Editorial Support, CME, and the Primary Care Companion

By now, everyone who has been paying attention should know that a journal article which lists "editorial support" is an article that was ghostwritten. Yet the average reader of these articles is apparently uninformed enough to not care. Why else would so many articles get published which feature "editorial support provided by [insert name of ghostwriter here]." One my my favorite journals, under the "so bad, it's good" category, is the Primary Care Companion to the Journal of Clinical Psychiatry. Good articles certainly make their way into the journal, perhaps by accident, but the journal can always be counted on to provide a steady supply of utter garbage.

Here's the acknowledgements section from one recent piece in the journal: "Editorial support was provided by George Rogan, MSc, Phase Five Communications Inc, New York, New York. Mr. Rogan reports no other financial affiliations relevant to the subject of this article." And in case you're wondering, "Funding for editorial support was provided by Bristol-Myers Squibb." If you've somehow guessed that this is an advertorial for Abilify, you win. Other ghostwritten pieces of fluff paid for by BMS include an article discussing the safety profile of Abilify in depression. It states that "In conclusion, this post hoc analysis extends previous findings demonstrating that aripiprazole is safe and generally well tolerated as an augmentation strategy to standard ADT in patients with MDD with a history of an inadequate response to antidepressant medication." But Abilify caused akathisia in a quarter of patients - I think that's a problem.

But wait... there's more. An article based on data from two trials, which showed (allegedly) that Seroquel improves anxiety in patients with bipolar disorder. This piece also acknowledges that it was ghostwritten. And we know that AstraZeneca, manufacturer of Seroquel, has cooked the books on Seroquel in the past. Feel free to look through the journal every month and have a giggle at some of the ridiculous pieces that make their way into print.

CME

You can get your continuing medical education (CME) from the Primary Care Companion as well. One particularly awesome piece of medical wisdom pimped Abilify educated physicians about the best ways to manage resistant depression. This one is a beauty. It was supported by cash from BMS, which features prominently in the "treat aggressively" message of the piece. The article features none other than Michael Thase as the leading discussant. The same guy who was the leading author on a paper which allegedly showed the wonders of Abilify for depression - despite the pesky fact that patients said it didn't work.

Back to the CME.. Thase starts off by stating that only a third of patients achieve remission of depressive symptoms during treatment. Given that Abilify is being marketed for treatment-resistant depression, this is a perfect way to start off this infomercial educational piece. He adds that failure to achieve remission increases the risk of suicide and puts people at risk for more depression, worse psychiatric outcomes, and all sorts of other bad things. So we better get rid of all symptoms of depression. Thase suggests that clinicians should closely monitor patients to see if their symptoms are remitting.

In particular, "Relying on the global statement “I’m definitely better” from the patient overlooks persistent, minor, or residual symptoms. Dr Thase recommended using a standardized symptom assessment measure and keeping track of the patient’s levels of symptom burden." So even if the patient says he or she is much better, don't believe it. Have the patient fill out rating scales and if any symptoms at any level are present, keep treating. In Thase's words, "If the current treatment is well tolerated and the individual has made significant symptom improvement but is still experiencing residual symptoms, then it may be necessary to adjust the treatment dose, add another medication, or combine pharmacotherapy and psychotherapy." Note that adding psychotherapy comes after adding another medication.

Then a series of other objective, expert psychiatrists chime in. Dr. Gaynes offers his wisdom, which includes "Dr Gaynes concluded that incomplete remission requires aggressive identification and management." Don't be afraid - be aggressive. The unspoken message: Hey, using an antipsychotic like Abilify for depression may seem freakin' crazy. But don't worry, you need to be aggressive. Dr. Trivedi then comments about using rating scales to measure side effects. I don't have much to say about his section, but things get worse momentarily...

Dr. Papakostas then checks in. "A meta-analysis of randomized, double-blind, placebo controlled studies found that augmentation of various antidepressants with the atypical antipsychotic agents olanzapine, risperidone, and quetiapine was more efficacious than adjunctive placebo therapy. In addition, Dr Papakostas noted that the atypical antipsychotic aripiprazole was recently approved by the US Food and Drug Administration (FDA) for use as an adjunctive therapy to antidepressants in MDD. Augmenting with atypical antipsychotics has so far been the best studied strategy for managing treatment-resistant depression, said Dr Papakostas." Dr. P was the coauthor of a meta-analysis that provided "considerable evidence" regarding the wonders of antipsychotic therapy for depression. The only problem was that the analysis actually did not find convincing evidence that the drugs were particularly effective, which I discussed in December 2009.

Next comes Dr. Shelton. Time to be aggressive, again: "Thus, said Dr Shelton, the long-term management of depression should be viewed in the context of acute treatment and the need for early aggressive management to get the patient as well as possible." Be aggressive by adding Abilify to the antidepressant regimen. If not, your patient won't achieve full remission and will suffer needlessly... "Dr Shelton advised clinicians to be aggressive in treatment and stay active over time, asking themselves if everything has
honestly been done to help the patient." Psychotherapy is given a brief mention in this section, but let's face it -- most physicians think of "be aggressive" as upping the dosage and/or adding medications - not as "let's be aggressive by adding psychotherapy."

Then there's the exam at the end. Write up your answers, mail them in, and get your medical education credit. Here's one of the questions...
3. Scores on both patient- and clinician-rated scales found that Ms B is still experiencing residual depressive symptoms. You optimize her current SSRI dose, which produces some improvement. She has not reported any problems with side effects. What course of action to improve her outcome has the most comprehensive efficacy data?
a. Increase the dose of her current SSRI again
b. Augment her current SSRI with another SSRI
c. Switch her to a serotonin-norepinephrine reuptake inhibitor
d. Augment her current SSRI with an atypical antipsychotic

If you guessed that D is the correct answer, you're one step closer to CME credit. And one step closer to writing a prescription for Abilify despite the fact that it is as likely to induce akathisia as to induce remission of depressive symptoms. Or that its advantage over placebo is small on several measures and nonexistent on a patient-rated measure of depression. But D is still the "correct" answer.



The offending educational piece is cited below:
Thase, M., Gaynes, B., Papakostas, G., Shelton, R., & Trivedi, M. (2009). Tackling Partial Response to Depression Treatment The Primary Care Companion to The Journal of Clinical Psychiatry, 11 (4), 155-162 DOI: 10.4088/PCC.8133ah3c

Lend Me Your Name

Journalism regarding the horrors of ghostwritten papers in medical journals is all the rage these days (1, 2, 3). Here's my very small contribution. The document shown below from a medical writing company has been described elsewhere. But it is worth seeing in its glory firsthand. The document is from Wyeth's ghostwriting firm, DesignWrite. It was part of the Premarin/hormone replacement therapy disaster (see below). Perhaps you remember the era when hormone replacement therapy was being prescribed for all sorts of people because it was supposedly a wonder treatment. So what if it increased risk for breast cancer and perhaps other conditions as well? Not to worry, DesignWrite could get around that...

In layman's terms, it goes like this... Wyeth -- you give us some hints about the marketing spin you'd like us to put on your studies. We'll then write up the studies accordingly and have big-name academics sign off as if they had something to do with our oh-so-objective "research". And don't worry, Wyeth, you get to review all papers we write up to make sure we market your drug appropriately.

We now know that several academics participated in this program. To quote one ethicist, regarding the academics who lent their names as authors: "They sold their credentials for false credit and money." DesignWrite's current slogan is: "Where we put clinical data to work." Hmmm. DesignWrite gets paid, Wyeth gets paid, and the academics who lend their names get paid and/or get another publication to boost their stock in the academic world.

Oh, and patients, what did they get out this... breast cancer. But who cares about them anyway -- patients are just little buckets of money; it's not like they're real human beings.

A summary of the results that led to the downfall of hormone replacement therapy

Three years after stopping hormone therapy, women who had taken study pills with active estrogen plus progestin no longer had an increased risk of cardiovascular disease (heart disease, stroke, and blood clots) compared with women on placebo. The lower risk of colorectal cancer seen in women who had taken active E+P disappeared after stopping the intervention. The benefit for fractures (broken bones) in women who had taken active E+P also disappeared after stopping hormone therapy. On the other hand, the risk of all cancers combined in women who had used E+P increased after stopping the intervention compared to those on placebo. This was due to increases in a variety of cancers, including lung cancer. After stopping the intervention, mortality from all causes was somewhat higher in women who had taken active E+P pills compared with the placebo.

Based on the findings mentioned above, the study’s global index that summarized risk and benefits was unchanged, showing that the health risks exceeded the health benefits from the beginning of the study through the end of this three year follow-up. The follow-up after stopping estrogen plus progestin confirms the study’s main conclusion that combination hormone therapy (E+P) should not be used to prevent disease in healthy, postmenopausal women. The most important message to women who have stopped this hormone therapy is to continue seeing their physicians for rigorous prevention and screening activities for all important preventable health conditions.

I'm glad to see that ghostwriting is now the topic du jour in health journalism. But in a few weeks, the attention will vanish as the drug industry and its associated writing firms will agree to allegedly stringent guidelines that ensure this never happens again. And nothing will actually change. I mean, seriously, do you think academic researchers are going to write their own papers? Do you think drug companies are going to stop hiring writers to expertly spin the data? The current system works too well for it to simply go away.

Thanks to an alert reader for sending this document along. You can search for more documents at the Drug Industry Document Archive, including those from Wyeth and DesignWrite. Happy digging!

Greedy and Ghostly Scientists

Story one: Zachary Stowe, psychiatrist at Emory University becomes Charles Nemeroff, Jr. Read all about it the Carlat Psychiatry Blog and University Diaries. And check out the WSJ Health Blog as well. The gist is that Stowe apparently did not report all of his external income from his many pharmaceutical industry gigs. Better yet, he was a frequent speaker for GlaxoSmithKline, which had the gall to cancel two of his commercial talks. He then wanted GSK to pay him even though he wasn't going to give the speeches. Read the relevant emails toward the bottom of this document. After reading about Stowe, refresh your memory about Golden Goblet Lifetime Achievement Award Winner, former Chair of Psychiatry at Emory University: Charles Nemeroff. Is there something in the water at Emory? Or is that just how we roll in modern academic psychiatry? Stowe is hereby nominated for a coveted Golden Goblet for his string of emails in which he attempted to shake down GlaxoSmithKline. Sometimes I think that the only thing worse than drug companies are the narcissistic academics who they employ as "key opinion leaders." Not all key opinion leaders are jerks; some are probably even able to reasonably balance their industry cash with being good scientists. But Stowe didn't really portray himself as Mr. Nice Guy in his string of soon to be infamous emails.

Oh, and this little gem:

"Especially disturbing is an email between employees at GSK and a public relations (PR) firm that the GSK hired. The email was titled “For your review/Paxil Breast Milk Press Release” and states:

"[P]lease review the attached press release and forward me any comments/edits.
As you may know, Dr. Stowe is on board for publicity efforts and NAME
REDACTED and I are coordinating time to meet with him next week to arm him
with the key messages for this announcement, which is slated for early February.
We are sending the release for your review at the same time in efforts to secure
distribution on Emory letterhead (as you know, would provide further credibility
to data for the media)."

In his testimony, Dr. Stowe confirmed that the press release was written by the PR
firm and concerned his research on Paxil and its presence in breast milk. He also
explained that placing the press release on Emory letterhead, as opposed to GSK letterhead, would make the data more credible to the public."

If I have this straight, Stowe was willing to place a press release written by a PR firm hired by GSK on official university letterhead to enhance its credibility. Apparently he wasn't concerned about his own credibility. Read the full document of Senator Charles Grassley's investigation of Dr. Stowe.

Part 2: Enter the Ghostwriters

One snippet, then go to Bloomberg for the rest:

Ensuring that medical journal articles presented Zyprexa study results in a positive light was one way for Lilly to reach its sales goal, company officials said in its plan, according to the documents. To do that, Lilly officials hired ghostwriters to prepare submissions to journals such as Progress in Neurology and Psychiatry, according to the unsealed documents. “The paper for the Progress in Neurology and Psychiatry supplement has been completed and sent to the journal for peer review,” Kerrie Mitchell, an employee of the public relations agency Cohn & Wolfe, wrote in a Feb. 23, 2001, e-mail to Michael Sale, a Lilly marketing official. The message was among the unsealed files. “We ‘ghost’ wrote this article and then worked with author Dr. Haddad to work up the final copy,” Mitchell said in the e- mail. Eric Litchfield, a spokesman for Cohn & Wolfe, didn’t immediately return a call requesting comment.

The Bloomberg story is based on a recently released set of internal Lilly documents. That's right -- more Zyprexa documents are on the loose. And the first round of documents provided some good stuff (1, 2, 3), so I can't wait to see what kind of chicanery will be revealed by the latest round. In one sense, it's not exactly news that Lilly ghostwrote Zyprexa papers. We all know that ghostwriting is rampant. How else do key opinion leaders get their names on dozens of papers per year when they are also flying around the country pimping drugs, holding administrative meetings, and doing all sorts of other tasks? But it's nice to have it officially documented that Lilly was playing the ghostwriting game with Zyprexa.

Abilify, Depression, and the Memory Hole

The Primary Care Companion to the Journal of Clinical Psychiatry has a piece on Abilify for depression that illustrates many of psychiatry's woes. Full text of the article is here. The journal published an article titled "Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of two studies." The paper combines data from two previously published studies which examined the addition of Abilify to existing antidepressant treatment (1, 2). One of psychiatry's big-name academics, Michael Thase, signed on as lead author. I'm hoping that he didn't actually write the paper. Actually, there are eleven authors of the paper, which seems a little ridiculous given that the paper is an analysis of data which had already been collected for two previously published clinical trials. Seven of the authors are employees of Bristol-Myers Squibb (BMS) or Otsuka, which both market Abilify. Wait... If you look closely, you can see my favorite disclosure... In the fine print on the first page...

In case you can't read the fine print: In defense of Thase and the other academic authors, they may have not actually written any of the paper. Much or all of the writing appears to be creditable to Ogilvy Healthworld Medical Education. On their site, they note that they perform:

Clinical Development and Publications Management
Experienced medical writers work closely with authors, editors and publishers to provide our clients with a full range of publishing options.

Whatever BMS/Otsuka paid you for this one simply was not enough. Why? Because whomever wrote this thing did an admirable job of focusing on the positive and completely ignoring the negative.

Erasing the Patient's Opinions: Remember, the article's title states that it examines the efficacy of adjunctive Abilify (adding Abilify to existing antidepressant treatment). So you'd think the article would mention all of the relevant depression data from the two relevant studies. Well, no. In the two stuides which are discussed in the article, patients were assessed on depression using the following measures:

• Montgomery Asberg Depression Rating Scale (MADRS)
• Inventory of Depressive Symptoms-Self Report Scale (IDS)
• Quick Inventory of Depressive Symptoms Self-Report Scale (QIDS)

Using the MADRS, the authors conclude that adding Abilify to antidepressant treatment is more effective than adding placebo to antidepressant treatment. OK, fine, though it's not by a particularly huge margin. Mysteriously, the authors do not even mention that the self-report scales (IDS and its subscale, the QIDS) were used in the two trials. And why would they? In both trials, Abilify was not significantly better than placebo on these measures. A letter to the editor pointed out this glaring weakness in Abilify's claims of efficacy, the response to which was weak:

Noting that Abilify did not outperform placebo on the self-report measure in the trial, he wrote that "this may be due to the lower sensitivity" of the measure. So the drug wasn't the failure -- blame the rating scale instead. The people at BMS picked the scale and when it doesn't give results they like, then suddenly it's a poor measurement of depression. I bet Dr. Berman would not have complained about the instrument had it yielded results in favor of Abilify.

In the publications of each of the two clinical trials, the authors tried to downplay the fact that Abilify was no better than placebo according to patient self-reports. Then, when publishing an analysis that combined the results of the two trials, the authors go a step further by not even mentioning that patients completed a self-report. Right down the memory hole. In my opinion, any reasonable academic author writing about such research would want to note the strengths and limitations of Abilify in treating depression. The lack of benefit on patient-rated measures is a major weakness. Yet several big-time academics signed off on this paper despite its complete scrubbing of negative data. For that, I hereby nominate each author for a coveted Golden Goblet Award. And I credit the ghostwriter at Ogilvy with a fantastic job of serving his/her corporate clients. You, sir or ma'am, deserve kudos for a marketing job well-done.

The instructions for authors who submit to the Primary Care Companion to the Journal of Clinical Psychiatry state: "Conclusions should flow logically from the data presented, and methodological flaws and limitations should be acknowledged." Um, does completely scrubbing negative data count as failing to acknowledge limitations? I can see that the peer reviewers and/or editor really paid close attention to this paper.

Safety: The authors note that "adjunctive aripiprazole is relatively well-tolerated in patients with MDD." Relatively? Relative to what -- being hit with a baseball bat repeatedly? They note that akathisia occurred in 25% of patients on Abilify compared to 4% of patients on placebo. Restlessness: 12% vs. 2%; insomnia: 8% vs. 3%; fatigue: 8% vs. 4%; blurred vision: 6% vs 1%. The authors report that akathisia resolved in 52% of patients by the end of the study, which would also mean that for 48% of patients with akathisia, they were stuck with it at the end of the study. But don't worry, it's "relatively well-tolerated."

Overall, another example of a "research" publication being little more than a puff piece in favor of a drug. With big-name academics signed on as authors to add credibilty and just a fine print mention of a ghostwriter.

I thank an anonymous reader for alerting me to this study.

Citation:

Thase ME, Trivedi MH, Nelson JC, Fava M, Swanink R, Tran Q, Pikalov A, Yang H, Carlson BX, Marcus RN, Berman RM (2008). Examining the efficacy of adjunctive aripiprazole in major depressive disorder: A pooled analysis of 2 studies Primary Care Companion to the Journal of Clinical Psychiatry, 10, 440-447

Effexor Beats SSRIs (Kind of, Sort of, In a maybe meaningless way...)

A recent study in the journal Biological Psychiatry claimed to show that Effexor's (venlafaxine's) alleged advantages over SSRIs "may be of public health relevance." Unstated in the article, but a more accurate reading of their findings, is that antidepressants yield little benefit over a placebo. I'm breaking this into two parts. The current post deals with the authors' claims regarding venlafaxine's superiority over SSRIs. A second post will examine their understated finding that antidepressants are not particularly impressive compared to placebo.

The study was a meta-analysis, where data from all clinical trials comparing Effexor to an SSRI were pooled together. The authors used remission on the Hamilton Rating Scale for Depression (HAM-D) as their measure of treatment effectiveness. On the HAM-D, a score of less than or equal to 7 was used to define remission. They found that remission rates on Effexor were 5.9% greater than remission rates on SSRIs. Thus, one would need to treat 17 depressed patients with Effexor rather than an SSRI to yield one remission that would not have occurred had all 17 patients received an SSRI. Not a big difference, you say? Here's what the authors said:

...the pooled effect size across all comparisons of venlafaxine versus SSRIs reflected an average difference in remission rates of 5.9%, which reflected a NNT of 17 (1/.059), that is, one would expect to treat approximately 17 patients with venlafaxine to see one more success than if all had been treated with another SSRI. Although this difference was reliable and would be important if applied to populations of depressed patients, it is also true that it is modest and might not be noticed by busy clinicians in everyday practice. Nonetheless, an NNT of 17 may be of public health relevance given the large number of patients treated for depression and the significant burden of illness associated with this disorder. [my emphasis]

Public Health Relevance/Remission: The public health claim is pretty far over the top. If one had to treat 17 patients with Effexor to prevent a suicide or homicide that would have occurred had SSRIs been used, then yes, we'd be talking about a significant impact on public health. But that's not what we're dealing with in this study. The outcome variable was remission on the HAM-D, which is a soft, squishy measure of convenience. The authors state that remission rates are "the most rigorous measure of antidepressant efficacy," but to my knowledge there is no evidence supporting their adoption of the magic cutoff score of 7 on the HAM-D as the definition for depressed/not depressed. Are people who scored 8 or 9 on the HAM-D really significantly more depressed than people who scored 6 or 7? Take a look at the HAM-D yourself and make your own decision. I know of not a single piece of empirical data stating that such small differences are meaningful. So I'm not buying the public health benefit -- in fact, I think it is patently ridiculous.

Outcome measures can be either categorical (e.g., remission or no remission) or continuous (e.g., change on HAM-D scores from pretest to posttest). Joanna Moncrieff and Irving Kirsch discuss how using cut-off scores (categorical measures) rather than looking at mean change (continuous measures) can result in the categorical measure making the treatment appear much more effective than examination of continuous measures. Applied to this case, one wonders why the data on mean improvement was not provided. One can make a very weak case that Effexor works better than SSRIs based on an arbitrary categorical measure but not one shred of data was presented to show superiority on a continuous measure. If the data supported Effexor on both categorical and continuous measures, then I'd bet they would have been discussed in this article, as it was funded by Wyeth (patent holder for Effexor). Thus, the absence of data on continuous measures (e.g., difference in mean improvement on the HAM-D between Effexor-treated patients and SSRI-treated patients), is suspicious.

Even if the authors decided to use only categorical measures, it would have been nice had they opted to use multiple measures. They could have used the equally arbitrary 50% improvement criterion (HAM-D scores drop by 50% during treatment), for example. However, such data were not provided. So the authors decided to use one highly arbitrary measure, on which they found a very small benefit for venflafaxine over placebo. Whoopee.

I received an email from a respected psychiatrist (who shall remain anonymous) about this study. He/she opined:

...it would have been interesting if the authors had used other cutoffs for the Hamilton scale besides 7 to define remission; i.e., if they had done a sensitivity analysis. Apparently, Wyeth has all the raw data from the studies, so a lot of interesting science could be done with this very large aggregate database. For example, there are robust factor analyses of the Hamilton scale that indicate reasonably independent dimensions of depressed mood, agitation/anxiety, diurnal variation, etc., and it would be of great interest to determine the relative effects of the various drugs on these different illness dimensions

In other words, the authors could have attempted to see if there were meaningful differences between Effexor and SSRIs on important variables, yet they opted to not undertake such analysis. A skeptical view is that they analyzed the data in such a fashion, found nothing, and thus just reported the "good news" about Effexor. I don't know if they conducted additional analyses that were not reported. However, it would seem to me that someone at Wyeth would have run such analyses at some point, perhaps as part of this meta-analysis, because any advantage over SSRIs would make for excellent marketing copy. In fact, Effexor has been running the "better than SSRIs" line for years, based on rather scant data. If there were more impressive data, they would have been reported by now.

Prozac and the Rest: The findings showed that Effexor was only superior to a statistically significant degree (i.e., we'd not expect such differences by chance alone) when compared to Prozac (fluoxetine). The authors, to their credit, pointed this out on multiple occasions. However, their reporting seems a little contradictory when, on one hand, they report that venlafaxine was superior to SSRIs as a class (see quote toward the top of the post), but then note that the differences were only statistically significant when compared to Prozac. The percentage difference in remission favoring Effexor over Zoloft (sertraline) was 3.4%, over Paxil (paroxetine) was 4.6%, Celexa (citalopram) was 3.9%, and Luvox (fluvoxamine) was 14.1%. I think just about anyone would concur that the difference versus fluvoxamine seems too high to be credible, and it was based on only one study, making the fluke factor more tenable. Again, the advantage of Effexor over all SSRIs except Prozac was not statistically significant. Even if these differences were statistically significant, would the authors claim that needing to treat 26 patients with Effexor rather than Celexa to achieve one additional depression remission would improve public health? Small differences on a soft, squishy, arbitrary endpoint combined with not performing (or not reporting) more meaningful data = Not news.

The Editor Piles On: In a press release, the editor of the journal in which this article appears jumped on board in a big way:

Acknowledging the seemingly small advantage, John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System, comments that this article “highlights an advance that may have more importance for public health than for individual doctors and patients.” He explains this reasoning:

"If the average doctor was actively treating 200 symptomatic depressed patients and switched all of them to venlafaxine from SSRI, only 12 patients would be predicted to benefit from the switch. This signal of benefit might be very hard for that doctor to detect. But imagine that the entire population of depressed patients in the United States, estimated to be 7.1% of the population or over 21 million people, received a treatment that was 5.9% more effective, then it is conceivable that more than 1 million people would respond to venlafaxine who would not have responded to an SSRI. This may be an example of where optimal use of existing medications may improve public health even when it might not make much difference for individual doctors and patients."

Seeing a journal editor swallow the Kool-Aid is not encouraging. Again, the 5.9% difference is based on an endpoint that may well mean nothing.

Ghostwriter Watch: Who wrote the study and who conducted the analyses? The authors are listed as Charles Nemeroff, Richard Entsuah, Isma Benattia, Mark Demitrack, Diane Sloan, and Michael Thase. Their respective contributions are not listed in the text of the article. The contribution of Wilfrido Ortega-Leon for assistance with statistical analysis is acknowledged in the article, as are the contributions of Sherri Jones and Lorraine Sweeney of Advogent for "editorial assistance."

Ortega-Leon appears to be an employee of Wyeth. So did an employee of Wyeth run all of the stats, then pass them along to the authors for writeup? Last time I checked, there were sometimes problems associated with having a company-funded statistician run the stats then pass them along without any independent oversight. I don't know what happened, but my questions could have been easily resolved: Describe each author's contributions in a note at the end of the article.

Sherri Jones and Lorraine Sweeney have served in an "editorial assistant" role for other studies promoting Effexor, such as this one. I suspect that they are familiar with the key marketing messages for the drug. An important question: What does "editorial assistance" mean? Did Jones and Sweeney simply spell-check the paper and make sure the figures looked pretty? Did they consult the authors to get the main points, then fill in a few gaps? Or did they write the whole paper then watch the purported authors rubber-stamp their names on the author byline? Simply listing "editorial assistance" is not transparency. I have no problem with medical writers helping with a manuscript, depending on what "helping" means. Many researchers are not skilled writers and cleaning up their writing is a good idea for all parties. But having a medical writer who is paid by a drug company to make sure that key marketing messages are included in the paper can lead to problems.

Part 2, regarding the unemphasized, but important, finding from this study that antidepressants yield mediocre benefits over placebo.

Update (03-03-08): See comments. A wise reader has pointed out that there are actually three authors from Advogent. Well, um, one author and two editorial assistants. A skeptical person would add that the presence of three medical writers and a Wyeth statistican who appears in a footnote at the end of the study obviates the need for those pesky academic authors except for the need to lend the study a stamp of approval from "independent scientists." Is that too cynical?

Advertising as Education: CME Part Deux

I had the good fortune to read the Journal of Clinical Psychiatry supplement which featured Dr. Henry Nasrallah (the author) sneaking in some friendly messages about ziprasidone (Gedon), the antipsychotic from Pfizer that has been dwarfed by its competitors such as Zyprexa, Seroquel, and Risperdal. The piece discusses the findings of the CATIE study, which compared several newer antipsychotics to an older medication, perphenazine, and generally found that the newer and older drugs were of roughly equal effectiveness and that olanzapine had the worst safety profile. I thank an alert reader for passing the article along.

CME Overview: The good news is that physicians can read this article and take a quiz as part of the continuing medical education (CME) that helps them maintain their licenses. The bad news is that these articles are often thinly veiled advertisements for a product or a message that supports a product.

Highlights: It is stated that the difference favoring olanzapine (Zyprexa) over ziprasidone in terms of efficacy was not significant after a statistical adjustment (granted, this seems like a legitimate argument). It then mentions that olanzapine had the worst metabolic profile in terms of effects on weight, blood glucose, glycosylated hemoglobin, cholesterol, and triglycerides. It then states “In contrast, patients treated with ziprasidone had the best overall metabolic profile.” It places some numbers in a table regarding the metabolic effects of the various drugs in the CATIE study but provides not a single statistical analysis (or reference to an analysis on CATIE data) backing its assertion that it is significantly better than all other drugs in terms of metabolic profile.

The piece then turns to a secondary phase of the CATIE study, in which patients who discontinued their medications in the first phase of CATIE were assigned to other medications. It mentions olanzapine weight gain then mentions that patients on ziprasidone lost weight. It then discusses weight loss on ziprasidone again, then moves on to ziprasidone being associated with decreases in cholesterol and triglycerides, whereas olanzapine was associated with gains in both of these measures.

In case readers have been sleep-reading through this piece, it then moves to state that “except for clozapine, olanzapine clearly caused the heaviest burden of metabolic side effects. Ziprasidone, on the other hand, was consistently associated with the most benign side effect profile.”

Then, the piece moves to scare the reader about older antipsychotics and their risk of inducing extrapyramidal symptoms [EPS]. “The clinician must carefully decide whether the lower cost of the typical antipsychotic is worth the potential striatal neurotoxicity manifested by acute extrapyramidal side effects and long-term TD [tardive dyskinesia].” Of course, he must be assuming that atypical antipsychotics never or rarely induce EPS, which appears to be wrong and that all older medications induce EPS at the same rate as Haldol, which is likewise incorrect (1, 2).

Overall Message: The bottom line message of the piece is clear. Geodon is safe; Zyprexa is unsafe. Don’t use older meds because they’ll cause EPS – ziprasidone won’t. In fact, Geodon is the safest of the second generation antipsychotics.

Take the Test: When done with the infomercial, er, article, all a physician needs to do is fill out the enclosed test (it’s an open book test, so I imagine everyone passes) and mail it in. Physicians can even complete the test online. [this section was taken directly from an earlier post]

Ghostwriter Watch. Who wrote the article? You tell me – I’m confused. Here’s what is written in the article…

This article is derived from the planning teleconference “Evaluating the Evidence: Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and Beyond,” which was held on May 10, 2006, and was independently developed by the CME Institute of Physicians Postgraduate Press, Inc., and Health and Wellness Education Partners (HWeP) pursuant to an educational grant from Pfizer and addition support from HWP Publishing

Dr. Nasrallah is a consultant for, has received honoraria from, and been on the speakers/advisory boards for Abbott, AstraZeneca, Janssen, Pfizer, and Shire and has received grant/research support from AstraZeneca, Janssen, and Pfizer.

Content development and writing support for this article was provided in part by an independent writer contracted by HWeP: Martin Korn, M.D., a psychiatrist in private practice in New York.

I may be piecing this together wrong, but here goes… Pfizer writes a check to the CME Institute and HWeP. Nasrallah and a few other bigwigs engage in a conference call and are reimbursed (likely quite well) for their time. HWeP hires Martin Korn to write the piece, which then is reviewed, likely in a cursory manner at most, by Dr. Nasrallah. The piece is then reviewed by a member of the CME Advisory Board. These "reviews" appear to be consist of a race to grab the rubber stamp as quickly as possible.

I’m not sure if Pfizer provided the talking points directly to Dr. Korn, but it seems he got the message that Zyprexa and older meds should be slammed while Geodon should come across looking angelic. The CME Institute then stamps their approval and we call all be assured that doctors are being “educated” about the latest and greatest treatments in a purely objective fashion.

Please also feel free to read my earlier piece on CME. I recall seeing Dr. Korn's name on an earlier CME piece similar to this, but I can't seem to track it down.

Don't be confused -- I'm not defending Zyprexa. Geodon appears to be a safer drug than Zyprexa, but this quite thinly veiled advertisement that masquerades as independent education is ludicrous -- how does reading or watching commercials passing for "education" help physicians make better decisions for their patients?

Paxil and Pimping

A preliminary ruling has indicated that GlaxoSmithKline should pay out $63.8 million to make amends for making misleading claims about its antidepressant Paxil (Seroxat) in kids. Of course, the company admits no wrongdoing.

I wonder if the authors who stamped their names on the the main ghostwritten "scientific" publication for Paxil in kids should also be shelling out some cash. After all, it was the paper (chock full of HUGE misinterpretations of the study data) with their names on it that was doubtlessly used as part of the Paxil in kids marketing campaign. Were these "independent" academics innocent parties who were misled by the corporate meanies at GSK? Or, conversely, were these academics an integral part of the marketing team and should they also be held accountable for making false claims? Like these claims made in the infamous GSK study 329 (from an earlier post)...

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.

What counts as safe and effective on Planet Paxil passes as ineffective and dangerous to us Earthlings. So while I'm glad to see that it appears GSK will be shelling out some dough to compensate its , consumers, the systemic problems of ghosted science and outright lying are not addressed. What is $64 million to GSK? Roughly a drop in the bucket. And the "key opinion leaders" who pimped Paxil escape unscathed.

Please read the fine post at Health Care Renewal about how academics might be brought to think twice before becoming drug pimps. I also think that giving out sarcastic awards to academics who participate in ghosted science is a good idea, so here goes...

Awards? I'd like to nominate Dr. Karen Wagner for a Golden Goblet, or perhaps a Krusty the Klown award for her pimping of Paxil as well as her stalwart work on the "SSRIs are great for kids" report authored on behalf of the American College of Neuropsychopharmacology. Her reports of clinical trials that overstated the efficacy and hid serious side effects of Zoloft also merit special mention. Overstating the efficacy of citalopram in kids was also nice work. While she was co-authoring the report saying that SSRIs are great for kids, she was also busy conducting trials of SSRIs for kids. Sound like a conflict of interest? Worry not, because she was also sitting on the conflict of interest committee at her own university!

Please feel free to add your nominations.

Oh, and as for the latest version of SSRIs are great for kids report (in JAMA). I'll hopefully get on that sometime in the near future. Suffice to say that it is highly misleading for now.

Medical Writers Moving Up The Ladder

I suppose that the American Medical Writers Association can stand proud and tall. After all, a medical writer seems to have some major pull at Lilly. What am I talking about?

According to documents reviewed by, and available on, Furious Seasons, it seems that the medical writer has a lot of input, perhaps more than the doctors who were running the study, such as Maricio Tohen.

OK, yes, she is a medical writer, so she should write about medical stuff. I'm not denying that. The writer seems to be doing much more than just summarizing study results -- she seems actively involved in spinning the data: "John [Saunders; Regulatory official for Lilly in Europe], here is how I rewrote the HGHL disposition section to try to soften the "only 66 completers language..."

In this study, 53 of 225 olanzapine patients made it to the end of one year on treatment without dropping out. That is a whopping 23.6%. Placebo patients also appeared to have not fared well (only 9.6% completed the year), but the numbers on efficacy and safety and not discussed in much detail in the document outside of some unfavorable data on glucose (more on that later). The point is that the writer is actively attempting to "soften" the language, likely in an attempt to make olanzapine appear more efficacious.

The medical writer is celarly deeply involved with writing whatever this publication turned out to be. I don't know what happened to this publication. Perhaps it was submitted to some refulatory agency? My concern is that this may be reflective of general practice -- the medical writer "softens" language as appropriate and the doctors whose names appear on the study may actually contribute a relatively minimal amount (or none at all) to the final study writeup.

Maybe I'm reading too much into this?

CPP Psychiatrist Wins Award

I'm not sure if this means I can say my site is "award winning," but I can say (with pride?) that one psychiatrist I mentioned on this site recently has been awarded the prestigious Krusty the Klown Award.

The award went to Dr. Siegfried Kasper. In the words of Furious Seasons' Philip Dawdy, who presented (and invented) the award:

[CPP had a post last week about] Siegfried Kasper who likes to affix his name to studies he's never written. Once upon a time, this same clown also stuck his name on a paper David Healy refused to slap his name on for a Phamra [sic] company. And while I know it's fun to bitch about docs doing shady unscientific things and then call the result double-blind, peer-reviewed gold-standard science, I think I need to get into the proper spirit of how medicine really works and give out awards for such behavior. It is in that spirit that I bestow Furious Seasons' first Krusty The Klown Award upon Dr. Siegfried Kasper.

And…

You remember Krusty, right? "I heartily endorse this event or product" was his mantra. I'm sure Kasper knows it by heart.

I only know for sure that Kasper put his name on one paper he did not write, but given that he has purportedly "authored over 800 research reports and reviews," I think it is certainly possible that some of his other work is ghostly. For a little background, see an earlier post here. For more on Krusty-endorsed products, see here.

More on the Krustification of psychiatric "research" coming soon, hopefully.

Puff Pieces and Ghostwriting

The journal European Neuropsychopharmacology ran a supplement issue in Sepotember 2006 titled:

September 2006, Pages S149-S155
From the Clinic to the Community: Treating the Whole Schizophrenic Patient and Innovation in Psychiatric Therapy: The Promise of the New Antipsychotics

What is a supplement issue? It is a journal issue paid for by drug companies (GlaxoSmithKline, in the case of this particular supplement) which control the content contained in this issue. Isn't that just an advertisement, you ask? I'm not sure what else you could call it, but the words independent and scholarly certainly do not apply.

Siegfried Kasper has an advertisement, er, article in which he says (with my emphasis): "The use of atypical agents to address the full range of psychotic symptoms with minimal adverse effects should ensure improved functionality and an improved patient quality of life in patients with schizophrenia: both can be regarded as positive reinforcers for long-term compliance."

Who is Siegfried Kasper? Let's find out. David Healy was given a ghostwritten article a few years ago to which he was expected to attach his name. However, he made several changes to the paper. In fact, it was altered to the extent that it no longer served its originally intended purpose as an advertisement for milnacipran. So, the paper that was originally ghostwritten and sent to Healy was forwarded to an Austrian psychiatrist. The psychiatrist was Siegfried Kasper and he attached his name to the paper, making not a single change. In other words, someone wrote an article intended to serve as an advertisement for milnacipran, and Kasper affixed his name to it as if it were his own work. In fact, to quote from the Guardian...

… the original, ghostwritten article which contained what they described as "the main commercially important points" was to be there too. "Siegfried Kasper has kindly agreed to author this one," they said. The name of Professor Kasper of the University of Vienna, editor of the journal, duly appeared on the unaltered, published article, complete with the original references to Dr Healy's work. Professor Kasper told the Guardian that he was happy with the content of the article.

According to one source, Kasper has “authored over 800 research reports and reviews.” One is left to wonder how many of those were actually written by him versus written by ghostwriters and rubber stamped under his name.

When academics are willing to sell their names and reputations, how can the university system function as an independent check on the claims made by drug manufacturers?

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.