Scientific Misconduct, Version 4309

According to the Center for Science in the Public Interest:

A chemist in India plagiarized or falsified more than 70 research papers published in 25 research journals over three years, according to documents obtained by his university. An investigation by Sri Venkateswara University in Tirupati, India, found that chemistry professor Pattium Chiranjeevi from 2004 to 2007 published scores of papers that plagiarized other researchers’ work and lifted statements from his own previous articles... A spokesperson of Venkateswara University says that Chiranjeevi retains his teaching position but has been barred from research and from holding administrative positions. "The chemistry in most of his papers is illogical—the chemistry itself is wrong,” said the spokesperson. “How did this get past reviewers?"

Gee, peer review might have dropped the ball? No way!

Welfare Queens on Fiapta Demand Confidential Peer Reviews

I've been very neglectful in linking to a number of very interesting stories by my compadres in the blogging world. So here is a limited attempt to catch up:

• Pfizer wants to pry confidential peer reviews away from the New England Journal of Medicine. This is utterly ridiculous. Pfizer is facing a pile of lawsuits and is hoping that a peer reviewer might have said something nice about their products Bextra or Celebrex in a peer review, which they could then try to use as a legal defense. This reeks of desperation.
  
• PharmaGossip notes that AstraZeneca is out a cool $215 million for Medicaid drug price fraud in Alabama. Sheesh, and to hear certain politicians and talk show hosts decry the so-called "welfare queens" -- it would appear that AstraZeneca is the real welfare queen!
• Aubrey Blumsohn has a fine sarcastic bit on Fred Hassan. Meanwhile, the British Medical Journal advertising watch continues.
• Philip Dawdy lays down the smack on Judith Warner from the New York Times regarding overmedicated kids.
  
• And ex-GSK CEO Jean-Pierre Garnier is now officially delusional. He can't stand that his company is being judged by those meanies in the media, who seem to just ignore the science which proclaims that all GSK products are wonderful. Don't worry, Garnier is still a hero. .
• Atypical Antipsychotics notes that (whoopee), Vanda Pharmaceuticals has finally submitted its application for iloperidone. The best part is that, apparently drunker than a skunk, Vanda opted to name the drug "Fiapta", which is possibly the lamest name yet for a prescription drug. I've thought previously that this drug looks like a flop, and we'll see if I'm right... Note that an article published in 1995 stated that clinical trials for iloperidone were underway. It is now 2008 and I cannot find a single published clinical trial on the drug. Does that seem strange to anyone else?
  
• Daniel Carlat notes how Lilly concocted an article to put a smiley face on Cymbalta.
• The heparin/Chinese pigs/who needs supervision/high CEO pay with little accountability/yuck story is at Health Care Renewal. It's not a fun read, which is why you should check it out.
• Pharma Giles places his usual brand of sarcasm onto the new FDA guidelines that would allow drug companies to engage in off-label promotion under the guise of science.
  

Next week, expect a post on the ceaseless marketing of Effexor in which researchers (and "editorial assistants") used a combination of a very small advantage for Effexor over other drugs in combination with a "soft" endpoint to make the case that Effexor is so advantageous as to improve public health.

Peer Review, GSK, Cash, and Limp Noodles

Stephanie Saul has a quite interesting story in the New York Times about a peer-reviewer who really dropped the ball.

A key member of the Senate said Wednesday that a prominent diabetes expert leaked an unpublished and confidential medical journal article to GlaxoSmithKline last year, tipping the company to the imminent publication of safety questions involving the company’s diabetes drug Avandia.

The doctor, Steven M. Haffner of the University of Texas Health Science Center in San Antonio, faxed the article to the drug maker after agreeing to read it as part of the peer-review process for the New England Journal of Medicine, according to a statement Wednesday by Senator Charles E. Grassley...

An article on the matter that was published online Wednesday by the journal Nature quoted Dr. Haffner. “Why I sent it is a mystery,” the quote says. “I don’t really understand it. I wasn’t feeling well. It was bad judgment."

OK, I have to give Haffner credit for admitting his error. However, "I wasn't feeling well" -- not a great excuse. According to a GSK spokesperson, Haffner sent the article to GSK for "advice from experienced statisticians." The spokesperson denied that GSK provided any feedback to Haffner. Um, couldn't Haffner have found a statistician who did not work for GSK? As you might guess, this type of behavior is a no-no; the New England Journal of Medicine (as well as virtually all journals) has a policy where peer reviewers are not to share the content of papers under peer review with others.

Why did Haffner go to GSK? Well, here's one possible reason...

Dr. Haffner has previously disclosed that he has conducted research and served as a paid speaker for Glaxo. [Iowa Senator] Mr. Grassley said that Dr. Haffner had received $75,000 in consulting and speaking fees from GlaxoSmithKline since 1999

Maybe it was his relationship with GSK, maybe not. Haffner is apparently not a fan of medical journals, as can be seen in the quote below:

“The three major medical journals are becoming more like British tabloid newspapers — all they lack is a bare-chested woman on page 3,"

Apparently if they changed their peer review process to include submitting papers critical of industry for "objective" peer review by precisely the companies they are criticizing, that would help to de-tabloid the journals??

At the end of the article, Saul notes a case of limp noodle punishment for a similar violation...

Last year the New England Journal sanctioned another physician, Dr. Martin B. Leon, for commenting on a study before its publication. Dr. Leon, who was a reviewer of a journal article on the effectiveness of heart stents, disclosed at a medical conference that the study’s findings were negative before the article appeared. As a result, the journal barred Dr. Leon from reviewing articles for five years, and said he could not submit commentary for publication in the journal during that period.

Oh, THAT will teach him a lesson! He can't spend his free time reviewing articles for a journal. Ouch, that might leave a mark. And he can't publish an editorial for five years in one journal?? With hundreds of other journals to choose from, how will he survive? See some interesting comments on the Leon case here.

Hat Tip: Furious Seasons

Defending the Hiding of Negative Clinical Trial Data

In the wake of the New England Journal of Medicine study that revealed a sizable discrepancy between the raw data on antidepressants and the data published in medical journals, a few people have jumped to the defense of drug companies. In this post, I will examine their arguments and compare them with evidence. As an extra feature, the DrugWonks' disconcerting love of Vioxx will be discussed toward the end of the post.

"Nathan", who posts frequently on the excellent Pharmalot blog, made several comments. Here's one of them:

For those of you that haven’t written up a scientific article for publication, I’ll make you aware of a few things:
1) Journals don’t accept an article just because it is written. Journal editors scrutinize it and submit it to reviewers who further scrutinize it — very frequently rejecting articles that aren’t conclusive or are poorly written.
2) Scientists write scientific articles — not public relations representatives.
3) Scientists generally don’t waste weeks (or months) of their time writing up articles that don’t prove anything and probably won’t be accepted by the journal. A negative result is generally meaningless in science. Do you think Thomas Edison wrote up articles about the 900 filaments that failed to light a light bulb?

Now I’ll ask again: Is it any surprise that the negative clinical trials were not written up as publications?

Here’s one example: The Paxil trial may have tried doses of 10, 25, and 50 mg. The 10 and 25 mg dose failed to show an effect. The 50 mg dose did show an effect. Why should anyone waste their time writing up a journal article explaining why the 10 and 25 mg dose failed? It’s obvious that drug levels just weren’t high enough to observe an effect.

The problems with the above post:

1. Well, let's face it, peer review does not exactly catch everything. In fact, peer review often results in the publication of very poor studies, like the infamous Paxil Study 329. But it actually appears that Nathan's point is that studies that "aren't conclusive or are poorly written" don't get published. So is he saying that the positive studies of SSRIs were more likely to written better than studies that found negative results? Not sure that makes much sense. Perhaps he is implying that a negative study is not "conclusive" -- well, neither is a positive study, for that matter. When one considers the small benefit of antidepressants over placebo, then even positive studies have not exactly yielded conclusive evidence of anything particularly impressive.

2. Nathan is either naive on this point or is being dishonest. It is well known that ghostwriters are frequently used in the publication process (1, 2, 3, 4, 5). This is not a problem when they are just helping a poor writer piece together a readable manuscript, but this is often a huge problem when one considers that ghostwriters often have a huge conflict of interest in that they are hired by drug companies to pen papers that will paint their product in a favorable light.

3. "A negative result is meaningless in science." That is an amazing comment. Truly amazing. So if 10 trials are conducted on a drug, and one turns up positive, then I suppose everyone should prescribe that drug because the nine negative results were "meaningless." Yeah, that makes a lot of sense.

3.5. The point about dosing would make sense except that it is irrelevant to the case at hand. Remember, Nathan is commenting specifically on the antidepressant studies that did not get published, and he is hypothesizing that the authors of that study included doses that were not approved as effective. Perhaps he missed page 253 of the article, which states:

We included data pertaining only to doses later approved as safe and effective; data pertaining to unapproved dosages were excluded.

Oh, so the authors did not include data for unapproved doses. So much for that critique. Reading a study before offering critiques of it: A good idea.

Nathan in another comment:

I understand how this APPEARS to be a smoking gun. But I’ll state again why I believe it is not: Let’s say I do a clinical trial with Paxil at 10 mg (once per day), 20 mg (once per day), 20 mg (twice per day), and 50 mg (twice per day). That’s a total of 4 trials. Only the 50 mg dose works. Are the other three trials counted as “negative” evidence that the drug doesn’t work? Of course not.

See above for why this critique holds no water.

Nathan:

As Bob pointed out, editors like to accept articles that make their journal look good. NEJM is probably not going to accept a bunch of articles about clinical trials that didn’t work. That doesn’t mean the editors are in some sort of under-the-table deal with the company. It simply means that they are looking out for the best interest of the JOURNAL, not the public.

I think we’re all missing the point. Of course scientists like to publish things that work, not things that fail. The point is that ALL clinical trial data (the good, the bad, and the ugly) is available to the public, the FDA, and anyone else interested. Whether or not the data makes it into a journal is irrelevant.

All clinical trial data is available to the public? Cue the laugh track. Turn it up a little. No, a little more still. Ah, there we go. Who is he kidding? There is absolutely no such thing as a repository for clinical trial data. That is part of the reason why the problem with ghosted science exists in the first place. There are clinical trial registries, but go ahead and check out clinicaltrials.gov. One can outline a study on such a registry then report the results in whatever manner one deems fit, or not at all.

Enter the DrugWonks: And, as you would have guessed, the dependable, fair and balanced DrugWonks weighed in as well. Here are pieces of Robert Goldberg's post:

The NEJM of medicine recycles the old story that many of negative studies about antidepressants were not published. That doesn't affect whether the drugs work or not. It does add to the distortion of what a negative study is and why they are negative. Most of the time they are negative because they simply confirm the hypothesis. Other times they are poorly designed or small studies of little statistical power. They don't prove that the drugs fail. There is a difference. Taken together they can often help guide who responds to what medicines or why not...which again is why we need the Critical Path. To suggest that the failure to publish negative studies is part of a coverup is wrong and leads to fearmongering once again. We have been down this road. And journalists are once again raising unfounded fears about the safety and efficacy of drugs...leading people to die because they stop taking medicines because of the fearmongering the media has engaged in regarding vaccines, SSRIs, Avandia, Vioxx and Vytorin

As for the argument that studies were negative simply because their sample sizes were small, please read the following from the article (page 254):

The difference between the sample sizes for the published studies (median, 153 patients) and the unpublished studies (median, 146 patients) was neither large nor significant.

In other words, Goldberg's analysis is wrong. As I stated above: Reading a study before offering critiques of it: A good idea. As for "Most of the time they are negative because they simply confirm the hypothesis." -- What the hell does that mean? Confirm what hypothesis? This is the sort of seemingly random statement that I have run across frequently on the DrugWonks site. As for the negative studies being poorly designed (so the positive studies are thus designed better?), this seems wrong as well. These studies aren't particularly complex. One group gets drug, the other gets placebo. Participants are assigned to groups randomly. In theory, participants are unaware of if they are receiving drug or placebo. It appears that there were not large differences in how these studies were designed. In any case, Goldberg provides not one single shred of evidence to support his claims. Nathan, mentioned above, also provided no evidence to support his critiques of the NEJM study.

Bring on the Vioxx Love. Goldberg then goes to a new level. He wrote, in part:

And journalists are once again raising unfounded fears about the safety and efficacy of drugs...leading people to die because they stop taking medicines because of the fearmongering the media has engaged in regarding vaccines, SSRIs, Avandia, Vioxx and Vytorin

Let's just focus on one of these medicines: Vioxx. I should mention that as I type this, I am quaking with rage. Goldberg is either incredibly ignorant or incredibly dishonest. For a person who claims expertise in matters of drugs, he should know much better than this. He is claiming that people died because they stopped taking Vioxx. He is apparently serious. Lord Jesus, tell me that this man is joking... First of all, how many people have died because they switched from one minor painkiller to another? Bob, please provide the data. PLEASE.

But (and this is where the rage is coming from), Bob, since you are a Drug Wonk, which would imply at the very least a firm understanding of important and highly publicized findings from the medical literature, how many people died because they did take Vioxx? According to a study by David Graham and colleagues published in the Lancet:

Using the relative risks from the abovementioned randomised clinical trials and the background rates seen in NSAID risk studies, an estimated 88000–140000 excess cases of serious coronary heart disease probably occurred in the USA over the market-life of rofecoxib. [If even a third of these people died, well, you do the math...]

But taking this drug off the market resulted in people dying? Are you *!@! kidding me? Because Graham is a "fearmonger," one of the favorite epithets thrown around on the DrugWonks site, how about we not take his word for it... What have other researchers found? One meta-analysis found an increased risk for heart attacks with COX-2 inhibitors relative to placebo and to some other drugs. Another meta-analysis also found elevated heart attack risk for Vioxx. How about this meta-analysis, which found increased risk for both cardiovascular and renal events on Vioxx? Another meta-analysis found cardiovascular events were related to Vioxx use.

So, Bob, there's my evidence on Vioxx. Where's yours? It's clear that Bob and I differ on a number of points. I think reasonable people can disagree on many items, but Vioxx is not one of them. A drug that has been clearly and repeatedly linked to serious health problems -- and Bob is defending it, while calling those who criticize it "fearmongers." Nice game plan.

A More Reasonable Critique. The Last Psychiatrist offers a more reasonable analysis, suggesting that academic authors did not want to publish the negative studies because publishing negative studies would make them look incompetent -- the mainstream culture of medicine would ask who runs a trial and finds negative results? And even if the studies were submitted to a journal, then they were likely to be rejected by peer reviewers and editors.

This may be true to an extent, but I tend to believe that some negative studies would have been published. There have always been journal editors who have some ability to think critically and publish material that runs counter to that of mainstream medicine. Sure, some of the studies would have been rejected a time or two, but I think they would have been published at some point. While I think his analysis is intelligent (and it thankfully does not involve the term "fearmonger"), I think it only offers a partial explanation.

Missing the Boat. I could certainly have missed something, but I have not even seen a lame attempt to critique part of the study that is quite damning. Remember, the study found that drug companies changed their primary outcome measures and statistical analyses in between submitting to the FDA and submitting for journal publication. This resulted in inflated effect sizes for every antidepressant. Kind of a big deal, as the medical literature ends up suggesting the drugs are more beneficial than they actually are. Not even DrugWonks has mentioned this rather major point.

Oh, and one more thing for Bob Goldberg: Before engaging in a variety of tactics that border on slander regarding Roy Poses of Health Care Renewal (in a recent often nonsensical post that I won't honor by linking to it), you might want to improve your own credibility.

If you missed it, read my post about the NEJM study that some folks are now critiquing.

Peer Review Is Mediocre at Best

Regarding bias in "science" and the utter balderdash that passes for peer-reviewed science, I sometimes feel like a lone voice in the wilderness. Well, thank God -- another blogger has thrown down the gauntlet on the topic. The Last Psychiatrist has a great post on the topic in which he notes a few huge problems with medical journals, of which I'll highlight a few in upcoming posts. Let's start with peer review...

"Most people think peer review is some infallible system for evaluating knowledge. It's not. Here's what peer review does not do: it does not try to verify the accuracy of the content. They do not have access to the raw data. They don't re-run the statistical calculations to see if they're correct. They don't look up references to see if they are appropriate/accurate."

Couldn't agree more with the Last Psychiatrist. We just assume the raw data are accurate. Every study likely contains some small data entry or calculation errors, but what if the whole paper is based on a significant misrepresentation of the raw data? Wouldn't that be a, large problem? What is reported and what is not reported? To put it in layman's terms, anybody can make up whatever the hell they want, and the peer reviewers are under the assumption that it is true. We're working on the honor system here and who knows how often the final paper reflects the real data, or if we are dealing with undisclosed errors due to sloppiness, an accident, greed, or just wanting to cover up the bad news, like in the following...

There is no way that even the world's greatest peer reviewer would catch this, as without access to raw data, we're trusting that relevant information is presented in the manuscript. Reviewers might catch an obvious statistical error, but they sometimes miss the most blatant errors, such as a paper that makes an important conclusion based on no evidence whatsoever.

What do peer reviewers do?

Again, quoting from The Last Psychiatrist...

They look for study "importance" and "relevance." You know what that means? Nothing. It means four people think the article is important. Imagine your four doctor friends were exclusively responsible for deciding what you read in journals. Better example: imagine the four members of the current Administration "peer reviewed" news stories for the NY Times.

And what determines if they think an article is important? Their bias, hopefully mixed with some basic understanding of research methodology and statistics. In maintream psychiatry, you are raised to believe that meds are safe and effective and that newer meds are better than older ones. Is this based on evidence? Sometimes, but quite often it is based on marketing that would make a user car dealer proud. Peer reviewers are often somewhat of an echo chamber than reflects whatever hooey marketing is going on lately. For example, consider that many poorly done studies on second generation antipsychotics were featured prominently in journals -- the mainstream psychiatry culture was overflowing with excitement about heavily promoted new antipsychotic meds, to the point where peer reviewers were willing to gloss over the flawed studies (for example, often using a control group receiving an unreasonable dose of an older antipsychotic) -- and now we have these drugs selling at a clip of well over $10 billion annually in the U.S.

No, I'm not claiming I don't have my own bias. Duh. You can see the cards I'm holding pretty clearly if you read this site with much regularity. The point is that peer reviewers need to realize their bias and take a better, more objective look at research they are reviewing. Too many industry-cheerleading pieces in journals leads to uncritical acceptance of treatments that nearly always fail to live up to their initial hype. After all, after a few trials have been published (even if poorly done and/or overstating efficacy, understating risks), the drugs are now based on "science," which leads to yet more marketing. Check the actual track record of benzos, SSRIs, Depakote, and atypical antipsychotics if you doubt me. Each treatment "revolution" is closely linked to peer review. So if you are pleased as punch with the current state of affairs in mental health treatments, then please make sure to send letters to your favorite medical journal editors thanking them for the present system. Don't let it change.

Or maybe the whole system needs a fundamental overhaul. More on that later.

Promo Time. I'll take yet another lead from the LP and humbly suggest that you promote this post via Digg, Reddit, or any other favorite service. I'd even more strongly suggest you hit up the LP's post and promote it. While you're sharing posts with the world, you should you read my take on SSRI's, Suicide and Dunce Journalism and send it to all of your friends. And while I'm in promotion mode, give your money to Philip Dawdy if you like good journalism on mental health issues. If you want to pledge money to support the operations of this unpaid anonymous blogger (and you know you do!), thanks, but take it and give it to Philip. Now!