Journal Editor Unapologetic Over Paxil/Seroxat Article

Dr. Mina Duncan is the editor of the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP), which, as she noted on Panorama is very widely read among child and adolescent psychiatrists. So, in this prestigious journal, one would expect high editorial standards.

Let’s go through what happened with study 329, which turned into a publication in JAACAP in July 2001 upon which Dr. Martin Keller (see here) was the lead author. The study was submitted (after the Journal of the American Medical Association had rejected it – good for them) to JAACAP, and Panorama nicely documented a couple of the reviewer comments. They included

Overall, results do not clearly indicate efficacy – authors need to clearly note this.

The relatively high rate of serious adverse effects was not addressed in the discussion.

Given the high placebo response rate… are (these drugs) an acceptable first-line therapy for depressed teenagers?

Remember that journals receive manuscripts, and then send them to be reviewed by researchers in the field as to their quality. These reviews are generally taken very seriously when considering what changes should be made to a paper and whether the manuscript will be published.

Yet, the paper was not only accepted and published in JAACAP, but the editor seems to have ignored the suggestions of the individuals who reviewed the paper. These issues mentioned in the review were obviously not addressed – feel free to read the actual journal article and you can see that the efficacy of paroxetine was pimped well beyond what the data showed and the safety data were also painted to show a picture contrary to the study’s own data. Again, please feel free to read my earlier post regarding the study’s data versus how such data were reported and interpreted in the journal article.

Read this carefully – we all make mistakes. When someone points out that a mistake was made, it is natural to become defensive – that’s okay. However, several years after the fact, one should be able to admit fault and learn from one’s errors; at least that is my opinion.

Dr. Duncan was asked if she regretted allowing Keller et al.’s Paxil/Seroxat study to be published – her response was less that I hoped for:

I don’t have any regrets about publishing [the study] at all – it generated all sorts of useful discussion which is the purpose of a scholarly journal.

Let’s follow this train of logic. If a study is either particularly poorly done or misinterprets its own data to a large extent, then there will be an outcry of researchers and critics who will point out the numerous flaws that occurred. This could, of course, be interpreted as “useful discussion,” which I suppose is what Duncan meant happened in the case of this article. After all, there were several letters to the editor that expressed their frustration with the study and how Keller et al interpreted their data. So, according to my interpretation of Duncan’s logic, we should publish studies with as many flaws as possible so that we can “usefully discuss” them.

Of further interest, Jon Jureidini and Anne Tonkin had a letter published in JAACAP in May 2003. In their letter they stated

…a study that did not show significant improvement on either of two primary outcome measures is reported as demonstrating efficacy (p. 514).

The tone of their letter was perhaps a bit catty as it discussed how Keller et al seem to have spun their interpretation well out of line with the actual study data. I can, however, hardly blame them for their snippiness. Another nugget from their letter:

We believe that the Keller et al. study shows evidence of distorted and unbalanced reporting that seems to have evaded the scrutiny of your editorial process (p. 514).

Thank you to Jureidini and Tonkin for their contribution to the “useful discussion” – indeed, their comments were likely the most useful of all that were contributed to the discussion. I give credit to Duncan for publishing their letter. I would be more impressed if she was willing to state that there were some problems with the editorial process in the case of this article, but I suppose you can’t win them all.

Disclaimer: I watched Panorama and took copious notes. I believe all quotes are accurate but please let me know if you think I transcribed something incorrectly.

Update (1/29/08): My apologies. I should have typed Mina Dulcan, not Mina Duncan. Sorry for the misspellings.

BPS: Getting Stranger and Stranger...

Newspeak has returned and this time a drug company had nothing to do with it. To my great disappointment, the British Psychological Society (BPS) has moved into a realm which is well past bizarre.

I’ve posted previously about Lisa Blakemore Brown, who is currently under investigation by the BPS regarding her fitness to practice psychology. The evidence against her has been described as entirely without merit by some who have seen it. For more on the evidence, go here and look at the comments.

Aubrey Blumsohn asked to be present at Blakemore Brown’s upcoming hearing in front of the BPS. What transpires next is something that would have been entirely fitting of 1984. In fact, I’m now motivated to re-read 1984 in order to better appreciate Orwell’s genius and prescient sense of what was to come.

Blumsohn was informed that the hearings were private (i.e., no guests such as himself allowed) in order to “protect Ms. Blakemore-Brown’s privacy.” To address this, Blumsohn received explicit permission from Blakemore Brown to attend the hearing. No matter, he was then denied permission to attend the hearing by the Chair of the Fitness to Practice Committee, who refused to provide a reason for denying his petition.

To really appreciate the utter insanity of an organization that unfortunately claims to represent psychology, you really must read the entire transcript of the correspondence between Blumsohn and the BPS on this matter. You will be floored. If you, like me, are a psychological researcher, practitioner and/or teacher, then I don’t know how you cannot feel ashamed that the psychologists in the UK are accountable to the BPS. And the BPS is accountable to…?

Lilly Takes A Shot

According to Reuters, Lilly's earnings fell for 4th quarter 2006 and it is also issuing guidance that its earnings may be lower than expected this year.

Eli Lilly and Co. (LLY.N: Quote, Profile, Research) said on Wednesday fourth quarter earnings fell, hurt by a charge for a settlement with users of its Zyprexa schizophrenia drug, and it forecast 2007 earnings at the low end of Wall Street estimates.

--SNIP--

Global Zyprexa revenue rose 12 percent to $1.16 billion, in large part because of price hikes. The company said U.S. demand remained flat for the pill, whose use has been crimped by concerns over weight gains that can increase risk of diabetes.

--SNIP--

Cymbalta sales leaped 85 percent to $424 million, amid soaring demand in the United States and introductions of the drug in more overseas markets. [Must be that catchy Depression Hurts campaign that miseladingly suggests Cymbalta lowers pain in depression]

And to think that there are still some relatively large lawsuits looming over Zyprexa. Ouch.

Keller, Bad Science, and Seroxat/Paxil

I will focus on Dr. Martin Keller and some seriously poor science in this post. Panorama did an excellent job of profiling Keller’s role in helping to promote paroxetine (known as Paxil in the USA and Seroxat in the UK). Note this is a lengthy post and that the bold section headings should help you find your way.

Who is Martin Keller? He is chair of psychiatry at Brown University. According to his curriculum vita, he has over 300 scientific publications. People take his opinions seriously. He is what is known as a key opinion leader or thought leader in academia and by the drug industry. What does that mean? Well, on videotape (see the Panorama episode from 1-29-07), Keller said:

You’re respected for being an honorable person and therefore when you give an opinion about something, people tend to listen and say – These individuals gave their opinions; it’s worth considering.

Keller and Study 329: GlaxoSmithKline conducted a study, numbered 329, in which it examined the efficacy and safety of paroxetine versus placebo in the treatment of adolescent depression. Keller was the lead author on the article (J American Academy of Child and Adolescent Psychiatry, 2001, 762-772) which appeared regarding the results of this study.

Text of Article vs. the Actual Data: We’re going to now examine what the text of the article said versus what the data from the study said.

Article: Paroxetine is generally well-tolerated and effective for major depression in adolescents (p. 762).

Data on effectiveness: On the primary outcome variables (Hamilton Rating Scale for Depression [HAM-D] mean change and HAM-D final score < 8 and/or improved by 50% or more), paroxetine was not statistically superior to placebo. On four of eight measures, paroxetine was superior to placebo. Note, however, that its superiority was always by a small to moderate (at best) margin. On the whole, the most accurate take is that paroxetine was either no better or slightly better than a placebo.

Data on safety: Emotional lability occurred in 6 of 93 participants on paroxetine compared to 1 of 87 on placebo. Hostility occurred in 7 of 93 patients on paroxetine compared to 0 of 87 on placebo. In fact, on paroxetine, 7 patients were hospitalized due to adverse events, including 2 from emotional lability, 2 due to aggression, 2 with worsening depression, and 1 with manic-like symptoms. This compares to 1 patient who had lability in the placebo group, but apparently not to the point that it required hospitalization. A total of 10 people had serious psychiatric adverse events on paroxetine compared to one on placebo.

What exactly were emotional lability and hostility? To quote James McCafferty, a GSK employee who helped work on Study 329, “the term emotional lability was catch all term for ‘suicidal ideation and gestures’. The hostility term captures behavioral problems, most related to parental and school confrontations.” According to Dr. David Healy, who certainly has much inside knowledge of raw data and company documents (background here), hostility counted for “homicidal acts, homicidal ideation and aggressive events.”

Suicidality is now lability and overt aggression is now hostility. Sounds much nicer that way.

Conveniently defining depression: On page 770 of the study report, the authors opined that “…our study demonstrates that treatment with paroxetine results in clinically relevant improvement in depression scores.” The only measures that showed an advantage for paroxetine were either based on some arbitrary cutoff (and the researchers could of course opt for whatever cutoff yielded the results they wanted) or were not actually valid measures of depression. The only measures that were significant were either a global measure of improvement, which paints an optimistic view of treatment outcome, or were cherry-picked single items from longer questionnaires.

Also, think about the following for a moment. A single question on any questionnaire or interview is obviously not going to broadly cover symptoms of depression. A single question cannot cover the many facets of depression. Implying that a single question on an interview which shows an advantage for paroxetine shows that paroxetine is superior in treating depression is utterly invalid. Such logic is akin to finding that a patient with the flu reports coughing less often on a medication compared to placebo, so the medication is then declared superior to placebo for managing flu despite the medication not working better on any of the many other symptoms that comprise influenza.

Whitewashing safety data: It gets even more bizarre. Remember those 10 people who had serious adverse psychiatric events while taking paroxetine? Well, the researchers concluded that none of the adverse psychiatric events were caused by paroxetine. Interestingly, the one person who became “labile” on placebo – that event was attributed to placebo. In this magical study, a drug cannot make you suicidal but a placebo can. In a later document, Keller and colleagues said that “acute psychosocial stressors, medication noncompliance, and/or untreated comorbid disorders were judged by the investigators to account for the adverse effects in all 10 patients.” This sounds to me as if the investigators had concluded beforehand that paroxetine is incapable of making participants worse and they just had to drum up some other explanation as to why these serious events were occurring. David Healy has also discussed this fallacious assumption that drugs cannot cause harm.

Did Keller Know the Study Data? I’ll paraphrase briefly from Panorama, which had a video of Keller discussing the study and his role in examining and analyzing its data. He said he had reviewed data analytic tables, but then he mentioned soon after that on some printouts there were “item numbers and variable numbers and they don’t even have words on them – I tend not to look at those. I do better with words than symbols. [emphasis mine].”

Ghosted: According to Panorama (and documents I’ve obtained), the paper was written by a ghostwriter. Keller’s response to the ghostwriter after he saw the paper? “You did a superb job with this. Thank you very much. It is excellent. Enclosed are some rather minor changes from me, Neal, and Mike. [emphasis mine].” And let’s remember that Keller apparently did not wish to bother with looking at numbers. It would also appear that he did not want to bother much with the words based upon those numbers.

Third Party Technique: This is a tried and true trick – get several leading academics to stamp their names on a study manuscript and suddenly it appears like the study was closely supervised in every aspect, from data collection to data analysis, to study writeup, by independent academics. Thus, it is not GlaxoSmithKline telling you that their product is great, it is “independent researchers” from such bastions of academia as Brown University, the University of Pittsburgh, and University of Texas Southwester Medical Center and the University of Texas Medical Branch at Galveston which are stamping approval of the product. More on this in future posts.

Keller’s Background… It is relatively well-known that Keller makes much money from his consulting and research arrangements with drug companies. In fact, several years ago, it was documented that Keller pulled in over $500,000 in a single year through these lucrative deals. When looking at how he stuck his name on a study he did not write, endorsing conclusions that were clearly far from the actual study data, can one seriously believe that Keller operated as an independent researcher? Can you believe that this is an isolated incident?

See, for example, Keller’s involvement in a study examining the effects of Risperdal (risperidone) for the treatment of depression. This study was presented a number of times, and he never appeared as an author of any of the presentations. Yet when the study was published, his name appeared as an author. The real kicker was that he allegedly helped to design the study, according to the published article. If he had played a major role in the study, he would have been acknowledged earlier (via being listed as a presentation author), so he apparently helped design the study after it was completed, which is obviously a major feat! The whole story is here. Why put his name on the paper? So that readers would believe more strongly in the study due to his big name status.

In addition, Keller wrote about how Effexor reduces episodes of depression in the long-term though he clearly misinterpreted the study’s findings. To be fair, many other researchers have made the same mistake in believing that SSRI’s reduce depression. To quote an earlier post:

In other words, because SSRIs and similar drugs (e.g., Effexor) have withdrawal symptoms that sometimes lead to depression, it looks like they are effective in preventing depression because people often get worse shortly after stopping their medication. The drug companies (Wyeth, in the case of Effexor) would like you to believe that this means antidepressants protect you from re-experiencing depression once you get better, that they are a good long-term treatment. A more accurate statement is that antidepressants protect you from their own substantial withdrawal symptoms until you stop taking them.

Again, Keller is way off from the study data.

Keller on Camera: Keller’s response to being asked about the increased suicidality among participants taking paroxetine in Study 329 was interesting:

None of these attempts led to suicide and very few of them led to hospitalization.

Well then I suppose a huge increase in suicidal thoughts and gestures is okay, then? This is the commentary of an “opinion leader” – if statements such as the above shape opinions among practicing psychiatrists, then we really are in trouble.

Next: Well, consider this post just the start regarding Paxil/Seroxat. The way the data were pimped by GSK merits more discussion as does more discussion of allegedly detached academics and their role in this debacle.

Seroquel For Everything Update: Anorexia

A reader recently made the following comment about Zyprexa

Rumor has it that zyprexa is now going to be marketed for anorexic hyperglycemics....

I assume that this was sarcastic -- I got a chuckle from it, though I think the reader meant hypoclycemics. In any case, a study was recently published (Powers et al; International Journal of Eating Disorders) in which quetiapine (Seroquel) was used to treat people with anorexia. Mind you, this was an uncontrolled study, so the improvements in depression and other symptoms may well just be placebo effects. Here are the authors' conclusions, as seen in the study abstract:

Quetiapine was well-tolerated and patients had significant improvements in several subscales of the PANSS as well as decreases in measures of anxiety and depression.

Hey, it's just a matter of time before we can perhaps all benefit from some Seroquel in the water supply, right? I wonder how many reprints AstraZeneca has purchased of this ever so rigorous study to disseminate to physicians and to discuss at those (in)famous doctor dinners. Background here and here.

Paxil/Seroxat: WOW

I just completed watching the Panorama investigation that aired yesterday on BBC. I ever so highly recommend it. You can check it out here. This lifts the curtains on the usual sets of lies, and does an excellent job of exposing how allegedly independent researchers served as puppets for GlaxoSmithKline. I will write more about it soon. Nice to see some good investigative journalism.

Seroquel for Everything: Update

You’ve surely seen me point out earlier that I’m more than slightly concerned with the proliferation of Seroquel (quetiapine) to treat virtually everything. What started out as an antipsychotic medication has spread into bipolar (with the help of some tricky statistics, naturally), then into being investigated for alcohol abuse, bipolar in preschoolers (assuming, of course, such a disorder actually exists!), generalized anxiety disorder, and now…

Fear of Public Speaking. Yep, Furious Seasons has just documented that the good folks at AstraZeneca are now aiming for people who are socially anxious. Hey, next time I’m feeling nervous prior to a conference presentation, I’ll make sure to pop one of these bad boys. Give me a break.

I can sense a fear of public speaking “disease awareness” campaign being planned at AstraZeneca’s corporate office as I type…

Seroxat Update

A nice little tidbit from PharmaGossip on the latest in the Paxil (US) / Seroxat (UK) fiasco

This is the story of how Britain's biggest drug company deliberately misled doctors into prescribing Seroxat, which it couldn't prove actually worked for teenagers. Not only that, one of its own clinical trials indicated that they were six times more likely to become suicidal after taking it.

Link here. I've got to get to the link to watch Panorama online. Should be eye-opening.

Becoming the Blakemore Brown Sounding Board

A few days ago, I posted regarding the case of Lisa Blakemore Brown, a psychologist who has run into trouble from the British Psychological Society. Since that time, the post has generated several comments (11 at the time of this posting, to be exact).

I will quote just a couple of choice snippets from them before encouraging you to check out the post and read the comments yourself. Feel free to add your two cents to the mix as well.

I have had the priviledge of reading all of the case documents and all of the transcripts of this fitness to practice "enquiry". I can assure you that none of the allegations have anything whatever to do with Lisa's diagnostic skills, her professionalism in terms of patient care, her competence as a professional, vaccine damage, Aliens or anything of the sort. The transcripts are quite simply appalling. The British Psychological Society is naturally not very keen on the idea that they should be made public. – Aubrey Blumsohn

Everyone has a RIGHT to question, and a RIGHT to search for answers, we were born with that facility built in as part of our survival instinct. That includes Lisa Blakemore Brown. – Paula

I too have read the transcripts of this so called "trial", and as Aubrey states they have nothing to do with patients or clinical practice. A single unsupportable complaint arose from a patient who was said to have been "coached" by a certain support group, and did not have anything to do with her skills. I hope the tranbscripts [sic] are placed in the public domain as soon as possible. – PM

Lisa and I are guilty of challenging a part of the belief systems of these professions and it is clear that the BPS are prepared to stoop to any underhand methods and to disregard the principles of due process, in order to seek to discredit Lisa and to thereby discredit her invaluable work on
behalf of families with autistic children. They must not be allowed to succeed. – Charles Pragnell

There are several other interesting comments, including one that takes a view quite different than the consensus of those whom I quoted above. Go here to check them out and go here to check out the story’s background in more detail.

Paxil/Seroxat -- Will it Ever End?

The AHRP blog has a great post on how academics sold out in the case of Paxil/Seroxat. The story includes the text of a likewise great piece from the British Medical Journal on the same topic. On at least one of the Paxil studies authored by "independent" academics, the suicidality of participants magically turned into "lability" and serious aggressive behavior turned into "hostility." The study authors simply renamed the adverse events to sound more tolerable -- I'd certainly rather be "labile" than suicidal, wouldn't you? Here's a link to the abstract of said study so you can see the names of the authors who let this slip by them. Sadly, these are some of the big names in child psychiatry.

A snippet from the AHRP post:

According to Joe Collier, Panorama shows how GSK had: "written up" the pediatric Paxil trial for publication; "bought and manipulated (apparently willingly) opinion formers; worked to promote the product for use in children (although it was not, and never has been, licensed for such use);" and how the information about the safety and efficacy of Paxil was distorted in letters to prescribers, in advice to their sales force, and in messages to the media.

The Panorama story on BBC running January 29th is likely to be big...

Neuronetics Swings... AND MISSES!

Neuronetics' transcranial magnetic stimulation was rejected by the FDA's advisory panel today. For a couple of stories on the panel's discussion and recommendation, try here and here.

According to one report:

The majority of the panel—made up of an engineer, several psychiatrists and neurologists, and a statistician—had no problem with rTMS's risks. There are almost none. The biggest worry with it is that it might accidentally spark a seizure, but that did not happen even once out of the 155 patients treated. The problem was that Neuronetics couldn't prove any benefit. Treated patients got a little better, but so did those patients that underwent a sham treatment.

According to another source:

But the panel was generally unimpressed with the company's data, which showed a slight statistical advantage in depression symptoms over dummy therapy after six weeks of treatment. Several panelists expressed dismay that patients showed no improvement on some depression scales and only minor improvement on ones that showed a difference.

"The panel seems to be in consensus that the primary analysis did not establish efficacy," said Thomas Brott, the committee's chairman.

"Perhaps a reasonable person could question whether there has been an effect at all," said Brott, a neurologist from Mayo Medical School in Jacksonville, Fla.

The panel did not formally recommend to FDA whether or not the machine should be approved. But the agency scientists suggested at a public hearing that they were also uneasy with the company's results.

Ann Costello, an FDA medical reviewer, questioned whether the mixed evidence of effectiveness in Neuronetics' studies contained "any clinically relevant information."

Peter Lurie, deputy director of Public Citizen's Health Research Group, told the panel that Neuronetics did not show that its device was substantially equal to ECT, a standard that many medical devices must meet for FDA approval. He focused on the fact that patients actively treated with the machine showed mild improvement on only one of three depression scales.

"The magnitude of the finding is trivial from a clinical point of view," he said in an interview.

Maybe the FDA panel learned something from the VNS approval (here and here)?

For-Profit Research Update

I recently wrote about a psychiatrist, Dr. Andrew Cutler, who made misleading statements regarding the BOLDER I study. I ran across a little clip that mentioned more about his research venture:

Still, some junior faculty members are now abandoning academia to get into the drug-study business. Dr. Andrew Cutler, a psychiatrist, left the faculty at the University of Chicago to join the Psychiatric Institute of Florida in Orlando, a private practice with a research business. Then last year, he formed his own company, Coordinated Research of Florida, to perform drug studies full time.

Without a patient base to draw from for studies, Cutler found other ways to recruit subjects, including serving as a nursing home consultant.

"I will strategically pick a nursing home that has a large population that meets the criteria for a study," he said. "If there is a large community practice in town, I may work out a referral arrangement, or make them a co-investigator, and the arrangement is that they would be providing the patients."

Interesting. If I understand this right (and I'm not sure that I do), then he goes to local nursing homes, chums with the people in charge, then gets them to help recruit their residents as participants in drug studies from which both he and the nursing home administrators who get listed as "investigators" stand to make some cash. This is not necessarily bad, but it shows that the reach of clinical research teams, funded solely by industry, is fairly wide. Making money from enrolling your own residents in a research trial must certainly raise some conflicts of interest for nursing home administrators and physicians.

The Big Day for Neuronetics

An FDA advisory panel will be reviewing Neuronetics' transcranial magnetic stimulation device today. Their recommendation will likely be followed by the FDA in either approving the treatment for depression or not. As soon as I see anything regarding the panel's decision, I'll let you know.

A Little Help?

I've made a couple updates to the site template today. I'm trying to catch on to the whole Web 2.0 thing and make it much easier for readers to send my posts to sites like Reddit, Digg, etc. Unfortunately, my skills in this area are obviously limited. If someone wants to help out, feel free to email me -- link in the sidebar. Thanks.

Likewise, if anyone has comments about switching to the new version of Blogger, please email me or feel free to post them. I'm debating if I should make the switch sooner or later.

The Blakemore Brown Case: Part One

A psychologist in the UK, Lisa Blakemore Brown, is facing all sorts of trouble. As I understand it, the British Psychological Society is in the process of examining Brown's purported fitness to practice psychology. Essentially, Blakemore Brown has taken controversial points of view regarding the relationships between vaccinations and autism as well as Munchausen's Syndrome. From my research on her case, it appears that this case is an example of a dissident being punished for offending the "wrong" people. It would appear to have little to do with her actual fitness to practice psychology. I'm not agreeing or disagreeing with her views; I am stating that she's got the right to state those views, regardless of whom is offended.

A much more in depth layout of the issues involved can be seen at the Scientific Misconduct Blog. To preview, much of this boils down to what appear to be unsubstantiated charges regarding Brown's mental state (alleged "paranoia"), which then allegedly makes her too unstable to practice psychology. I've heard rumors that there is a lot more to come in this saga. Stay tuned.

So Funny It Hurts

Everyone must immediately read PharmaGiles, the blog that details the story of a fake drug company names Phoni (among other items). It is incredible satire regarding the drug industry. My only warning is that you may laugh so hard that you need an ambulance.

BOLDER Statements

In this post, I will discuss statements of a couple academic thought leaders regarding the BOLDER I study and how these statements compare to the actual evidence.

Cutler: Dr. Andrew Cutler, one of the authors on the BOLDER I study to which I referred earlier, had some nice things to say about the study’s findings in Clinical Psychiatry News. For example, he said “It’s a landmark study.” In addition, the article paraphrased Cutler as saying, “The study used one dose each evening, and had several other unique features, he noted. Almost all previous data on treating bipolar depression focus on bipolar I patients, but this study included rapid cyclers and bipolar II patients.”

What Dr. Cutler failed to note is that Seroquel was not more effective than placebo at the end of the eight week trial for bipolar II patients. If Cutler is going to introduce bipolar II participants into the mix, then he has an obligation to mention that treatment was not significantly more effective than placebo for this group. He may have been misquoted – I don’t know – but it does read directly like PR for the drug that goes well beyond the findings of the study which he is discussing.

It is worth noting that Cutler runs a private research firm and that it can’t hurt his standing among drug companies who hire his firm to run clinical trials when he makes statements such as those mentioned above. I found it interesting that on his firm’s website, it is mentioned “We are also noted for low placebo response.” How do you get a low placebo response besides not treating participants very well? I’m not making an accusation – I am just really curious. If placebo response has to do with expectations of getting better and these expectations are influenced by how the study personnel treat participants, then what’s the deal? Maybe you can treat participants well and still quash the placebo response; I just wish I knew more about how this was done.

Calabrese: Dr. Joseph Calabrese, BOLDER I’s primary investigator, had the following to say about the study: “There was a dramatic response within eight days of beginning treatment in patients who were symptomatic with bipolar depression.” I’m not sure if “dramatic” is the right word. Looking at Figure 2 in the article, I see that after week one, placebo patients seem to have changed by 5 points on the Montgomery-Asberg Depression Rating Scale (MADRS), while those on Seroquel seem to have changed by about 9.5 points. That’s an average difference of about 4.5 points on a rating scale where the average patient had a score of about 30 coming in. So is a score of 25 (on placebo) “dramatically” different than a score of 20.5 (on medication)? Methinks that the language itself is a little dramatic. Don’t get me wrong – it’s good that the medication was better than placebo after a week. But let’s not get hyped up beyond what is reasonable.

It is troubling when academics are willing to make PR statements that go beyond the evidence and, in Cutler’s statement regarding bipolar II, are demonstrably false. Academic thought leaders are frequently featured in news articles, review articles, PR releases, and continuing medical ‘education’ events making these types of statements that go well beyond the evidence. It seems that too few professionals in the mental health arena have picked up on the fact that marketing and science have largely melded into a witches’ brew in which what is good for a product’s sales often trumps the actual data on its efficacy and safety.

Before anyone gets upset because I mentioned people’s names here, keep in mind that I’m not saying either Cutler or Calabrese is a “bad person.” I don’t know them personally. They may well conduct top-notch research and possess saintly personalities. All I am talking about here is how their remarks seem to differ from the studies that the remarks are based upon, and how such practice is widespread.

Major Hat Tip: Depression Introspection.

BOLDER Still

I’ve written before regarding the BOLDER II study, in which Seroquel was compared to placebo in the treatment of bipolar individuals experiencing depression. My main qualm was the way that the authors calculated the size of the treatment effect. Essentially, there are a couple ways to calculate the treatment effect, and they calculated the treatment effect in a manner that made the treatment effect appear much larger. For more on this, please read my earlier posts here and here.

Well, I have since gone back to the BOLDER I study, and I can see now that the same trick was in place. We’re talking about last observation carried forward effect size (the traditional method) versus mixed-model repeated measures (MMRM; the ‘new’ method) effect size here. It may sound boring and wonky, but it is the backbone of interpreting how strong of an effect was generated by the treatment. For more details, please see my earlier post.

In BOLDER II, I could at least calculate the last observation carried forward effect size in the traditional sense based on data provided in the article. In BOLDER I, this was actually not possible. To calculate the size of the treatment effect, one must examine the means and standard deviations of all groups. This information was not provided in full, as there were no standard deviations reported. Given that reporting means and standard deviations is standard practice in medical journals, this is quite odd.

So, I just decided to use the standard deviations from the BOLDER II study to see what would happen. They seemed to be fairly comparable groups. Yes, the standard deviations of the groups in the two studies are likely to be different, but since the authors didn't report them in BOLDER I, I had little other choice. For the 300 mg Seroquel group, I found an effect size of .49, which is a moderate treatment effect. The study authors in BOLDER I, using the alternative MMRM method, found a treatment effect of .67, which is moderate to large. Using their method seemed to boostthe effect size by 37%. For the 600 mg Seroquel group, I found an effect size of .52 (moderate), whereas the study authors came up with .81, which would typically represent a large treatment effect. Using the authors’ methods, the effect size apparently increased by 36%.

The authors did not bother even reporting the standard deviations or the effect sizes calculated the traditional way. Regarding similar issues being raised about BOLDER II, one of the authors replied by saying essentially that the authors thought nobody would be interested in the traditional analysis. Call me old-fashioned, but when a new statistical analysis comes on the scene that dramatically increases the apparent magnitude of treatment effects, making treatments appear more powerful just because data are analyzed in a different way, I’m suspicious. When the old method, which has been used to calculate effects for decades, is just tossed out the window as old-fashioned, one can’t help but wonder if these drug company funded statisticians are just licking their chops because through statistical maneuvering, they have figured out how to make their sponsor’s products look better.

So, when you see that the apparent effects of treatments have grown, keep in mind that you may well be staring at the effects of newfangled statistics rather than the actual treatment.

PharmaGossip: On a Roll

No, this is not really news. PharmaGossip is about as good of a blog as you can find regarding the drug industry. We already knew that. If you’ve not been paying attention lately, please check out the following recent posts:

Sex, Drugs and Quarterly Goals

Merck – Vioxx: Order in the Court!

PharmedOut Makes the WaPo

And especially: Any suggestions for the "Cutting Edge Information Pharma Marketing Library"

Furious Seasons is Off Da Hook

In a post that can only be described as “off the hook,” Philip Dawdy at Furious Seasons describes what 2007 appears to hold in terms of psychiatric treatment research. I read the same article as did Dawdy last week regarding this year's psych med research and thought, “yeah, I’ll get to that.” Well, I’m glad I never got around to it because I could not have matched what he has written. Here are some snippets from Dawdy…

“There was an interesting story last week in Psychiatric Times. It was a curtain raiser on what the reporter promises will be a big year of data for psych MDs. Lots of studies on using atypicals in kids and adolescents--I predict that these short-term studies will show limited efficacy with big weight gain in the kiddos”

—SNIP—

"And new data on one drug, Zyprexa (olanzapine), will likely be submitted to the FDA this year in anticipation of earning a pediatric indication for either schizophrenia or bipolar disorder."

Oh my. After all the problems that have cropped up around Zyprexa's use in adults, Eli Lilly is pushing to have it approved for kids? That ought to be one very interesting filing with the FDA.

—SNIP—

I am against sticking four to six year olds full of an antipsychotic, especially Seroquel. It's well known to cause weight gain in adults and creates so much cognitive slowing and the fifth of whiskey head the next morning that it is utterly unfair to give this to children.

OK, I have to stop stealing his words. Believe me – it just gets even better in his post; I only scratched the surface. In fact, it is one of the best posts I have ever read. So get going and read it in full. Warning: His post contains adult language (and appropriately so, in my humble opinion).

UK Paper on Zyprexa

Much of the writing about the Zyprexa documents has appeared in the New York Times, but the Times of London is now chiming in as well. Here's a couple of choice cuts:

In one document dated October 9, 2000, Robert Baker, a senior Lilly clinical research physician, e-mailed colleagues about a meeting of an academic advisory board he had attended in Atlanta. It had “reinforced my impression that hyperglycemia remains quite a threat for olanzapine and may merit increasing even further medical attention and marketing focus on this topic”. Dr Baker added: “[The board was] quite impressed by the magnitude of weight gain on olanzapine and implications for glucose.”

Another internal document dated October 14-15, 1998, described the risk of weight gain as a “top threat” to Zyprexa.

Link here. Background here, here, and here.

Chemical Imbalance Watch

I have ranted before about the alleged chemical imbalance in depression. Any time I've seen a commercial for any of the SSRI's, I've just shaken my head (0r banged it against the wall), as the ads love to tout how "experts" (i.e., their marketing department ?) believe that depression is caused by some sort of chemical imbalance. The evidence, as you can read here, is scant, at best, to support such an assertion.

Well, Wyeth is still on the chemical imbalance train with their knockoff of their current bestselling antidepressant Effexor, which may be gracing your pharmacy before long. The new drug is called Pristiq and Wyeth is offering up the following as part of its early PR campaign for the drug:

In the area of depression, Pristiq is expected to improve the balance of serotonin and norepinephrine as compared with serotonin reuptake inhibitors (SSRI) because of its pharmacologic profile as a dual reuptake inhibitor.

Well, whoopee! Will it work any better than antidepressants that attempt to target either norepinephrine or serotonin? Nope. Why? Because a reliable imbalance of either neurotransmitter has never been found in depression. That's right -- never. But Wyeth continues to run with the chemical imbalance program because a lot of people have been indoctrinated, through advertising or perhaps through teachers who themselves lacked much education on the topic, to buy into this whole chemical imbalance deal.

I'm not saying that biology does not impact depression. I am saying that our current level of understanding in this area is much more speculation than it is fact. I do not believe there is a single serious scientist who would stick his/her name behind the simple "chemical imbalance" theory of depression.

And the name Pristiq? It would appear that Wyeth is aiming for a close resemblance to "Pristine," which is a bit ironic given the side effect profile of Pristiq (which will likely resemble that of Effexor closely).

More on Pristiq in an interesting post at Depression Introspection.

SSRIs and Osteoporosis

Fresh from the Archives of Internal Medicine, a study by Richards and colleagues has indicated that daily SSRI usage is associated with an increased risk of falling and lower bone density, among others. Here are the results as stated in the abstract (I’ve not read the full study):

Daily SSRI use was reported by 137 subjects. After adjustment for many potential covariates, daily SSRI use was associated with substantially increased risk of incident clinical fragility fracture (hazard rate, 2.1; 95% confidence interval, 1.3-3.4). Daily SSRI use was also associated with increased odds of falling (odds ratio, 2.2; 95% confidence interval, 1.4-3.5), lower bone mineral density at the hip, and a trend toward lower bone mineral density at the spine. These effects were dose dependent and were similar for those who reported taking SSRIs at baseline and at 5 years' follow-up.

Significant sexual side effects, suicide (here and here) and now this? It’s not adding up very nicely for SSRIs. If you are at risk for bone problems, may I suggest Actonel? With such strong research backing it, you can’t beat Actonel for your osteoporosis-related needs (as you can see here and here).

Effexor For Life

In a study that parallels an earlier study (and accompanying post – Lexapro for Life), Dr. Martin Keller (presumably a primary investigator on this study) found that long-term venlafaxine (Effexor) use reduces risk for depression. In fact, he said,

these data showed that venlafaxine extended release can help prevent new episodes of depression -- providing an option to the millions of adult patients with depression who have experienced a disappointing setback or who are still seeking symptom relief.

Please note that I have text of a document from PR Newswire indicating that he made the above statement, but I don’t have a link to the text.

His comments are not all that different than those of Dr. Susan Kornstein, who was quoted as saying the following about the long-term effects of Lexapro:

These findings indicate the importance of maintenance therapy for patients with recurrent major depressive disorder beyond four to six months of improvement, even if a patient’s depressive symptoms appear to be resolved

This study: The Effexor results have not been published to my knowledge, but from what I gather from the study description, this study examined people who were on Effexor and received some sort of therapeutic response while taking it. Then, some of them kept taking Effexor and some were assigned to take a placebo (of course, not knowing they were switched to placebo). Those who took Effexor were significantly less likely to experience a recurrence of their depressive symptoms compared to those on placebo. So, apparently, you should be on Effexor forever. As noted above, Keller (and in a similar study, Kornstein) say this means that you should stay on your meds long-term because they prevent depression.

Withdrawal from Effexor: Just like Kornstein, Keller has absolutely misinterpreted the evidence. For example, in one small study, discontinuation of venlafaxine was associated with adverse events in 78% of patients compared to 22% of patients who stopped taking a placebo. Another, larger study found, similarly, that Effexor was related to increased rates of discontinuation symptoms compared to placebo. There are frequent reports to a national medication hotline in the UK regarding discontinuation symptoms when patients stop taking Effexor. In addition, there are also case reports of experiencing shock-like sensations during venlafaxine withdrawal. For a brief read on these shock-like sensations, check out this brief read in the British Medical Journal. In addition, it is now known that for paroxetine (Paxil), another antidepressant, healthy (not depressed) volunteers at times experienced depression upon ceasing taking their medication. Given the similar mechanism of action between Effexor and Paxil, one would expect a similar result for Effexor.

A quote from Dr. David Healy helps to summarize this fundamental manipulation of evidence by drug companies (and their allied “independent” academics):

It is clear now that the companies must have known that a certain proportion of these patients re-randomised to placebo, who subsequently complained of depressive and anxiety symptoms, will have been suffering from withdrawal problems. These withdrawal problems however appear to have been used as a basis for claiming that continued SSRI intake had a prophylactic effect against nervous and depressive problems. Based on such studies companies sought and have received licences to make these claims regarding prophylaxis.

In other words, because SSRIs and similar drugs (e.g., Effexor) have withdrawal symptoms that sometimes lead to depression, it looks like they are effective in preventing depression because people often get worse shortly after stopping their medication. The drug companies (Wyeth, in the case of Effexor) would like you to believe that this means antidepressants protect you from re-experiencing depression once you get better, that they are a good long-term treatment. A more accurate statement is that antidepressants protect you from their own substantial withdrawal symptoms until you stop taking them.

See No Withdrawal, Mention No Withdrawal: I do not say this as a personal affront to Keller, Kornstein, or any other academic who has made public statements regarding the long-term efficacy of antidepressants, but it seems odd that anyone, particularly anyone with research credentials, could ignore the solid evidence that there are substantial withdrawal symptoms associated with antidepressants. Many researchers apparently continue to toe the line of the drug companies that “it’s the depression, not the drug” that causes depression to return.

The Current Verdict on Long-Term Outcomes: Depression is indeed a nasty condition that often returns after it is successfully treated or after it just vanishes due to the passage of time. So yes, we should treat it. However, let’s keep in mind that antidepressants are barely more effective than a placebo in the short-term and, as we see here, can lead to problems in the long-term, where one can either choose to stay, for years, on an antidepressant (perhaps indefinitely) or have a good chance of risking some heinous withdrawal effects. Psychotherapy is much better in the long-run for depression, but it still does not positively impact many people. Like it or not, psychotherapy for depression has the best (though limited) success rate, perhaps due solely to its lack of causing withdrawal effects, or at least causing them at a much lower rate than meds.

Great Rant on Abilify Advertising

Intueri has a great rant on Abilify advertising appearing on the sides of pay phones. Read it and you too may feel the urge to say You Go Girl!

Infant Depression & Anxiety More Prevalent

...according to the headline of a "news" story at a Boston TV station.

A growing number of hospitals and universities are now offering mental health therapy. Experts believe that if they can address these issues early, they can avoid bigger problems later in the child's life.

And by 'early,' they mean as early as one year old.

Psychologist Douglas Goldsmith says "even by the first birthday, some of the research is saying we should be able to start to see signs of more serious social disorders."

Well, Dr. Goldsmith, I'd love to become more familiar with such research. I actually don't think there is any research of any decent quality addressing anxiety and/or depression in children prior to their first birthdays. If any of y'all have access to such research, please address it in my direction. I'd especially be interested in research that shows that interventions with pre-one year olds helps children avoid "bigger problems" later on.

Hat Tip: Depression Introspection.

Zyprexa Inquiry Expands

Alex Berenson of the New York Times has another in what may be an endless stream of stories regarding olanzapine and its questionable (at best) marketing practices. I’ll start by quoting from his latest piece:

Illinois and Vermont are now part of a coordinated five-state civil investigation into the way Lilly promoted Zyprexa, a treatment for schizophrenia and bipolar disorder. The states are investigating whether Lilly tried to hide Zyprexa’s risk of causing weight gain and other risks associated with diabetes and whether the company promoted Zyprexa for use in patients who do not have schizophrenia or bipolar disorder.

Federal laws prohibit such so-called “off label” marketing, although doctors may prescribe any drug for any disease that they believe the drug will help.

The orders on Thursday and yesterday are the first formal demands for Lilly documents from state attorneys and they indicate an escalation of the investigation, according to Ms. Hagan and Julie Brill, who is an assistant attorney general in Vermont.

For background on this story, please feel free to see such posts as this, this, this, and this. Make sure to also check out the AHRP site for much information on the Zyprexa case.

Greed and Cancer Docs

This is rich, bloody rich. I'll just let Bloomberg do the talking:

Cancer doctors must disclose all financial ties to investment firms, said a leading U.S. physician group seeking to stop the leak of insider information on clinical drug trials.

The American Society of Clinical Oncology described the new policy, the most strict of any medical group, in a Jan. 20 article in the Journal of Clinical Oncology. The Alexandria, Virginia-based professional organization has more than 23,000 members worldwide.

Cancer physicians must disclose all consulting or advisory arrangements they have with either investment or commercial interests, the policy says. Investment firms cultivate doctors with lucrative consulting arrangements, and traders can use their inside knowledge to buy and sell stocks of companies developing new therapies before the information becomes public.

--SNIP--

The policy was crafted in response to reports about the growing practice of physicians consulting for Wall Street firms about confidential drug research, typically for $300 to $500 an hour, the authors wrote. The practice was described in an August 2005 investigative report by The Seattle Times, and it later attracted scrutiny from Senator Charles Grassley, Republican of Iowa, and the U.S. Securities and Exchange Commission.

The Times found 26 cases in which doctors leaked critical information about ongoing drug research to investment firms, despite signing confidentiality contracts with sponsors of drug trials.

--SNIP--

Peter Eisenberg, a prominent cancer physician in Marin County, California, said the newly strengthened ethics policy for cancer doctors was a ``necessary step.'' He said the advice will help physicians who want to do the right thing, yet, ``for those who aren't scrupulous, no policy will suffice.''

Eisenberg said he stopped his $600 an hour consulting with Wall Street firms after reading the Seattle Times report about how investors elicit inside information from doctors. The Jan. 20 journal article cited instances where analysts have posed as fellow doctors or patients in order to elicit information from doctors.

``They know how to get the information, and basically, I don't know how to keep it to myself, so I decided to stop,'' Eisenberg said of working with investment firms.

So, basically, many oncologists involved with research trials are sneakily disclosing research findings so that investment firms can either buy or sell shares of drug developing firms. Pretty sleazy, eh?

Why this is even worse than it looks: Many physicians are breaking confidentiality agreements because they are getting paid quite a handsome sum. But when research results show that a drug is ineffective and/or dangerous (think SSRIs for child/adolescent depression, for example), research docs do not disclose the negative information to the people who actually need to know these results -- patients. This leaves tens of thousands of people taking medication that is dangerous and/or ineffective. So, to summarize, if they get paid off, many docs will break their confidentiality agreements with drug companies, yet when trial results show that a drug is not a good treatment option, nearly all research doctors will hide behind their confidentiality agreements and let people suffer. This does not exactly engender faith in the academic-pharmaceutical complex, does it?

Many thanks to an anonymous reader for the link.

Arkansas Antipsychotic Update

Dr. X did some digging and found a couple of resources that shed more light on the apparent overdrugging of child and adolescent inmates at an Arkansas prison facility run by Cornell Companies at the time of the incidents.

Check this out:

An internal affairs unit report studied “forced psychotropic medications/chemical restraints” over a 45-day period beginning Sept. 1. Video surveillance of injection procedures was part of the investigation.

A log showed 22 juveniles had been given 52 injections of Thorazine and Benadryl as chemical restraints. But a separate incident report showed 16 injections were not recorded on the log and a total of 25 juveniles received injections. There were signed physician orders for injections in only 11 of the 25 cases.

--SNIP--

Though not allowed as discipline, the report concluded that medication was used as a disciplinary tool.

Nice. REAL Nice. Thanks to Dr. X for the update. I only posted some of the lowlights. Feel free to check out the links to read more.

Thanks for Your Support

The results are in for the 2006 Medical Blog Awards. While I did not win in the category of Best New Blog, I thank all who voted for my site. It was an honor to receive quite a few votes and to be listed next to some excellent sites. For results, please go here. Congrats to all winners, especially to the NHS Blog Doctor, who won in three categories.

Antipsychotics Will 'Correct 'You

A youth correctional facility in Arkansas had some problems in the fairly recent past. What kind of problems?

Well, the private firm that was formerly contracted to run the facility, Cornell Companies, "was fired last year for inappropriately injecting children with antipsychotic medications" according to an AP report.

Nice. Now the State of Arkansas has hired another private firm, G4S Youth Services of Virginia, which will assume control of the facility in a few days. I couldn't find any further information on this, but it certainly jumped out at me.

Daily Zyprexa Post

Noting that earlier Zyprexa lawsuits have included gag orders (i.e., we pay you off and you shut up!), a quote in an excellent post I ran across went like this:

So there you have it. My point, if any? Gag orders protecting the guilty should not be permitted as part of any civil settlement. Prohibit it by law, and we won't have to put up with this nonsense. If civil litigation is supposed to be a mechanism for protecting the public, it will work best if it includes public airing of the relevant facts and evidence. An outcome in which a few of the people who were injured get compensated, at the cost of keeping the truth from everybody else, is not in the public interest, and it should never be allowed to happen.

Good point. Every time we have a lawsuit, there is the potential for docs to become public. That’s how David Healy got access to files indicating that SSRI manufacturers were cooking the books on the suicide numbers to make placebo look more dangerous than it actually was. Yet in many cases, the documents vanish and hidden information about the safety and/or efficacy (or lack thereof) is again relegated to the company archives.

Billy LOVES the Free Market

We’re going to play a neat game. It’s called ‘Free Market’ Billy Tauzin versus ‘I Hate Competition’ Billy Tauzin. You can pick the winner at the end.

The drug industry loves to discuss the free market and its wonders. Billy Tauzin is the president of PhRMA, the leading drug industry trade group and former Louisiana Congressman. For a brief yet entertaining story on how Billy ended up as PhRMA president, see this column in Slate.

The following are quotes from Billy Tauzin, excerpted from a speech titled Free Market Health Care Solutions Are Best for Patients at something called an American Legislative Exchange Council Annual Dinner in San Fransico, CA. I added the color highlights.

Tonight, I salute you for your dedication to the fundamental principle that free-market based solutions work best for preserving our liberties and building a strong country, strong states and strong communities.

—SNIP—

The strength and success of America’s pharmaceutical research industry, I am proud to say, is just one example of what we work for when we fight for free-markets, reducing government interference in the economy and for fostering of an economic environment that promotes opportunity and innovation.

—SNIP—

But while we marvel at the promise of these new health care technologies and medicines, we should also not lose sight of the fact that patients are the ultimate beneficiaries of this revolution.

—SNIP—

We must work together to make sure that the healthcare market remains free because the best, most efficient and cost-effective solutions will come from a free market.

—SNIP—

And, if you want to work for free-market solutions to the problem of access to medicines, we also are there to work with you and support you.

—SNIP—

The free-market in health care helped save my life.

Okay, you get the point – Billy loves the free market and the free market in health care saves lives. And those good folks in PhRMA (e.g., essentially all major developers of medications) are all in favor of the free market.

News Flash -- PhRMA does NOT believe in the free market: While PhRMA likes when the market works in their favor, they also believe in circumventing that same market when it comes to competition. When drugs are slated to come off-patent, which would allow generic version of the drug to be made, PhRMA members have increasingly turned to buying off the competition. That’s right; they simply pay the generic manufacturer to not make a generic version of the patented drug, so that the consumer can continue to pay a hefty price for the drug which is still under patent. Ain’t that a nice deal? Here’s a quote from a recent AP story regarding this practice:

“Sadly, the incentive to enter in such pernicious pay-for-delay settlements are substantial,” FTC commissioner Jon Leibowitz told lawmakers.

In a typical settlement, the payment is still less than the potential loss in sales to a brand-name company once a generic competitor enters the market, said Michael Wroblewski, of Consumers Union. And the generic manufacturer makes more from the payment that it would from actually selling its version of a drug, he said.

But wait, Billy had this to say about pay-for-delay arrangements:

“Courts and experts have stated unequivocally that settlement of litigation should be encouraged and that settlement of patent litigation can benefit consumers. Blanket prohibitions on certain types of settlements could force both sides to spend valuable resources litigating their patent dispute to judgment,” said former Rep. Billy Tauzin, R-La., president and chief executive of the Pharmaceutical Research and Manufacturers of America.

What does he mean? Well, the makers of the patented drugs nearly always try to stretch out their patents through a variety of complicated legal maneuverings. So he’s saying that these pay-to-delay arrangements help to defray PhRMA member legal costs. Well, then, by all means, keep doing what you’re doing – we certainly wouldn’t want a drug company to have to hire an attorney to try to stretch out a patent. Between stretching patent expirations and fighting in court to keep their internal documents that likely reveal questionable marketing practices (or worse) secret, these poor drug companies must be drowning in legal fees. Cry me a river.

On one hand Billy loves the free market. On the other hand, Billy hates competition, which, incidentally is the foundation of the free market! Billy is likewise not a fan of Americans importing drugs from Canada; after all, they would also be a source of competition. Adam Smith must be rolling over in his grave.

Background on this story can be found here and here.

Shadow Statisticians

An interesting new study is available in PLoS Medicine (Gotzsche et al., 2007). Due to the open access of all PLoS articles, you can read it in full for free and I encourage all of you to do so.

In this study, the authors examined 44 trials supported by industry. They examined whether there were contributors listed on the original study protocol (submitted prior to the start of a study) who did not appear on the final published manuscript, which was of course published after the completion of the trial. They found evidence for ghost authorship in 75% of cases. In almost all ghost-suspected cases, the protocol listed that a company statistician would help interpret the data, yet the statistician in question was not listed as an author on the publication.

Why does this matter? This is important because when you are reading an article, you are expecting that the listed authors were responsible for the study design, data collection, data analysis, interpretation, and writing of the paper. Look at the following example:

A paper is listed as having “Independent” Academic Author X, Company Statistician Y, and “Independent” Academic Author Z. It concludes that a drug is highly effective and very safe. Given that it has a company statistician, do you trust its results entirely? Well, if the company statistician is removed, leaving only two “independent” academic authors, then the potential influence of the statistician is removed from plain sight. We are thus more apt to assume the analyses were done objectively, not with an eye toward cherry picking data to show positive results.

To quote from the PLoS article, “[Ghostwriting] might happen because the study ‘looks’ more credible if the true authors (for example, company employees or freelance medical writers) are not revealed.”

But wait, there’s more: The 75% figure is almost certainly an underestimate. Why? Because this study could not detect the presence of ghostwriters – it is rare for a company to mention in a study protocol that a ghostwriter will be used to write a draft of the study manuscript for publication. So how often are ghostwriters used? Healy estimated that among psychiatry papers, perhaps 50% are ghostwritten. If we look at papers that were written up by professional medical writers and/or used company statisticians yet failed to acknowledge them properly in the final manuscript, we are clearly looking at an exceedingly high percentage of papers!

Conclusion: To be clear, a company statistician may conduct analyses properly and a medical writer may write a manuscript that accurately and fairly represents the study’s data as well as the research design’s strengths and limitations. Yet there have been many cases where the statistics in industry-supported studies have been dodgy (for example, here and here) and in which a medical writer has written a draft that is clearly overly optimistic (such as this and this) regarding a treatment.

Analyzing data in a “friendly” manner to a product is just another way in which industry-supported science has largely merged with marketing. I don’t believe that hiding the identities of people who analyzed the data and of the hired gun(s) who wrote the manuscript can be viewed in any other way.

Great Comment on Lilly's Comments

An anonymous reader made a comment suggesting that Lilly may either be losing their minds or that they have reached strange new heights in their attempt to protect Zyprexa. Maybe they need a safe, gentle psychotropic such as Zyprexa to ease their concerns. Anyway, the quote is below, with my added color highlighting and replacing Arthur with Joseph:

Arthur [correction] Joseph Heller could no better than:

"Eli Lilly, in email messages to the BMJ, states that it is pursuing action because 'these individuals have violated a federal court order by leaking the documents' and that it has not released its internal documents publicly because the company 'has no intention of violating that order by releasing documents ourselves.'"

A judge can only require that individuals other than a company do not make a company's proprietary documents public. A company itself can make any and all of its internal memos public at any time. This is a idiotic as a battered wife claiming that a restraining order on her husband also means that she cannot approach within 300 yards of herself.

Some of the people at Lilly were once deemed to be pretty sharp. Either they need something like Zyprexa, or they're blowing deliberate nonsense at the BMJ about an issue that has already made it onto Page One of the Grey Lady.

Neither scenario makes Eli Lilly look all that good.

Sharp witted comments are always welcome -- keep 'em coming!

The Latest On the Zyprexa Docs

From around the blogosphere, here’s what a few folks are saying about the latest Zyprexa developments. Below are quotes from various sites. Some may be reordered and I also provided only snippets. Go to the original posts for more. Any color highlighting is my addition, while italics are from the original authors.

Site: Measuring Up.

I thought I’d seen it all. But Judge Jack B. Weinstein, the presiding justice in the case against Eli Lilly and its hot selling antipsychotic drug, Zyprexa, showed me I hadn’t…

So how does he react? The judge tells this same lawyer that he needs to provide a list of every single recipient who received the “stolen” documents and collect all copies. On top of this, Judge Weinstein ordered that each of these 14 recipients communicate this injunction to everyone else who has since made copies, posted them to a web site or facilitated in the distribution of any information taken from the documents...

What planet is this judge from? It’s simply hilarious that this highly respected individual believes he can control the flow of this information after it has spread virally to thousands or points across the Internet. I’m not sure if he understands what the Internet is (or isn’t for that matter), but by executing this order, it has also made Eli Lilly look extremely foolish in the process. My guess is that most of the individuals who continue to distribute this information have absolutely nothing to do with Eli Lilly’s litigation and are probably passing on interesting fodder like this simply because of their interest in health related issues. Will he prosecute every ordinary citizen (including me) who has passed on the information at hand?

The genie is out of the bottle and no one can put him back. Legal issues aside, it’s time for Eli Lilly to focus on saving its reputation and come clean now.

Site: Health Care Renewal.

I cannot comment on the legal merits of the argument that the Eli Lilly memos about Zyprexa should not have been published.

It does seem to me that any effort to restrict discussion of the case by parties not involved in the case would be a serious general affront to free speech.

Furthermore, to make the best possible medical decisions for individual patients, the patients and their health care professionals need the best possible evidence about the benefits and harms of therapy. Thus, patients, health care professionals, and ultimately the public have a need to know about the benefits and harms of medications like Zyprexa, and about any attempts to suppress or manipulate such evidence by interested parties, particularly the medications' manufacturers.

Although I can appreciate Eli Lilly's interest in having a fair day in court, the company's attempts to corral documents that put its managers in an unflattering light do not enhance trust in how the company is run.

Site: More Health Care Renewal.

The latest issue of the British Medical Journal featured a news article by Jeanne Lenzer about how Lilly has tried to suppress publication of the internal memos on which the Times based its series. [Lenzer J. Drug company tries to suppress internal memos. Brit Med J 2007; 334: 59. ] [BMJ quotes follow]

After the injunction was granted to Eli Lilly the documents rapidly disappeared from the internet. The company was given access to Dr Egilman's [a leaker of said documents] computers for three days for 'forensic examination'; and Mr Reinert said that Eli Lilly has indicated that it wants to seek 'all possible sanctions' against Dr Egilman. The consequences, Mr Reinert said, 'could be very severe' and could conceivably extend to compensatory damages and time in jail.

Mr Gottstein said that Eli Lilly has also warned him of possible 'disciplinary action at the bar.'

Eli Lilly, in email messages to the BMJ, states that it is pursuing action because 'these individuals have violated a federal court order by leaking the documents' and that it has not released its internal documents publicly because the company 'has no intention of violating that order by releasing documents ourselves.'

It added, 'We intend to try the remaining cases in court—not in the news media.' [end of BMJ quote]

This is a chilling development. It seems to me that patients, physicians, and the public ought to know whether Lilly marketed Zyprexa honestly, or whether it sought to deceive, and particularly whether it sought to suppress or manipulate data from trials on patients who thought that the information about them was to be used for the advancement of science, not commercial marketing purposes.

Lilly, of course, has a right to explain its actions, and defend itself from any allegations about its conduct.

But for a drug company to threaten whistle-blowers with "very severe" sanctions, including jail time, in a case like this does not exactly inspire confidence in their commitment to transparency, or to putting the welfare of patients, particularly patients in drug trials, ahead of marketing concerns.

Site: Electronic Frontier Foundation. No quotes here. Contents from some of the legal docs are provided here. If you’re really serious about this case, this is a great resource. It’s the site from whence the above picture came.