note to self…

Posted on Friday 5 September 2014

My last post about Zoloft® and it’s approval [an echo that needs to keep reverberating…] got me thinking about a number of things. In the UPDATE, I finally found that Laura A. Plumlee et. al. v. Pfizer had been denied on a technicality for the second time just this week. I also found a Louisiana Suit filed on the same grounds:
Courthouse News
October 29, 2013

Pfizer defrauded the public about its blockbuster antidepressant Zoloft by writing its own articles about it for medical journals and paying medical researchers to put their names on them, in a brazen campaign of "fraudulent and wanton marketing, selling and labeling," Louisiana’s attorney general claims in court. Attorney General Buddy Caldwell claims Zoloft is barely more effective at treating depression than a placebo, but Pfizer has persuaded doctors and consumers otherwise. In its lawsuit in East Baton Rouge Parish Court, the state claims Pfizer engaged in "false, misleading, unfair, and deceptive acts in the marketing, promotion, and sale" of Zoloft, affecting the elderly, disabled and "most needy" Louisiana citizens covered by the state’s Medicaid program…
Long before Zoloft was approved by the FDA, Pfizer knew it had "serious issues with efficacy" because in early Zoloft trials, the placebo group actually had better results, the state claims. "These early trials showed that ‘placebo still seems to be the most effective group’ and that "there is still no striking evidence of beneficial drug effect with placebo often being the superior treatment,’" the complaint states. "Nonetheless Pfizer chose to go forward in attempting FDA approval."

The attorney general claims that to do this, Pfizer published only information that pertained to Zoloft efficacy, and suppressed conflicting studies. Pfizer then engaged in a "ghostwriting program to misleadingly enhance Zoloft’s credibility," the lawsuit states. "Ghostwriting is a process where someone with a vested interest in an article, like Pfizer, that does not want their association with the article to be known, provides a written draft to an author who then publishes the article under that author’s name," the complaint states. "The published article contains no express or implied association with the interested person – Pfizer’s involvement in drafting the article is unknown to the public. Not surprisingly, ghostwritten articles tout the benefits and efficacy of the drug in question."

In fact, the state claims, Pfizer realized it could ensure Zoloft’s success through "manufacturing ‘research’ and articles that enhance Zoloft’s safety and credibility." Pfizer, or a company hired by Pfizer, would write a study specifically designed to showcase Zoloft’s effectiveness, and Pfizer would then pay prominent members of the medical field to put their name on the articles, and to "ultimately conceal all Pfizer involvement," the complaint states. "Publication of clinical findings is the ultimate basis for treatment decisions; thus Pfizer’s misleading publications regarding Zoloft efficacy are a key component of its fraudulent scheme," the attorney general says.

"An internal Pfizer document demonstrates its ghostwriting and selective publication scheme in full effect," the complaint states. "First, the document clearly reveals the intent to manipulate inefficacy results in a published manuscript: ‘… but now we need some help in dealing with the most important issue … i.e. the huge placebo response in the continuation phase which wiped out the significant superiority of Zoloft at six weeks.’ "The email goes on to list a number of ways to deal with the placebo response, including ‘using less stringent criteria for relapse’ and the suggestion that ‘Table III certainly must be deleted.’ Lastly, the email requests ‘the list of French investigators identifying the proposed authors. [Emphasis added.]

"Pfizer’s ghostwriting operation and its selective publication of data, prevented healthcare providers, consumers, and ultimately the State of Louisiana from obtaining accurate information regarding the efficacy of Zoloft. Pfizer’s scheme directly influenced the prescribing practices of healthcare providers through its misleading and inaccurate information bolstering Zoloft’s efficacy"…
I don’t know if the Louisiana v. Pfizer was piggy-backed onto Plumlee v. Pfizer and whether it was also blowing in the wind [Note to self: Find out]. But moving right along, George Dawson of Real Psychiatry commented on my last post bringing up a large meta-analysis of the antidepressants published in 2009 that looked at head-to-head studies of the antidepressants [studies comparing multiple drugs] and picked Zoloft® as the first-line drug [published after Zoloft’s patent expired]:
by Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, and Tansella M, and Barbui C
Lancet. 2009 373[9665]:746-58.
BACKGROUND: Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression.
METHODS: We systematically reviewed 117 randomised controlled trials [25 928 participants] from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis.
FINDINGS: Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine [odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively], fluoxetine [1.37, 1.32, 1.28, and 1.25, respectively], fluvoxamine [1.41, 1.35, 1.30, and 1.27, respectively], paroxetine [1.35, 1.30, 1.27, and 1.22, respectively], and reboxetine [2.03, 1.95, 1.89, and 1.85, respectively]. Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine.
INTERPRETATION: Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.
It is an extensive review, in fact, part of a family of publications in journals and the subject of several Cochrane Systematic Reviews by this group analyzing the head to head antidepressant studies. It seems to be well conducted by a credible team. But there’s another side to the story. It relies on published papers. And whole lot of those published papers were funded by Pfizer and prepared by Current Medical Directions, a medical writing firm:

BACKGROUND: Changes in the character of medical authorship. Aims To compare the impact of industry-linked and non-industry linked articles.
METHOD: We compared articles on sertraline being coordinated by a medical writing agency with articles not coordinated in this way. We calculated numbers of Medline-listed articles per author, journal impact factors, literature profiles and citation rates of both sets of articles.
RESULTS: Non-agency-linked articles on sertraline had an average of 2.95 authors per article, a mean length of 3.4 pages, a mean Medline listing of 37 articles per author [95% CI 27-47] and a mean literature profile of 283 per article [95% CI 130-435]. Agency-linked articles on sertraline had an average of 6.6 authors per article, a mean length of 10.7 pages, a mean Medline listing of 70 articles per author [95% CI 62-79] and a mean literature profile of 1839 per article [95% CI 1076-2602]. The citation rate for agency articles was 20.2 [95% CI 13.4-27.0] and for non-agency articles it was 3.7 [95% CI 3.3-8.1].
CONCLUSIONS: The literature profiles and citation rates of industry-linked and non-industry-linked articles differ. The emerging style of authorship in industry-linked articles can deliver good-quality articles, but it raises concerns for the scientific base of therapeutics.
Am I suggesting that the ghostwritten literature on Zoloft® is extensive enough or distorted enough to skew a meta-analysis of all published head-to-head clinical trials? I don’t know that, so I guess the answer is currently unknown. But after reading the Louisiana suit and this article, I’m curious [Note to self: Look for the emails and documents referenced above]. There has to be some explanation for the discrepancy between the lackluster FDA Approval data and its glowing performance in the literature [and in the marketplace]…
    September 5, 2014 | 3:51 PM

    I believe the distortion of Cochrane reviews by pharma-sponsored publications is a major protest point brought up by the Nordic Cochrane Center.

    James O'Brien, M.D.
    September 9, 2014 | 11:03 AM

    One way to keep ourselves honest is to maintain the same standards of critical analysis to the treatment we all seem to like (psychotherapy). However, I found this article from 2007 comparing psychotherapy to Paxil, finding both equally efficacious. However, if we are claiming Paxil is hardly better than placebo, what does this say about psychotherapy?

    My anecdotal experience with psychotherapy is that it works, not just for symptom relief but for personality change. However, “in my experience” is not EBM.

    What is the right control group in a psychotherapy experiment? I see a lot of problems with the wait list. For one, being waitlisted on anything creates anxiety and frustration. I think a good control group placebo is to train intelligent actors with no experience as a psychotherapist to listen and imitate what a psychotherapist does.

    James O'Brien, M.D.
    September 10, 2014 | 12:24 PM

    I found this John Grohol article expressing the same concerns and a similar solution:

Sorry, the comment form is closed at this time.