why data transparency? III… »
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why data transparency? II…

Posted on Thursday 1 January 2015

In why data transparency? I…, I was looking at the recently published RCT of Symbiax®, an Eli Lily COMBO drug with Prozac® and Zyprexa® in various doses [Olanzapine/Fluoxetine Combination in Children and Adolescents With Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Trial]. I was disappointed that the JAACAP was publishing such an obviously COI-laden experimercial with a guest author. I’d hoped we’d moved on a notch in that arena. I wandered the FDA sites looking at its approval, and I hope I got that part right. I’ve haunted the Drugs@FDA and Orange Book sites for several years, and while I’m glad they’re there, I find them difficult. Speaking of haunting, I’ve also hung around on ClinicalTrials.gov and that was going to be my next stop [NCT00844857]. I’ve actually been waiting for an RCT like this one to say some things about that site. The paper says:
    This was a phase 4, randomized, double-blind, placebo-controlled study conducted between March 2009 and February 2012 at 41 centers in the United States, Mexico, and Russia.
    and
    A total of 255 patients [170 OFC, 85 placebo] comprised the mITT population.
That comes out to 255÷41=~6 subjects/sit,e which seemed mighty thin to me. They use multiple sites to speed up recruitment, but… And on ClinicalTrials.gov, they listed sites in US California and five places in Russia. But then below that, they listed US, Russia, Mexico, and Turkey under regulatory authorities. Pretty confusing. But that gets me to a complaint I have about the ClinicalTrials.gov site in general. Five or six years ago when I first started looking at this site, they told us where the site actually was. But for the last several years, it has said stuff like this:

  • United States, California: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon – Fri from 9 AM to 5 PM Eastern Time (UTC/GMT – 5 hours, EST), or speak with your personal physician. San Diego, California, United States, 92123
  • Russian Federation: For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon – Fri from 9 AM to 5 PM Eastern Time (UTC/GMT – 5 hours, EST), or speak with your personal physician. Lipetsk, Russian Federation, 399313

That feels like a trick to me. I want to know if it’s an academic center, or a flophouse on the Bowry, or a village in the third world. I’m not going to call Russia or San Diego, and they know that. As I’ll mention in a bit, NIH Director Collins wants to beef up the use of ClinicalTrials.gov, and this would be one place to do that – go back to telling us where the trial actually took place.

But where there’s a will, there’s a way. The ClinicalTrials.gov site includes a small link, History of Changes, with each trial up at the top of the opening page [go ahead, click it]. And when you get a pop-up window, there’s another link, ClinicalTrials.gov Archive Site [don’t be shy, click it too]. It has all the changes made over the course of the study. I’ve looked at a lot of these, but I’ve never seen one that looks remotely like this!

There are over thirty changes that have to do with recruitment and site location. If you have the energy, click on the second one [2009_03_16], then uncheck the box that says "Hide non-essential portions (contact info, locations, etc.)". You can scroll through the changes by clicking the arrow on the right. What you’ll see is them moving all over the world adding and shutting down different sites. The CRO must’ve had a hell of a time with recruitment and had to pull out all stops to find subjects. I want to know if that happened [and it ought to be easier to do]. It makes me think that the Pediatric Bipolar patients with a Depressive episode [or whatever these cases are] just aren’t that easy to find – but who knows?

And I’ve never seen a change in the Protocol during a trial. That one at 2011_05_16 removes the Placebo Control from the Protocol! It made me wonder if that’s why they had the 2:1 ratio of subjects, maybe to recruit more easily – but again, who knows? So that brings me to another complaint about ClinicalTrials.gov. On the opening page, the describe the Protocol in a narrative, but they don’t post the a priori Protocol – the ones that go to the Institutional Review Board. They have it, and I think they ought to post it. I could then easily look at the Protocol and see if what they say in the paper is true …
    A 2:1 randomization ratio was used to reduce potential exposure to placebo.
… I come by that kind of paranoia honestly after looking at a lot of these trials.

If you’ve made it this far, you probably are wondering why I’m being so picky. Remember back in November, NIH Director Francis Collins announced that he was going to put teeth into the ClinicalTrials.gov website [Honoring Our Promise: Clinical Trial Data Sharing and see promises, promises…]. For one thing, the pharmaceutical companies and even academic researchers had just ignored the Results Section of ClinicalTrials.gov – a requirement for a lot of these trials [see transparency…]. They just didn’t ever get around to filing the results. And while the Results Section is pretty skimpy, it’s a right move in the right direction for DATA TRANSPARENCY. And part of that move was to enforce and even expand the Results Section. He put out a call for comments on his proposed plan, so I’ve been waiting for an industry RCT to come along so my comment will have example to show the why of my complaints – and this study is the very thing I’ve been waiting for. So the last blog, this one, and the nextl are my formulating what I want to say. Hope springs eternal in the new year. [This is the working link for comments: http://www.regulations.gov/#!documentDetail;D=NIH-2011-0003-0003 with a deadline of February 19, 2015].

And I’m in luck! Apparently Dr. Collins’ plan is already at work, because this study has uncharacteristically got a Results Section filled out, so on to my comments about that section [why data transparency? III…].
  1.  
    Ferrell Varner
    January 1, 2015 | 11:52 AM
     

    FYI cost at lowest that I could find. For lowest dose
    Fluoxatine 1 per day, for 30 days–$7.50
    Olanzepine 1 per day for 30 days- $30
    Symbyax 1 per day for 30 days $170. Most much higher.

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