the empty pipeline…

Posted on Thursday 3 March 2016

Last night, I spent some time writing a letter to the FDA. It was about Vortioxetine [Brintellix®] and their application for an approval for Cognitive Dysfunction in Major Depressive Disorder [see indications… and more vortioxetine story…]. This morning I got a confirmation that it had been passed along to "the Division" [which I suppose is better than the alternative]. My letter was a less "bloggy" version of indications… and more vortioxetine story…. While I’m hardly holding my breath, it felt kind of good to actually send a letter to the place that ought to hear it rather than just post it to the universe at large on a blog at the edge of the galaxy.

I see this as something of a dangerous time. We’re at the end of a pipeline period in psychopharmacology – one that lasted for a really long time considering that there were only a couple of classes of drugs involved. But then the pipeline dried up. The approval of Brexpiprazole® as an Adjunct to Antidepressants in Treatment Resistant Depression is an example of why it’s a dangerous time. They presented two trials with the amazing pixie dust of changing the outcome definitions in the middle of the trial to bring the second study into statistical significance. The FDA reviewer didn’t buy it…

7.4.1. The Sponsor conducted two adequate and well – controlled trials to assess the efficacy of brexpiprazole for the adjunctive treatment of MDD. Based on the prespecified statistical analysis plan, only one of these trials [Study 331-10-228] was positive. The Sponsor acknowledges that Study 331-10-227 was not positive based on the pre-specified plan, but provides a number of arguments to support the concept that brexpiprazole should nonetheless be approved for this indication.

Approval of the adjunctive MDD indication would have to rest on one of two possible scenarios: 1. Study 331-10-227 can be considered a positive trial based on the retrospective application of Amendment 3 criteria and use of the per protocol population instead of the intent – to – treat population for the primary analysis. 2. Study 331-10-228 can be considered “strongly positive” and, thus, approval can be based on this single study. Study 331-10-227 would then be viewed as “supportive evidence” for this approval.
but then ended with…
One can also reasonably consider Study 331-10-228 a “strongly positive” study — in a population of individuals with a history of multiple failed antidepressant trials and prospectively demonstrated suboptimal response to an additional antidepressant, the addition of 2 mg/day of brexpiprazole yielded an average additional symptom improvement of just over 8 points on the MADRS. This was 3 points beyond the improvement in placebo — a difference that was highly statistically significant at p=0.0001. These results are both clinically and statistically meaningful.

Thus, with one strongly positive trial and supportive evidence from two additional trials, there is adequate evidence of efficacy to approve this product for the adjunctive treatment of MDD.
That’s a peculiar conclusion. The FDA standards are low, actually shamefully low. Two positive trials out of as-many-as-you-want-to-do. And positive means statistically significant rather than clinically significant. For example, this drug for this indication flunked clinically significant by any objective measure I know – Subject Rated Scales and Effect Sizes. But I’ve said that so much I might get thrown off the Internet for terminal monotony. My point this time is that the reviewer’s logic is upside down. Given what we know about Clinical Trials, a better interpretation would be that the second study did not replicate the first. Replication is something of a gold standard, and it should be. That’s what we do in practice, count on the fact that the results of a clinical trial will be replicated in our patients. So I’m concerned that in the face of the empty pipeline, the FDA will do things like this, stretch their already too-low standards even lower – something they did in this case.

The story with this Brintellix® application for approval is the same issue – a failed replication. Their second study [CONNECT] did not reproduce the results of the earlier trial [FOCUS]. While there are lots of other questions about approval for this indication, they’re in the background to this non-replication. So it’s a dangerous time because here’s another situation where they’re about to give a drug the benefit of the doubt if they follow the recommendations of the advisory committee [see more vortioxetine story…]. There’s no reason to do that. Brintellix® has never beaten another antidepressant head-to-head – and this indication [Cognitive Dysfunction in Major Depressive Disorder] seems both contrived and unproven.

The only result from this approval will be to allow Takeda/Lundbeck to create misleading advertisements. It’s not going to help any of our patients in any substantive way…
  1.  
    March 4, 2016 | 11:56 AM
     

    Umm, isn’t the inherent process to righting a wrong is marginalizing and then ostracizing the immoral or illegal behaviors and choices? SO, if the majority of colleagues have the skills and abilities to discern what is appropriate vs inappropriate promotion of a treatment intervention, wouldn’t the simple lack of use of the product or service lead to the failed intervention effort being dismissed?

    Therefore, maybe the question at the end of the day isn’t why does Big Pharma continue to promote irresponsible and unfounded indications for their drugs, but, why haven’t clinicians realized that new drugs need to be continually challenged and used in tertiary care environments alone that are part of this discovery process to legitimate use? And, why haven’t clinicians remembered the simple adage “fool me once, shame on you, fool me twice, shame on me”?

    Oh, my bad, I assumed I work with colleagues who still possess shame and humility in their souls.

    Where are those gravesites those two concepts are buried?

    (don’t know if this image will work at the thread, but I offer it to amuse and perhaps empower some readers?)

    https://www.pinterest.com/pin/197384396145582054/

  2.  
    1boringyoungman
    March 4, 2016 | 12:05 PM
     

    That’s a neat effect on your webpage with the pipe graphic.

  3.  
    James O'Brien, M.D.
    March 5, 2016 | 12:24 AM
     

    What is the point of psych recertification? To review the lack of progress in the past ten years and what wasn’t in the pipeline? No sour grapes, I’m grandfathered. Thank God. I feel bad for younger psychiatrists.

    http://www.psychiatrictimes.com/blog/maintenance-certification-exam-fetish

    Love the fetish analysis. Refreshing antidote to Insellian?Inseli? Insellesque? breakthrough hype.

    Money quote:

    “The logic of a 10-year MOC is to keep us current, so it’s fair to wonder what has changed in 10 years and what the major advances were. Depakote was loudly considered the default maintenance mood stabilizer despite no supporting evidence, but that fell into disuse at a time oddly coinciding with its patent expiration, which is suspicious, but I’m no epidemiologist. Anyway, it wasn’t on the test. Anything else? A few new medications have come to market, although none of those appeared on the test either. There’s money to be made in the West Coast using giant magnets, (fortunately) also not on the test. Psychoanalysis? The astonishing truth is that psychiatry has made no progress in almost 20 years, let alone 10, a claim no other medical specialty can make, and the truth which cannot be allowed into consciousness. Therefore a test.”

    Well this one will probably be on the next MOC:

    Which antidepressant has been FDA approved for cognitive deficits in MDD?

  4.  
    March 5, 2016 | 8:13 AM
     

    To Dr. O’Brien, is your ending question about approval of medications for treating cognitive deficits based on removing such symptoms, or causing them?

    The FDA should not have approved a lot of antipsychotics for the cognitive problems they cause, especially at higher dosages that shouldn’t be used in the first place for depression!

    It’s just absurd what goes on these days, and so many doctors are beyond complicit…

  5.  
    James O'Brien, M.D.
    March 5, 2016 | 1:03 PM
     

    We trusted that the journals would remain dedicated to quality, when all of the financial incentives are toward quantity. Look at the absurdity of some of the journal titles. They exist to peddle pablum. Hence, 95% of studies cannot be replicated. There needs to be a 1boringoldman type site dedicated to the fraud of academic publishing.

    The problem is that most physicians especially younger ones think it’s “mean” to be skeptical (as opposed to cynical, which is dysfunctional). Without it, you’re going to be practicing a lot of quackery. The mensch doctor is a dupe doctor.

  6.  
    March 5, 2016 | 1:51 PM
     

    “The mensch doctor is a dupe doctor.”

    and that’s the nice way to say it. I wrote about the Alinsky rules in a recent post at my blog, how did he say it…

    first, “Make the enemy live up to its own book of rules.” If the rule is that every letter gets a reply, send 30,000 letters. You can kill them with this because no one can possibly obey all of their own rules.”

    and also he said, "“Keep the pressure on. Never let up.” Keep trying new things to keep the opposition off balance. As the opposition masters one approach, hit them from the flank with something new."

    One has to wonder when out “illustrious” colleagues in positions of authority and influence tell you to be the mensch, and yet they are either fully insulated from the attacks by the slime, or are in collusion with the slime.

    No, you as the physician do what is right, but, don’t give a pass or respectful consideration to others out to disrupt and destroy. My response to the users of Alinsky tactics is simply make sure the audience is aware of what is being done. Alinsky devotees shun the spotlight like the vampires many of them see to be at the end of the day, except they don’t want actual blood, just the public’s souls and money.

    Sorry Gordon Gekko, greed is not good. Nice try though…

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