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.