smell a campaign…

Posted on Wednesday 29 February 2012

Why the sudden interest in Cymbalta and Pristiq, you ask? Something got stuck in the back of my mind that lit up finally this morning: Why would Robert Gibbons still be trying to debunk the FDA Black Box Warnings about suicidality on antidepressants [Suicidal Thoughts and Behavior With Antidepressant Treatment]? Why would he study Prozac and Effexor? The drugs are off patent. I’ve gotten so suspicious that my mind immediately looks for some angle – and this morning an angle occurred to me. Eli Lilly [Prozac] and Pfizer [Effexor] are the two manufacturers that still have antidepressants on the market under patent [Cymbalta and Pristiq], carrying that pesky FDA required warning on the package insert with every bottle. Having used nor read about either drug, I thought I’d take a brief look:
    DULOXETINE [Cymbalta] Eli Lilly
    Duloxetine was created by Lilly researchers. David Robertson, David Wong, a co-discoverer of fluoxetine, and Joseph Krushinski are listed as inventors on the patent application filed in 1986 and granted in 1990… Initial trials conducted in patients using regimens of 20 mg/day or less did not convincingly demonstrate its efficacy and the dose was increased to as high as 120 mg in subsequent clinical trials.

    In 2001 Lilly filed a New Drug Application [NDA] for duloxetine with the US Food and Drug Administration [FDA]. However, in 2003 the FDA "recommended this application as not approvable from the manufacturing and control standpoint" because of "significant cGMP [current Good Manufacturing Practice] violations at the finished product manufacturing facility" of Eli Lilly in Indianapolis. Additionally, "potential liver toxicity" and QTc interval prolongation appeared as a concern. The FDA experts concluded that "Duloxetine can cause hepatotoxicity in the form of transaminase elevations. It may also be a factor in causing more severe liver injury, but there are no cases in the NDA database that clearly demonstrate this. Use of duloxetine in the presence of ethanol may potentiate the deleterious effect of ethanol on the liver." The FDA also recommended "routine blood pressure monitoring" at the new highest recommended dose of 120 mg, "where 24% patients had one or more blood pressure readings of 140/90 vs. 9% of placebo patients."

    After the manufacturing issues were resolved, the liver toxicity warning included in the prescribing information, and the follow-up studies showed that duloxetine does not cause QTc interval prolongation, duloxetine was approved by the FDA for depression and diabetic neuropathy in 2004. In 2007 Health Canada approved duloxetine for the treatment of depression and diabetic peripheral neuropathic pain… The FDA approved duloxetine for the treatment of generalized anxiety disorder in February 2007.

The FDA Review for Duloxetine was complex. There were initial submissions in 2001 and follow-up studies later. Here’s a rough summary. The paired studies are identical in design:
    POSITIVE: drug separates from placebo.
    NEGATIVE: drug does not separate from placebo, but comparator does.
    FAILED: both drug and comparator fail to separate from placebo.

These two graphs are the kind of separations seen in the rest of these studies.

And, of course, no one likes reading this:

    DESVENLAFAXINE [Pristiq] Pfizer [Wyeth]
    Desvenlafaxine … is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class developed and marketed by Wyeth [now part of Pfizer]. Desvenlafaxine is a synthetic form of the major active metabolite of venlafaxine [sold under the brand names Effexor and Efexor]. It is being targeted as the first non-hormonal based treatment for menopause.
    UNITED STATES: Wyeth announced on 23 January 2007 that it received an "approvable" letter from the Food and Drug Administration for desvenlafaxine. Final approval to sell the drug was contingent on a number of things, including:
    •   a satisfactory FDA inspection of Wyeth’s Guayama, Puerto Rico facility [manufacturer];
    •   several post-marketing commitments;
    •   clarity by Wyeth around the company’s product education plan for physicians and patients;
    •   approval of desvenlafaxine’s proprietary name, Pristiq.
    The FDA approved the drug for antidepressant use in February 2008, and was to be available in US pharmacies in May 2008.
    CANADA: On February 4, 2009, Health Canada approved use of desvenlafaxine for treatment of depression in Canada. Pristiq is now available in Canadian pharmacies.
    : In the European Union desvenlafaxine succinate has not been approved for any indication. In 2008, Wyeth withdrew its application for Ellefore, the product under review for treatment of major depressive disorder. The reasons given by Wyeth, and comments regarding the findings of the reviewing agency are provided in a "question and answer" format document The European Medicines Agency explained that the [Committee for Medicinal Products for Human Use] had some concerns and was of the provisional opinion that Ellefore could not have been approved for the treatment of major depressive disorder [and] overall, the effectiveness of Ellefore had not been shown convincingly. In relation to its parent substance, venlafaxine, desvenlafaxine seemed to be less effective with no advantages in terms of safety and tolerability.

The FDA Review for approval was based on two identical studies:

Something else we don’t much like reading:

As many of these graphs of Clinical Trials as I’ve compiled and posted, I’m still not used to them. Even in my own experience of prescribing these drugs, the graphs don’t make any sense. The small differences confound me. I’ve never prescribed these two, but I’ve written enough prescriptions for SSRIs [almost always Citalopram if it’s up to me], and patients either say, "I can’t tell any difference" or "yeah, it’s helping" which just doesn’t fit a 2 or 3 point rise on a HAM-D17. I assume these curves have a lot to do with the Clinical Research Organizations way of recruiting subjects, but who really knows? I sure don’t. But every time I paste the tables into a spread sheet and do the graph, I’m jarred by what I see.

It looks like Lilly and Pfizer were aiming for when their existing drug’s patents expired, but the FDA messed up the schedule [not shown is Forest‘s recent acquisition, the newly approved Viibryd – another SSRI]:

So now I consider myself up to speed on the new ones. No great shakes, by my read. Have there been any Clinical Trials of Cymbalta or Pristiq in kids? You bet there have! Just click on the links. Look closely at the studies of each drug that say "has results" and the suicidality data prominently displayed. So maybe my hypothesis that this ongoing interest in debunking the suicidality warning for children and adolescents is not so paranoid after all. In fact, I smell a campaign brewing with Gibbons et al on board. And tomorrow is the advertised date for Robert Gibbons et al’s second paper to be published on-line with the title, Who benefits from antidepressants? synthesis of 6-week patient-level outcomes from double-blind placebo controlled randomized trials of fluoxetine and venlafaxine
    March 1, 2012 | 12:04 AM

    Mickey, see the article about Traci Johnson, college student who killed herself in the Lilly lab while healthy, and only earning money for college by trialing Cymbalta, which began as a drug for incontinence…

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