university administration are small compared to the potential for trouble with your own professor, and in many cases there's not a damn thing you can do about it - even being in the right may help least of all. The students dismissed from the Sames group over Sezen's work appear, from this vantage point, to have been quite correct about her conduct and the quality of her work. In vain.

Comments (68) + TrackBacks (0) | Category: Graduate School | The Dark Side

July 8, 2011

The Sames / Sezen Fraud Case: Holy Cow

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Posted by Derek

C&E News has an extraordinary piece on the long-running Bengü Sezen case at Columbia U. They've obtained two detailed reports from the federal government on the matter, and, well, pretty much all ones worst suspicions are confirmed:

By the time Sezen received a Ph.D. degree in chemistry in 2005, under the supervision of Sames, her fraudulent activity had reached a crescendo, according to the reports. Specifically, the reports detail how Sezen logged into NMR spectrometry equipment under the name of at least one former Sames group member, then merged NMR data and used correction fluid to create fake spectra showing her desired reaction products.

The documents paint a picture of Sezen as a master of deception, a woman very much at ease with manipulating colleagues and supervisors alike to hide her fraudulent activity; a practiced liar who would defend the integrity of her research results in the face of all evidence to the contrary. Columbia has moved to revoke her Ph.D.

. . .the reports echo sources from inside the Sames lab who spoke with C&EN under conditions of anonymity when the case first became public in 2006. These sources described Sezen as Sames’ “golden child,” a brilliant student favored by a mentor who believed that her intellect and laboratory acumen provoked the envy of others in his research group. They said it was hard to avoid the conclusion that Sames retaliated when other members of his group questioned the validity of Sezen’s work.

For more on this, see ChemBark, where the same documents have been obtained (via FOIA requests). Here's Part One, and Part Two. The site has been on this case for a long time now, and that's the place to go for the details - and if you're a chemist, or are interested in what human beings are capable of getting up to, you'll want to read them. Years of faked NMR spectra, faked reaction products, faked logbooks - this is surely one of the longest-running and most thorough frauds in modern organic chemistry history. I await Part Three!

Comments (126) + TrackBacks (0) | Category: The Dark Side

The Duke Cancer Scandal and Personalized Medicine

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Posted by Derek

Here's a good overview from the New York Times of the Duke scandal. Basically, a team there spent several years publishing high-profile papers, and getting high-profile funding, and treating cancer patients based on their own tumor-profiling biomarker work. Which was shoddy, as it turns out, and useless, and wasted everyone's time, money, and (in some cases) the last weeks or months of people's lives. I think that about sums it up. It was Keith Baggerly at M. D. Anderson who really helped catch what was going on, and Retraction Watch has a good link to his presentation on the whole subject.

The lead investigator in this sordid business, Anil Potti, ended up retracting four papers on the work and left Duke last fall (although he's since resurfaced at a cancer treatment center in South Carolina). That's an interesting hiring decision. Looking over the case (and such details of it as Potti lying about having a Rhodes Scholarship), I don't think I'd consider hiring him to mow my yard. Perhaps that statement will be something for his online reputation management outfit to deal with.

But enough about Dr. Potti himself; I hope I never hear about him again. What this case illustrates are several very important problems with the whole field of personalized medicine, and with its public perception. First off, for some years now, everyone has been hearing about the stuff: the coming age of individual cancer treatment, biomarkers, zeroing in on the right drugs for the right patient, and so on. You'd almost get the impression that this age is already here. But it isn't, not yet. It's just barely, barely begun. By one estimate, no major new cancer biomarker has been approved for clinical use in 25 years. Update: changed the language here to reflect differences of opinion!)

Why is that? What's holding things up? We can read off DNA so quickly these days - what's to stop us from just ripping through every cancer sample there is, matching those up with who responded to which treatment regime and which cancer targets are (over)expressed, and there you have it. That's what all these computers are for, right?

Well, that sort of protocol has, in fact, occurred to many researchers. And it's been tried, over and over, without a whole lot of success. Now, there are some good correlations, here and there - but the best ones tend to be in relatively rare tumor types. There's nowhere near as much overlap as we'd like between the cancers that present the most serious public health problems and the ones that we have good biomarker-driven treatment data for. Breast cancer may be one of the fields where things have moved along the most - treatment really is affected by checking for things like Her-2. But it's not enough, nowhere near enough.

So why, then, is that the case? Several reasons - for one, tumor biology is clearly a lot more complex than we'd like it to be. Many common forms of cancer present as a host of mutated cells, each with a host of mutations (see this breast cancer work for an example). And they're genetically unstable, constantly changing. That's why so many cancers relapse after initially successful treatment - you kill off the tumor cells that can be killed off, but that may just give the ones that are left a free field.

Given this state of affairs, and the huge need (and demand) for something that works, the field is primed for just the sort of trouble that occurred at Duke. Someone unscrupulous would have no problem convincing people that a hot new biomarker was worthwhile - any patients that survived would praise it to the skies, while the ones that didn't would not be around to add their perspective. And even without criminal behavior, it's all too easy for researchers to honestly believe that they're on to something, even what that isn't true. The statistical workup needed to go through data sets like these is not trivial; you really have to know what you're doing. Adding to the problem, a number of judgment calls can be made along the way about what to allow, what to emphasize, and what to ignore.

The other problem is that cancer is such an emotional issue. It's very easy for anyone with a drum to beat to join in at full volume. Do you think that the FDA is letting all sorts of toxic junk through? Or do you think that the FDA is killing people by being stupidly cautious? Are drug companies ignoring dying patients, or ruthlessly profiteering off them? Are there too few good ideas for people to work on, or too many? Come to oncology; you can find plenty of support for whatever position you like. They can't all be right, but when did that ever slow anyone down? Besides, that means that there will invariably be Wrong-Thinking Evil People on the other side of any topic, and that's always stimulating, too.

It is, in fact, a mess. Nor are we out of it. But our only hope to is to keep hacking away. Wish us luck!

Comments (22) + TrackBacks (0) | Category: Cancer | Clinical Trials | Regulatory Affairs | The Dark Side

July 5, 2011

Fakery, As Revealed By Figures

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Posted by Derek

I note via Retraction Watch that the Journal of Biological Chemistry has issued retraction notices for four papers published from the group of the late Maria Diverse-Pierluissi, at the Mt. Sinai School of Medicine. One of their readers looked over the papers (which had been cited a few times, without making any particular huge impact, it seems), and found that some of the figures (Western blots and so on) repeat, even though they're supposed to represent different things (e.g., Figure 3A and 3C here).

Mt. Sinai told the Retraction Watch people that an internal investigation turned up the evidence of misconduct, and that the matter has been referred to the NIH, which funded the work. What those duplicate figures make me wonder, though, is how long it'll be before we have a plagiarized-figure search tool, in the same way that we have plagiarized-text tools running? There's already something similar out there - TinEye - and I'm sure that much nicer systems are available for a fee. Have any scientific journals implemented something like this?

Comments (18) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 30, 2011

An Unethical Clinical Trial

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Posted by Derek

Well, here's one from the Archives of Internal Medicine that most certainly did get published. It's an analysis of an old clinical trial, STEPS, which was conducted for Neurontin (gabapentin) during the 1990s.

But that's not quite right. The authors find, by analyzing a large trove of documents released during lawsuit discovery proceedings, that STEPS was not really intended to be a clinical trial. Instead, it was a marketing program:

Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles.

Here's more at Medscape. STEPS was allegedly a Phase IV post-approval trial, but it was unblinded and pretty much uncontrolled. Instead of taking place at a small number of centers, it seems to have been set up to enroll as many physicians as possible (they ended up with 772!), with each of them bringing in a handful of patients.

This is an extremely foul technique, which brings the companies who use it, the entire drug industry, and the whole idea of clinical research into disrepute. For money. I feel like spitting on the floor.

Comments (14) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

June 7, 2011

Even Worse Than Reality

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Posted by Derek

I found this article in The American Scholar via Arts and Letters Daily, entitled "Flacking for Big Pharma". As you might have possibly guessed from the title, it's a broadside against the advertising practices of the drug industry, and particularly against its interactions with physicians and the medical journals.

And I'll say up front that the piece is not, in fact, completely wrong. It's probably not even mostly wrong. There really are big problems in these areas, such as too-aggressive promotion, minimization of side effects, too many payments to "key opinion leaders", too many studies that don't see the light of day, and so on. And these things really do lower the respect that people have for the drug industry - assuming, by this point, that there's much respect left. But overall, this article is sort of a summary version of Marcia Angell's book, for people who would like to hate the drug industry but find themselves pressed for time. And as such, it manages to get some important things wrong in the process of getting some things right.

For example, it makes much of subgroup analysis of clinical trials, but as a way for drug companies to pull the wool over readers' eyes. I wonder how much this really happens, though, since overzealous data mining of a trial that wasn't powered to generate such conclusion is (you'd think) a well-known pitfall by now. Perhaps not, though. But the example given in the article is BiDil:

BiDil proponents published studies that supported their claim of a racially mediated genetic anomaly that was addressed by BiDil, making it an ideal drug for blacks but not for whites.. . .

NitroMed won FDA approval of a new trial that included only 1,050 black subjects, with no white subjects to provide comparison data. Furthermore, BiDil was not tested alone, but only in concert with heart medications that are already known to work, such as diuretics, beta-blockers, and angiotensin-converting enzyme (or ACE) inhibitors. The published results of the trial were heralded as a success when subjects taking the drug combinations that included BiDil enjoyed 43 percent fewer heart-failure deaths.

. . .excluding whites was a medically illogical but financially strategic move because it eliminated the possibility that the drug would test well in whites, thereby robbing NitroMed of its already thin rationale for calling BiDil a black drug. The “black” label was crucial, because BiDil’s patent covering use in all ethnic groups expired in 2007, but the patent for blacks only allows NitroMed to profit from it until 2020. BiDil is a case study in research methodology “flaws” that mask strategies calculated to make a dodgy drug look good on paper, for profit.

But this doesn't appear to be correct. First off, as the article itself mentioned earlier, the BiDil combination was originally tested (twice) in racially mixed (in fact, I believe, mostly white) trial groups. Secondly, the 1,050-patient trial in black patients was done with other therapies because to do otherwise would be unethical (see below). And what you wouldn't realize by reading all this is the BiDil, in fact, was a failure. No one's making piles of profits on BiDil until 2020, especially not NitroMed. You wouldn't even know that NitroMed itself gave up trying to sell BiDil three years ago, and that the company itself was acquired (for a whopping 80 cents a share) in 2009.

Now, about those placebo-controlled trials. This article makes much of a British Medical Journal satire from 2003 on how to make a drug look good. But it's confused:

A placebo, such as a sham or “sugar” pill, has no active ingredient, and, although placebos may evoke some poorly understood medical benefits, called the “placebo effect,” they are weak: medications tend to outperform placebos. Placebo studies are not ethical when a treatment already exists for a disorder, because it means that some in the study go untreated. However, if you care only that your new drug shines in print, testing against placebo is the way to go.

Well, which is it? We can't, in fact, run placebo-controlled trials just to "shine in print" when there's a standard of care, you know. You can only do that when there's no standard of care at all. And in those cases, what exactly should we use as a comparison? Using nothing at all (no pills, nothing) would, in fact, make our drugs look even better than they are, because of that placebo effect. This is a specious objection.

And when there's a standard of care that a new drug will be added to (as was the case with BiDil), then you actually do have to run it with those therapies in place, at least when you get to Phase III. The FDA (and the medical community) want to know how your drug is going to perform in the real world, and if patients out in that real world are taking other medications, well, you can't pretend that they aren't.

In another section, the article makes much of the Merck/Elsevier affair, where Elsevier's "Excerpta Medica" division set up some not-really-journals in Australia (blogged about here). That was, in fact, disgraceful (as I said at the time), but disgraceful apparently isn't enough:

. . .Elsevier, the Dutch publisher of both The Lancet and Gray’s Anatomy, sullied its pristine reputation by publishing an entire sham medical journal devoted solely to promoting Merck products. Elsevier publishes 2,000 scientific journals and 20,000 book-length works, but its Australasian Journal of Bone and Joint Medicine, which looks just like a medical journal, and was described as such, was not a peer-reviewed medical journal but rather a collection of reprinted articles that Merck paid Elsevier to publish. At least some of the articles were ghostwritten, and all lavished unalloyed praise on Merck drugs, such as its troubled painkiller Vioxx. There was no disclosure of Merck’s sponsorship. Librarian and analyst Jonathan Rochkind found five similar mock journals, also paid for by Merck and touted as genuine. The ersatz journals are still being printed and circulated, according to Rochkind, and 50 more Elsevier journals appear to be Big Pharma advertisements passed off as medical publications. Rochkind’s forensic librarianship has exposed the all-but-inaccessible queen of medical publishing as a high-priced call girl.

Fifty journals? Really? As far as I can tell, that figure comes from this analysis at the time, and seems to be mostly nonce publications, one-off conference proceedings, and the like. There is a whole list of "Australasian Journal of So-and-Sos", which would be the same reprint advertorials as the other Excerpta Medica stuff, but do these still exist? (Did all of them on the list, in fact, ever actually publish anything?)

You'd get the impression that Elsevier is (or was, until Big Pharma came along) an absolute shining pinnacle of the medical establishment - but, with apologies to the people I know who work there, that is unfortunately not the case. They're big, and they're very far from the worst scientific publishers out there, but some of their titles are, in fact, not adding much to the total of human knowledge. Nor has the conduct of their marketing department always been above reproach. But no, this has to be built up to look even worse than it is.

The irritating thing is that there's plenty to criticize about this industry without misrepresenting reality. But does that sell?

Comments (10) + TrackBacks (0) | Category: Press Coverage | The Dark Side | The Scientific Literature | Why Everyone Loves Us

June 3, 2011

More Insider Trading at the FDA?

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Posted by Derek

Today's Wall Street Journal has the news that the Liang insider-trading case may not be the end of the story at the FDA. The SEC has amended their complaint against Liang, adding another company's stock and another relief defendant (Liang's 87-year-old father in Shanghai, who also had his name on a brokerage account). Here's a chart of his trading, for those who are interested - make note that he did manage to lose money twice, on Pozen and Mannkind, but otherwise he hit 'em over the fence, time after time, in a most unnatural manner. (The chart also backs up my earlier speculation that Liang's trading in Vanda was what rang the alarm bells - it's far and away the biggest on the whole list).

But the Journal says that "people familiar with the case" think that Liang may have involved several other federal employees. The word is also that the insider trading may have begun well before 2006, and run to a lot more money than has been totaled so far. This might account for the delay in hearing the case - it could well be that the SEC is trying to get Liang to implicate more people as part of a plea-bargain deal. Another scientist at the FDA is apparently involved, according to the paper's sources, but that's all anyone is saying.

Rather weirdly, Liang appears to have refinanced his house ten times in the last few years - four times in as many months at one point - and taken out $350,000 in equity lines against the property. I'm not sure if he was rounding up more capital for his trading business or what. . .

Comments (18) + TrackBacks (0) | Category: Regulatory Affairs | The Dark Side

April 12, 2011

Scientific Fraud: How Often and How Much?

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Posted by Derek

A new paper in PLoSOne goes over the existing studies that have tried to put a number on how many scientists falsify data (or have done so at least once) or commit other scientific offenses (ranging from the quite grave to the pretty questionable).

For what it's worth, the meta-analysis comes out with a figure of about 2% of scientists admitting that they've fabricated, falsified, or modified data. Of course, that group itself is a wide one, and deserves to be broken into various levels (which is just what Dante ended up doing, come to think of it, for similar reasons). To my mind, people who are modifying data want to make the numbers look better than they are, and people who are falsifying data want to make the numbers just flat-out say things that they don't say. And the far end of that process is fabrication, where you give up on tweaking and bending and processing, and just make the stuff up. As the PLoS paper says, you slide along from what could be explained as carelessness all the way to what can only be described as blatant fraud.

There are, of course, a lot of difficulties in getting good numbers on this sort of thing, and the whole purpose of this meta-analysis was to try to set a lower bound. There are limits to what people will admit, and limits in how objectively they see their own behavior:

The grey area between licit, questionable, and fraudulent practices is fertile ground for the “Mohammed Ali effect”, in which people perceive themselves as more honest than their peers. This effect was empirically proven in academic economists and in a large sample of biomedical researchers (in a survey assessing their adherence to Mertonian norms, and may help to explain the lower frequency with which misconduct is admitted in self-reports: researchers might be overindulgent with their behaviour and overzealous in judging their colleagues. In support of this, one study found that 24% of cases observed by respondents did not meet the US federal definition of research misconduct.

There's another interesting possibility raised:

Once methodological differences were controlled for, cross-study comparisons indicated that samples drawn exclusively from medical (including clinical and pharmacological) research reported misconduct more frequently than respondents in other fields or in mixed samples. To the author's knowledge, this is the first cross-disciplinary evidence of this kind, and it suggests that misconduct in clinical, pharmacological and medical research is more widespread than in other fields.

He goes on to speculate whether this is due to financial pressures, or different levels of self-awareness or self-reporting. And this brings up another reaction I had to the whole paper, for which I'll have to go back to its introduction:

The image of scientists as objective seekers of truth is periodically jeopardized by the discovery of a major scientific fraud. . .A popular view propagated by the media and by many scientists sees fraudsters as just a “few bad apples”. This pristine image of science is based on the theory that the scientific community is guided by norms including disinterestedness and organized scepticism, which are incompatible with misconduct. Increasing evidence, however, suggests that known frauds are just the “tip of the iceberg”, and that many cases are never discovered. The debate, therefore, has moved on to defining the forms, causes and frequency of scientific misconduct.

I wonder about some of that. Is the image of science really as pristine as all that, at this date? And does the media really help to propagate such a view? I think that the real world is quite a bit messier. I would guess that you'd have to go back to the 1950s (or perhaps before the Second World War) to find a solid majority of people thinking that scientists were pretty much all pristine truth-seekers, and perhaps not even then. And as for media depictions of scientists, those have been mixed for a long time now.

I think that you'll definitely find more objective truth-seeking in the physical sciences than you'll find in most other human endeavors, but science is done by humans with all the failings that humans come equipped with (and it's quite a list). One should always be open to some possibility of misconduct in any field and any situation; lying is one of the things that people do. That's not to condone it, of course - but being shocked by it doesn't seem to be too useful, either.

Comments (35) + TrackBacks (0) | Category: The Dark Side

March 30, 2011

Insider Trading at the FDA

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Posted by Derek

Ah, insider trading. It's the province of Wall Street types in really expensive shirts, right? Like in the movies? Well, read on.

Even the most clueless know that you're not supposed to trade on material nonpublic information, and the only really fuzzy part is what constitutes material information. A lawyer once told me that if you're an employee of a company, material information is "anything that makes you think about trading the stock". That's a pretty intelligent rule, and one that the recent Matrixx Supreme Court decision would seem to have reaffirmed. If someone could think it's nonpublic material information, odds are that it is.

In the drug business, the hottest potatoes in this category are the results of clinical trials and FDA decisions. People (a very short, well-defined, and well-paperworked list of people) inside a given company know the first news before anyone else, and people inside the FDA get to hear about the second. And there is no way that you can act on such information legally before it's released. Those tempted to try realize that, of course, and act accordingly.

They do, in fact, what Cheng Li Yiang (a chemist, regrettably) and his son Andrew Liang were accused yesterday of doing since 2006: they used the accounts of at least least seven other people to trade on knowledge of FDA approval decisions, pulling in over three million dollars in the process. The single biggest winner (over $1 million) appears to have been front-running the surprise approval of Vanda Pharmaceutical's Fanapt in 2009. It wouldn't surprise me if this was the one that blew up the whole business. That was such an unexpected move by the FDA (after which the stock went up by a factor of six) that the SEC must have gone back and carefully checked to see if anyone had been building up a position beforehand.

Liang got in on most of the big percentage moves of the last few years: Mannkind, Momenta, Pharmacyclics and many others, all small companies whose stocks saw some major action in both directions. If you want more details, here's the SEC complaint (PDF). It's a blueprint for getting caught, I should add. The various friend-and-family brokerage accounts mostly listed Liang's phone numbers as contact information, and almost always transferred money to an account held by Liang and his wife. The trading was done (one account right after the other) from IP addresses associated with his home account or voice lines billed to his name - this for accounts like the one ostensibly held by his 84-year-old mother back in China. Honestly, ten minutes after the SEC got suspicious about this guy and started checking him out, they must have known that they had him by the valuable body parts. It was really just a matter of time - well, time and greed.

Interestingly, Liang worked for the FDA for ten years before he seems to have decided to cash in. It would be interesting to know what went on, but my guess is that it's a familiar story. I think that he watched these decisions being made, watched the stocks jump around, thought about the profits to be made, and didn't act on those desires. Until one day he finally did - and nothing happened. So he probably told himself that he got away with it that time, and really shouldn't do that again for fear of getting caught - until he did it again, and didn't get caught. By this time, from the accounts you read of people in such situations, the hook is well and truly set. There may be a few people who are philosophical enough to take a set amount of money and walk away, but I'll bet that they're mighty scarce compared to the number of people who can't keep themselves from riding the train until, to their surprise, it suddenly pulls into a station.

Comments (25) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

March 23, 2011

Laboratory Sabotage?

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Posted by Derek

The topic of lab sabotage has come up here now and again. And while there are some documented cases, I agree with Chemjobber that these stories are often more in the realm of legend. He'd trying to bring some of them into the light, though, by offering a valuable prize to the most interesting and well-attested story of deliberate action that he can find. If you know of any, go for the glory!

Comments (21) + TrackBacks (0) | Category: The Dark Side

February 9, 2011

Thallium Poisoning? In This Day and Age?

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Posted by Derek

Thallium poisoning? Now someone in the lab has really lost it. But that seems to be what happened in New Jersey, with a chemist from Bristol-Myers Squibb accused of doing in her husband.

A note to the Newark Star-Ledger and some other newspapers: even though a hot isotope of it is occasionally used in medicine, the thallium in this case was not radioactive. It doesn't have to be; it's a good old-fashioned chemical poison. The element enters cells readily, being taken up as if it were potassium, but once it's there it starts disrupting all kinds of processes by latching on to sulfur atoms. It was good enough for Agatha Christie to use it for one of her plots, which (interestingly) seems to have publicized it enough that several other thallium plots were discovered or foiled because of her novel.

As even Wikipedia points out, thallium was "once an effective murder weapon", but the emphasis is one "once". That time is long past. Forensically, it's not the first thing that you think of, certainly, but it got picked up at autopsy in this New Jersey case. And it's not like there's any other way a person could get a high level of the element in their tissues, nor, with modern analytical techniques, can it be mistaken for anything else. Honestly, anyone who believes that they have a good chance of getting away with a thallium murder is just not thinking the whole business through.

There are no details about how the crime was done, but we can assume that some kind of soluble thallium salt was put into the victim's food. Thallium chloride is the cheapest source (as usual - Primo Levi was right when he said "chlorides are rabble"), but I'm not sure how cost-conscious the accused was. She very likely got the compound from work - and even there, it wouldn't surprise me if she had to order it up on some pretext, which will certainly make the investigation easier. Thallium's not a very common metal in organic chemistry - I've seen some uses for it, but nothing compelling enough to make me want to try it.

It's odorless and tasteless stuff, by all accounts. But it's a stupid poison. I'm not going to speculate on better methods - I haven't put that much thought into the topic, really - but there have to be some, possibly with obscure and nasty natural product toxins. Not that it's so easy to get ahold of those, but the Engineer's Triangle still applies, to murder as to everything else: Good, Fast, Cheap: Pick Any Two.

So in the end, we have what looks like a vindictive (but not very competent) poisoner, a dead victim, and all kinds of trouble and fallout for the innocent bystanders in all the families concerned. A sordid business.

Comments (63) + TrackBacks (0) | Category: The Dark Side | Toxicology

February 8, 2011

Whistleblowers: Paid Too Much?

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Posted by Derek

A former prosecutor says that the huge payouts in some recent whistleblowing cases in the drug industry have gotten out of hand. The law, says Michael Loucks, was never intended to reach up into these sorts of figures, and he's suggesting a cap of $2 million as a reasonable incentive.

I'm not sure if I agree with that or not. It's true that a New England Journal of Medicine report last year found that most pharma informants in such cases say that they were not motivated by the money involved:

Although the relators in this sample all ended up using the qui tam mechanism, only six specifically intended to do so. The others fell into the qui tam process after seeking lawyers for other reasons (e.g., unfair employment practices) or after being encouraged to file suit by family or friends. Every relator we interviewed stated that the financial bounty offered under the federal statute had not motivated their participation in the qui tam lawsuit. Reported motivations coalesced around four non–mutually exclusive themes: integrity, altruism or public safety, justice, and self-preservation.

And that seems believable. But what I'm thinking about is the motivation for the people who are promulgating the behavior that the whistles get blown on. These are not people for whom personal integrity is as strong a motivating factor (although self-preservation would certainly still rank high). Many of them, I'd venture to guess, are in fact people who would fear that others might be motivated mostly by a large payout. And if that's true, the publicity around the large whistleblower awards might help restrain them.

Why don't such people just take the money and run, themselves? Several reasons, I'd say, not least of which is the fact that they're generally quite implicated in the very behavior that the Department of Justice would like to prosecute. But another motivation for that sort of personality is the loss of status and position that such a decision would mean. I'm convinced that having power is a strong motivator for most people, and for some it's the primary one. Money is great, and the other benefits are great, too - but for many people, it's being the boss that is the sweetest part of the job (along with the prospect of working one's way up to being an even bigger boss, of course). Blowing the whistle means saying goodbye to that, irrevocably.

As an aside, people for whom personal power is the prime motivation do not tend to turn out well if they get their wish, to put it mildly. This is a good time to quote Lord Acton. I also recall Gore Vidal's essay "Robert Graves and the Twelve Caesars", pointing out what a depressing spectacle they tended to make once the experience of empire got through with them:

Yet what, finally, was the effect of absolute power on twelve representative men? Suetonius makes it quite plain: disastrous. Caligula was certifiably mad. Nero, who started well, became progressively irrational. Even the stern Tiberius's character became weakened. In fact, Tacitus, in covering the same period as Suetonius, observes: 'Even after his enormous experience of public affairs, Tiberius was ruined and transformed by the violent influence of absolute power.' Caligula gave the game away when he told a critic, 'Bear in mind that I can treat anyone exactly as I please.' And that cruelty which is innate in human beings, now give the opportunity to treat others as toys, flowered monstrously in the Caesars.

And there's always this:

The Party seeks power entirely for its own sake. We are not interested in the good of others; we are interested solely in power. Not wealth or luxury or long life or happiness: only power, pure power. . .Power is not a means, it is an end.

It is, fortunately, a long way from Mr. O'Brien there (or Tiberius) to a typical hard-charging, rule-bending executive. But it's a difference of degree - not of kind.

Comments (12) + TrackBacks (0) | Category: Business and Markets | The Dark Side

January 17, 2011

Reboxetine Doesn't Work. But That's Not the Real Problem.

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Posted by Derek

Some time ago, I took nominations for Least Useful Animal Models. There were a number of good candidates, many of them from the CNS field. A recent report makes me think that these are even stronger contenders than I thought.

The antidepressant reboxetine (not approved in the US, but sold in a number of other countries by Pfizer) was recently characterized by a German meta-analysis of the clinical data as "ineffective and potentially harmful". Its benefits versus placebo (and SSRI drugs) have been overestimated, and its potential for harm underestimated. It was approved in Europe in 1997, and provisionally by the FDA in 1999, although that was later rolled back when more studies came in that showed lack of efficacy.

Much has been made of the fact that Pfizer had not published many of the studies they conducted on the drug. These do seem, however, to have been available to regulatory authorities, and were the basis for the FDA's decision not to grant full approval. As that BMJ link discusses, though, there's often not a clear pathway, especially in the EU, for a regulatory agency to go back and re-examine a previous decision based on efficacy (as opposed to safety).

So the European regulatory agencies can be faulted for not revisiting their decision on this drug in a better (and quicker) fashion, and Pfizer can certainly be faulted for letting things stand (in the face of evidence that the drug was not effective). All this is worrisome, but these are problems that are being dealt with. Since 2007, for example, trials for the FDA have been required to be posted at clinicaltrials.gov, although the nontranparency of older data can make it hard to compare newer and older treatments in the same area.

What's not being dealt with as well is an underlying scientific problem. As this piece over at Scientific American makes plain, reboxetine, although clinically ineffective, works just fine in all the animal models:

And this is a rough moment for scientists studying depression. Why? Because reboxetine works beautifully in our animal models. It’s practically a poster-child antidepressant. It produces acute effects in tests such as forced-swim tests and tail-suspension tests (which use changes in struggle as a measure of antidepressant efficacy). It produces neurogenesis in the hippocampus, which is thought to be correlated with antidepressant effects. When behavioral pharmacologists are doing comparisons between older antidepressants and newer ones, reboxetine is often used as a positive control, a drug known to have an effect in the behavioral test of choice.

But it doesn’t work in patients. And patients are what matters. Now, scientists are stuck with a difficult question: What went wrong?

A very good question, and one without any very good answers. And this certainly isn't the first CNS drug to show animal model efficacy but do little good in people. So, how much is the state of the art advancing? Are we getting anywhere, or just doing the same old thing?

Comments (48) + TrackBacks (0) | Category: Animal Testing | Clinical Trials | Regulatory Affairs | The Central Nervous System | The Dark Side

January 7, 2011

More On Homemade Street Drugs

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Posted by Derek

I wrote here about a Wall Street Journal article covering illegal street-drug labs in Europe. Well, maybe that should be not-quite-illegal, because the people involved were deliberately making compounds that the law hadn't caught up with yet.

The article mentioned David Nichols at Purdue as someone whose published work on CNS compounds had been followed/ripped off/repurposed by the street drug folks. Now Nature News has a follow-up piece by him, and he's not happy at all with the way things have been turning out:

We never test the safety of the molecules we study, because that is not a concern for us. So it really disturbs me that 'laboratory-adept European entrepreneurs' and their ilk appear to have so little regard for human safety and human life that the scant information we publish is used by them to push ahead and market a product designed for human consumption. Although the testing procedure for 'safety' that these people use apparently determines only whether the substance will immediately kill them, there are many different types of toxicity, not all of which are readily detectable. For example, what if a substance that seems innocuous is marketed and becomes wildly popular on the dance scene, but then millions of users develop an unusual type of kidney damage that proves irreversible and difficult to treat, or even life-threatening or fatal? That would be a disaster of immense proportions. This question, which was never part of my research focus, now haunts me.

Well, that's absolutely right, and it's not terribly implausible, either. The MPTP story is as good an example as you could want of what happens when you just dose whoever shows up on the street corner with that cool stuff you made in your basement lab. All we need is a side effect like that, which comes on a bit more slowly, and there you'd have it. That's one of the reasons I have such disgust for the people who are making and selling these things - they show a horrifying and stupid disregard for human life, all for the purpose of making a few bucks.

At the same time, I think that Nichols himself should try not to blame himself. His article comes across rather anguished; I have a lot of sympathy for him. But the actions of other people, especially scum, are outside of his control, and I think he's taking every reasonable precaution on his end while he does some valuable work.

Homo homini lupus: the sorts of people who see basement drugs as a fun business opportunity would likely be doing something equally stupid and destructive otherwise. Dr. Nichols, you have nothing to be ashamed of, nothing to apologize for - and, honestly, nothing to keep you up at night. You're the responsible member of the human race in this story.

Comments (40) + TrackBacks (0) | Category: The Central Nervous System | The Dark Side | Toxicology

January 6, 2011

MMR Vaccine and Autism: Lies, All Lies

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Posted by Derek

The 1998 paper that linked MMR vaccination with autism has had a long way to fall. It made, of course, a huge media sensation, and energized the whole vaccination/autism controversy that still (in spite of evidence) goes on. But it didn't look very robust from the start, scientifically. And over the years it's gone from "Really needs shoring up" to "hasn't been reproduced" to "looks like there's something wrong with it" to "main conclusions retracted" to the final, lowest level: outright fraud.

Here's a good history of the whole affair in the BMJ. And here's the first part of a series of articles by Brian Deer, the journalist who dug into the study and found how fraudulent it really was. Not one of the 12 cases in Wakefield's original study hold up; the data were manipulated in every single one to make it fit his hypothesis. His hypothesis that he was getting grant money for. His hypothesis that he was already planning lawsuits around, before the study even started.

His hypothesis, I might add, that has led to completely unnecessary suffering among the unvaccinated children this scare has produced over the years, and has diverted enormous amounts of time, energy, and money away from useful study of autism. This sort of deliberate action is really hard to contemplate, as a reasonable human being - it's like some sort of massive campaign to persuade people to throw bricks through the windows of ambulances.

In a better world, we'd be getting expressions of sorrow and contrition from all the celebrities and others who've profited from this business. But that's not going to happen, is it?

Comments (75) + TrackBacks (0) | Category: Autism | Snake Oil | The Dark Side

December 1, 2010

The Sames-Sezen Case: The Feds Speak

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Posted by Derek

Paul Bracher at Chembark broke the news that the Office of Research Integrity has issued a finding on the Sames-Sezen misconduct case at Columbia. This was big news back in 2006 and 2007, and it should still be news now.

For those who haven't followed this, the case concerns a series of papers published from Dalibor Sames' lab at that university on some interesting C-H activation chemistry. This work was largely performed by a graduate student, Bengü Sezen, but none of it has proven to be reproducible, and there was a string of retractions. (Sezen herself maintained that there were no problems with the work). So far, so bad - but what gives the story more depth is that papers were retracted where Sezen was not even a co-author and the apportionment of blame is still very much arguable. That last point gets into a lot of speculation, but the investigations into the matter haven't done much to clear any of it up.

Here's a PDF with some more background for those wanting to get up to speed, and Paul's earlier posts on the matter have a lot of information for those wanted to dig into this case. I'm not sure that we're ever going to know what really happened here, which is a shame, because we'd all like for it not to happen again.

Comments (24) + TrackBacks (0) | Category: The Dark Side

November 12, 2010

99% Yield? That, Friends, Is Deception

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Posted by Derek

Here's an attention-getting paper from Tomas Hudlicky (and his co-author Martina Wernerova), and I'd like to help it get some more. It begins:

One who has been reading the literature concerned with organic synthesis in recent years, be it methodology, catalysis, or total synthesis of natural products, may have noticed considerable inflation in the values reported for isolated product yields, ratios of diastereomers, and enantiomeric excess values. A comparison of papers published during the period 1955 to 1980 with those published between 1980 and 2005 reveals that those from the more recent period frequently report isolated product yields of reactions >95%. Such large values were rarely found in the older literature and are all but absent in Organic Syntheses, a journal that only publishes procedures that have been independently reproduced. . .

There, does that sound like the chemical literature you know? Just a bit? Hudlicky has tackled this issue before, and the reasons he advances for the problem remain the same: pressure to make your methods stand out (to the scientific community, to the journal editors, to the granting agencies), a decrease in scale in reactions (making accuracy and precision more difficult), and, finally, what he refers to as "deliberate adjustment". That's well put; the rest of us know it as fraud.

He identifies the mid-1980s as roughly the period when things really started to go to pieces, saying that most procedures in reputable journals before that era are reproducible by, as they say, one skilled in the art, while the numbers have been decreasing since then. And he puts some numbers on the problem, performing a series of test experiments with extremely careful weighing and analysis.

These confirm what every working organic chemist knows: the more manipulations, the more sample you lose. Filtration through a plug of silica gel, into one flask, can give you pretty much complete recovery. But if you cut fractions, you're going to lose about 1%. And if you have to do a separation, even between two widely separated compounds on silica, you're going to lose about 2%. So people who report a >98% yield after chromatography from a real-world crude mixture are kidding themselves. The same goes for extractions and other common methods. In general, every manipulation of a reaction is going to cost you 1 to 2% of your material, even with careful technique. Hudlicky again:

Given that most academic groups do not subject day-to-day reactions to serious optimization or matrix-optimization [6] as is done in industry, it is reasonable to assume that the vast majority of the reactions reported in the literature do not proceed with quantitative conversions. Such aspect would approximate our experiments with mixtures of pure compounds. Because a minimum of three operations (extraction, filtration, and evaporation) is required in working up most reactions, we conclude that yields higher than ca. 94% obtained by work-up and chromatography of crude reaction mixtures are likely unrealistic and erroneous in nature. Such values may arise as a direct consequence of not following correct protocols, which would be expected in the fast-paced academic environment. (An astute student of the organic literature may discover that this very author has been guilty of reporting yields in this range from time to time!)

He goes on to detail the limits of error in weighing, which depend greatly on the amount of sample and the size of the flask. (The smaller the sample-to-container ratio, the worse things get, as you'd figure). And he turns to analyzing mixures of diastereomers by NMR, LC, and the like. As it turns out, NMR is an excellent way to determine these up to about a ratio of 95:5 , but past that, things get tricky. And "past that" is just where a lot of papers go these days, with a precision that is often completely spurious.

Here's the bottom line:

The conclusion drawn from this set of experiments points to the prevalence of serious discrepancies in the reporting of values for yields and ratios in the current literature. We have demonstrated that the facilities and equipment available in a typical academic laboratory are not adequate to support the accuracy of claims frequently made in the literature. . .The current practice of reporting unrealistically high isolated product yields and stereoisomer ratios creates serious problems in reproducibility and hence leads to diminished credibility of the authors.

He recommends a rigorous disclosure of the spread of product yields over multiple experiments, calibration of LC and GC apparatus, or (failing that) at least admitting that no such analysis has been done. (He also recommends getting rid of the concepts of diastereomeric and enantiomeric excess, in line with my fellow Arkansan Robert Gawley's advice). But I think that these ideas, while perfectly reasonable, don't get at the underlying problems - the inflationary pressure to produce more and more noteworthy results. Hudlicky's rules should be adopted - but I fear that they might just push the self-deception (and outright fraud) into newer territories.

I'm glad he's published this paper, though. Because everyone knows that this is a real problem - we complain about it, we joke about it, we mutter and we grit our teeth. But "officially", in the published literature, it's never mentioned. Let's stop pretending, shall we?

Comments (67) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

November 1, 2010

Drugs At Home

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Posted by Derek

This article reminds me of the "designer drug" era in the 1980s. The Wall Street Journal profiles one of the many European chemical entrepreneurs making a fortune by synthesizing and selling new psychoactive drugs. And they're all labeled "Not For Human Consumption", so hey, everything's perfectly legal. Until the authorities ban the specific substance, naturally, and then he moves on to another one down the list.

As someone who doesn't see a new chemical structure go into humans until years of testing have been done, you can imagine what I think of this. The small amount of amazement I feel is completely overwhelmed by contempt for anyone who would dose people with an untried CNS drug. Oh, but he's not dosing anyone, is he? All he's doing is selling them little vials of white powdery stuff for $30/gram, and it says right on the label that they're not supposed to take it. Right? How people like this sleep at night is a continuing mystery to me.

Making new psychoactive drugs is not that hard. There are plenty of chemotypes out there that will drop you right into the CNS receptors. In many cases, it looks like this guy and his ilk are hanging single-atom changes off of existing drugs. They also monitor the chemical literature, specifically mentioning papers by David Nichols of Purdue, who's well aware of what's going on (and has the same reaction I do). No, there are plenty of small changes to ring on known scaffolds; it's not like anyone's having to invent any new chemical classes here.

So, how do they make these things in quantity? The article treats a rota-vap as an exotic piece of equipment, so we're not going to learn too much from it. But I imagine that there's a lot of used lab equipment floating around, which must help. But the article also mentions that this particular business has labs in the Netherlands and Scotland, outfitted with custom stainless-steel gear made by a welder, so as to not draw attention by buying standard chemistry apparatus. (This is as good a time as any to mention that one of the things that irritates me about these people is the way they make owning any kind of chemistry equipment at home instantly suspicious in the eyes of the law).

That takes a back seat, though, to my feelings about the other aspects of this business. I'm not, admittedly, a good person to ask about recreational drug use, because I don't use any. I have what I think are well-justified reasons for avoiding the whole spectrum, from alcohol on up. The more I've learned about brain chemistry, the less inclined I am to mess around with it.

But even if you take a more lenient attitude, I don't see how the sort of business that this article details can be excused. Advocates for decriminalized various drugs often make the point that we know what their effects are, and that society would be better off dealing with them than dealing with the effects of trying to suppress the drugs themselves. They may be right, actually - I haven't made up my mind about that one yet - but this line of thought can't extend to the new-drug-of-the-month-club. We don't know what the effects of these substances are, what neurological damage they might do, and what other side effects they might have. That's for the customers to find out! Here's the safety testing method this moron uses:

Mr. Llewellyn, meanwhile, is unfazed. He boasts that his safety testing method is foolproof: He and several colleagues sit in a room and take a new product "almost to overdose levels" to see what happens. "We'll all sit with a pen and a pad, some good music on, and one person who's straight who's watching everything," he says.

Well, fine, then. Foolproof! This sort of thing shows that nothing is foolproof, because fools are just too ingenious. I'm ashamed to share a phylum with these people, much less a scientific discipline.

Comments (53) + TrackBacks (0) | Category: The Central Nervous System | The Dark Side

October 1, 2010

Three Times Is Enemy Action

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Posted by Derek

Now here's a disturbing case: research sabotage. It involves a (former) postdoc at Michigan:

(Vipul) Bhrigu, over the course of several months at Michigan, had meticulously and systematically sabotaged the work of Heather Ames, a graduate student in his lab, by tampering with her experiments and poisoning her cell-culture media. Captured on hidden camera, Bhrigu confessed to university police in April and pleaded guilty to malicious destruction of personal property, a misdemeanour that apparently usually involves cars: in the spaces for make and model on the police report, the arresting officer wrote "lab research" and "cells". Bhrigu has said on multiple occasions that he was compelled by "internal pressure" and had hoped to slow down Ames's work.

The student's account of what happened (later in that linked article) is creepy and compelling. Things started going wrong with her experiments, one after the other. At first she couldn't figure out what was happening, then the suspected her own mistakes, but ultimately (like the man who furnished the title for this post), suspected sabotage.

What tipped her off, apparently, was the the same sorts of things went wrong over and over - and when one was fixed, something else would appear. Lanes looked switched on her Western blots, which turned out to be because the labels had been switched on her cell cultures. That happened a few times, then when she switched the labeling system to something that couldn't be messed with, contaminants started showing up in her media. Running experiments in another lab late at night showed that they were working the way they should - when something (someone) wasn't messing with them.

It would certainly take a while for sabotage to become a working hypothesis - after all, there are a lot of ways for things not to work. But this case seems to have been helped along by the crudity of the tampering. Even so, there was suspicion that the grad student herself was trying to blame someone else for her own failures. The university's public-safety officers put her through interrogations before they would go as far as installing cameras in her lab. But those cameras caught the post-doc messing around in the lab fridge in the hours before yet another experiment went awry, and he confessed when confronted.

How often does stuff like this go on? To be honest, I'm surprised that there isn't more of it in academic labs. The competition between individuals is much more fierce than it is in industry (where people tend to work much more in large teams), and frankly, there are more unstable personalities in academia than there are in industry as well. At the same time, this is a thoroughly nasty thing to do, striking right at the basic workings of any research lab. You have to be able to reproduce things, of course, and you have to trust that the reagents and equipment are going to allow you to do that.

Most of all, in science we have to take the word of others on trust pretty often. Experiments are always out there to be reproduced, but you really can't do that to everything, every time. It's just impossible. When someone says that they got a particular reaction to work, or protein to express, the default setting is to assume that yeah, they probably did. If you have to reproduce it and there's trouble, well, then you start checking things out step by step. But there's no way science could work if you automatically assumed that everything in the literature or in every presentation was probably a lie.

And there's no way it can work if someone's going to sabotage experiments, either. I have been around two or three situations in my career when there was a suspicion of this happening. For most of the cases I'm pretty sure that this wasn't the explanation, but in one other (which I was the most removed from) I still don't know. That one got me to thinking, though, about how terribly easy it would be to do such things. As I said, this case was pretty crude, but there are many, many more subtle ways of messing things up. Some of them would be quite hard to detect, but would definitely indicate foul play if they were, and some of them would still be obscure even if tracked down. Truly excellent sabotage, though, would require as much work as generating real results.

I'm not going into details - any scientist with sufficient imagination can think of such things (homo sum, humani nil a me alienum puto). But it is interesting, when you do that thought exercise, how strange it feels. You can see how it would be done, you can see what would motivate someone to do it, but it's something of a relief to find out how little thought you've given to the mechanics of it all.

Comments (53) + TrackBacks (0) | Category: The Dark Side

September 10, 2010

Cut-and-Paste Your Way to Publication

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Posted by Derek

The topic of plagiarism in scientific journals has come up here several times. In recent years, automated systems for checking similar blocks of text have become available, and a number of journals now run their submissions past such software.

The first journal in China to sign up for the most well-known of these (CrossCheck) is the Journal of Zhejiang University–Science. I'll freely admit that I'd never heard of it, not that I've heard of a lot of the Chinese-language journals. But I also have to take my hat off to them, both for using the plagiarism-detection service and especially for writing in to Nature with the results.

Since October 2008, they've found "unoriginal material" in 31% of all their submissions, a number they themselves call "staggering". (Here's an earlier report on their progress). The letter mentions some possible cultural problems, such as Chinese students traditionally being asked to copy things word-for-word from authorities, but I'd guess that there's plenty of the good old publish-or-perish at work here, too. At any rate, congratulations to them for publicizing such problems; that's the only way they'll ever get any better.

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

July 27, 2010

How Sleazy It Can Get

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Posted by Derek

I've written several times about pharma/biotech companies whose stock promotion strategies seem suspect. But there are always more layers below. A reader sends along this headache-inducing promotion for a company called A5 Laboratories (no link from me to their website). They have, you'll all be interested to hear, a wonderful new method to produce "natural" interferon, which is going to turn them into a multi-billion dollar behemoth.

Sure it is. If you look through that come-on, you notice that it starts diverging from consensus reality very quickly, and never looks back. It's clearly written for people who know no biology, no medicine - in fact, for people who know as little as possible save that they want to get rich. Rich fast. And who believe, for some reason, that breathlessly touted penny stocks are the way to do it. Alas, these sorts of advertisements are generally paid for by some of the existing shareholders of such companies, in order to recruit a fresh generation of investors to take a few truckloads of stock off everyone's hands. This is the bottom of the pond, folks.

Need I note that the CRO assets that the company excitedly announces purchasing were controlled by A5's sole director and officer? And that both companies have the same address in Quebec? Or that A5 Laboratories itself was formerly known as El Palenque Vivero, incorporated in 2006 to run a plant nursery in Cuernavaca, Mexico? Could I make such stuff up myself? No, I could not. My imagination is vivid, but it has limits. Shameless avarice, on the other hand, has none.

Comments (34) + TrackBacks (0) | Category: Business and Markets | The Dark Side

July 13, 2010

Avandia: Was the Evidence Buried?

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Posted by Derek

The New York Times has added to the arguments over Avandia (rosiglitazone) this morning, with an above-the-fold front page item on when its cardiovascular risks were first discovered. According to leaked documents, that may have been as early as the end of 1999 - just a few months after the drug had been approved by the FDA.

According to Gardiner Harris's article, SmithKline (as it was at the time) began a study that fall, and "disastrous" results were in by the end of the year that showed "clear risk" of cardiovascular effects. (They must have been disastrous indeed to show up in that short a time, I have to say). He quotes a memo from an executive at the company:

“This was done for the U.S. business, way under the radar,” Dr. Martin I. Freed, a SmithKline executive, wrote in an e-mail message dated March 29, 2001, about the study results that was obtained by The Times. “Per Sr. Mgmt request, these data should not see the light of day to anyone outside of GSK,” the corporate successor to SmithKline.

The only possible way I can see this being taken out of context would be if the rest of the memo talked about how poorly run the study was and how unreliable its data were - in which case, someone was an idiot for generating such numbers. But that puts the company in the situation of "idiots" being the most benign (and least legally actionable) explanation. Which is not where you want to be.

Without seeing the actual material, it's hard to comment further. But what's out there looks very, very bad.

Comments (29) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Diabetes and Obesity | The Dark Side | Toxicology

June 28, 2010

That Schering-Plough Lawsuit Isn't Going Away

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Posted by Derek

Last summer I mentioned a shareholder lawsuit against Schering-Plough over the way that the ENHANCE clinical data were handled for Vytorin. One of the interesting features here is that the plaintiffs are claiming that the company knew that the clinical trial was showing troublesome data, but elected to sit on the numbers for as long as possible - and they're introducing a series of posts on Cafe Pharma as evidence. These seem to foretell the 2008 announcement of the bad numbers in early 2007, with disturbing accuracy.

Now, as Jim Edwards points out, this case has not gone away. In fact, the most recent attempt to get it thrown out has failed, and former CEO Fred Hassan faces a possible deposition on the matter. This will be quite interesting to watch, since Merck is on the hook for any judgments that might result. Stay tuned. . .

Comments (3) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | The Dark Side

June 3, 2010

Sequenom: Faking It

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Posted by Derek

I wrote here about Sequenom, a company which claimed to have developed an in vitro test for Downs Syndrome. The whole story dissolved into a heap of lawsuits, allegations of fraud, questions about whether Sequenom ever had such a test at all, and other craziness.

Now the SEC has charged a former executive of the company with lying to investors. Elizabeth Dragon publicly touted the accuracy of the company's test several times, in front of large groups, before the roof came in. Here's the official complaint (if that doesn't work, try here) and it's most interesting reading:

Dragon knew that all but six of the 51 samples had been tested on an unblinded basis, and also knew that, of the six blinded samples, her scientists incorrectly called one of the three T21 samples. In fact, in an e-mail to her lead scientist, Dragon asked how close the call was when she learned that the third T21 sample had not been called correctly on a blinded basis.

On June 3, 2008, Dragon presented data regarding the Down Syndrome Test at an analyst-and-investor briefing during the ISPD conference, which was simultaneously made available to the public via a webcast. . .The slides in Dragon's presentation indicated that the Test performed with 100% accuracy. . .

. . .Additionally, following her presentation, Dragon was asked a question regarding whether there was ambiguity in calling the samples. In response, she stated that T21 samples were very clear, and that "[t]he overall call is strongly positive . . ., you know it's definitely a Downs and you can read it as a Downs without any problem . . . "

She's also charged with stating that the unblinded tests were, in fact, blinded, and apparently never mentioned that unblinded tests were even being conducted. When blinded tests were run later, their accuracy was below that of the tests already on the market, actually. The SEC charges Dragon with pressuring the scientists involved to drop samples and re-evaluate their calls until the accuracy numbers came up. Her presentation of these runs also showed "100% accuracy", with no false positives and no false negatives. None of it was true.

I'm glad to see this prosecution happening. We live by accurate data, and seeing it sawed off and spray-painted like this makes me furious. If the SEC's allegations are true, I hope it can serve as an example to others who might be tempted to try the same sort of thing.

Comments (35) + TrackBacks (0) | Category: The Dark Side

April 16, 2010

Generex: Who Buys This Stuff, Anyway?

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Posted by Derek

I've been meaning to do another post on Generex, the company that says it's developing an oral spray form of insulin as an alternative to the injected forms. This is the outfit that's suing Adam Feuerstein of TheStreet.com over his dismissive comments on their business, and here I stated that after looking the operation over a bit, that I agreed with him. In short, I have doubts about the real-world efficacy of buccal insulin delivery, doubts about the acceptance of it in the diabetes patient (and physician) population, and doubts that spring from Generex's own statements about the drug's development. A handful of patients in Ecuador does not make for a convincing reason to move into Phase III - not to me - and you don't press-release your Phase III results when you've only enrolled 10% of your targeted number of patients. And so on. . .but who am I to question the buccal spray delivery technology, when (as Generex states on their web site) it's also being used to develop an "energy spray" called Ba-Boom? (Be sure to turn up your speakers so you can hear the theme music; it's going to play when you click that link. And yes, that is Generex - look at the bottom of the page).

It's been a very busy week around here, but what I do have time to do is take a look at the recent infusion of capital the company has experienced. An investment group called Seaside 88 has announced their intention to buy a large amount of Generex stock. Among the Generex investors calling for my head (and other parts of my anatomy), opinion seems divided about Seaside 88 and my relationship to them (which, let me state right up front, is completely nonexistent - I'd never heard of the outfit until this stuff came up). Some of the hardy GNBT folks point to this deal as evidence that I'm a fool, because here's this big investment outfit pouring money into this wonderful company and its promising product. Others seem to think that I'm being paid off by said big investment outfit, that I'm a black-hatted stock-basher out to secure Seaside 88 a better deal as it scoops up this wonderful stock on the cheap.

Which exciting story to believe? Not for the first time, I'm reminded that too many people who invest in small "story" stocks have worldviews that resemble the story lines of profession wrestling. I'd call it Manichean, but that's a bit too elevated. No, it's all Good Guys and Bad Guys, and there's no room for someone like me, a person with no money in the game who finds the whole thing bizarre and amusing. The smaller the stock prices involved, by the way, the crazier the investors seem to be.

So, Seaside 88. If you go do an EDGAR search on them, you find that they've done similar stock-purchase deals with a number of small companies (and other deals show up as you Google for press releases). Flywheel energy storage companies, obscure fuel-cell makers - it's quite a collection. My personal favorite is Ensurge, Inc., and if you'd like to know what business they're in, you'll just have to read the language in their 10-K. If you're not snorting in derision by the time you get to the South-American-gold-mining stuff, then you're a born penny-stock investor. You'd have to use threats of bodily harm to make these things a centerpiece of my own investment strategy - but hey, that's why I'm going to finish up eating off-label cat food in a trailer while the Generex shareholders are sailing their yachts through the Greek islands. These things have a way of evening out.

So, who are these Seaside 88 people, anyway? Well, as is often the case, there's a whole little constellation of related companies. There's your Seaside Analytics, your Seaside Capital Management, your Seaside Capital II, and so on. One person who figures prominently in all of them is William Ritger, who's been in the investment business for some years now. Here's a biography of him from one of the companies he's helped to found.

In fact, he's been in the business long enough for this article from the the New York Times to turn up. It refers to a former venture of his, Research Works, which seems to have issued favorable reports on obscure stocks - causing their prices to jump - but without making much of the fact that he was being paid by the companies involved to write those reports. One hopes that he is no longer in the business of promoting small stocks in this manner.

Another name that shows up when you search the Seaside family of investment partnerships is Denis O'Donnell. Looking over the EDGAR filings featuring his name, you find his ongoing relationship with a company called American Bio Medica, which I note has also been listed as one of the house favorites of a micro-cap "pump and dump" junk-fax operation. He's also been involved with Columbia Laboratories - now of New Jersey, but formerly of Hollywood, Florida, where (interestingly enough) they were mentioned in that same New York Times article as the subject of one of those paid-for investment reports back in the 1990s. One hopes that he is keeping better company now.

So, Generex investors, enjoy your stock, and enjoy the company of the others who have seen fit to invest in it. I will not be putting any of my own money into it, and they won't let a person short companies that trade at 60 cents a share. Which is too bad, in a way, because the great majority of such companies go to zero.

Comments (43) + TrackBacks (0) | Category: Business and Markets | Diabetes and Obesity | The Dark Side

March 22, 2010

Benford's Law, Revisited

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Posted by Derek

I mentioned Benford's Law in passing in this post (while speculating on how long people report their reactions to have run when publishing their results). That's the rather odd result that many data sets don't show a random distribution of leading digits - rather, 1 is the first digit around 30% of the time, 2 leads off about 18% of the time, and so on down.

For data that come from some underlying power-law distribution, this actually makes some sense. In that case, the data points spend more time being collected in the "lag phase" when they're more likely to start with a 1, and proportionally less and less time out in the higher-number-leading areas. The law only holds up when looking at distributions that cover several orders of magnitude - but all the same, it also seems to apply to data sets where there's no obvious exponential growth driving the numbers.

Lack of adherence to Benford's Law can be acceptable as corroborative evidence of financial fraud. Now a group from Astellas reports that several data sets used in drug discovery (such as databases of water solubility values) obey the expected distribution. What's more, they're suggesting that modelers and QSAR people check their training data sets to make sure that those follow Benford's Law as well, as a way to make sure that the data have been randomly selected.

Is anyone willing to try this out on a bunch of raw clinical data to see what happens? Could this be a way to check the integrity of reported data from multiple trial centers? You'd have to pick your study set carefully - a lot of the things we look for don't cover a broad range - but it's worth thinking about. . .

Comments (9) + TrackBacks (0) | Category: Clinical Trials | In Silico | The Dark Side

March 15, 2010

Stem Cell Politics

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Posted by Derek

There have been complaints that something is going wrong in the publication of stem cell research. This isn't my field, so I don't have a lot of inside knowledge to share, but there appear to have been a number of researchers charging that journals (and their reviewers) are favoring some research teams over others:

The journal editor decides to publish the research paper usually when the majority of reviewers are satisfied. But professors Lovell-Badge and Smith believe that increasingly some reviewers are sending back negative comments or asking for unnecessary experiments to be carried out for spurious reasons.

In some cases they say it is being done simply to delay or stop the publication of the research so that the reviewers or their close colleagues can be the first to have their own research published.

"It's hard to believe except you know it's happened to you that papers have been held up for months and months by reviewers asking for experiments that are not fair or relevant," Professor Smith said.

You hear these sorts of complaints a lot - everyone who's had a paper turned down by a high-profile journal is a potential customer for the idea that there's some sort of backroom dealing going on for the others who've gotten in. But just because such accusations are thrown around frequently doesn't mean that they're never true. I hate to bring the topic up again, but the "Climategate" leaks illustrate just how this sort of thing can be done. Groups of researchers really can try to keep competing work from being published. I just don't know if it's happening in the stem cell field or not.

Comments (16) + TrackBacks (0) | Category: Biological News | The Dark Side | The Scientific Literature

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

February 4, 2010

Here's a Business Plan For You

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Posted by Derek

On another front, we now have an ex-BMS associate scientist who's apparently been arrested for stealing company materials in preparation for starting his own company back in India. I presume he was planning to get into the advanced pharmaceutical intermediates business (or perhaps the biotech end of it), using as much proprietary information as he could download in order to get a quick leg up. The company's security folks seem to have flagged him over the Christmas break, and he's since been spending time with the FBI. . .

Comments (22) + TrackBacks (0) | Category: Current Events | The Dark Side

January 27, 2010

Sequenom: Strike Up the Music, Bring On the Cream Pies

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Posted by Derek

Now here's a weird one. The San Diego diagnostics company Sequenom came up with a non-invasive test for Down's Syndrome, and sold it to another outfit, Xenomics, for development. Update: I've got this transfer backwards - Xenomics licensed some of its nucleic acid technology to Sequenom, and has now regretted it. But late last year, things unraveled spectacularly. In April, Sequenom announced that there were problems with the test and announced that it had launched an internal investigation. In September came the unwelcome news that the data backing up their product were (quoting here) "inadequately substantiated". And they meant it, too, as the CEO and six other higher-ups all left the company under a cloud of confusion, recrimination, and very bad acronyms (like SEC and FBI). Last week it settled a dozen shareholder lawsuits over the whole affair.

But as that story at Bnet makes clear, the terms of the settlement were rather alarming, with Sequenom promising to do things like. . .make sure that everyone involved knew which studies were blinded and which weren't. And requiring bar-codes on the tissue sample vials. And not giving everyone access to the storage room where they were all kept. And. . .well, you get the idea. It's like seeing a sign at the burger place that says "Healthy Choice - Now With 30 Per Cent Less Aardvark Meat! And Try Our New No-Salmonella Menu!"

It can always get worse, though. Now Xenomics is suing, claiming that not only were the data weak and the controls insufficient, but that there never was a test in the first place. The complaint (available as a PDF at that link) is pretty zippy stuff by legal standards, featuring phrases such as "Defendant maintained the charade that it had. . ."

Way before all this lunacy, some people were skeptical about the company's prospects even if things went well. But hey, let's not dwell on the negatives here. If you'd like "Three Reasons to Buy Sequenom Today", this guy has them. I think I'll let this opportunity slip past, personally.

Comments (20) + TrackBacks (0) | Category: Analytical Chemistry | Business and Markets | The Dark Side

January 7, 2010

Extortion, Retractions, And More

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Posted by Derek

Now here's a strange tale, courtesy of Science magazine, about some retracted work from Peter Schultz's group at Scripps. Two papers from 2004 detailed how to incorporate glycoslylated amino acids (glucosamine-serine and galactosamine-threonine) directly into proteins. These featured a lot of work from postdoc Zhiwen Zhang (who later was hired by the University of Texas for a faculty position).

But another postdoc was later having trouble reproducing the work, and in 2006 he made his case for why he thought it was incorrect. Following that:

Schultz says the concerns raised were serious enough that he asked a group of lab members to try to replicate the work in Zhang's Science paper in addition to several other important discoveries Zhang had made. That task, however, was complicated by the fact that Zhang's lab notebooks, describing his experiments in detail, were missing. Schultz says that in the early fall of 2006, the notebooks were in Schultz's office. But at some point after that they were taken without his knowledge and have never resurfaced.

After considerable effort, Schultz says his students were able to replicate most of the work. The biggest exception was the work that served as the basis for the 2004 Science and JACS papers. "It was clear the glycosylated amino acid work could not be reproduced as reported. So we tried to figure out what was going on," Schultz says.

So far, so not-so-good. But here's where things get odd. Around this time (early 2007), Zhang started to get e-mails at Texas saying that unless he send $4000 to an address in San Diego, the writer would expose his "fraud" and cause him to get fired. The messages were signed "Michael Pemulis" - Science doesn't pick up on that pen name, but fans of the late David Foster Wallace will recognize the name of the revengeful practical joker from Infinite Jest.

That brings up another point: the e-mails quoted in the Science article are in somewhat broken English: "you lose job. ... Texas will fire you before you tenure. . ." and that sort of thing. But my belief is that no one who drops the second person possessive while writing would make it far enough into Infinite Jest to meet Micheal Pemulis and use him as an appropriate alias for an extortion plot.

At any rate, after the San Diego police got involved, they told Zhang that they had a suspect, but Zhang decided not to press charges. That fall, though, "Pemulis" dropped the bomb, with a hostile anonymous letter to everyone involved - officials at Scripps and UT-Austin, the editors at Science, etc. In 2009, Zhang was denied tenure. The postdoc mentioned above (now at Cardiff) has published a paper in JBC detailing the problems with the original work. (He denies having anything to do with the missing lab notebooks or the threats made to Zhang). And everyone involved is still wondering just what is going on. . .

I certainly have no idea. But I can say this: although I've spent a lot more time in industry than in academia, a disproportionate number of the people I've worked with over the years that I consider to have had serious mental problems are still from my academic years. Whoever "Pemulis" is, I'd put him or her into that category. Grad students and post-docs are under a lot of pressure, and some of them are at a point in their lives when their internal problems are starting to seriously affect them.

Comments (49) + TrackBacks (0) | Category: Biological News | The Dark Side | The Scientific Literature

December 22, 2009

GE Healthcare's Idiotic Libel Suit

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Posted by Derek

Courtesy of Pharmalot (and my mail!), I note this alarming story from London. GE Healthcare makes a medical NMR contrast agent, a gadolinium complex marketed under the name of Omniscan. (They picked it up when they bought Amersham a few years ago). Henrik Thomsen, a Danish physician had noted what may be an association with its use and a serious kidney condition, nephrogenic systemic fibrosis, and he gave a short presentation on his findings two years ago at a conference in Oxford.

For which GE is suing him. For libel. Update: the documents of the case can be found here. They claim that his conference presentation was defamatory, and continue to insist on damages even though regulatory authorities in both the UK and in the rest of Europe have reviewed the evidence and issued warnings about Omniscan's use in patients with kidney trouble. Over here in the US, the FDA had issued general advisories about contrast agents, but an advisory panel recently recommended that Omniscan (and other chemically related gadolinium complexes) be singled out for special warnings. From what I can see, Thomsen should win his case - I hope he does, and I hope that he gets compensatory damages from GE for wasting his time when he could have been helping patients.

And this isn't the only case going on there right now. Author Simon Singh is being sued by the British Chiropractic Association for claiming in a published article that chiropractic claims of being able to treat things like asthma as "bogus". Good for him! But he's still in court, and the end is not in sight.

This whole business is partly a function of the way that GE and the chiropractors have chosen to conduct business, but largely one of England's libel laws. The way things are set up over there, the person who brings suit starts out with a decided edge, and over the years plenty of people have taken advantage of the tilted field. There's yet another movement underway to change the laws, but I can recall others that apparently have come to little. Let's hope this one succeeds, because I honestly can't think of a worse venue to settle a scientific dispute than a libel suit (especially one being tried in London).

So, General Electric: is it now your company policy to sue people over scientific presentations that you don't like? Anyone care to go on record with that one?

Comments (40) + TrackBacks (0) | Category: Analytical Chemistry | Current Events | The Dark Side | Toxicology

December 21, 2009

Faking X-Ray Structures. . .For Fun? Or Profit? Or What?

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Posted by Derek

Well, this isn't good: an ex-researcher at the University of Alabama-Birmingham has been accused of faking several X-ray structures of useful proteins - dengue virus protease, taq polymerase, complement proteins from immunology, etc. There have been questions surrounding H. M. Krishna Murthy's work for at least a couple of years now (here's the reply to that one). The university, after an investigation, has decided that 11 of the published structures seem to have been falsified in some way and has asked that the papers be retracted and the structures removed from the Protein Data Bank.

The first controversy with these structures was, I think, the one deposited in the PDB as 2hr0. Here's a good roundup of what's wrong with it, for those of you into X-ray crystallography. And as that post makes clear, there were also signs that some other structures from this source had been suspiciously cleaned up a bit.

So how do you go about faking an X-ray, anyway? Here's some detail - basically, you could take something that's structurally related (from a protein standpoint) but crystallographically distinct, and use that as a starting point. As that post says, add some water and some noise, and "bingo". The official statement from UAB's investigation gives you the likely recipes for all eleven faked-up structures.

As for Dr. Murthy, he left UAB earlier this year, according to this article, and the university says that they have no current contact information for him. If these accusations are true, he's spent nearly ten years generating spurious analytical data. What, then, do you do with that skill set?

Comments (30) + TrackBacks (0) | Category: Analytical Chemistry | The Dark Side

December 8, 2009

Pfizer's Pearl River Layoffs

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Posted by Derek

Pfizer's rounds of layoffs after the Wyeth merger are continuing, and look to go on for some time. A reader in New York state sends along word that there's been some controversy over the cuts at the Pearl River site. New York law requires a company to give both the state (and employees) 90 days notice if it lays off more than a set number or percentage of its staff. Pfizer's definitely over both limits, but according to the local newspaper (the Times Herald-Record), employees were told that the law didn't apply to them.

One Pearl River employee, whose identity was confirmed by the Times Herald-Record and who was granted anonymity, said company representatives told the laid-off employees the WARN law didn't apply to them. That source expressed concern that Pfizer was intentionally laying off small pockets of people to skirt WARN.

Now the paper (taking credit for the change) reports that Pfizer has indeed filed with the state that 200 employees will be let go in March. The paper has heard that a total of about 600 people will be laid off, although there are no state papers filed to cover that number yet.

Comments (9) + TrackBacks (0) | Category: Business and Markets | The Dark Side

December 1, 2009

Climategate and Scientific Conduct

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Posted by Derek

Everyone has heard about the "Climategate" scandal by now. Someone leaked hundreds of megabytes of information from the University of East Anglia's Climatic Research Unit, and the material (which appears to be authentic) is most interesting. I'm not actually going to comment on the climate-change aspect of all this, though. I have my own opinions, and God knows everyone else has one, too, but what I feel needs to be looked at is the scientific conduct. I'm no climatologist, but I am an experienced working scientist - so, is there a problem here?

I'll give you the short answer: yes. I have to say that there appears to be several, as shown by many troubling features in the documents that have come out. The first one is the apparent attempts to evade the UK's Freedom of Information Act. I don't see how these messages can be interpreted in any other way as an attempt to break the law, and I don't see how they can be defended:

Can you delete any emails you may have had with Keith re AR4?
Keith will do likewise. He's not in at the moment - minor family crisis. Can you also email Gene and get him to do the same? I don't have his new email address. We will be getting Caspar to do likewise.

A second issue is a concerted effort to shape what sorts of papers get into the scientific literature. Again, this does not seem to be a matter of interpretation; such messages as this, this, and this spell out exactly what's going on. You have talk of getting journal editors fired:

This is truly awful. GRL has gone downhill rapidly in recent years.
I think the decline began before Saiers. I have had some unhelpful dealings with him recently with regard to a paper Sarah and I have on glaciers -- it was well received by the referees, and so is in the publication pipeline. However, I got the impression that Saiers was trying to keep it from being published.

Proving bad behavior here is very difficult. If you think that Saiers is in the greenhouse skeptics camp, then, if we can find documentary evidence of this, we could go through official AGU channels to get him ousted. Even this would be difficult.

And of trying to get papers blocked from being referenced:

I can't see either of these papers being in the next IPCC report. Kevin and I will keep them out somehow - even if we have to redefine what the peer-review literature is !

Two questions arise: is this defensible, and does such behavior take place in other scientific disciplines? Personally, I find this sort of thing repugnant. Readers of this site will know that I tend to err on the side of "Publish and be damned", preferring to let the scientific literature sort itself out as ideas are evaluated and experiments are reproduced. I support the idea of peer review, and I don't think that every single crazy idea should be thrown out to waste everyone's time. But I set the "crazy idea" barrier pretty low, myself, remembering that a lot of really big ideas have seemed crazy at first. If a proposal has some connection with reality, and can be tested, I say put it out there, and the more important the consequences, the lower the barrier should be. (The flip side, of course, is that when some oddball idea has been tried and found wanting, its proponents should go away, to return only when they have something sturdier. That part definitely doesn't work as well as it should.)

So this "I won't send my work to a journal that publishes papers that disagree with me" business is, in my view, wrong. The East Anglia people went even farther, though, working to get journal editors and editorial boards changed so that they would be more to their liking, and I think that that's even more wrong. But does this sort of thing go on elsewhere?

It wouldn't surprise me. I hate to say that, and I have to add up front that I've never witnessed anything like this personally, but it still wouldn't surprise me. Scientists often have very easily inflamed egos, and divide into warring camps all too easily. But while it may have happened somewhere else, that does not make it normal (and especially not desirable) scientific behavior. This is not a standard technique by which our sausage is made over here.

What I've seen in organic chemistry are various attempts to steer papers to particular reviewers (or evade other ones). And I've seen people fire off angry letters to journal editors about why some particular paper was published (and why the letter writer's manuscript in response had not been accepted in turn, likely as not). The biggest brawl of them all was still going early in my career (having started before I was born): the fight over the nonclassical norbornyl cation, the very mention of which is still enough to make some older chemists put their hands over their ears and start to hum loudly. That one involved (among many others) two future Nobel Prize winners (H. C. Brown and George Olah), and got very heated indeed - but I still don't recall either one of them trying to get journal editors fired after publishing rival manuscripts. You don't do that sort of thing.

And that brings up an additional problem with all this journal curating: the CRU people have replied to their critics in the past by saying that more of their own studies have been published in the peer-reviewed literature. This is disingenuous when you're working at the same time to shape the peer-reviewed literature into what you think it should look like.

A third issue I want to comment on are the problems with the data and its analysis. I have deep sympathy for the fellow who tried to reconcile the various poorly documented and conflicting data sets and buggy, unannotated code that the CRU has apparently depended on. And I can easily see how this happens. I've been on long-running projects, especially some years ago, where people start to lose track of which numbers came from where (and when), where the underlying raw data are stored, and the history of various assumptions and corrections that were made along the way. That much is normal human behavior. But this goes beyond that.

Those of us who work in the drug industry know that we have to keep track of such things, because we're making decisions that could eventually run into the tens and hundreds of millions of dollars of our own money. And eventually we're going to be reviewed by regulatory agencies that are not staffed with our friends, and who are perfectly capable of telling us that they don't like our numbers and want us to go spend another couple of years (and another fifty or hundred million dollars) generating better ones for them. The regulatory-level lab and manufacturing protocols (GLP and GMP) generate a blizzard of paperwork for just these reasons.

But the stakes for climate research are even higher. The economic decisions involved make drug research programs look like roundoff errors. The data involved have to be very damned good and convincing, given the potential impact on the world economy, through both the possible effects of global warming itself and the effects of trying to ameliorate it. Looking inside the CRU does not make me confident that their data come anywhere close to that standard:

I am very sorry to report that the rest of the databases seem to be in nearly as poor a state as Australia was. There are hundreds if not thousands of pairs of dummy stations, one with no WMO and one with, usually overlapping and with the same station name and very similar coordinates. I know it could be old and new stations, but why such large overlaps if that's the case? Aarrggghhh! There truly is no end in sight... So, we can have a proper result, but only by including a load of garbage!

I do not want the future of the world economy riding on this. And what's more, it appears that the CRU no longer has much of their original raw data. It appears to have been tossed over twenty years ago. What we have left, as far as I can see, is a large data set of partially unknown origin, which has been adjusted by various people over the years in undocumented ways. If this is not the case, I would very much like the CRU to explain why not, and in great detail. And I do not wish to hear from people who wish to pretend that everything's just fine.

The commentator closest to my views is Clive Crook at The Atlantic, whose dismay at all this is unhidden. I'm not hiding mine, either. No matter what you think about climate change, if you respect the scientific endeavor, this is very bad news. Respect has to be earned. And it can be lost.

Comments (171) + TrackBacks (0) | Category: Current Events | General Scientific News | The Dark Side | The Scientific Literature

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

November 9, 2009

Selling It, And Selling It Hard

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Posted by Derek

There's a long, detailed article up over at Bloomberg on the recent run of huge fines for off-label promotion of drugs. Pfizer, Lilly, Bristol-Meyers Squibb, and Schering-Plough all get mentioned in great detail.

And there's a key point from the whole depressing thing: the reason that marketing departments do this kind of thing is that it makes money. Even after you pay a billion dollars in fines, you can still come out ahead, and you might not even have to pay the fines. It's just being put down as a cost of doing business - it's a speeding ticket, and it's being weighed against the cost of driving under the legal limit.

But there's no way that our industry will gain - or regain - respect as long as we operate this way. Have the people involved priced that out as well?

Comments (17) + TrackBacks (0) | Category: Business and Markets | The Dark Side | Why Everyone Loves Us

October 9, 2009

I'll See Your Conflicts, and Raise You?

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Posted by Derek

There seems to be some finger-pointing going on about conflicts of interest in the scientific and medical literature. According to this piece in Nature Medicine, a recent conference in Vancouver on peer review featured statements such as this:

"We absolutely should not let up on our scrutiny of industry," says Karen Woolley, a co-author of one of the new studies and chief executive officer of the professional medical writing company ProScribe, based in Queensland, Australia. "But why are we always pointing our finger over there? There's an elephant in the room, and that's the nonfinancial conflicts of interest in academia."

I hope that ProScribe wasn't involved in that Australian journal scandal. But even though the head of a medical writing company clearly has a gigantic axe to grind here, the point isn't invalid. Academia has pressures of its own to publish, and lot of shaky stuff gets sent out under them.

Under the auspices of (the Council on Publishing Ethics), (consultant Liz) Wager dug through PubMed files to see how many papers had been retracted between 1988 and 2008. She found 529, and, in a close study of a randomly selected set of 312, she judged that only 28% were due to "honest error". Among the rest, some of the largest chunks were due to authors found publishing the same results more than once (18%), plagiarism (15%), fabrication (5%) and falsification (4%) of data. Taking into account an additional 1% in the 'other misconduct' category, the unethical reasons stacked up to 43%.

Many, perhaps most, of these papers seemed to have been unlikely to have been funded by industry. And there are, of course, plenty of rotten papers out there that never get retracted at all, in many cases because no one reads them or notices that they're a rehash of what someone else has already published. The Deja Vu people are starting to cut into that pile, though, and it's a big one.

There's a danger of all this turning into an exchange of tu quoque arguments between industry, academia, and the publishers. I think there's common ground to agree, though, that all sorts of pressures exist to publish work that shouldn't be published, and that everyone has a common interest in making sure that this doesn't happen. And industry still has a bigger responsibility, since (1) it has more money to cause trouble, if it wants to, and (2) the sorts of things it works on often have more immediate relevance to the outside world. If some obscure faculty member somewhere published reheated work in a series of low-end journals, he's only wasting the time of a limited number of people. A publication involving clinical trial data, though, can send ripples out a lot farther and faster.

Comments (15) + TrackBacks (0) | Category: Academia (vs. Industry) | The Dark Side | The Scientific Literature

September 25, 2009

Faked Data at the ETH

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Posted by Derek

A data-fabrication scandal has erupted at a place that doesn't see many of those: the ETH in Zürich. Peter Chen, a physical organic chemist there, has been dealing with problems with some earlier publications (from 2000) on the spectra and ionization energies of carbon radicals. Here's one of the papers, which has now been retracted.

These data couldn't be reproduced, as became clear in the years after these papers came out. An investigation by the ETH showed what appears to be clear evidence of fakery - things like the background noise being exactly the same in what are supposed to be several different experimental spectra of different species. In fact, all the parties involved with the suspect papers agree that data have been fabricated - but none of them admit to having done it.

That's not a happy situation, is it? The official ETH news release on the topic is informative, but only up to a point. It leaves things hanging and announced that Chen is stepping down as the ETH's vice president for research. The Swiss press has picked up the story this week, though, and they're not shy about saying what the ETH doesn't seem to want to. Here's the Neue Züricher Zeitung, saying (translation mine):

The experts who have investigated the scientific fraud case at the ETH-Zürich are sure of the guilty party. Peter Chen, leader of the research group, has been clearly exonerated. . .The Commission came unanimously to the conclusion, that. . .it was likely that a former doctoral student "manipulated and fabricated" the published data. He performed most of the measurements, and could (through these machinations) have considerably shortened his work."

It also appears, if the reports I'm seeing are correct, that this person's lab notebooks have turned up missing, and are the only primary sources for the whole affair that can't be found. Lawyers representing this former student have blocked release of the entire ETH report, but it's leaked to a number of other outlets, including C&E News and Science. One way or another, the story has come out, and it's a pretty damned familiar one, too.

Comments (16) + TrackBacks (0) | Category: The Dark Side

September 4, 2009

Pharma Whistleblowing: How It Works

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Posted by Derek

Here's more detail on the case that led to Pfizer's 2.3 billion dollar fine/settlement, courtesy of Bloomberg. Here's how things got started, apparently:

Pfizer Inc. sales folks had one tough customer in psychiatrist Stefan Kruszewski. He didn’t buy their pitch to prescribe the anti-psychotic drug Geodon to children, a use that hadn’t been approved by federal regulators.

Nor did he go for the so-called off-label uses they suggested, such as treating dementia in the elderly.

Kruszewski didn’t just say no. He went and checked the research and saw Geodon could have serious cardiac side effects not mentioned by the salesmen, who boasted of its relative safety, according to his lawyer, Brian Kenney. And he noticed that Pfizer was paying his peers to promote the drug to other psychiatrists.

But the worst for Pfizer was that Kruszewski didn’t keep it to himself. He found a lawyer, Kenney, who specializes in whistleblower cases, and they took what they had to the government.

So did John Kopchinski, who sold Pfizer’s arthritis drug Bextra but not as aggressively as the bosses wanted. They told the sales force to pitch it for post-surgical pain, acute pain, migraines and a host of other conditions for which the drug had been rejected by the U.S. Food and Drug Administration, says Kopchinski’s lawyer, Erika Kelton.

The six whistleblowers in the case are getting anywhere from $2.3 million to $51 million now that the settlement has been announced (that upper figure is Kopchinski, who seems to have provided the most serious evidence). As I mentioned the other day, I think this is a good thing. It takes a lot of nerve to step up when your employer is doing something outside the limits of the law (and asking you to do it as well). A chance to make up for the certain loss of your job (and the near-certain loss of any future prospects in the field) goes a long way.

And there's an interesting perspective on why a settlement was reached:

. . .Pfizer is the pharmaceutical equivalent of insurance giant American International Group Inc., which was too interwoven into the global economy to be allowed to fail. Likewise, if Pfizer were convicted of a crime, it would face debarment from federal programs. And that would mean that Medicaid and Medicare patients would have to either somehow pay pocket for vital medicines the company produces or go without.

Hadn't thought of that one. I wonder if any company will have the nerve to use this as a negotiating tactic? Perhaps Pfizer already did, come to think of it. . .

Comments (20) + TrackBacks (0) | Category: Business and Markets | The Dark Side

September 3, 2009

A 2.3 Billion Dollar Attention-Getter

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Posted by Derek

No sooner do I write another post about pharma marketing than Pfizer finds itself paying 3.2 2.3 billion dollars in fines for doing it improperly. 1.2 billion of that is a criminal penalty, and needless to say, they've set the current record.

The issues were off-label promotion of Bexxtra, Geodon, Zyvox, and Lyrica, with the largest penalties coming from the first two. Pfizer's had three other settlements of this kind in the last few years, and that record was definitely a factor this time, as the Justice Department looked for a figure that might get the company's attention. Also supposed to get the company's attention is a five-year "integrity agreement" with the Department of Health and Human Services, but it's worth noting that the company was already supposedly operating under an earlier such agreement when it was promoting Bexxtra. I think the money has a better chance of being noticed, myself.

I think that these kinds of penalties should be levied, in case anyone's wondering. Our current system almost makes sure that it will happen over and over, but that's because we're splitting the difference between two competing principles. The first one is that physicians should have the freedom to practice medicine as they best see fit, which means that they can write prescriptions for drug uses that have not (yet) been approved by the FDA. The second principle, though, is that drug companies should not be free to promote such uses. And I agree with both of those, but sticking to both of them simultaneously leaves open a constant temptation to break the law.

But there are a lot of industries that operate under such conditions, and in each case, they're supposed to control themselves (and get hammered on when they don't). Perhaps this latest fine will be enough of an example to keep the marketing people thinking ahead a bit. If that won't do it, then the way this whole case came up might - it's another example of whistleblower laws at work. John Kopchinski, a sales rep who left Pfizer in 2003, looks to get around $50 million of the settlement for bringing key information to the government's attention, and others are involved as well. I think that's a good thing, too, a useful counterbalance to the financial incentives on the other side.

But for now, we're left with another huge black mark on the industry's reputation. Thank you, Pfizer.

Comments (16) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

August 6, 2009

Ghostwriting

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Posted by Derek

As much as I defend the industry I work in, I have to talk about things that we do that I don't think are so defensible. Another one of those has come up thanks to the New York Times and PLoS Medicine, who obtained a pile of records from a current court case.

This article has the details. Wyeth seems to have contracted with a medical writing outfit (DesignWrite) to produce and place a number of review articles covering hormone therapy for menopausal women. (Wyeth, of course, was the main player in that market). The articles seem to have been entirely written by the staff at DesignWrite - authors are listed as "TBD", and then academics were recruited to serve as lead authors and to submit the papers to journals.

No mention was ever made in the published papers of the medical writing group's role, nor of Wyeth's (who were paying them for this service). As far as the readers could see, these were the standard sorts of review articles that show up in the medical literature all the time. And that's the part that bothers me. For all I know, these articles were reasonable reviews of the field - I'm no great expert in the field, so I can't judge if they're truly fair summaries. But even if they are, the readership of a journal is entitled to know that a drug company was the impetus behind them, and they're also most certainly entitled to know the actual authors (as opposed to the people who would appear to have been the authors, but just signed off on the stuff).

I think that drug companies are entitled to promote their products. But full disclosure should be the the standard to try to reach in any market: put it all out on the table, and let physicians make their own decisions. It doesn't help, not one bit, to get papers into the journals this way - because when a company goes to such lengths to hide its participation, it almost looks as if it has something to hide. . .

Comments (25) + TrackBacks (0) | Category: Business and Markets | The Dark Side | The Scientific Literature | Why Everyone Loves Us

June 25, 2009

What's With Those People at Elsevier, Anyway?

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Posted by Derek

Via a reader comes this article, which takes us to Elsevier's hard-hitting textbook publishing operation. The co-authors of a psychology text for the publisher were recently taken aback to get this e-mail from a publicist at the company:

""Congratulations and thank you for your contribution to Clinical Psychology. Now that the book is published, we need your help to get some 5 star reviews posted to both Amazon and Barnes & Noble to help support and promote it. As you know, these online reviews are extremely persuasive when customers are considering a purchase. For your time, we would like to compensate you with a copy of the book under review as well as a $25 Amazon gift card. If you have colleagues or students who would be willing to post positive reviews, please feel free to forward this e-mail to them to participate. We share the common goal of wanting Clinical Psychology to sell and succeed. The tactics defined above have proven to dramatically increase exposure and boost sales. I hope we can work together to make a strong and profitable impact through our online bookselling channels."

George Tremblay of Antioch U. blew the whistle on this one, which is a good deed. But, cynical person that I am, it makes me wonder how many others on the list might have been ready to pitch in. And given that this has apparently been done before (hey, this is a "proven" strategy), you also have to wonder about five-star reviews of other textbooks published by Elsevier. And other houses, too?

I ask because the company's director of public relations has come out to explain just where this latest tactic went too far - and I have to say, it's a bit further along the line than many people might have thought:

"Encouraging interested parties to post book reviews isn't outside the norm in scholarly publishing, nor is it wrong to offer to nominally compensate people for their time, some of these books are quite large," he said. "But in all instances the request should be unbiased, with no incentives for a positive review, and that's where this particular e-mail went too far."

So when you're encouraging people to write reviews, and offering them some baksheesh for doing so, that's fine. You just don't want to be so gauche as to actually come out and say that you want the reviews to be positive. This does not make Elsevier look good, of course, coming as it does after the reheated-tray-of-friendly-leftovers journal scandal in Australia. (And let's not forget the, um, unusual case of El Naschie and his private Elsevier journal of nonsense). They either are the poor victims of widely scattered unethical promotions staff, or (just perhaps) there's a general culture in that department that allows people to think that these things are acceptable practice.

Comments (14) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 12, 2009

Selling Zyprexa

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Posted by Derek

Well, this doesn't look good for Lilly. A huge pile of court documents has been unsealed in the ongoing lawsuits about Zyprexa's off-label promotion. The company has already paid some serious fines, and is now fighting it out with insurance companies and other plaintiffs who are seeking to recover their costs. Several states are suing them as well; those cases are still on their way.

Bloomberg News was given a lengthy list of internal company statements that will surely be difficult to explain in court. These were provided by one of the plaintiff's attorneys, Hagens Berman Sobol Shapiro LLP, so it's hardly a neutral selection (as Lilly is saying in response). But it's going to be interesting to see what sorts of explanations the company has for these. On the one hand, you have this:

In 1998, Lilly went back to the FDA seeking approval to market Zyprexa to those battling Alzheimer’s, the most common form of dementia, the company said in its 2003 request for a meeting on a proposed label change. Lilly withdrew its bid to promote Zyprexa for Alzheimer’s cases in 1999, according to the document.

In a November 2000 memo to Lilly salespeople, company executives said the dementia marketing initiative was abandoned because the FDA questioned Zyprexa’s effectiveness in treating the ailment.

“It was withdrawn due to vagueness on the FDA’s part regarding a definition of efficacy,” Lilly officials said in the document.

In a 2003 memo to FDA regulators citing the clinical studies, Lilly researchers acknowledged the death rates among older dementia patients on Zyprexa in the reviews were two times higher than their counterparts taking placebos.

Deaths among the patients taking Zyprexa in the studies were “significantly greater than placebo-treated patients (3.5 percent v. 1.5 percent, respectively),” Lilly officials said, according to the unsealed documents.

The studies didn’t find Zyprexa was effective in treating dementia, the company acknowledged in this document.

Lilly recognized this earlier, according to a 2002 document entitled “Zyprexa in serious mental illness (65 plus years) -- A Strategy Review.”

“The treatment of serious mental illness for people over the age of 65 has been identified as a growing opportunity for Zyprexa,” the authors wrote. “Unfortunately, attempts to gain the data to support an application for an indication in the treatment of dementia have to date been unsuccessful.”

But on the other hand, we have:

Lilly’s long-term care unit also saw Zyprexa sales rise 2.9 percent in the second quarter of 2002 as sales of Risperdal, Johnson & Johnson’s rival antipsychotic, fell, according to the 2002 marketing plan.

At that time, long-term care sales made up about 20 percent of Zyprexa prescriptions, according to the summary. Of that number, 65 percent were written for nursing-home patients.

Overall, prescriptions for older patients were the “2nd biggest money-producing segment” for Zyprexa in the U.S., according to a Feb. 15, 2002, e-mail from Lilly researcher Peter Feldman to Denice Torres, the company’s global marketing director.

In that e-mail, Feldman said company officials were saying in internal memos that they were going to stop studying Zyprexa’s potential health benefits for elderly consumers.

That would risk “killing the goose that lays the golden eggs to save on poultry feed costs,” Feldman said in the unsealed messages.

Torres assured him older consumers would continue to be a prime target for Zyprexa sales, according to the e-mail.

“Elderly remains an important aspect of target PT and affiliate focus,” she said in the message.

Increased Zyprexa sales to elderly patients also won Lilly’s long-term care unit praise in a 2003 newsletter unsealed as part of the documents.

“For two consecutive years, you have been on top and have turned in above-plan performance,” Grady Grant, Lilly’s national sales director, wrote in the newsletter. “I look forward to working with you as we set our sights on overtaking Risperdal as the number one antipsychotic in the marketplace!”

Lilly says these are cherry-picked quotes taken out of context. I'll await seeing what context they can be put in that will make them look less like. . .what they look like now.

Comments (19) + TrackBacks (0) | Category: Regulatory Affairs | The Central Nervous System | The Dark Side

Another Sack of Raving Nonsense Is Slated For Publication

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Posted by Derek

I spoke here about Scigen, the program that'll concoct a load of total nonsense for you and make it look - from a distance - like a journal paper. It's a surprisingly valuable tool, since the scientific publishing world apparently has a bigger demand for total nonsense than you might think, especially after the checks clear.

The latest example of this comes from The Scholarly Kitchen, where Philip Davis generated "Deconstructing Access Points", a paper that's nothing but a string of gibberish and non sequitars from first to last. It's here (in PDF form) if you want to try reading it. You won't get far; no human could.

Ah, but what if no human bothered to? That's what happened when Davis submitted this compost pile to the Open Information Science Journal, which is one of the new Bentham "open access" journals. You see, Bentham (like some other publishing houses) has heard that this open access stuff is like, the new trend, so they've started a line of their own journals. Once your paper's accepted, anyone can access it. Of course, there is a fee up front - to be fair, there pretty much has to be, if someone is actually going to do the back-end reviewing and editing work of a real journal. But what if you don't do any of that, and just charge the fee anyway?

Yes, the paper was accepted - of course it was accepted. It was accepted despite it being an unreadable mass of pseudo-English, and despite the fact that it was sent in under the banner of the Center for Research in Applied Phrenology. (Nice touch!) Here's the acceptance letter from an assistant manager at Bentham. All Davis had to do was send $800 to a tax-free zone in the United Arab Emirates and this manuscript would be inflicted on the world.

He pulled back at this juncture, but the point had been made. As he puts it, in milder tones than I would have: ". . .it does raise the question of whether, at least in some cases, the producer-pays-to-publish model may unduly influence editorial decision-making." Indeed it does, especially with a lower-tier publisher. Too much of the scholarly publishing world is involved in this sort of thing (and too much of the conference-organizing world, too, for that matter). I know that it's hard for many people to realize this, but it really is better not to publish at all than to abet this sort of thing.

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 10, 2009

Word For Word - But Why?

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Posted by Derek

I missed this a couple of months ago, but there was a paper withdrawn from the Journal of Organic Chemistry. The original is here, a contribution from the Indian Institute of Chemical Technology in Hyderabad on 2-aryl benzothiazoles.

The JOC editor's note is here, and states:

This manuscript was withdrawn from publication by the Editor-in-Chief of The Journal of Organic Chemistry. The basis for the withdrawal was a violation of the Ethical Guidelines to Publication of Chemical Research of the American Chemical Society. . .

The reason given is plagiarism from a paper in Angewandte Chemie in 2008, which is from Carsten Bolm's lab in Aachen on S-arylation of thiols. And here we find the trouble. Below are two sections - the first from the JOC paper, and the second from the original Ang. Chem.:

Among the various intramolecular reactions, S-arylation is comparatively less studied.(14) Two factors make this process difficult: First, thiols are prone to undergo oxidative S−S coupling reactions which result in the undesired formation of disulfides, and second, organic sulfur compounds can be effective metal binders, which leads to catalytic modification (or deactivation).(15) However, given the prevalence of C−S bonds in a wide range of pharmaceutically active compounds and polymeric materials,(16) it is desirable to find novel procedures that provide efficient access to such highly useful organic products.


Among the various cross-coupling types, S-arylation is comparatively less studied.[3] Two factors make this process difficult: First, thiols are prone to undergo oxidative SS coupling reactions, which result in the undesired formation of disulfides, and second, organic sulfur compounds can be effective metal binders, which leads to catalyst modification (or deactivation).[4] However, given the prevalence of CS bonds in a wide range of pharmaceutically active compounds and polymeric materials,[5] it is desirable to find novel catalytic procedures that provide efficient access to such highly useful organic products.

There's no doubt that this is a copy-and-paste job. And I believe that the ACS policy cited doesn't leave much wiggle room - if you do this, you get slapped down. What's silly about it is that it didn't have to happen. People borrow such background material all the time, to greater or lesser extents. But word for word? Bad idea. Frankly, if the Hyderabad authors had spent twenty minutes rewriting those sentences, no one would have ever noticed a thing. The automated similarity searches that can be done now (which I presume led to this incident) would have passed right over.

But (as far as I know) the conclusions of the JOC paper are still valid. And if you care about 2-arylbenzothiazoles, you might even want to see them. I note that the paper is still on the JOC web site, even though it's been "withdrawn". Is this the middle ground, then, a way to discipline people without yanking the results completely from the literature?

Comments (31) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

June 4, 2009

Perpetual Patents: A Nasty Thought Occurs

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Posted by Derek

A colleague of mine read the "Perpetual Patent" item below, and had a thought of his own. "If I were the head of a company that just discovered something like Lipitor", he said, using the example that the Xconomy piece used as well, "I'm probably going to fire all the early stage research people. Who needs 'em? We've got a never-ending patent on a huge drug".

And you know, I hate to say it, but I can't completely rule that one out myself. Not every management team would do this, but some would indeed transform the place from "Company That Looks For New Drugs" to "Company That Found One And Will Now Live Off It For As Long As Possible". After all, the R&D part of the operation is, most of the time, a huge drag on the bottom line. You only keep it around because you need it to come up with something that'll bring in the revenue eventually. So what happens if you decide that your current level of revenue is pretty good - and would look even better if you got rid of that big cost center?

Comments (18) + TrackBacks (0) | Category: Business and Markets | Patents and IP | The Dark Side

May 15, 2009

Competing (And Competing Unethically?)

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Posted by Derek

Sean Cutler, a biologist at UC-Riverside, is the corresponding author of a paper in a recent issue of Science. That’s always a good thing, of course, and people are willing to go to a lot of trouble to have something like that on their list of publications. But Cutler’s worried that too many scientists, especially academic ones are willing to do a bit too much for that kind of reward. He tells John Tierney at the New York Times that he approached this project differently:

” Instead of competing with my competitors, I invited them to contribute data to my paper so that no one got scooped. I figured out who might have data relating to my work (and who could get scooped) using public resources and then sent them an email. Now that I have done this, I am thinking: Why the hell isn’t everyone doing this? Why do we waste taxpayer money on ego battles between rival scientists? Usually in science you get first place or you get nothing, but that is a really inefficient model when you think about it, especially in terms of the consequences for people’s careers and training, which the public pays for. . .

. . .Obviously there is a balance between self and community interests, but as it stands there are very few metrics of scientific “niceness” and few ways to reward community-minded scientists (some grants consider “broader impact,” but that is not the same thing). What is even worse, is there are even fewer mechanisms for punishing selfish (sometimes horribly so) scientists. If it were their own money or private money they were spending on their research — fine, they can be as selfish as they want and hold others up. But 99 times out of 100, it’s not their money- it’s the public’s money and it drives me absolutely crazy that there is no meaningful oversight of behavior.

That brought in a flood of comments, and Teirney followed up a couple of days later. Addressing the general issue of scientific competition, which is where many of the comments took issue, Cutler added:

” I am in full favor of competition. My message is: Compete ethically. Sadly, there is a lot of unethical competition that goes on in science. This year alone, I have heard of cases that are the scientific equivalent of insider trading, where reviewers of important papers exploit their access to privileged data to gain unfair advantages in the “race” to the next big discovery. I have heard of researchers being ignored when they request published materials from scientists.

Not sending materials described in papers or exploiting privileged information is a clear violation of journal policies, but unethical behavior of this kind is common in science and is usually perpetrated with a proud smile in the name of “competition. . .”

Well, he’s right that this sort of thing goes on all the time in academia. I don’t know how many tales I’ve heard of pilfered grant application ideas, shady conduct when refereeing papers, and so on. To tell you the truth, though, you don’t see so much of that in industry, at least not in the discovery labs. It’s not that we’re just better human beings over here, mind you – it’s that the system doesn’t allow people to profit so much by that particular sort of conduct. Patent law is one big reason for that, as are the sheer number of lawyers that corporations can bring to bear on someone if they feel that they’ve been wronged. There’s more money involved, in every way, so the consequences of being caught are potentially ruinous.

Update: does this mean I've never worked with sleazeballs? Not at all! Credit-stealing and the like does happen in industrail research labs; they're staffed with humans. But direct theft of someone else's work - that's rare, because being inside an organization is the academic equivalent of being inside the same research group, and it's harder to get away with blatant theft. Academic lab vs. academic lab, though, is more the equivalent of "company vs. company", and (at least in the researchstage of things) we have far fewer opportunities for chicanery in industry at that level.

Anyway, unethical conduct in industrial research, when it happens, tends to occur closer to the sources of the money – over in the marketing department, say, or perhaps regulatory affairs. In academia, grants are the source of money, with high-profile publications closely tied to them. The sharp operators naturally tend to concentrate there, like ants around honey.

Cutler’s proposed solution is to go right to that source:

My call to scientists, journals and granting agencies is this: What I’d like to see implemented are rewards for ethical behavior and consequences for unethical behavior. If you knew you might not get a grant funded because you had a track record of unethical practices, then you’d start behaving. It is not much more complicated than that. The journal Science has a “reviewer agreement” that bars the unsavory behavior I described above. After my discussion of the matter with Bruce Alberts, editor in chief of Science, it is clear to me that Science considers the matter very important, but that the journal currently lacks a written policy on the consequences for ethical violations of the reviewer agreement. Without clearly advertised consequences, why behave?

My take is that two issues are being mixed here, which is the same difficulty that led to Tierney having to address this story twice. The first issue is unethical behavior, and I’m with Cutler on that one. There’s too much of that stuff around, and the reason it doth prosper is that the risk/benefit ratio is out of whack. If there were stiffer (and more sure) consequences for such things, people would act on their underhanded impulses less frequently. And for the kinds of people who do these things, the only factors that really matter to are money and prestige, so hit ‘em there, where they can feel it.

But the second issue is competition versus cooperation, and that’s another story. Prof. Cutler’s points about wasting grant money don’t seem to me to necessarily have anything to do with unethical behavior. It’s true that holding back cell lines and the like is slimy, and does impede progress (and waste public money). But without going much further, you could talk about waste when you have multiple research groups working on the same problem, even when they’re all behaving well.

That’s what went on here, if I understand the situation. Cutler basically went out to several other groups who were pursuing the same thing (abscisic acid signaling) through different approaches, and said “Hey folks, why don’t we get together and form one great big research team, rather than beat each other up?” I certainly don’t think that he was expected these other labs to do something sleazy, nor was he trying to save them from temptation.

And the problem there is (as many of Tierney’s commentors said) that competition is, overall, good for scientific progress, and that it doesn’t have to involve unethical conduct. (More on this in a follow-up post; this one’s long enough already!) That’s why Cutler had to go back and clarify things, by saying “Compete, but compete ethically”. The difficulty with talking about all this at the same time is that the groups he ended up collaborating with were (presumably) doing just that. They’re two separate issues. Both topics are very much worth discussing, but not tangled together.

Comments (18) + TrackBacks (0) | Category: Academia (vs. Industry) | The Dark Side | Who Discovers and Why

May 11, 2009

Merck, Elsevier, and Fakery

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Posted by Derek

I've been meaning to write about the latest advance in salesmanship, pioneered by Merck and Elsevier. As most of you will have heard, the two collaborated to produce something called "The Australasian Journal of Bone and Joint Medicine". This appears to have looked like a real journal, complete with the Elsevier logo and a board of review editors, but it apparently featured nothing but articles (complimentary article, needless to say) about Merck products.

Update: It appears that Merck and Elsevier actually set up a whole publishing division, Excerpta Medica, to handle these things. More here and many more details here.

The news broke about a month ago in The Australian, and the story has been rolling downhill ever since, getting larger all the way. Now Elsevier has issued a public apology for their part in the whole affair, as well they should.

As Orac points out, there are a lot of "throwaway" journals out there, particularly in the medical field. These are sort of once-over-lightly review journals, condensing the literature down into short reads. And that's not all bad, although you wouldn't want a physician to be getting all his or her news that way. But this latest venture was designed to look like a real journal, and was, in fact, full of real articles which had been reprinted from other Elsevier journals. That's well over the line.

I'm not sure who to be more mad at here: Merck or Elsevier. This one really looks like a team effort. If Merck wants to assemble a bunch of previously peer-reviewed studies and put them out under some banner to show how wonderful their drugs were, well, that's fine by me. But that banner shouldn't be something that's deliberately designed to look like a peer-reviewed journal itself. And the collection should have a disclaimer on the cover that it's being paid for by Merck, and the first page of every article should have another box: "As originally reported in (journal citation) - brought to you as a service by Merck". I wouldn't have a problem with that at all.

But that (completely above-board) style seems to be just what the company wanted to avoid, and they got Elsevier, a large and (apparently spottily) respectable scientific publisher to say "Yes, indeed!". Merck's marketing people should be ashamed of themselves, but they should be ashamed for doing what they're paid to do too vigorously. Elsevier, on the other hand, shouldn't be doing this sort of thing at all.

Comments (18) + TrackBacks (0) | Category: Business and Markets | The Dark Side | The Scientific Literature

April 29, 2009

No MAGIC Involved

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Posted by Derek

What a mess! Science has a retraction of a 2005 paper, which is always a nasty enough business, but in this case, the authors can’t agree on whether it should be retracted or not. And no one seems to be able to agree on whether the original results were real, and (even if they weren’t) whether the technique the paper describes works anyway. Well.

The original paper (free full text), from two Korean research groups, described a drug target discovery technique with the acronym MAGIC (MAGnetism-based Interaction Capture). It’s a fairly straightforward idea in principle: coat a magnetic nanoparticle with a molecule whose target(s) you’re trying to identify. Now take cell lines whose proteins have had various fluorescent tags put on them, and get the nanoparticles into them. If you then apply a strong magnetic field to the cells, the magnetic particles will be pulled around, and they’ll drag along whichever proteins have associated with your bait molecule. Watch the process under a microscope, and see which fluorescent spots move in which cells.

Papers were published (in both Science and Nature Chemical Biology), patent applications were filed (well, not in that order!), startup money was raised for a company to be called CGK. . .and then troubles began. Word was that the technique wasn’t reproducible. One of the authors (Yong-Weon Yi) asked that his name be removed from the publications, which was rather problematic of him, considering that he was also an inventor on the patent application. Early last year, investigations by the Korean Advanced Institute of Science and Technology came to the disturbing conclusion that the papers “do not contain any scientific truth”, and the journals flagged them.

The Nature Chemical Biology paper was retracted last July, but the Science paper has been a real rugby scrum, as the journal details here. The editorial staff seems to have been unable to reach one of the authors (Neoncheol Jung), and they still don’t know where he is. That’s disconcerting, since he’s still listed as the founding CEO of CGK. A complex legal struggle has erupted between the company and the KAIST about who has commercial rights to the technology, which surely isn’t being helped along by the fact that everyone is disagreeing about whether it works at all, or ever has. Science says that they’ve received parts of the KAIST report, which states that the authors couldn’t produce any notebooks or original data to support any of the experiments in the paper. This is Most Ungood, of course, and on top of that, two of the authors also appear to have stated that the key experiments (where they moved the fluorescent proteins around) were not carried out as the paper says. Meanwhile, everyone involved is now suing everyone else back in Korea for fraud, for defamation, and who knows. The target date for all this to be resolved is somewhere around the crack of doom.

Emerging from the fiery crater, CGK came up with another (very closely related) technique, which they published late last year in JACS. (If nothing else, everyone involved is certainly getting their work into an impressive list of journals. If only the papers wouldn’t keep sliding right back out. . .) That one has stood up so far, but it’s only April. I presume that the editorial staff at JACS asked for all kinds of data in support, but (as this whole affair shows) you can’t necessarily assume that everyone’s doing the job they’re supposed to do.

The new paper, most interestingly, does not reference the previous work at all, which I suppose makes sense on one level. But if you just came across it de novo, you wouldn't realize that people (at the same company!) had already been (supposedly) working on magnetic particle assays in living cells. Looking over this one and comparing it to the original Science paper, one of the biggest differences seems to be how the magnetic particles are made to expose themselves to the cytoplasm. The earlier work mentioned coating the particles with a fusogenic protein (TAT-HA2) that was claimed to help with this process; that step is nowhere to be found in the JACS work. Otherwise, the process looks pretty much identical to me.

Let’s come up for air, then, and ask how well useful these ideas could be, stipulating (deep breath) that they work. Clearly, there’s some utility here. But I have to wonder how useful this protocol will be for general target fishing expeditions. Fluorescent labeling of proteins is indeed one of the wonders of the world (and was the subject of a recent a well-deserved Nobel prize). But not all proteins can be labeled without disturbing their function – and if you don’t know what the protein’s up to in the first place, you’re never sure if you’ve done something to perturb it when you add the glowing parts. There are also a lot of proteins, of course, to put it mildly, and if you don’t have any idea of where to start looking for targets, you still have a major amount of work to do. The cleanest use I can think of for these experiments is verifying (or ruling out) hypotheses for individual proteins.

But that's if it works. And at this point, who knows? I'll be very interested to follow this story, and to see if anyone else picks up this technique and gets it to work. Who's brave enough?

Comments (9) + TrackBacks (0) | Category: Biological News | Drug Assays | The Dark Side | The Scientific Literature

March 20, 2009

What Results Did You Have In Mind?

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Posted by Derek

Of course, no sooner do I come out defending drug company research than we have this to think about:

"An influential Harvard child psychiatrist told the drug giant Johnson & Johnson that planned studies of its medicines in children would yield results benefiting the company, according to court documents dating over several years that the psychiatrist wants sealed. . .much of (Dr. Joseph Biederman's) work has been underwritten by drug makers for whom he privately consults. An inquiry by Senator Charles E. Grassley, Republican of Iowa, revealed last year that Dr. Biederman earned at least $1.6 million in consulting fees from drug makers from 2000 to 2007 but failed to report all but about $200,000 of this income to university officials.

. . .One set of slides in the documents referred to “Key Projects for 2004” and listed a planned trial to compare Risperdal, also known as risperidone, with competitors in managing pediatric bipolar disorder. The trial “will clarify the competitive advantages of risperidone vs. other neuroleptics,” the slide stated. All of the slides were prepared by Dr. Biederman, according to his sworn statement."

There are other examples. Some of this is marketing-speak, to be sure. But mixing up the marketing stuff with the inner workings of the clinical trials is a very bad idea. For sales and marketing people, it's always onward and upward, positive attitude, create-your-own-successful-reality. You most definitely do not want that worldview in a clinician: "Just the facts, ma'am" is more like it. And that doesn't sound like what we're seeing here.

Comments (10) + TrackBacks (0) | Category: Clinical Trials | The Dark Side

Drug Industry Research: Reliable or Not?

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Posted by Derek

So, in light of the Reuben scandal of forged data about pain management in surgery patients, the question naturally comes to mind: how much role did industry play? I’ve seen articles (and had comments here) to the effect that industry-sponsored research is worthless: discount it, can't trust it, bought and paid for, and so on.

The problem is, you can't completely shake that accusation. Industries (and not just the drug industry, by any means) are willing to pay for results that tell them what they want to hear. And while at times that's crossed over into outright fraud, many times it's just that you can set up all kinds of studies, in all kinds of ways, and get all kinds of answers. Run enough of them, and you can choose the ones you like and pretend the others aren't there.

The whole idea of scientific research is that you don't operate like this, of course, and eventually these things do get settled out. If the drug industry really did make sure that only happy results came out, we'd never have catastrophic clinical trial failures, and never have any drugs recalled from the market. And things like the (Nobel-worthy) H. pylori story behind stomach ulcer formation never would have seen the light of day if the industry were capable (on the other hand) of burying everything it didn't want to hear about.

But there are biases, real and potential, and they always have to be looked out for. One error, though, is to assume that these biases can be eliminated by turning to academic research instead. That's the point of a recent Op-Ed in the Washington Post by David Shaywitz, who's worked both sides of the business:

Part of the problem is that we've been conditioned to trust university research. It is based, after all, on the presumably lofty motives of its practitioners. What's not to like about science carried out by academics who have nobly dedicated their lives to understanding the unknown, furthering knowledge and serving humanity?

. . .University researchers are in a constant battle for recognition and the rewards associated with success: research space, speaking engagements, funding and autonomy. Consequently, while academic research is often described as "curiosity-driven," the reality is messier, as (curiously) many researchers tend to pursue the trendiest technologies and explore topics that happen to be associated with the most generous levels of research support.

Moreover, since academic success is determined almost exclusively by the number and prestige of research publications, the incentives to generate results are exceedingly powerful and can encourage investigators to see patterns that may not exist, to disregard contradictory observations that might be important, to overvalue data that might be preliminary or unreliable, and to embrace conclusions that deserve to be viewed with far greater skepticism.

Shaywitz goes on to make the same point I did above - that the system is ultimately self-correcting - but is calling for people to recognize that academic research is also done by human beings, with all that entails. John Tierney at the New York Times had taken up this topic last fall, and wondered about what would happen if enough researchers decided to stop taking industry funding because they were tired of having their integrity questioned.

Tierney's responded to the Shaywitz piece now as well. The comments from his readers are all over the place each time. Some of them are (correctly, to my mind) going along with the idea that research always comes in with various potential biases and agendas, and should be judged case-by-case no matter the source. There are, naturally, some who aren't buying anything that might get industrial research off the hook.

"In industry sponsored comparative studies of medical treatments, the sponsor’s product always comes out on top," says one commenter there. But that's not true. I can give you plenty of examples right off the top of my head. For sure, we try to run studies that will show a benefit for our therapies - but we also have to pin these down to the real world for people (and the FDA) to have a better chance of trusting the results. We're not going to set up a trial that we have good reason to think will fail: life is too short, and the supply of funds is not infinite. You target the diseases (and the patients) that you think will benefit the most (and show the most impressive results, naturally).

And that's a bias to consider right there: we don't set up our trials randomly, so keep that in mind. But no one sets up drug trials randomly, anywhere. There's always a reason to do something so expensive and time-consuming - you should always keep that in mind, weigh it in your calculations, and decide from there.

Comments (16) + TrackBacks (0) | Category: Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us

March 19, 2009

Fraud: How, and Why, and How Again

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Posted by Derek

Readers may have seen the recent stories of an academic anaesthesiologist, Dr. Scott Reuben, who published an entire string of fraudulent papers in the pain management field. Various rabble-rousing sources have used this as a chance to run “Big Pharma Pays For Deception” stories, but I’m not going to give that angle much time at all. I’m sure that the companies involved (Pfizer, prominently) were glad to see studies that showed that their compounds worked and were glad to cite them, but the idea of some bigwig picking up the phone and saying “Fake me up some clinical data” is too much for me.

The biggest problem is that the physican involved seems to have decided that he could make a good living by telling people what they wanted to hear. That’s always a danger, and it works the same way in all sorts of fields. It isn’t always money that drives this kind of thing, either, although that’s a good place to start. Prestige is often a big part of it, too. And there's a problem on the receiving end, too - when someone brings you a company news that their compounds perform well and should be prescribed more often, the first impulse isn't necessarily to ask "Gosh, are you sure?" (It's worth keeping in mind, though, that asking just that question is a key part in making scientific research work - but if someone is going to fake numbers from top to bottom, it's not going to be enough to catch them at it, either).

There’s another factor at work that I think about every time a major fraud or plagiarism case comes up. The minor ones I can understand, actually – someone at an obscure school rewrites an equally obscure paper, slaps their name on it and sends it off to a third-rate journal, keeping their publication rate up so as to keep their better-than-the-alternatives academic position propped up for a while longer. It’s shabby and sad, but it makes a dingy sort of sense. The major cases, though, puzzle me.

I think this topic last came up around here during the Korean stem cell fiasco a few years ago. That one set off a lot of sniping among journal editors, and a lot of speculation about how someone can think that they'll get away with fraud in an area that hotly contested.

Now, it's not like post-operative pain management is the cutting edge of medical science - no Nobels are likely to be on the line - so the question of how Reuben thought he could keep doing this doesn't apply as much. He seems, in fact, to have gotten away with doing it for many years, with no apparent problems until recently. (How, in fact, was he caught? The only details I've been able to find were that it was an internal reviewer at his medical center who noticed something). But how someone can do this sort of thing is what baffles me: not the mechanics of it, but the mental aspect is what's a mystery. How do you look at yourself after turning out fake results of any kind? Especially, how do you do it when you're affecting how people are treated for pain after surgery? And year after year. . .no, I just can't get a handle on this. There are aspects of human behavior which apparently are closed off to me, and I hope that they stay that way.

Comments (18) + TrackBacks (0) | Category: The Dark Side

March 9, 2009

The Merck Deal and the SEC: Not a Joke

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Posted by Derek

And I thought that I was kidding, at least a bit, in my post where I warned some of the folks buying into Schering-Plough last week that they might be hearing from the SEC. Well, maybe not - whenever a deal like this goes through, the first place they look is in the options market:

Some lucky option players appeared to have reaped a windfall with Schering-Plough call options rocketing after Merck on Monday announced a proposed $41.1 billion takeover of the drugmaker.

. . .a burst of activity in the stock's call options last Tuesday and again on Friday may be too much of a coincidence to overlook and prompted some option traders to ask if inside word of the pending deal reached some investors.

"Our examination of the data suggests a high degree of likelihood that someone did indeed place what I will be politically correct and call nicely timed trades," said Jon Najarian, a founder of Web information site optionmonster.com, in an email to Reuters.

Good luck explaining these, is all I can say. Telling them how lucky you felt that day won't make the folks from the enforcement division go away. As a lawyer in this business once said to me at a meeting, "I have to make sure that no one in this company trades our stock on material information. And material information is defined as something that makes you think about trading the stock."

Comments (3) + TrackBacks (0) | Category: Business and Markets | The Dark Side

February 27, 2009

Your Paper Is A Sack Of Raving Nonsense. Thank You.

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Posted by Derek

You don’t often get to see the sort of fistfight that’s detailed in the latest issue of Organic Process Research and Development. Patents whose procedures are hard to reproduce are familiar to every industrial chemist, unfortunately, but coming across one that seems completely mistaken in its most important details is rare. And this is the first time I’ve seen one of these dragged out into the open literature for a give-and-take with the original authors about whether they’re delusional or not. (The editors of the journal seem to be in new territory themselves on this one).

I should add here that the great majority of patent preps I’ve followed have worked pretty much as described, and I don’t think that my success rate in reproducing them is any worse than procedures from the chemical journals. Some journals more than others, of course, (another topic!) but OPRD is known to be very, very reproducible indeed. As it should be: it’s a journal for process chemists, whose livelihood is refining chemical routes until they’re scalable, economical, and (very importantly) until they work exactly the same way every time they’re run.

So here’s the situation. In 2007, the journal published a paper by a group from Dr. Reddy’s Laboratories, a large Indian company that does both generic drugs and has their own drug discovery operation. (There are, I should note, some academic co-authors who seem to have completely disappeared during this current food fight). The paper covered a synthesis of S-citalopram, and it caught the attention of the process chemists at Lundbeck, in Denmark. And well it might – citalopram (Celexa and other brand names), an antidepressant, was discovered there in the late 1980s, and has been generic since 2003.

The original paper (Eliati et al.) described a new alkylation reaction route to produce a key intermediate and a resolution of it (and of citalopram) into pure enantiomers by forming chiral salts. So far, so good – these sorts of things are the heart of process chemistry, and entirely appropriate for a paper in OPRD. But only if they work.

The Lundbeck group (Dancer and de Diego), had tried that exact resolution of citalopram many times themselves, though, without success, so they were rather taken aback to see it published as working just fine. They detail their attempts to reproduce the Eliati procedure, and demonstrate in great detail that it indeed does not work as written. I won’t go into their experimental work, which is very extensive and painstaking, but nothing the Lundbeck team could do resulted in anything better than a 55:45 mixture, which is a rather poor substitute for a pure compound. Midway through their paper, they start putting the word “resolution” in quotation marks when discussing the Eliati procedure, and the arm’s-length-and-holding-the-nose attitude is very successfully conveyed. The phrases “enormous disparity”, “effectively impossible”, “extremely unlikely”, and “not feasible in any meaningful, practical sense” all make appearances.

They also were surprised at the alkylation reaction reported in the Eliati paper, which is the only one of its kind reported in the literature – well, other than a patent by the same team from Dr. Reddy’s, that is. The weird thing about it is that it uses 3-chloropropylamine, apparently as the isolated free base. My chemistry audience will now be raising their eyebrows, because this is not a compound that you’d expect to be very happy as anything but a salt. It should, in fact, start reacting with itself quite vigorously, with plenty of HCl being given off in the process. But the Eliati procedure doesn’t have enough base to allow for anything else, and they use (supposedly) 12 grams of the stuff in 2.5 mL of DMSO. Since no paper or patent has ever reported isolation of this free base, it’s a rather odd compound to drop into your manuscript without explanation.

Another example of the same reaction in the Eliati paper is even weirder. Not only do they use this never-before-seen chloropropylamine, but this time they do the reaction in acetone, at 60 to 65 degrees C, by first adding 7.5 grams of potassium t-butoxide to 40 mL of the acetone. Now that prep should get the attention of the organic chemists in the audience, because that sounds like an excellent way to make a bunch of hot polymerized gunk. For one thing, acetone boils at 56, so how you get it to 65 is a real stumper. And adding a strong base to it is a surefire way to deprotonate it and start the famous aldol condensation (and every other base-catalyzed ketone reaction you can think of, for that matter). The Lundbeck group tried it, out of sheer curiosity, and got:

”. . . a vigorous/violent reaction. . .with the formation of a quantity of a white solid. (It had) an odor of higher ketones/alkenes, and analysis by NMR indicated that it was a complex mixture of products, with peaks consistent with condensation products of acetone.

A solid majority of the chemists reading that sentence, you can bet, finished reading that and added a “No shit” to the end. This is the sort of thing a sophomore undergraduate should be able to spot, and my guess is that whoever reviewed the Eliati paper for OPRD has had some interesting correspondence with the journal. The resolution is one thing – that’s impossible to spot if you haven’t worked with that exact reaction. But this alkylation step is ridiculous.

The journal gave Eliati and co-workers a chance to respond to all this, and followed that with a last word from Dancer and de Diego at Lundbeck. These things are all published back to back; it's like watching a boxing match. The Dr. Reddy’s group runs up the white flag immediately on the chiral salt resolution, actually, agreeing that their published procedure doesn’t work. But they claim that a modified version of the procedure does work, and that they “inadvertently missed incorporating a few words in the text” of the article which would have made this clear. The Lundbeck group isn’t buying this for a minute. They point out that the manuscript would have been had to have been substantially reworked to make it into this different procedure, for one thing. And even worse, the details of it as reported by Eliati are internally inconsistent, with the masses and ratios not even adding up. And finally, they report their own attempts to reproduce the new procedure, and find that it, too, is basically impossible.

And as for the alkylation, Eliati et al. claim that if you work quickly, you can use the chloropropylamine free base as they described. They also present a table showing how long it lasts under different conditions and in different solvents, and claim to have done the best variation of the reaction on a six-kilo scale. The acetone reaction, they admit, wasn’t as clean, but they didn’t spend much time talking about that because their “aim was to isolate the desired product instead of the aldol product.” Dancer and de Diego aren’t very happy with that either, continuing to insist that the acetone procedure is “completely unworkable”. As for the chloropropylamine, they welcome the clarifications in the second Eliati paper, but point out that said details contradict themselves at one point, and at any rate, none of them are to be found in the corresponding Dr. Reddy’s patent application, which continues to talk about using only the free base, and (on top of everything else) in a way that makes no sense.

The final Lundbeck reply has a telling line in the acknowledgements, which is, in its way, even more pointed than anything else in their paper: “One of us (R.J.D.) thanks Sir John Cornforth for inspiration derived from a series of his articles in a similar case some years ago.” That’s the famous “Some Comments on a Paper by Samir Chatterjee” affair, Tetrahedron Letters 1980 709 and 1982, 2213. Cornforth completely demolished some heterocyclic chemistry work by the unfortunate Chatterjee, pointing out by several lines of evidence that the whole thing had to have been faked. Name-dropping this example is about as direct a statement of your opinion as the scientific literature will allow. . .

Comments (43) + TrackBacks (0) | Category: Chemical News | Drug Development | The Dark Side | The Scientific Literature

February 26, 2009

Ranbaxy in Trouble

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Posted by Derek

There are reports this morning that the FDA is halting further review of drug applications from one of the largest generic drug manufacturers, India's Ranbaxy. It appears that some test results submitted to the agency have been found to be falsified. Update: here's the FDA's complaint (PDF).

I'm not seeing any details on what sorts of numbers look to have been cooked, or how the FDA caught on - more may come to light later. But it's for sure that this is trouble no company needs, and behavior no company should engage in. It's going to be especially hard in this case, because Ranbaxy (and India) have been trying to prove themselves as major, trustworthy players in the industry. I would have put the company in that category already, unfortunately, until this.

But it's important to remember that US companies have had their own compliance issues with manufacturing over the years - ask Schering-Plough about that, among others. Until we have more details about what's going on, I think it would be prudent to hold off on the "see what those cheap foreign plants will try to get away with" rhetoric. Who knows, that may come later.

Comments (39) + TrackBacks (0) | Category: Current Events | The Dark Side

January 15, 2009

Lilly Pays the Price

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Posted by Derek

Eli Lilly has been in trouble for some time now regarding off-label promotion of their antipsychotic Zyprexa – specifically, their sales reps seem to have gone around saying that it was useful in treating the dementia of Alzheimer’s patients, although there was no FDA approval for that indication. (Whether it actually is any good for that, or whether much of anything is, I don’t know).

Word is this morning that the company will pay a total of about 1.4 billion dollars to settle the regulatory and civil complaints. That appears to be the new record. The idea is to send a strong message to other companies about aggressive off-label promotion, and a billion dollars should certainly get attention. Lilly will also be operating under a special monitor for five years, which is no joke, either.

But still. . .this is going to happen again, at some point. As we run things in the US, physicians are free to prescribe medications as they see fit (and I have to say, I agree with that principle). Insurance companies can pay for these or not as they wish, but the doctors can write for what they like. Drug companies, on the other hand, can only market for the indications that they’ve been approved for, and in this gap you can lose 1.4 billion dollars.

Despite these problems, I think the lines need to stay about where they are, although this is always going to cause problems. There’s a temptation to try to broaden your market when you have only preliminary data – worse, there’s a temptation to broaden it when you have no data at all. That’s got to be kept in check somehow. If you want to mark the limits of my libertarian leanings, there’s one of them. I worry that if every company were free to market every drug for everything, the resulting free-for-all would drag us all back down to the level of the late-night infomercial hucksters. The potential profits are just too great; they’re a moral hazard, and they’re not commensurate with the benefits for society at large.

The only middle ground I can think of at the moment would be a category of “Some evidence exists for. . .”, which would be in between an approved and unapproved indication. Perhaps then the sales reps could mention it? Maybe not, though, because where would you draw the line for how much promotion you could do? How would we keep this from turning into a battle zone? And there are too many ways that it could be abused: running a few sloppy studies to try to get some arrows pointing the right way, for example, and then turning the marketing department loose. (You know, the sort of thing that critics of the industry figure that we do already). No, again, I think that the temptation would be too great.

So here’s a general principle: we need enough regulation in the industry to keep ourselves from turning into what our worst critics think we are already. Not the most stirring call to arms, but there it is.

Comments (14) + TrackBacks (0) | Category: Business and Markets | Regulatory Affairs | The Dark Side

December 15, 2008

Insider Trading in Drug Stocks? Not Unknown. . .

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Posted by Derek

With all the financial scandals going on these days (really, a multibillion-dollar Ponzi scheme run by the former head of NASDAQ?), it’s worth asking how often such shady dealing goes on with the stocks of drug companies. From what I can see, it does happen, but it’s certainly not endemic.

The first thing that comes to mind is insider trading. Since many companies see their stock move abruptly on the single news items pertaining to clinical trials results, regulatory actions, adverse events, and so on, front-running is always going to be a problem. And I’m sure that it goes on, but I also know that companies put a lot of effort into trying to keep it from happening. For clinical trial results, that means that such information is strictly need-to-know, and believe me, not that many people need to know. Most companies have a rather short list of people who see such numbers before a public release, which makes tracking down suspicious trades a bit too easy for comfort, if you’re inclined to reach for the easy money. I’m certainly not on any such list myself, and never have been.

There are other kinds of material information, but it’s still rare for anything that goes on in my end of the industry to affect the stock price. We’re just too far from the clinic and from the FDA to make that much of a difference. But in any case, I agree with a definition of “material information” that I once heard: if it makes you think about trading the company’s stock, and it’s not in a press release already, it’s material information. And you act on it at your peril.

But that doesn’t mean that people don’t act. Sam Waksal of Imclone is merely the most famous executive to place a phone call to his broker at an inopportune time. The chief legal counsel over at Biogen Idec got in hot water a couple of years ago about a suspicious options trade around the time of the bad news about the company’s Tysabri. (The case was settled with the SEC, with no language about wrongdoing involved - there was still some reasonable doubt about the timing of the trade, although it would have been far more prudent to not have made it). A few years before that, the chief attorney at Vertex got into trouble with another ill-advised trade of his own company's stock. And there are others, naturally.

Then there's the problem with theoretically-embargoed information from the big clinical meetings like ASCO. In recent years, it's become clear that this stuff is leaking out in one form or another, because interesting trading patterns become evident in the run-up to the meetings themselves. I think that sending out an abstract book while trying to keep the lid on them is probably futile. Of course, in many cases the real stock-moving news in such cases doesn't come from anything in the abstract book, but from the information in the presentations themselves, which is all later-breaking stuff added long after the abstract submission deadline. So you could argue that people trading on the pre-meeting stuff are still kidding themselves. . .

The closest I've ever come to this sort of thing myself was some years ago. A colleague attending a clinically-oriented meeting in a particular medical specialty called some of us back at our company to say that an anticipated series of posters and talks from another company didn't look like it was going to materialize. No one from that organization was putting anything up for the poster session. We guessed that there was some last-minute problem with their compound - and so it proved in a press release the next morning.

It occurred to me during that afternoon that a stock or options trade could well be profitable, but I didn't go through with it. It would have been profitable (especially the options, naturally), but in the end I didn't quite have the nerve. I still don't think that it would have been illegal, but I didn't like the idea of explaining actions of mine in those terms. "Not illegal as far as I know" isn't exactly the rock on which one wishes to make one's stand, you know?

Comments (10) + TrackBacks (0) | Category: Business and Markets | The Dark Side

April 18, 2008

Cut It Out. Cut It Out Now.

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Posted by Derek

File this under “does no one any good”. As many of you will have seen, JAMA just published a report on various studies that Merck has conducted and published over the years on Vioxx. The conclusion was that the company basically wrote the papers, and then went shopping for well-known academic names as authors. No, this one isn’t going to be good for anyone involved.

There seems little doubt that this practice does go on. I’ve never been in a position to see it happen, but it’s been reported for years. There are whole companies whose business is “scientific writing and communication”, and some of these seem to be in the business of turning studies into manuscripts, with no mention of their work in the final version. (The JAMA article found evidence of this sort of thing as well).

Scientific authorship is a messy business, true, and there are a lot of journal articles whose entire list of authors might have trouble with a pop quiz on the details of the paper. It is, in my mind, perfectly acceptable for one or two people on the author list to do most of the writing, with everyone else contributing suggestions and revisions. That’s how every paper I’ve been on (or written) has been done. But the worst of these Merck cases look like a search for a lead author or co-author, which is just unacceptable.

At least one of the authors named in the article is disputing its conclusions. Stephen Ferris of NYU says that he was no figurehead, and calls the JAMA paper “egregious” for having done no follow-up with the people it names. I suspect that there will be others in his category – the JAMA offices are getting a lot of testy e-mails this week, I’m sure. Of course, even the guilty are going to be sending them, since no one wants acquiesce to the label of “paid shill for publication”.

And that’s the problem. I can believe that the JAMA authors (Joseph Ross of Mt. Sinai et al.) could have cast their net too widely as they dug through the piles of discovery documents from the Vioxx litigation. But, unfortunately, I can’t believe that all their examples are mistaken. Enough chicanery goes on with authorship in purely academic settings – I can well believe that it happens in industry/academic collaborations.

But that’s the problem right there: the idea behind such a collaboration is, at least partly, to lend credence to the study’s results. Rightly or wrongly, industry studies on marketed drugs are perceived as needing the help. It’s the money involved, of course. When an industrial group publishes a paper on cell physiology or on a new method for cleaning up palladium-catalyzed reactions, no one doubts the results. But when it’s something that might have a direct and immediate effect on millions of dollars in revenue, doubts naturally set in. They always will, even if the research is beyond reproach.

And that’s why this ghostwriting business just makes the problem worse. I haven’t seen anyone suggesting that the Merck studies themselves are bogus – they had damn well better not be – but by playing games with the external author list, the company invites suspicion. I’m willing to bet that many people outside our industry who have just read the headlines on this story have assumed that the results were cooked up, just like the authorship. This is not what the industry needs. It never has been, and we need it less now than ever.

If we’re going to win back the trust of the general public – which we’ve lost, in case anyone hasn’t noticed – we’re going to have to cut out the shortcuts, stop the doubletalk, and act as if what we’re doing (drug discovery) is something to be proud of. Sure, this is a business – we sell improved health for money, and since it sure costs money to do it, there’s nothing in that transaction to be ashamed about. So why are we acting as if the only way to do business is under the cover of darkness?

We’re not going to have much of a business if these practices keep going on. Want price controls, real industrial-strength ones? Want lots and lots of marketing restrictions? Want the FDA to raise the bar for approval to levels never before seen? Want flocks of lawyers beating their wings, circling around our every move? Just keep it up, just keep this stuff up. We’ll get all that and more.

Comments (19) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature | Why Everyone Loves Us

April 1, 2008

Vytorin: It's A Pity

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Posted by Derek

Ezetimibe, known as Zetia and as the key component of Vytorin, was invented by friends and colleagues of mine. It was the first drug I ever saw discovered after I joined the drug industry. The initial discovery of the whole compound class happened around the corner from my lab, and the compound that became ezetimibe itself was synthesized down the hall. So, no, I’m not taking the current news about it very well. The situation is still quite confused, but there looks to have been enough stupidity, greed, and plain bad luck involved to make anyone despair. Read on – but I should warn you, I’m probably just going to get madder and madder as the post continues.

As anyone unfortunate enough to be holding Merck or Schering-Plough stock already knows, both companies took a pounding yesterday after the American College of Cardiology issued its recommendation on the use of Vytorin (ezetimibe / simvastatin). This call was based on the now-infamous ENHANCE trial, which was just published in the New England Journal of Medicine. The main points of the study had already come out in January, of course, but a closer look at the data has done nothing to help explain its results: no improvement over existing therapy. Addition of the cholesterol absorption inhibitor to the statin appears to have done nothing to help clear arteries (based on measurement of intima-media thickness) over what could be done with the statin alone. Ezetimibe seems to have had no bad effects, fortunately, but no good ones, either.

The ACC’s verdict is that Vytorin should only be used as a last resort, and that patients currently taking it should strongly consider going back to plain statin therapy. Based on these study results, that seems like a reasonable recommendation. There’s a large outcome trial (IMPROVE-IT) underway comparing the two treatments, but we’re not going to see results from that one for another three years at the earliest. Until then, there doesn’t seem to be any reason to recommend Vytorin. (There may not be any reason to recommend it afterwards, either, but we’ll have to wait to see about that). Fortunately for everyone involved, no one seems to have been harmed, outside of the insurance companies who have paid out for Vytorin for the last few years – they not doubt have their own views on the subject.

It’s important to remember that this result is indeed a surprise, since the combination definitely does do a better job at lowering LDL. (As an editorial in the NEJM puts it, this "dramatically contradicts our expectations"). You’d think that extra LDL reduction would be associated with a better outcome, but one of the panelists at the ACC, Dr. Harlan Krumholz, points out (PDF) that hormone therapy lowers LDL as a side effect, but isn’t associated in that case with better atherosclerosis outcomes, either. Does that mean that there’s more to the effect of statins than just lowering LDL, too? That possibility has to be taken seriously. The non-lipid effects of inhibiting HMGCoA reductase, the statin target, may be part of the answer, although the authors of the NEJM paper are reluctant to make that their whole explanation.

What they suggest instead is disturbing. The study may have been doomed from the start. The ENHANCE subjects were not taken from the general population, but rather were patients with a genetic abnormality in LDL handling, familial hypercholesterolemia. The idea was that these patients would be even more likely to show a benefit from Vytorin. But as the NEJM authors make clear, this may at one time have been a good patient population to show benefits in, but now the great majority of people with this condition are treated with statins starting at an early age. This, naturally, has an effect on their arterial walls. So the subjects of this trial may have already had a head start on reducing their arterial thickness, which means there may well have been a limit on what any particular therapy could have accomplished. Instead of being a better group to demonstrate your LDL-lowering powers in, they could well be worse.

If that’s true, there is, in fact, a chance that the IMPROVE-IT trial could show a clear benefit for Vytorin, since it’s being run in a broader population. (Just watch the confusion if that happens). But what will that mean? The results will be far too late to help Merck and Schering-Plough, and will be a clear disservice to the patients that could have benefited from the drug before then. ENHANCE would then turn out to have been a huge mistake.

But not content with that, the companies have managed to make it into a complete disaster. The controversy has been whether Merck and Schering-Plough sat on the results of the trial or spent extra time trying to find a way to make them look more appealing. This has drawn the attention of Sen. Charles Grassley and an investigative committee, which is the sort of thing that no company can wish for. Yesterday Grassley released some of the text of his letters to the management of both companies, and these include quotes from e-mails sent by John Kastelein, the lead investigator on ENHANCE. They do not look good, not by any stretch of the imagination:

” Is it correct that SP has decided not to present at AHA, but to await the two other, completely unvalidated, endpoints, which analysis is going to take us straight into 2008??!!??

If this is true, SP must have taken this decision without even the semblance of decency to consult me as PI of the study. I can tell you that if this is the case, our collaboration is over…This starts smelling like extending the publication for no other [than] political reasons and I cannot live with that.”

In another e-mail, Kastelein expresses more frustration that the results would not be presented at that AHA meeting (as indeed they weren’t, in the end), and says that ”. . . you will be seen as a company that tries to hide something and I will be perceived as being in bed with you!”

Schering-Plough, for its part, says that these statements are taken out of context, but good grief, what other context could that possibly be? Kastelein has also backed off, saying that he wasn’t accusing the company of “deliberately withholding data for political reasons”, but again, it’s hard to read those excerpts in any other way. These days, no one should make statements in e-mail that they’re not comfortable seeing printed in the Wall Street Journal, which is where I got these.

And does it need to be said that this is exactly, I mean exactly the kind of thing that the drug industry does not need? Vytorin as a drug is easy to forgive – the combination makes perfect sense, and the fact that it didn’t show a good result in ENHANCE took everyone by surprise. (And, as mentioned above, it may in the end turn out to be a good therapy in the end). But the marketing of Vytorin is perhaps another thing – the companies really made a huge aggressive push to get as much of the cholesterol-lowering market as they could. That’s no sin by itself, unless business is a sin, but if you’re going to push that hard, you’d better make sure that you’re standing on something firm.

This trial definitely wasn't that sort of foundation, and the fallout from it has been made much, much worse by its handling. It's distressing to me that the management at Merck and Schering-Plough would even take the chance, in this climate, of being seen as data-massaging study-burying slime. What words do I find if that's what they turn out to be?

Ezetimibe was (and is) a wonderful scientific story in the drug discovery labs, and its development is a testament to some very dedicated and persistent people. What a pity that it's all come to this.

Comments (19) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Press Coverage | The Dark Side | Why Everyone Loves Us

March 6, 2008

Fakery And Its Ends

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Posted by Derek

Thinking about that plagiarizing Indian professor brings up the same thought I always have in these situations: what on Earth is going through the heads of these people?

I can tell you, honestly, that I have never faked any data. (That phrase makes me remember, though, that one of the most crazed fabulists I’ve ever known started a good number of his sentences with the phrase “I tell you honestly”). I would feel nervous and guilty about making up so much as an NMR coupling constant – I freely admit to having put down “10 Hz” for something that might well be 9 on closer inspection, but making it up without having even looked? No way. It’s not like I have a halo over my head, but hey, these things are real numbers that people can check. You’d think that if a person feels the need to lie about things that they’d pick something else to lie about. I can see telling people that the check is in the mail, or that yes, I did indeed read every word of your insightful memo, but I can’t see telling someone that I made some compound that I didn’t make.

So, then, faking up a whole publication? How can you do that and sleep at night? Even if it’s just some obscure analytical method, published in a journal that no one has ever read an issue of front to back, how can you do that? Well, then, how about sixty or seventy of the damn things over a period of a few years – that’s what this guy did, after all.

And I think that, other than the (to me) incomprehensible mental angle, what I feel about this sort of thing is anger. Although I work in a very applied research field, I think that scientific research is generally a good thing in and of itself. I’m signed up with Francis Bacon and his program “for the effecting of all things possible”. (Peter Medawar's thoughts on this are well worth reading). So this sort of cynical fakery really gets to me, because it’s the work of someone who, in the end, figures that science and data are just stuff to use to get what you want. They’ve no intrinsic value. It’s not like anyone cares, right?

It’s like watching a pastry shop mix ground cardboard into their muffins – hey, you get more muffins that way, and what good are the damn things anyway if not to unload them on the idiot customers for cash? So for anyone who came to Chiranjeevi’s work for anything useful (God help ‘em), well, his message to you is to stick it in your ear. “Useful for you” isn’t anything he cares about. What he’s interested in, of course, is “useful for him”, and that’s what the whole enterprise of science comes down to for someone like this: a means to an end. And what mighty end is that? Why, advancement at Sri Venkateswara University, of course. And some pocket money. And a longer CV. Noble stuff, isn’t it?

Comments (17) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

March 3, 2008

Big Steaming Heaps of Fraud

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Posted by Derek

Since I had a blog entry here recently talking about plagiarism, I thought I should point out a whopping case of it that’s come to light. One Pattium Chiranjeevi, a professor of chemistry at Sri Venkateswara University in Triupati, India, has been accused of cranking out dozens of forged publications over the last few years.

I don’t see how there can be any doubt about the guy. He published 60 or 70 papers in under four years, which is enough to make you wonder right there. Unless you’ve got a monster research group, and you’re constantly breaking everything down into the tiniest bites and repeating lots of stuff to boot, that’s just not possible. But these papers, mostly on analytical methods development, are just too similar to things that were already in the literature. Elsevier has already retracted thirteen papers from the list, and no doubt other publishers are working on doing the same. A panel at his university has concluded that he plagiarized data and included “unjustified co-authors”. My favorite part of the whole affair is that some of his publications include data from instruments that don’t even exist at SVU.

We owe P. K. Dasgupta at UT-Arlington for catching on to all this. As detailed here in C&E News, he realized that one of Chiranjeevi's papers sent in for review was identical to something he'd seen last year. Well, mostly identical - Chiranjeevi had gone so far as to substitute the word "arsenic" for the word "chromium", but other than that demanding find-and-replace job, the manuscripts were identical. That should give you some idea of the level this guy was working on. Interestingly, he doesn't seem to show up in that Deja Vu database I linked to earlier, even though some of the journals he published in are in PubMed - is this because of these sorts of word games?

Science managed to get ahold of Chiranjeevi for comment, and his response does not inspire visions of a man unjustly accused. He blames colleagues and journal editors for the whole thing, says the charges are “baseless”, and (you won’t see this one coming) says that he plans to take action in an “international court of justice” to clear his name. Science left that last phrase in quotes, too, even though it’s a perfectly recognizable English term, which is the equivalent of putting “sic” after it: “That’s really what he said, folks; we’re not making that one up”. What sort of person starts blowharding (no offense!) about international courts of justice in a situation like this? Quite possibly the sort of maniac who’s capable of, well, plagiarizing up a new publication every three weeks or so without even bothering if the experimental section includes equipment that he’s ever seen or used. What goes through the heads of these people is a mystery that the rest of the population may never solve.

That Science news article tries to tie this to the recent scandals in stem cell research and low-temperature physics, but I don’t think the comparison holds up. For one thing, those two weren’t plagiarism, but featured results that had been completely made up. And they were spectacularly focused on hugely popular fields of research while Chiranjeevi’s papers are small and relatively obscure. It’s doubtful that anyone was led down the wrong path by reading them – in fact, it’s doubtful if anyone read them to any great extent at all, which is how something like this can go on so long. These sorts of papers are specialized reference material, not breaking news. Actually, it makes more sense to plagiarize that kind of work than to claim to have performed groundbreaking work in stem cells or superconductivity. If Chiranjeevi had cut back to a few papers per year, he probably could have made a career out of it. For some values of the word “career”.

Note: if I'm lucky, maybe one of the professor's defenders (!) will show up in the comments section, as one seems to have here and here!

Comments (28) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

February 25, 2008

More On Merck and Taranabant

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Posted by Derek

My piece on Merck last week seems to have touched a few nerves, if some of the comments and e-mails I’ve received are any sign. To clarify things: I agree that Merck is still doing some excellent science, as they always have. And they still have a lot of good people there, as they always have. Those aren’t the problems. And they’re still introducing some innovative drugs, arguably more than a lot of other companies, and that’s not the problem, either. These are all are admirable things.

And Vioxx, as I said here at the time, was not, in my opinion, necessarily a bad drug. It and the other COX-2 inhibitors have a real place in the pharmacopeia. The problem is that Merck – or, to put the usual face-saving perspective on it, Merck’s marketing department – oversold the stuff. The prospect of an aspirin-sized market was too much for them to resist, so the company pushed Vioxx just about as hard as they possibly could.

Yep, Vioxx was for all kinds of patients, all kinds of pain, all the time – and under those conditions, whatever side effects were there were finally revealed. It’s the company’s bad luck (not to mention the bad luck of their patients) that those effects were as potentially severe as they were. Even so, the increased risk of a heart attack with Vioxx use is extremely small in any absolute sense. For people with severe pain who can’t get relief with other drugs, I think a COX-2 inhibitor is absolutely worth it.

But that’s not what you’d think from reading the newspapers, or from listening to the lawyers. It was expedient to paint the company as a bunch of callous poisoners; Merck’s reputation has been hooked to the back of a pickup truck and pulled through a swamp. (They didn't always do themselves much good during that period, either). And while the good name was bouncing off the tree stumps and scooping up the mud, the company had to spend vast amounts of money to deal with all those lawsuits, which is money that presumably could have been used for something else. (OK, some of that is coming from insurance – but think of how much more they’ll be paying for that coverage now).

Which is what worries me about taranabant. I realize, as several commenters to the previous post pointed out, that it may well differ in selectivity and CB-1 receptor activity from rimonabant. If the compound is an inverse agonist instead of an antagonist at the receptor, that could well be good news. Or, you know, it might not be, since we have no idea of what an inverse agonist will do, either. (More on the difference between those terms in a future post). At any rate, discovering new things about human CNS functions while a bunch of lawyers watch doesn’t sound like a good idea. If Merck does end up going down the Vioxx path again, another run through the swamp will do it no good at all.

Comments (26) + TrackBacks (0) | Category: Diabetes and Obesity | The Dark Side

February 20, 2008

What You Become Known For

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Posted by Derek

A recent item from InVivoBlog about Merck which brought up some interesting points. They aren’t cheerful ones. The article is largely about Merck’s reputation, which has taken some dents in recent years, to put it lightly. The Vioxx debacle is the main reason for this, but the hits have kept on coming, such as the latest controversy over the release of the disappointing Vytorin study data.

So, although this is a painful question, perhaps it needs to be asked: remember when Merck was above all that stuff? Maybe there should be a “seemed” in that sentence somewhere; that might take some of the sting away. But the company really did have a singular reputation at one time. Depending on your point of view, you could have used words like “insular” or “arrogant” to describe the culture over there, but they were distinctive.

Merck didn’t merge with anyone. They stuck with targets and projects for years and years if they thought something would come out of them. And (until Vioxx) they avoided the sorts of disasters that seemed to hit other companies. That’s gone. Not all gone – they still seem to run on longer timelines over there – but one of the most distinctive things about the company was how it guarded its reputation, and that seems to have slipped down the list. They didn't have to do ad campaigns like this one. The company's trying to convince people, or convince themselves, that things haven't changed, but they're wrong.

The other thing that struck me about the article was about the development of the company’s CB-1 antagonist. That’s the same mechanism as rimonabant, Sanofi-Aventis’s failed wonder drug for obesity. (OK, it’s on the market as Acomplia in several countries, but considering what people had thought it would do, it’s a failure, all right). I question Merck’s judgment in pushing another compound into that area, although these programs do take on a life of their own. And as the In Vivo post points out, Merck’s current reputation of pushing every drug as hard as possible won’t help it when it comes to getting the drug through the FDA.

The biggest problem with rimonabant was the comparison of its side effects to its efficacy. It does seem to help people lose weight, although not to any startling extent, but in a large patient population various psychiatric side effects showed up. Taranabant's side effect profile isn't yet clear. Merck is going to have to tread lightly, but can they? The situation is a bit too much like Vioxx, with a huge, lucrative market out there if you can just expand the patient population. And we can argue about just how bad Vioxx really was, and about its risk/benefit ratio, but that won't change the fact that it was a catastrophe for Merck. The last thing they need is another one. I don't think I would have picked this time to push another CB-1 antagonist forward, but I suppose we don't get to pick that sort of thing. . .

Comments (20) + TrackBacks (0) | Category: Diabetes and Obesity | Drug Development | Drug Industry History | The Dark Side

January 30, 2008

Recycle, Reuse, Republish

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Posted by Derek

There’s an analysis in the latest Nature that puts some numbers on a problem that scientists the world over have suspected for some time: the number of duplicate papers that show up in the literature. The authors used this online text-similarity tool to go through papers in Pubmed, and found a small (but not as small as it should be) percentage of papers that seem to be the same damn things, recycled.

As it turns out, the “most similar papers” function over on the right-hand side of the Pubmed results was a good starting point for tracking these down, and this shortcut allowed them to search the entire Pubmed database. The authors have set up a web site where they've deposited their data and their lists of duplicate papers. Out of about 7 million abstracts, some 70,000 were flagged as being highly similar to their corresponding "most related article" on Medline. Manual checking suggests that about 50,000 of these are going to be true duplicates - they've gone through about 2700 by hand so far (statistics here).

They have drawn some preliminary conclusions from their data set. For one thing, duplication seems to have been steady or trending down in the database during the 1990s, but has been increasing since 2000 (and is currently at the highest level). Their explanation - the rising number of print and online journals, making copying easier to perform and harder to detect - seems right to me. Another interesting graph is the frequency of duplicates by country of origin, versus that country's relative contribution to the Medline database as a whole. Looked at that way, the US is under-represented in the duplicates (which is good to know), and Japan and China are quite over-represented. Several explanations for this are considered – original publication in a language less used for scientific publication, followed by a chance to expose the same work to a wider audience, for one. But the authors don't hesitate to cite "differences in ethics training and cultural norms" as a factor, too.

A further fascinating detail is that the papers which seem to have been duplicated in different journals by the same author (or authors) very often appear too soon after the first publication to have gone through the reviewing process sequence. In other words, they were most likely submitted simultaneously to both journals, which isn't a nice thing to do. By contrast, when the same stuff appears under someone else's name, there's generally an appropriate time lag.

This study notes that their manual inspections have, so far, found over seventy cases of what looks like outright plagiarism, and that they're starting to contact journal editors and universities for more details. And they also seem to have found a number of what they term "serial offenders", and are investigating those cases as well. They don't go into details, but my guess is that some of those people could possibly be found here.

Their hope is that if such authors realize that such tools exist, that plagiarism and duplication will be seen as more risky. Thus all the publicity. Want to try it out yourself? The list of potential duplicates can be found here. Here's the list of journals, and you can plug those into this search page and see what you come up with. Here are some of the manually checked papers - click on the left-hand side ID number to see a side-by-side comparison.

Comments (16) + TrackBacks (0) | Category: The Dark Side | The Scientific Literature

July 17, 2007

Visfatin: Real Or Not?

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Posted by Derek

A commentor to my Proteomics 101 post the other day brought up an important point: that before you can have a chance to figure out what a protein is doing, you have to know that it exists. Finding the darn things is no small job, since you're digging through piles of chemically similar stuff to unearth them. What's more, we can't just ignore 'em: some of the low-concentration proteins are also correspondingly important and powerful.

Nasty arguments can erupt over whether a given protein and its proposed functions even exist. Crockery is flying over one of those right now, an insulin-like protein hormone dubbed "visfatin" by its discoverers in Osaka a couple of years ago. Well, in this case the protein probably exists, but does it do what it's advertised to do? An insulin mimic secreted by fat cells would be worth knowing about, but there doesn't seem to be enough of it present in the blood to do much of anything, given how well it binds to its putative targets. There are also reports that some of that data in the Osaka paper are hard to reproduce.

Complicating things even more is the (apparently well-founded) contention that visfatin is a re-discovery of a protein already known as PBEF, which is identical to another protein named Nampt. (Each "discovering" group assigned their own name, a situation that happens so often in biology that people don't even notice it any more).

The whipped topping on the whole thing is a accusation of misconduct by someone in Japan, which led to an investigation by Osaka University, which has now recommended that the original paper be retracted. Its lead author, Iichiro Shimomura, does not agree, as you might well imagine. The points of contention are many: whether the misconduct was real at all, or whether it describes real events that don't rise to the level of misconduct, or whether the conclusions of the paper are invalidated or not by them, and so on.

An early solution appears unlikely. And we still don't know what exactly visfatin/PBEF/Nampt is doing. Next time you wonder how things are going over in the proteome, consider this one.

Comments (4) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity | The Dark Side

June 3, 2007

Pecunia Non Olet?

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Posted by Derek

Today's New York Times had a long front-page story from Janet Roberts and the paper's Scourge of the Drug Industry, Gardiner Harris. Titled "After Sanctions, Doctors Get Drug Company Pay", it details (through the example of one particular Minnesota psychiatrist) a practice of physicians who have had medical board problems continuing to get money for participating in clinical studies.

Dr. Faruk Abuzzahab has definitely had his run-ins with the medical authorities. And over the years he's also definitely had payments from various companies. It's not a story to make you feel warm and fuzzy, that's for sure. There are some things about it that puzzle me, though. For one thing, it appears that Abuzzahab is no bargain as a clinical investigator:

"Separately, the F.D.A. in 1979 and 1984 concluded that Dr. Abuzzahab had violated the protocols of every study he led that they audited, and reported inaccurate data to drug makers. He routinely oversaw four to eight drug trials simultaneously, often moved patients from one study to another, sometimes gave experimental medicines to patients at their first consultation, and once hospitalized a patient for the sole purpose of enrolling him in a study, the F.D.A. found. . .

A simple Google search reveals Dr. Abuzzahab’s 1998 medical board disciplinary file, which was reported at the time by a local newspaper and a TV station. In 1998, The Boston Globe featured Dr. Abuzzahab in a front-page article questioning the safety of psychiatric drug experiments. And in 1999, the NBC program “Dateline” did a segment about a woman who committed suicide while in a drug experiment he supervised.

In June 2006, the medical board criticized Dr. Abuzzahab, this time for writing narcotics prescriptions for patients he knew were using false names, a violation of federal narcotics laws.

Despite all this, drug makers continued to hire him. Dr. Abuzzahab’s résumé lists 11 publications or research presentations since 2000, when the medical board lifted its restrictions on his license."

Well, I haven't seen the guy's résumé, but a PubMed search shows only one paper since that year, and only one other since 1983. His publication record thins out drastically after the early 1980s; this is not someone who cares about blazing across the sky of the scientific literature.

What exactly does he care about, though? Money? According to the graphic that accompanies the story, Abuzzahab received $55,000 from several drug companies over an eleven-year period. That's better than a kick in the ankle, but it doesn't seem like enough cash to turn a busy psychiatrist's head, either. I've not had the opportunity to find out if I can be bought or not, fortunately, but I can tell you this: it would take more than five grand a year to do it.

And just what is it that GSK, Wyeth, J&J and the other companies who've paid him are hoping to get? The first thought is that they're hoping to influence his prescribing habits, because it doesn't sound as if the clinical data he's generating are worth all that much. Is that amount of money enough to do it? Presentations by a well-known and well-respected figure could also be expected to influence the scrip-writing of others, but Dr. Abuzzahab doesn't seem, in recent years, to have been that kind of person.

No, this sort of thing doesn't look good at all. The Times story gives a reader the impression that companies are disproportionately funding physicians with disciplinary problems, although there's no evidence to back that up. But the funding should be disproportionate in the other direction, which doesn't seem to be the case. Not good, not good at all.

Comments (5) + TrackBacks (0) | Category: Clinical Trials | The Dark Side | Why Everyone Loves Us

March 22, 2007

FDA Advisory Panels: Pay, No Play

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Posted by Derek

Jim Hu has a good post on some proposed new FDA rules for its advisory panel members. Some sort of changes have been coming for a while now - here's an op-ed that I wrote on the subject back in 2005. I argued that many of the best scientists and clinicians in a given field already work with the industry (which isn't such a bad thing when you think about it), and that restrictive requirements for serving on advisory panels could do more harm than good.

Well, here's the new proposal: the cutoff is $50,000 in the previous 12 months. At that or above, you won't be allowed on the panel. Between $1 (presumably) and $50,000, you can sit on the panel, but won't be allowed to vote. My guess is that that's going to have a pretty big impact if it goes through, and that we're going to see some very different committee rosters.

Or, of course, maybe we're going to see some new forms of relationships between drug companies and their consultants. That's what happens whenever efforts are made to regulate money in the political world, and it wouldn't surprise me a bit here. There are two ways to look at this: if you're suspicious of the FDA's motives (like, say, Rep. Maurice Hinchley of New York, who has a bill mandating these changes and more coming along), then you'll probably see the whole process as a form of organized bribery, wheel-greasing to get defective drugs past the regulatory authorities. Another way to look at it, though, is that outside experts have something that the drug companies need (expertise, and more importantly, expertise from another point of view than the one from inside the company), and that they're willing to pay for it. This may seem odd, but these consultants don't always tell us what we want to hear.

The tough part is when a drug is on the edge of getting approved or not - it has some good points, some bad ones, and the decision could go either way. That's when suspicions are raised that an extra $50,000 here and there is what tipped things over to approval. I don't see that happening, myself (although readers are invited to submit counterexamples). Many approvals can be honestly argued either way, because these medical questions are inherently one big grey area.

The media reaction to this story is rather more toward the former point of view, though. The Washington Post's take on the story is that ". . .the new guidelines implicitly acknowledge what critics have long said -- that it is possible to find enough qualified experts who do not have ties to drug and device manufacturers." And Gardiner Harris in the New York Times gives one sentence to someone at the American Enterprise Institute, while leaving plenty of space for words from Rep. Hinchley and my own representative, Rosa DeLauro, both of whom are good places to go for "corporate poisoners" quotes.

Well, this is the first act of a rather long session of political theatre. There are 60 days of public comment on this proposal, then more wrangling comes along after that. Then there are the bills in the House, which if things go on long enough will get thrown into the next election cycle, and on it goes. It's worth watching, but be ready for a protracted show.

Comments (5) + TrackBacks (0) | Category: Clinical Trials | Drug Development | Press Coverage | The Dark Side | Why Everyone Loves Us

August 10, 2006

The Great Plavix Disaster

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Posted by Derek

I've been remiss in not covering the Plavix situation, which is quite a story. The huge-selling anticoagulant is marketed in the US by Bristol-Meyers Squibb and in the rest of the world by Sanofi-Aventis. It's been the target of the Canadian generic firm Apotex, who've maintained that key parts of its patent coverage are invalid. They won the right from the FDA back in January to sell their generic form - but keep in mind that the FDA is not concerned with patent law, only the drug's manufacturing standards and identity with the original version.

The company was in the middle of their patent suit with BMS and S-A, and were holding back to see how that would go. In March, though, a deal was cut: Apotex agreed to wait until 2011, the lifetime of the (unchallenged) patent, and in return they got paid by the larger firms and received a guarantee that they wouldn't be undercut until then.

Paying generic firms to go away is not unheard of, but companies can put themselves at risk when such deals are made too blatantly. This one fell apart, big-time, last month. Not only was it rejected by various state attorneys-general, but a criminal investigation was launched into the whole matter.

The ceiling tiles really began to rain down at that point. There was a clause in the agreement that if the deal didn't go through, Apotex could start selling its generic version with five days notice, and that's exactly what they've started doing as of earlier this week. The generic isn't all that much cheaper, but it's enough to torpedo the branded version.

What's more, it appears that BMS and Sanofi-Aventis limited their potential recourse. Under the usual rules, they'd be able to sue and obtain triple damages if they won, but they seem to have waived that right, along with several others. This would seem to be an indicator of just how much they wanted to keep the generic off the market, and how hard a bargain Apotex drove. It's enough to make you wonder if Apotex factored in, up front, the chance of the whole thing being rejected and decided to give their rivals enough rope with which to hang themselves.

Update: as pointed out in the comments, the CEO of Apotex is making it sound like that was exactly the plan. Perhaps he's laying it on a bit thick, but he's in a position to, isn't he?

Shares of both Bristol-Meyers Squibb and Sanofi-Aventis took a fine hammering, as you can well imagine, since Plavix represents about 30% of BMS's profits. (Here's a read-'em-and-weep chart). Apotex is privately held, which is a shame in a way, because it would have been something to see what the trading in their stock would have been like. Sanofi may try to obtain an injunction to stop the generic sales, but no one seems to think that it will be granted - partly because of all those Apotex-favoring terms that the companies agreed to originally.

It's difficult to see how this could have worked out more horribly for the two big companies here: their best-selling drug is under attack five years early, they've signed away their rights to do much about it, the analysts are downgrading their stock and the financial rating agencies are looking at lowering their credit ratings, and the criminal investigation is rolling right along. Short of a meteor strike or a plague of frogs, I'm not sure what else could go wrong. And the worst part is, they brought it on themselves. Their patent position should have been stronger in the first place to protect a compound of this importance, and they shouldn't have pushed the envelope so much with their go-away payments to Apotex. It didn't have to be this way. Did it?

Comments (36) + TrackBacks (0) | Category: Business and Markets | Cardiovascular Disease | Patents and IP | The Dark Side

May 16, 2006

The New England Journal And Its PR Flacks

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Posted by Derek

The Wall Street Journal ran an interesting article by David Armstrong the other day on the New England Journal of Medicine and the Merck/Vioxx affair. It's subscriber-only on the WSJ site, but the Pittsburgh Post-Gazette picked it up here. It brings up an angle that I hadn't completely considered:

While Merck has taken the brunt of criticism in the affair, the New England Journal's role in the Vioxx debacle has received little attention. The journal is the most-cited medical publication in the world, and its November 2000 article on Vioxx was a major marketing tool for Merck. . .Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article. He said the journal sold more than 900,000 reprints of the article, bringing in at least $697,000 in revenue. Merck says it bought most of the reprints.

The article goes on to detail the role of a public relations consultant in the release and timing of the "Expression of Concern", which I've expressed my own concerns about. The journal seems to have been worried about its own name, and seeking to put the focus back on Merck. And some of these efforts may have gone a bit over the line. Remember the infamous missing data?

Perhaps the most sensational allegation in the journal's expression of concern was that the authors of the November 2000 article deleted heart-related safety data from a draft just two days before submitting it to the journal for publication. The journal said it was able to detect this by examining a computer disk submitted with the manuscript.

The statement was ambiguous about what data the authors deleted, hinting that serious scientific misconduct was involved. "Taken together, these inaccuracies and deletions call into question the integrity of the data," the editors wrote.

In reality, the last-minute changes to the manuscript were less significant. One of the "deleted" items was a blank table that never had any data in it in article manuscripts. Also deleted was the number of heart attacks suffered by Vioxx users in the trial -- 17. However, in place of the number the authors inserted the percentage of patients who suffered heart attacks. Using that percentage (0.4 percent) and the total number of Vioxx users given in the article (4,047), any reader could roughly calculate the heart-attack number. . .

. . .Many news organizations, including The Wall Street Journal, misunderstood the ambiguous language and incorrectly reported that the deleted data were the extra three heart attacks -- which, if true, would have reflected badly on Merck. The New England Journal says it didn't attempt to have these mistakes corrected.

So, the matter of the missing heart attacks, which was the subject of a lot of heated language around here, appears to be closed. This sheds an interesting light on last December's "reaffirmation" of concern, where the NEJM made so much of the heart attack data and how it should have been included. Just about everyone who read that came away thinking that the whole fuss was about the deletion of the three MI events in the Vioxx treatment group. As you'll see from the comments to that post, many of us spent our time arguing about whether they should have been included or not, what the clinical cutoff date was, and so on.

We could have saved our breath. The heart attacks weren't deleted from the manuscript, and those who thought that they had been were responding to a well-thought-out public relations campaign. My opinion of the NEJM is not being enhanced by these revelations, let me tell you.

Problem is, my opinion of Merck isn't at its highest level these days, either. More on that tomorrow. . .

Comments (10) + TrackBacks (2) | Category: Cardiovascular Disease | The Dark Side | The Scientific Literature | Toxicology

November 22, 2005

Serono's Suitors

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Posted by Derek

If you stopped one hundred people on the street and asked them to name a drug company, I'd be astonished if a single one of them mentioned Serono. But they're one of the largest biotechs in the world, even though their profile is low. Being a privately held (indeed, family-owned) concern surely has something to do with that, because if people can't talk about your stock, they often don't talk about your company.

Serono has been around for about a century, and for a long time they made their living in hormones and fertility treatments (some of which were extracted directly from urine, which must have been a joyful task). They really took off though, in the last ten years, making the current family CEO Ernesto Bertarelli one of the hundred wealthiest people alive. Their recent growth has been due to Rebif, a recombinant beta-interferon for multiple sclerosis, but before that one of their big products was Serostim.

And that's one part of the company history they'd like to forget. Serostim is a growth hormone preparation approved in 1996 for treatment of HIV-related wasting. But newer antiretroviral drugs came on the market very soon after that and AIDS wasting became less of an issue (in fact, some of the HIV protease inhibitors are well known for redistributing and perhaps even adding body fat). Serono fought back, as any company would, but they comprehensively crossed the line.

Their first tactic was to promote a medical device to measure wasting in HIV patients, which gizmo (wouldn't you know) indicated that people needed Serostim even though they looked fine. The idea was, er, that their cells were losing mass, even though their outward appearance might not indicate it. Another campaign tried to promote the same device (and Serostim) to diagnose and treat the adipose effects of the retroviral drugs. Neither were approved for such a use, as you might well have guessed. And their third method was more to the point: to flat-out pay physicians for the number of Serostim prescriptions they wrote, in one notorious case by picking up the tab for a free vacation in the south of France.

The company recently settled with the US government, agreeing to their guilt and paying $725 million in fines. It's worth noting that the whole scheme was done in by five employees with knowledge of the matter, who will now share some $50 million of the fine under Federal whistleblower statutes. (This seems to be a perfect example of what the law was designed to do).

So having put this behind them, Serono finds themselves in the position of several other companies over the years, with most of their revenue coming from a single product and not much else looking fit to replace it. And, as some other companies have done in such times, they've called in the investment bankers.

But I'm not sure who's going to line up to buy them. Right now, you'd be getting Serono for nearly the highest price it's ever commanded. If someone decides that they want Rebif for the rest of its patent life, that would be the best reason I could think of to go ahead with a deal. . .of course, it would have to be someone with a huge marketing arm and the conviction that they could make more money than Serono could with the stuff, which I'd guess narrows it down even more to companies whose names start with a silent "P".

Comments (3) + TrackBacks (0) | Category: Drug Industry History | The Dark Side

October 20, 2005

This Had Better Be Good

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Posted by Derek

I wrote a brief wrap-up on the FDA's concerns about the new Bristol-Meyers Squibb / Merck diabetes drug Pargluva (muraglitazar). It's officially "approvable", but the FDA wants more cardiovascular safety data before it can be sold. But just this morning the JAMA web site has rushed out an article from a team at the Cleveland Clinic on the drug's clinical trial data. (Accompanying editorial here). It's very disturbing, in more ways than one.

At the time, I said that "By my reading, the cardiovascular event profile of the drug subjects looks slightly but noticeably worse than that of the placebo group. There are plenty of possible extenuating factors, and the number of patients involved is small, but I think that this is going to be a problem for the companies during the FDA hearing. Here's the list of questions the FDA has proposed for discussion (PDF again), and you can see that edema and cardiovascular safety loom large. . ." That's fine, as far as it goes, but I didn't dig far enough into the data, and I wonder if the advisory panel did, either.

What the authors of this new paper have noticed is the number of patients taking a low dose of muraglitazar - lower than the companies ended up seeking approval for. They didn't show enough beneficial effects for that dose to be worthwhile, but since muraglitazar's cardiovascular problems appear to be strongly correlated with dose, these patients also had no cardiovascular events at all. The problem is that these patients were included in the risk calculations, and that makes the drug look safer than it would be under real-world conditions.

The Cleveland group's recalculations now put the risk of cardiovascular events with clinically relevant doses of muraglitazar at 20% higher than the placebo group, and at 67% higher than the combined placebo-standard of care group. (That includes patients treated with pioglitazone, a PPAR-gamma compound that's been approved for some years now). Put that way, this sounds like a huge increase, but it's important to remember that both of these figures, though real, are pretty small. The placebo group had about 34 events per 1000 patient years, and the drug treatment group, in the new analysis, had around 40 events. So, back-of-the-envelope, for every thousand patients on muraglitazar, you might expect an extra 6 cardiovascular incidents per year. The similarities to the Vioxx data are not hard to spot, and in fact the authors of this paper have been very much involved in that controversy as well.

But I'm not going to push that comparison. This is a different case than Vioxx, a drug that (for many patients) really does seem to do more than existing compounds can. The problem here is that muraglitazar (and all the PPAR alpha-gamma compounds that have gone into development) was supposed to be better for cardiovascular outcomes than the plain PPAR-gamma compounds that are already out there. Needless to say, it was also supposed to be better than a damned placebo, which it isn't. The entire dual-PPAR-agonist idea is in trouble. The whole point of adding PPAR-alpha activity was to improve blood lipid profiles, and pretty much the whole point of doing that is to improve cardiovascular health. The first part is working, but the second part, the important part, just doesn't seem to be happening. Looking at the data, I find it hard to imagine why anyone would take muraglitazar over the exisiting therapies, when there's no evidence for what is supposed to be its main advantage.

As if that weren't bad enough, there's also a background worry about cancer rates with PPAR compounds. The muraglitazar data aren't totally reassuring on this front, either. Other compounds in this class died because of carcinogenicity in long-term rodent studies, and muraglitazar is the first compound to actually make it past such studies. But the data submitted to the FDA show that rats given the compound at high doses do indeed show bladder cancer - it just seems to be less of a problem than it was for the earlier compounds from Merck, Kyorin, Novo, Dr. Reddy's, et al. For a marginal compound, though, this is a real issue.

I don't necessarily think that the people at BMS (and Merck, a latecomer to this compound) were sitting around wondering about just how to snow the FDA. But it would certainly cheer me up if I could rule that out, wouldn't it, now? At the very least, the companies weren't being as critical of themselves as scientists have to be, and they've committed a mistake that would flunk a PhD candidate or get a paper tossed back from a well-refereed journal. Something has gone seriously wrong here. We're supposed to be better than this.

What on Earth were they thinking, submitting data in a way that makes it look like they were trying to pull a fast one with the cardiovascular risk factors? Now, of all times? Who knows, maybe people at BMS had just convinced themselves that things were fine, somehow - the capacity for human self-deception is limitless. But didn't anyone at Merck turn pale and have to sit down when they saw these numbers? I didn't realize how bad the situation was back in September, but even then I wondered about this, saying: "I can't predict which way this one is going to go, and neither can anyone else. But post-COX-2 is a bad time to be coming to the FDA with possible low-level cardiac risks in your clinical data. . ." Now that the risks look even worse, I'm baffled. You people want the sky to come down on your heads?

Comments (6) + TrackBacks (0) | Category: Clinical Trials | Diabetes and Obesity | The Dark Side

May 3, 2005

Ghostly Influences

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Posted by Derek

Via Matthew Herper at Forbes, here's a real grit-your-teeth article on the ghostwriting of journal articles from inside my industry. Now, I know that this stuff has been going on for a long time in the medical world, and I know that it happens constantly with newspaper op-ed pieces. It's a growing trend/problem in the blog world, too, for that matter.

But all that doesn't mean that I have to approve of it, and I don't. This practice is not only wrong on the face of it, it's counterproductive. (I don't expect to convince anyone who needs convincing just by pointing out the ethical problems, you know.) The medical and scientific journals don't need any more junk in them than they have already, thanks very much. And the pharma industry doesn't need any more opportunities to be seen as a bunch of shady influence peddlers, either. We're already long that position pretty thoroughly, wouldn't you think?

Comments (5) + TrackBacks (0) | Category: The Dark Side

July 1, 2004

So What's Wrong With A Little Money Changing Hands?

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Posted by Derek

The marketing practices mentioned in the last posting sound a lot like radio-station payola - paying to get a song on the air. There was an interesting defense of this practice mounted recently over at Marginal Revolution (see the first three postings here.

Is there a difference in this case? (I mean, short of the "we're-talking-about-people's-lives-here" argument, which can be valid but ends things before you have a chance to do any potentially useful thinking.) I think there is, and it has to do with market efficiency.

Whether a song becomes a hit or not is based on a relatively quick aesthetic call by a large audience: "I like that." The pro-payola argument (or at least the non-anti-payola one!) is that you can't force a song to be a hit by paying for airplay - all you can do is pay enough to give it a chance to become one. There are historical examples of songs and artists that likely wouldn't have had a chance without someone opening their wallets.

But paying doctors to prescribe certain drugs is a different sort of market perturbation. For one thing, there's not such a good feedback mechanism as there is with listener choice. It takes a while before you can tell if most medications are working or not, days or weeks. And even then, it may not be apparent to the patient. Blood pressure therapies don't make you feel much different at all, even when they're lowering life-threatening hypertension. And most chemotherapy (to pick an extreme case) makes you feel absolutely worse, immediately and continuously, even if it's managing to put your cancer into remission.

And songs are more clearly differentiable, making their market more efficient. Listeners can pick out a new song by an established artist quickly, and if it's someone they've never heard before, they'll notice that, too. But the differences between, say, the different statins are more subtle. You won't feel your HDL increasing a bit more with one of them versus the other - heck, unless they look at a large statistical sample, physicians won't notice that, either. And there's the large question, in this case and others, of whether that real difference is enough to have a real clinical effect. No one's in doubt for very long about whether a song has accomplished what it's trying to do.

In radio payola, you're trying to seed a large market and hope that something will then take off through the free choice of the consumers. But who are the consumers in the prescription drug market? There are areas where direct-to-patient marketing works, in which case it's clear that the patients are regarded as the real consumer. The hope is that they'll storm their doctors offices clamoring for the latest therapy (much to the irritation of the doctors involved, I think!)

But in many other fields, it's the physician that's clearly the consumer and the target of advertising. Schering-Plough appears to have been paying for their interferon to be prescribed for hepatitis patients, among other things, and there's never been much (any?) direct-to-patient advertising there. One physician can write for a large number of patients, so the temptation for well-targeted payola is strong. And wrong.

Comments (14) + TrackBacks (0) | Category: Drug Prices | The Dark Side | Why Everyone Loves Us

June 28, 2004

No Defense

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Posted by Derek

In case anyone has me pegged as a reliable apologist for the pharmaceutical industry, I'd like to direct you to this article in the Sunday New York Times. It details marketing practices (in this case, from Schering-Plough) that, if reported accurately, amount to little more than programmatic bribery of physicians. I can't defend this stuff, nor do I want to.

I have a brief message for anyone involved in this kind of thing. We're having a rough enough time in the industry already, don't you think? As you're doing your job, ask yourself if your work is the sort of thing you'd care to have spread all over the business pages of the newspaper. It had better be.

Comments (7) + TrackBacks (0) | Category: The Dark Side | Why Everyone Loves Us

March 31, 2004

No Better Than the Rest of Them

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Posted by Derek

I noticed this post over at A Scientist's Life on some recent instances of retracted papers and scientific fraud. Those two phenomena aren't linked in every case, but they're often seen in each other's company. People do tend to think they're a couple.

The papers were from Science and Cell, two of the really top-shelf journals (links are at the blog above.) I suppose that makes sense, because there's really no point in faking your way into the Transactions of the Ruritanian Academy or something. It would be like counterfeiting nickles. Lou, the biology post-doc blogger, rightly says (with reference to the recent Jan Hendrik Schon case at Bell Labs):

"I've never thought about falsifying data. That goes against my education and belief as a scientist. Naive as it may be, I thought the whole point of science was to look for answers in what is already there - how nature works. I was about to state that it must be biological sciences, but physicists do it too...hey, where are the chemists then?"

Well, clearly, it's because we're too, ahem, upstanding and - haaarrgh - intrinsically honest to do anything of th-aaaackh. . .sorry, couldn't make it all the way to the end of that one. I second that thought about never thinking about faking data, of course, but much as it pains me, I can give some examples of fraud in the chemistry world. To start with, I'll reprise a post from a couple of years ago on my old site, which pointed readers to an article in the journal Synthesis (p. 29, 2002). That paper belongs to the select group of those whose sole purpose is to demolish another one.

The original, now discredited paper was in the same journal over a year before, presenting an interesting reaction that I thought we could make use of in my lab. We actually tried the chemistry out, but it flopped cleanly and completely, giving exactly the wrong product. I chalked it up to the weirdness of our compounds, which was not to be underestimated. Some things worked on them, and some just didn't. We poured the reaction into the red waste can and did something else, which is almost always an option in medicinal chemistry.

But the author of that reference I cite had the same thing happen to him, and he didn't take it as quietly. Going back over the original examples, he showed that the first published work wouldn't, didn't, and couldn't go the way it was reported. Some of the discrepencies could have been put in the "honest mistake" category, subheading "really sloppy honest mistakes," but it seems to me, in the end, that some of it couldn't. The editors of Synthesis seem to have agreed, and to their credit the criticism found its way quickly into print. The (single) author of the non-reproducible work is still listed, though, as a faculty member at the institution he published his paper from - if there have been any consequences of this affair, I haven't heard of them.

I'll dredge up some other examples in future posts. Many of them involve self-deception, at least at first. But as time goes on, the deception becomes contagious, as the originator of the suspect work realizes just how far out from shore he is. "Stepp'd in so far that, should I wade no more, Returning were as tedious as go o'er. . .", as it's put.

Comments (1) | Category: The Dark Side | The Scientific Literature

October 1, 2002

Silver Tongues, Golden Hands?

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Posted by Derek

I've been thinking more about Sam Waksal's interesting career (see the September 29 post below, and this link for an online version of the story - thanks to Charles Murtaugh for coming up with it.) What I'm specifically wondering about is the phenomenon of the silver-tongued hot-talking scientist that he represents.

Charles mentions that he's run across a few of these himself (and I'm pretty sure we overlap on a couple of them, research being the world that it is.) There's no doubt that in every scientific field, some people are better at creating a mystique, at getting other people to talk about them and their work. My question is: is there any correlation between the ability to do these things and the ability to do great science?

If you go Cartesian and map out four quadrants, you get these categories:

Fluent Talker and Really Good Scientist (the late Peter Medawar comes to mind here, but there are a number of examples)
Awkward Speaker but Really Good Scientist (even more examples - think about the various Big Cheeses you've heard giving seminars.)
Fluent Talker but Poor Scientist (Waksal and his ilk.)
Awkward Speaker and Poor Scientist (legion, unfortunately.)

I'm willing to hazard that if there's a correlation, that it's a slightly negative one. Scientific prowess and a gift for communication can be orthogonal to each other, because the results can speak for themselves (they don't, always, but if they hit at the right moment, they can.) Meanwhile, if someone does low-quality work, the only way for them to achieve recognition is to be able to talk a good game.

By the way, I'm simplifying here by classing written and spoken fluency as the same thing. They certainly aren't - Vladimir Nabokov, for example, said once that he thought like a genius, he wrote like a distinguished author, and he spoke like a child. (Which is why he never gave extemporaneous interviews!) I'd say that the spoken fluency is more important for making a big splash, the written more important for lasting impact.

That doesn't mean, of course, that you should give the next wonderful scientific speaker you hear a fishy glance of suspicion. Sometimes a person's verbal facility outruns their scientific ability, but they don't necessarily use it for harm. It's the BS artists that we have to watch out for - the ones who can spin out wonderful ideas and stories, and who always make sure to leave themselves a starring role.

Comments (0) + TrackBacks (0) | Category: The Dark Side

September 29, 2002

A Rake's Progress

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Posted by Derek

Friday's Wall Street Journal has an extraordinary front-page story on the career of Sam Waksal, late of Imclone. If you haven't heard, it turns out that at every stage in his research career, these pesky. . .questions arose, bred by these nagging. . .doubts that what he was saying about his work was true.

The reporter, Geeta Anand, has obviously done a tremendous job on this one. You can't help but think that the folks at Bristol-Meyers Squibb found it pretty damn interesting. Here's the short history:

1974: post-doc at Stanford with Leonard Herzenberg. Asked to leave after a story about obtaining antibodies from another lab doesn't check out.
1975-1977: National Cancer Institute. Not offered a permanent position because of "disturbing patterns" in his research.
1977-1982: Tufts (Cancer Research Center.) Draws suspicion (results not backed up by actual research, trouble delivering actual data when backed to the wall on it.) Asked to leave.
1982-1985: Mt. Sinai. Asked to leave suddenly under circumstances which are still sealed. Rumors of falsified data.
1985: Founds Imclone.

Quite a trail. The article spends time trying to figure out how someone like this could go on from position to position without anyone ever putting a stop to him. A number of reasons are aired (potential legal action waiting if you trash someone in a recommendation, e.g.) - but there's another factor that I don't think is mentioned. That is, the desire to get someone the heck out of your lab.

And the best way to do that is provide them with a recommendation that'll get them employed somewhere else, where they can be somebody else's problem. I've seen this in action several times myself - grad students who went off to post-doc positions with everyone breathing a sigh of relief that they were finally out the door, post-docs hired in because everyone at their old lab was greasing the skids to shoot them out of the place.

And I've seen one or two people who were Waksal-ish, in a small-time way. I actually heard a "my NMR spectra were stolen" story - like someone needs a stack of NMRs. (You can tell that that one is from the days before digitized spectra, can't you?) And one post-doc I knew of spent some time on a large natural product project before floating off to another lab, leaving a pile of spectral data that the next guy had to sit down and figure out before he could get started. After going through the whole pile (two hours of stony silence, broken only by swishing paper,) this unlucky fellow looked up and said "This is not a very funny joke."

There has to be something more that we can do about such people. Any ideas?

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