Misconduct: Where are the Consequences?

A story on Bloomberg starts as follows:

James C. Vestal, a Texas urologist, exposed his patients to ``unnecessary risk'' and ``submitted false information in required reports'' during the clinical trial of a prostate cancer drug, according to the U.S. Food and Drug Administration. The agency's drug division ``believes that you repeatedly or deliberately violated regulations governing the proper conduct of clinical studies,'' the FDA said in a letter to Vestal. ``Accordingly, FDA proposes that you be disqualified as a clinical investigator.'' The FDA didn't send the letter starting disciplinary action against Vestal until May 2007, more than three years after his violations of agency rules were detailed in reports by the FDA's own staff investigators. Vestal continued to conduct drug trials as recently as last year, as he was permitted to do. He has stopped voluntarily while negotiating with the FDA on his case. The agency has failed to complete disciplinary action against 12 researchers, including Vestal, after proposing that they be disqualified from trials based on findings that they violated rules designed to protect patients and ensure accurate data, FDA records show. Cases have remained unresolved for as long as a decade.

Read the whole piece. Regular readers will be angered, but not surprised. David Linden has sex with patients along with other transgressions and gets a slap with a limp noodle. And if you think Linden's record is frightening, check out that of Dr. Louis Fabre (1, 2). Whether it is serious scientific misconduct, high-level sexual misconduct, or whatever else, the penalty is the same -- a slap on the wrist at most. So expect more of the same.

P.S. My post on Effexor is developing quite slowly. I hope to have it up next week.

Nominee for Career Achievement Award: Dr. David Linden

Remember him? The guy who gave herpes to two patients and lost his license for three months as a result (pretty stiff penalty, eh?). According to KLAS TV in Las Vegas, he was recently arrested for allegedly passing bad checks at a casino. To quote the news story:

The District Attorney is charging Linden with passing $300,000 worth of bad checks at three local casinos. According to the complaint, $150,000 in bad checks were passed at the Las Vegas Hilton, $100,000 at Caesars Palace and $50,000 at the Hard Rock.

I had wondered previously why only his Oklahoma license was suspended after he had sexual relations with two patients -- why not his Nevada license? Apparently, his Nevada license was put on probation, meaning he could still practice medicine. Apparently, Nevada is serious about defending its reputation as the state where anything goes. His track record of conducting psychiatric clinical trials is impressive for its violations of several FDA regulations. Giving herpes to patients is quite an accomplishment as well; not many physicians can match that claim to fame. As I noted earlier, Linden has run clinical trials for a wide variety of large drug firms. As long as you can recruit patients, who cares what actually happens to them during the clinical trials?

For the above list of accomplishments, I hereby nominate Dr. Linden for a Career Achievement Award. Even if he is not guilty of the present check fraud charges, I still believe he is a worthy nominee based on prior accolades and accomplishments.

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!

Antidepressants: Meet the New News, Same as the Old News

A recent meta-analysis from Irving Kirsch and colleagues (available here in PLoS Medicine) indicated that for the great majority of depressed people, the advantage of antidepressants over placebo was small. No kidding. For the most part, this study actually says nothing new. In fact, the same authors did a very similar study not once, but twice, showing that antidepressants were mostly hype (1, 2). So we've known for years that there is a good deal of publication bias (i.e., burying negative results) and that the difference between antidepressants and placebos is quite modest. Wait, you didn't know that? Ah, therein lies the problem. News such as this survives for one to two media cycles then vanishes, as the media attends to more important matters, such as Britney's latest bout of trouble, who won an Oscar, and the like. I mean no disrespect to Kirsch and his colleagues -- their work is tremendously important -- but shouldn't the media make damn sure that the public is aware that the collection of published and unpublished data from clinical trials indicates that antidepressants give only a small benefit over placebo? Or should we learn more about K-Fed, Michael Jackson, and various other trivia?

Note that there is, indeed, a small benefit for drug over placebo. Is the small benefit worth the side effects? Well, that's a different question... An even better question is "Please define the term 'small benefit'..." The benefits for medication over placebo appear to be an underwhelming 1.8 points on the Hamilton Depression Rating Scale. Considering that it is a 52-point scale, with many of those points being determined by ratings of sleep and anxiety, any advantage for a drug relative to a placebo might be unrelated to the core symptoms of depression.

What this study adds is that the most severely depressed patients appear to show somewhat more benefit on antidepressants relative to placebo. Their analyses indicate that the placebo response tends to decline among the most severe cases of depression while the antidepressant effect remains about the same. But most people who take antidepressants are not severely depressed. And, shock of all shocks, Kirsch and colleagues found that data from some trials showing no advantage for drug over placebo were simply not available.

Warning: This paragraph is a bit wonky, so you might want to skip ahead. The authors adopted a standard that anything under an effect size of .50 is not clinically significant, which is a standard adopted by the National Institute of Clinical Excellence (NICE) in the UK. According to conventional criteria (e.g., Cohen), an effect size of .50 translates to a moderate effect and an effect size of .20 translates into a small effect. The average effect in this analysis for drug over placebo was .32. Such an effect is certainly not impressive, but should not be confused with no effect. The problem (as noted above) is we don't really know what a small effect means -- on what items on the rating scale was there typically a difference between drug and placebo? Were these items relevant to depression? In any individual study, one can cherry pick items from a rating scale and show a difference favoring a drug, but I'd be more interested in what a large meta-analysis such as Kirsch's most recent study would show on the individual items of the HAM-D or other rating scales. One more thing: The effect for antidepressants really looks bad at the lowest end of severity. Go to Table 1 in the study and look at the effect sizes for the studies where the baseline depression rating is under 24. My own back of the envelope calculations, factoring in sample size, gives an effect size of about .10, which equates to about nothing for the least depressed folks.

Fortunately, the Independent has a nice little story on the topic, though the headline is a little obnoxious. I quote as follows:

Alternative treatments for depression, such as counselling or physical exercise, should be tried first, Professor Kirsch said. The pharmaceutical companies had withheld data that was available to the licensing authorities so that doctors and patients did not understand the true efficacy, or lack of it, of the drugs.

"This has been the frustration. It has made it very difficult to answer the question of whether the drugs work. The pharmaceutical companies should be obliged when they get a drug licensed to make all the data available to the public. When you analyse all the trials of these SSRIs, both published and unpublished, it leads you to more sober conclusions," he said.

Tim Kendall, deputy director of the Royal College of Psychiatrists' research unit, said the findings, if proved true, would not be surprising. As head of the National Collaborating Centre for Nice guidelines on mental health, he said it had proved impossible to get access to unpublished trials in the past.

"The companies have this data but they will not release it. When we were drawing up the guidelines on prescribing antidepressants to children [in 2004] we wrote to all the companies asking for it but they said no. The Government pledged in its manifesto to compel the drug companies to give access to their data but that commitment has not been met."

But, to be fair and balanced, here are the critiques of the pharma companies, which provide the usual nonspecific and bogus mumbo-jumbo

GlaxoSmithKline, makers of Seroxat, said the authors of the study had "failed to acknowledge" the very positive benefits of SSRIs and their conclusions were "at odds with the very positive benefits seen in actual clinical practice." A spokesperson added: "This one study should not be used to cause unnecessary alarm for patients."

Lilly said in a statement: "Extensive scientific and medical experience has demonstrated that fluoxetine [Prozac] is an effective antidepressant.

Wyeth said: "We recognise the need for both pharmacological and non-pharmacological treatments for depression."

If there is such "extensive" evidence about the "very positive" effects of these medications, why wouldn't a single one of these companies cite a single study? Oh, right, because Kirsch already examined the relevant studies. This study, in combination with the recent study in the New England Journal of Medicine that showed how every single drug company with an antidepressant on the market twisted their data regarding the efficacy of antidepressants, should serve as a wakeup call for those who have not been paying attention to the issues of mediocre antidepressant efficacy and how inconvenient data are buried. Overplay the positive data, hide or lie about the negative data. As for depressed patients: Let Them Eat Prozac.

Also see discussion at Furious Seasons.

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.

American Psychological Association: A Wink and Nod Toward Torture?

I've monitored the issue of psychologist involvement in torture on and off for the last few years. Honestly, if I wasn't spending my spare time writing this blog, I'd probably be following the issue much more closely. The American Psychological Association, easily the largest organization of psychologists in the nation, has never really forbidden its members from participating in some practices that many would consider to be tantamount to torture. Sound strange to you?

I'd like to write in more detail on the topic, but a group of concerned professionals is far ahead of me on the issue, so I'll refer you to a couple of spots:

• Stephen Soldz's blog; in particular, this list is instructive.
  
• A document that examines in depth what appear to be some tricky moves on the part of the APA to give a wink and nod to some of its military members that participation in some forms of, um, "enhanced interrogation" might be okay.

I've only followed the issue sporadically, unfortunately, but the evidence I've seen lends much credence to the position of those who claim that APA is unwilling to take a strong moral stand on this issue.

Keep this in mind -- this post is not meant in a disrespectful manner toward psychologists serving in the military. Providing mental health services to members of the military is laudable. Engaging in torture, however, is not acceptable professional behavior, regardless of what the APA might think. The good majority of psychologists are ethical professionals who would not engage in torture, but when you place a decent human being in a situation where he/she is expected to engage in ethically dubious behavior, then all bets are off.

Hat Tip: Mind Hacks.

Medical Bribery: We Want Details

When drug companies provide kickbacks and bribes to physicians, they sometimes make the news for a brief spin around the news cycle, followed by shock when the same thing happens again a few news cycles later. But the point of this post is not to describe the amnesia that has befallen the media, but to wonder why nobody calls out the recipients of such lucre.

To give credit where it is certainly due, Health Care Renewal and some other blogs keep a close on such behavior. But my take is that the occasional sense of outrage regarding bribes, kickbacks, and other goodies tends to be shoved nearly entirely in the direction of the drug/medical device industry. Don't get me wrong -- they deserve some serious blame and shame, but if physicians wouldn't take the enticements, then there would be no problem to begin with. As the hackneyed phrase goes, it takes two to tango.

And these legal deals work out great. Merck or Bristol-Myers Squibb or whomever can simply settle the claims with the feds, pay out a sh*tload of cash, but admit no wrongdoing. And the doctors who were bribed -- we rarely know much about them. They seem to get a free pass. Yet when we catch an occasional whiff of what these doctors are up to, it is quite telling.

To quote from my post in May 2007 (which I humbly suggest that you should read in its entirety)...

"Anya’s doctor, George Realmuto gave several educational marketing speeches for Concerta, manufactured by Johnson & Johnson, which also makes Risperdal. He had the following to say (and I hope he was misquoted) when asked about why he gives marketing speeches for drugs.

“To the extent that a drug is useful, I want to be seen as a leader in my specialty and that I was involved in a scientific study,” he said. [i.e. I wanna be a key opinion leader???]

The money is nice, too, he said. Dr. Realmuto’s university salary is $196,310. “Academics don’t get paid very much,” he said. “If I was an entertainer, I think I would certainly do a lot better.”

Hey, can someone fetch me the Kleenex? Making $196,310 per year is a sign that he does not “get paid very much.” Cry me a river. In-blanking-credible."

And I'm just referencing legalized bribery, the kind where docs take cash to become product spokespersons. It would be quite tantalizing if we actually had a better idea of what, exactly, these bribes and kickbacks entailed. Yeah, we know that drug companies blatantly buy off some doctors in developing countries, providing cars, air conditioners, cameras and a wide variety of other products. We also know that drug companies must be a bit more subtle in how they bribe doctors in the so-called developed world. Sure, we have the vacations disguised as "educational meetings", the speaking engagements, seeding trials, and the like -- dressing up bribery as a form of education and/or research. Please feel free to add a few more tricks of the trade in the comments section. I've hit my limit for press releases which mention legal settlements and bribing doctors, yet fail to mention what "bribing" actually means.

Andorra Ain't In Africa?

Nation Of Andorra Not In Africa, Shocked U.S. State Dept. Reports

Why I Love the Discussion Section

A recent study in the Journal of Clinical Psychopharmacology found that aripiprazole (Abilify) offered no benefit over placebo in treating biploar depression. Well, at least that's what the results showed, but the discussion section told a bit of a different story. At the end of eight weeks, Abilify failed to beat placebo on either the Montgomery-Asberg Depression Rating Scale or the Clinical Global Impressions -- Bipolar Severity of Illness Scale.

It is rare that an industry-sponsored article reports negative results and it would be nigh-impossible to find a published industry-sponsored study that failed to put a happy spin on the negative results. Sure, the results were negative in this study, but if the dosing was different, the treatment could have worked. There's always a loophole, some possibility that results would have been dandy if something were different. Check this out:

It is possible that the dosing regimen used in the current studies may have been too high for this patient group, or that titration was too rapid. Specifically, the unexpectedly high rates of discontinuation caused by any reason or because of AEs suggest that the aripiprazole starting dose (10 mg/d) may have been too high and that the dose titration (weekly adjustments in 5-mg increments according to clinical response and tolerability) may have been too rapid...

However, because preliminary data indicate that aripiprazole may have a potential value as adjunctive therapy in patients with bipolar depression, future studies that focus on the use of aripiprazole as adjunctive therapy using a better-tolerated dosing schedule with a more conservative escalation may be of greater value for the treatment of patients with bipolar depression...

And my favorite part...

Although the improvements in MADRS total scores in the current aripiprazole studies did not separate statistically significantly from placebo at end point, the significant effects observed with aripiprazole monotherapy within the first 6 weeks are clinically meaningful and similar to the effects seen with olanzapine monotherapy and lamotrigine monotherapy in patients with bipolar depression.

OK, so the argument is that while treatment did not work at the end of 8 weeks, the effects after 6 weeks were really super-duper impressive. Gimme a break. The authors did not present the actual numbers on the MADRS (the primary manner in which depression was assessed); rather, the data were presented in figures. Um, isn't science supposed to be based on numbers -- shouldn't they be provided in the text of the paper? At 6 weeks, the difference in scores between Abilify and placebo looks to be a little more than 2 points on the MADRS, a rating scale that spans from 0 to 60. And if a drug makes a person 2 points better relative to placebo, then the findings are "clinically meaningful"? Keep lowering that bar, fellas. While the discussion reaches out to rescue the reputation of Abilify, it does (to be fair), also point out on a couple occasions that Abilify was not particularly efficacious at the end of 8 weeks and was related to a worse safety/tolerability profile than placebo. In fact, relative to some other studies I've dissed regarding their sunny presentation of unimpressive results (like this one), the current Abilify article is a model of fair discussion.

Side note: Akathisia was reported by about a quarter of patients taking Abilify. The funny thing about akathisia is that it is not well-defined in this study or in many others. Is it a problem with movements, mental tension, something else, or what? It would seem important to know, given that Abilify apparently causes akathisia in droves. Do a Pubmed search for aripiprazole and akathisia and you'll see what I mean. A couple descriptions of akathisia follow:

• Increased tenseness, restlessness, insomnia and a feeling of being very uncomfortable
• On the first day of treatment he reacted with marked anxiety and weepiness, on the second day felt so terrible with such marked panic at night that the medication was cancelled
• Another: A movement disorder characterized by a feeling of inner restlessness and a compelling need to be in constant motion as well as by actions such as rocking while standing or sitting, lifting the feet as if marching on the spot and crossing and uncrossing the legs while sitting. People with akathisia are unable to sit or keep still, complain of restlessness, fidget, rock from foot to foot, and pace.

Key Opinion Leaders and Information Laundering: The Case of Paxil

Joseph Glenmullen’s testimony regarding GlaxoSmithKline’s burial of suicide data related to Paxil, which was discussed briefly across the blogosphere last week (Pharmalot, Furious Seasons, for example), was quite interesting in many respects.

One important aspect that needs public airing is how key opinion leaders in psychiatry were used by GSK to help allay fears that Paxil might induce suicidal thoughts and/or behaviors. When GSK issues statements indicating that Paxil is not linked to increased suicide risk, many people will think “Gee, of course GSK will say Paxil is not linked to suicide – it’s their product, after all.” But when purportedly independent academic researchers make the same claims regarding the alleged safety of Paxil, then people tend to think “Well, if these big-name researchers say it’s safe, then I suppose that there’s no risk.” But what if GSK simply hands these big-name researchers (aka “key opinion leaders") charts with data, and then the “independent” researchers go about stating that Paxil is safe? Mind you, the researchers in question don’t see the actual raw data – just tables handed to them from GSK – in other words, they simply take GSK’s word that the data is accurate. In essence, these researchers are serving as information conduits for GSK.

But wait a second, what if the charts and data tables handed to them by GSK are not an accurate representation of the raw data; what if GSK is lying? Well, of course, it turns out that GSK was lying in a big way for several years. This post will not go into depth on the suicide data, as it has been covered elsewhere (1, 2, 3 ) -- even GSK now admits that Paxil is related to an increased risk of suicidality.

My main question in this post is how we are supposed to trust our "key opinion leaders" in psychiatry if they are willing to simply look at data tables from GSK (and others), then make pronouncements regarding the benefits and safety of medication without ever examining the raw data. To put this in layman's terms, suppose an election occurs and candidate A wins 70% of votes while candidate B wins 30% of votes. As the vote counter, I then rig the results to say that candidate B won the election by a 55% to 45% margin. Suppose that the election certification board shows up later and I show them a spreadsheet that I created which backs up my 55% vote tally for candidate A. The election board is satisfied and walks away, not knowing that the vote counting was a sham. Obviously, the election board should have checked the ballots (the raw data) rather than simply examining the spreadsheet (the data table). In much the same way, these so-called thought leaders in psychiatry should have checked the raw data before issuing statements about Paxil.

What did these key opinion leaders say about Paxil? Some quotes from Glenmullen's testimony follows, based upon documents he obtained in GSK's archive. Here's what David Dunner (University of Washington) and Geoffrey Dunbar (of GSK) reportedly said at a conference

Suicides and suicide attempts occurred less frequently with Paxil than with either placebo or active controls.

John Mann of Columbia University, regarding how data were collected:

We spent quite a bit of time gathering data from various drug companies and formulating it into the publication of the committee's findings

The committee he references is a committee from the American College of Neuropsychopharmacology, the same organization that issued a dubious report blessing the use of antidepressants in kids.

More from Mann, after being asked if he saw raw data or just data summarized in tables:

To be perfectly honest, I can't recall how much of the statistical raw data we received at the time that we put these numbers together...No, I think we all went through the tables of data that were provided at the time.

To use the analogy from above, the election board did not actually see the ballots. Stuart Montgomery is next. He was an author, along with Dunner and Dunbar, on a paper in the journal European Neuropsychopharmacology that stated:

Consistent reduction in suicides, attempted suicides, and suicidal thoughts, and protection against emergent suicidal thoughts suggest that Paxil has advantages in treating the potentially suicidal client.

Did Dunner see any raw data?

Dunner: I didn't see the raw data in the case report forms. I did see the tables. I work with the tables. The tables came before any draft, as I recall. We -- we created the paper from the tables.

Attorney: And -- and you never questioned, did you, or did you not question the validity of the data in Table 8?

Dunner: No

The above-mentioned paper that gave a clean slate to Paxil? According to a GSK document examined by Glenmullen, it was used by GSK to help convince physicians that they need not worry about Paxil inducing suicidality.

If you are an academic researcher, and you simply take data tables from drug companies then reproduce them in a report and/or publication, you are not doing research -- you are laundering information. People think that you have closely examined the data, but you have not, and you are thus doing the public a disservice.

I am unaware of any of the above researchers ever issuing a public apology. I can respect the context of the times; researchers may not have been aware of how pharmaceutical companies fool around with data in the early 90's. So if anyone wants to issue a mea culpa, I'd respect such an apology, but I have a feeling that not a single one of the above named individuals (nor this guy) will make an apology. Instead, it will be more business as usual, as these key opinion leaders, knowing who butters their bread, will continue to launder information and tell the public that everything will be fine and dandy if they just take their Paxil, Seroquel, or whatever hot drug of the moment is burning up the sales charts.

Today's Teachers Tackle The Tough Issues

You'd think this was from The Onion, but no, it is from the latest edition of American Teacher, the official publication of the American Federation of Teachers. Check out the above link to see it in all of its glory.

Where do the presidential candidates stand on this pressing issue? Believe it or not, I will try to write on a more important issue than the Great Water Bottle Debate of '08 tomorrow.

Go To Furious Seasons

Philip Dawdy has written many interesting posts of late and I encourage everyone to read his blog religiously while I take some time to attend to my paying job. My fave post is about the Lilly email fiasco -- that's truly hilarious.

Mood Stablizers and Suicide

As reported on Pharmalot and Furious Seasons, the antiepileptic/"mood stabilizer" class of drugs has been stuck with a suicide warning by the FDA. Granted, the FDA wasn't exactly quick to come to their conclusion -- these drugs have been on the market for quite some time, but better late than never. Others have noted similar concerns prior to the FDA's interest in the topic. Hey, does this remind anyone else of the SSRI-suicide story (1, 2, 3, 4, 5, 6, 7, 8)?

But wait a minute, aren't these supposed to be "life saving" medications? Wait, I can hear it coming now... Drug Wonks and others with similar views will be complaining that because the FDA is irresponsibly "fearmongering," people will stop taking their life saving medications and masses of suicide will ensue.

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

Fred Hassan's Hindquarters: Meet Peter Rost's Boot

Schering-Plough CEO Fred Hassan gets served (link contains adult language) by Peter Rost. Badly. While Hassan has been hailed as some sort of genius by some in past years, Rost offers a take on his record that is much less flattering. Here's Rost's lead-in to the story:

In this article BrandweekNRX will take you behind the glossy numbers and show you what really happened during Hassan’s tenure as CEO of two major drug companies and how he managed to fool almost everyone into thinking he had created successful turn-arounds.

Gee, Peter, that's not very nice. Then again, neither is this:

And that’s not all--there is also evidence that a significant part of Pharmacia sales were based upon selling drugs to its wholesalers ahead of demand, “stuffing the channels,” resulting in revenue of $500 million from such sales.

It just gets even more intriguing from there. I've not posted on the Schering-Plough sinking ship until now, but I've been watching the story, which just keeps looking worse for the company. I thank Rost for keeping a close eye on this saga and look forward to reading more about it at Brandweek.

The Serotonin Monster Strikes Again

Last Halloween, I discussed the legendary Serotonin Monster, that is, the alleged chemical imbalance that causes depression, anxiety, aggression, and God only knows what else. I ranted briefly and referred interested readers to an excellent article in PLoS Medicine from Jeffrey Lacasse and Jon Leo.

Turns out that Leo and Lacasse are still on the case of the Serotonin Monster. They have a newer article, recently published in the journal Society, that sheds further light on this mysterious creature. The full text of the article is freely available online; I encourage everyone to read it. They are concerned that most people get their information from magazines or newspapers, which they believe presents the overly simplistic "chemical imbalance" theory of depression as if it were based on solid science. Here's what they did to investigate how the media presented such theories:

To determine the evidence behind the media’s claims about chemical imbalances, for approximately 1 year we performed weekly Internet searches of the media for “chemical imbalances” and sent e-mails to the authors asking them for the evidence they were basing their statements on.

Can you guess their results? I bet you can. Think for a minute. OK, here's one example of what they found:

In an article for the Sacramento Bee (3/9/07), about how to handle teenagers with depression, the author states: “Act promptly and accept that they may have a chemical imbalance [italics added] or need help with coping skills.”In reply to our questions, the author mentioned that: psychiatrists would be the best people to talk with about chemical imbalances; mental illnesses have been linked to chemical imbalances; psychiatrists are trained to figure this out through a variety of tests; and that “numerous studies have been done” and “the research is definitely available.” We pointed out to her that, if there are “numerous studies” which are “definitely available,” then it should be relatively easy to cite at least one article. She did not reply. We also mailed a copy of our e-mails to an editor at the Sacramento Bee.

Another example:

In another New York Times article (6/19/07), “On the Horizon, Personalized Depression Drugs,” Richard Friedman, the chairman of psychopharmacology at the Weill Cornell Medical College, stated: “For example, some depressedpatients who have abnormally low levels of serotonin respond to SSRIs, which relieve depression, in part, by flooding the brain with serotonin.” For his evidence he supplied a 2000 paper by Nestler titled, “Neurobiology of Depression,” which focuses on the hypothalamic pituitary system but not on serotonin.

One more:

The Bradenton Herald (3/24/07), published an article entitled, “Seniors Sought for Depression Study.” The primary source for the article was Dr. Andrew Cutler, the director of the Florida Clinical Research Center, who is extensively quoted and referred to by the reporter. “True depression,” Cutler says, “has its roots in a chemical imbalance in the brain.” Neither the reporter nor Dr. Cutler replied to e-mails.

Sidebar: Dr. Cutler. Andrew Cutler has appeared previously on this site.

• One was about a misleading statement he made when stumping for Seroquel. He spoke of a Seroquel trial having several advantageous features, including its inclusion of Bipolar II patients. The problem, however, that was unacknowledged by Dr. Cutler, was that Seroquel was no better than a placebo for this group of patients.
  
• I think that if a researcher makes a statement that "true depression has its roots in a chemical imbalance in the brain," that researcher should respond to emails asking him to back up his argument.
  
• I also found it curious that he noted that he keeps his placebo response low when running clinical trials. Some of his patient recruitment practices also raised potential ethical questions, at least in my mind. These were just questions -- I'm not saying what he was doing was either right or wrong.
• Standard disclaimer: For all I know, Cutler is a great guy. I am not issuing a personal attack here -- Just noticing a few things that raised questions for me.
  

Back to the Article. In the piece, there were several other examples of bogus claims about chemical imbalances in the media. In not a single instance was a journalist able to drum up convincing evidence to support the claims regarding a serotonin deficit. Here are some questions for the media to ponder...

Considering the media’s inability, or unwillingness, to cite evidence in support of their own statements, can the same group really be expected to go one step further and actively investigate these issues? The solution is not simply for the media to modify, or tone down, their own statements about the chemical imbalance theory, but is for them to take a more analytical approach with those who promote the chemical theory as ineluctable truth. In other words, rather than us questioning the media, shouldn’t the media be doing the questioning? It’s almost as if these reporters are blinded by the term, “peer reviewed,” and operate under the mistaken assumption that the words are some sort of stamp declaring that the results are unquestionable and that they can check their skeptical radars at the door when given a press-release mentioning a peer-reviewed article.

The article then mentions that Pfizer tried to pimp the chemical imbalance theory to a reporter who was interested in Lacasse and Leo's prior investigation. To encourage my audience to read the article, I won't discuss it here, but will mention that Leo and Lacasse's dissection of Pfizer's evidence is intriguing, as it involves conflicts of interest, buried data, and other such tricks that have been discussed often on this blog.

Enter Judith Miller. As I was reading this article, I had thoughts of Judy Miller, so I was apparently on the same wavelength as the authors when they wrote toward the end of their paper:

A comparison of the media’s reporting about mental illness to the biased reporting in the New York Times about the events leading up to the Iraq War does not seem far-fetched. In hindsight, as the Times editors now acknowledge, Judith Miller’s war coverage was overly one-sided. Her fundamental flaw could be described as a lack of professional skepticism toward the Bush administration, as she willingly parroted what those pushing for war were saying, while giving little credence to the stance of the other side. Writing in the New York Review of Books, Michael Massing commented that the Times and Miller’s reporting were examples of media “submissiveness.”

This depiction could just as well apply to the media’s reporting of mental health issues. As just one example, in some cases, the media still go to the people responsible for the original problems. For instance, several of the researchers involved with the studies of SSRIs in children are still cited in the press even though the following information has come out about their published studies: they downplayed the suicide risk; they exaggerated the benefits; and the papers published under their names were actually written by ghostwriters paid by the pharmaceutical industry.

Indeed, SSRIs for child/adolescent depression will make fodder for the ages; the role of key opinion leaders/leading lights in child psyshciatry as either "dupes" or willing co-conspirators should be read by EVERYONE (1, 2, 3, 4, 5).

In sum, another nice piece of work from Leo and Lacasse. I understand that being a journalist is not an easy job. Essentially, one is tasked with writing on a wide variety of topics, generally outside of one's areas of expertise. Thus, journalists must rely on their sources, but at the same time, it is quite important that journalists do more than simply accept whatever their sources tell them without any sort of thoughtful evaluation.

Bribing Physicians: Where My Money At?

An utterly fascinating article in the Wall Street Journal by Vanessa Fuhrmans notes that insurers are moving to bribe doctors for prescribing generics. Snippet below, but you really should read the whole article.

Health plans are drawing scrutiny for offering financial incentives to entice doctors to prescribe cheaper generic medicines, including paying doctors $100 each time they switch a patient from a brand-name drug.

Pharmaceutical companies have long gone to great lengths to try to get doctors to prescribe their brand-name pills. They spend billions of dollars, plying physicians with samples, educational lunches and speaker fees. But as the patents for a growing number of blockbuster medicines expire, some health insurers are trying to trump those perks with bonuses or higher reimbursements for writing more generic prescriptions.

The idea, health plans say, is to save everyone -- patients, employers and insurers -- money. And many doctors argue that it's only right to reimburse them for spending time evaluating whether a cheaper generic alternative is better or as good for a patient.

But the more aggressive approaches, such as cash rewards for each patient switched from a given list of drugs, are coming under fire for injecting financial incentives into what some patient advocates and legislators say should be a purely medical decision. Medical societies are also concerned that such rewards may put doctors in the ethically questionable position of taking a payment that patients know nothing about.

There is little doubt that many newer medications offer little to no benefit over generics and this site and others have frequently noted that prescription practices often appear quite irrational. In psychiatry, for example, the movement to place everyone on Depakote and/or atypical antipsychotics for treating bipolar disorder was a marketing miracle considering that the evidence base never showed superior efficacy relative to lithium. The same story goes for treating schizophrenia with atypical antipsychotics over conventional antipsychotics (as well as ignoring psychosocial interventions) based on a set of obviously flawed studies. Or treating depression with newer antidepressants rather than generics or (especially) with psychotherapy, which is generally linked to better long-term outcomes.

Of course, as has been documented here and many other places, we know that Big Pharma utilizes a variety of methods to ensure that physicians prescribe newer drugs, even if such prescriptions are irrational. If we just consider this as a battle of mega-industries who want to maximize their profits (Pharma vs. Insurance), then maybe this is the unfettered free market at its best?

On one hand, we have Pharma using a variety of tricks, including: buying meals, providing all sorts of gifts, infomercials disguised as medical education, tricky statistics, burying negative findings, and just being sooooo good looking, and on the other we now have insurers providing kickbacks to doctors for prescribing generics. Both pharma and insurers are attempting to influence prescribing through methods far outside of providing objective medical information to physicians. I know that some favor a pure free market approach and if so, then I suppose that this is just the latest and greatest maneuver in which companies attempt to pimp their wares (Pharma) or buy physician loyalty to a different set of products (Insurers).

As for the patients, um, who is looking out for their interests? I realize that physicians genuinely want their patients to improve (well, maybe not this one), but is a system of competing interests trying to irrationally manipulate physicians' prescribing practices really the best way to ensure patient wellness?

By the way, how much $$$ could insurers save? See below.

Hat Tip: PharmaGossip

To sum up the current state of affairs in four words: Dolla Dolla Bill Y'All

My Political Leanings Are Out in the Open (Sort of)

As noted on the Scientific Misconduct Blog and PharmaGossip, there is an online test available (the Political Compass) that claims to measure one's political leanings. If one is inclined to think that one's political views might influence a person's writing, then my potential bias is revealed in the graph below. I encourage everyone who blogs about pharma, mental health, or related topics to take the test and post the results on your blog. If you're not a blogger, it is still an interesting test that is probably worth your time.

Disclaimer: I can't attest to the validity of this test. It is not intended to diagnose, treat, cure, or prevent any disease.

Key Opinion Leaders, Continuing Medical Education, and Utter B.S.

Psychiatrist Bernard Carroll has another brilliant post on corrupt, er, continuing medical education (CME) and how the process has been co-opted by various commercial interests. His post a few days ago was certainly great, and in combination with his current post, I officially declare that Bernard Carroll is ON FIRE!

Here's a bit of what he had to say. Commit this paragraph to memory:

Medical journals are not the only compromised medium. Continuing Medical Education (CME) is a second front in the campaign to expand the AAP [atypical antipsychotic] drug market. The standard formula calls for corporate sponsorship channeled through an “unrestricted educational grant” to a medical education communications company (MECC). The MECC employs writers to prepare the “educational content,” and academic KOLs are recruited to deliver this content. The KOLs are chosen for their willingness to be “on message” for the corporate sponsor. If they go “off message” they know they will not be invited back. The talk of “unrestricted grants” is window dressing. The MECC also secures the imprimatur of a nationally accredited CME sponsor, typically an academic institution. The sponsor is paid to certify that the CME program meets the standards of the Accreditation Council on Continuing Medical Education (ACCME). Everybody turns a buck: the MECC and its staff are handsomely paid (CME is now a multi-billion dollar business); the KOLs are generously rewarded with honoraria and perquisites; the academic sponsor is well paid by the MECC; the ACCME receives dues from the academic sponsor; the audience obtains free CME credits rather than having to pay for these required educational experiences; and the corporate sponsor gets what it considers value for its marketing dollar.

Guess what... Charles Nemeroff is also featured -- regular readers will note that his name has appeared on a few occasions on my site. Carroll takes apart a recent CME exercise in which Nemeroff featured information that appears to be false. In fact, I detailed some of the problems with this CME exercise here. Carroll's post has a number of updates. Chances were given for this CME exercise to be redeemed in some form, but misinformation apparently prevailed yet again.

Regarding another of the atypical antipsychotics discussed in this wonderful CME piece, Carroll wrote (in part) the following:

When discussing aripiprazole for nonresponding depression, Dr. Nemeroff once again was economical with the truth. Note that Bristol-Myers Squibb, the marketer of aripiprazole, sponsored this PeerView/UCLA program. To document his claims about aripiprazole, Dr. Nemeroff cited one Abstract from the American Psychiatric Association meeting in May 2007. That does not meet ACCME standards of documentation for learners, most of whom would be unable to access the cited Abstract (not that it would tell them much even if they could). For some reason, Dr. Nemeroff did not inform learners that the complete report of the aripiprazole study had appeared in June 2007 (Berman RM et al. J Clin Psychiatry 2007;68: 843-853), fully 5 months before the CME event went on-line. From that readily available report it is clear that the Number Needed to Treat (NNT) for response with aripiprazole is 10, which compares unfavorably with a NNT of 4 for lithium, the best established augmenting option in placebo-controlled trials. A NNT of 10 means a clinician would need to treat 10 patients with aripiprazole before obtaining one remission that would not have occurred anyway with placebo. That does not constitute compelling clinical benefit. Dr. Nemeroff did not candidly discuss these troubling data. Dr Nemeroff provided his CME audience none of the remission or response data from the published aripiprazole study, though these data were readily available. These omissions of published, highly relevant information signify disrespect for his audience by Dr. Nemeroff, incompetence by the MECC, and failure of due diligence by the accrediting institution, UCLA, to ensure that accurate, balanced information and adequate documentation are provided.

I shall not steal any more of Carroll's thunder. Head over the Health Care Renewal and check it out in full.

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.