put a cork in it…

Posted on Thursday 19 March 2015

In November [2014], the NIH announced  that it was going to put some teeth into the ignored requirement that completed Clinical Trials post their results in the Results Database of ClinicalTrials.gov [see speaking of about time!…, Honoring Our Promise: Clinical Trial Data Sharing and promises, promises…]. I had looked at the ClinicalTrials.gov Results Database several years ago and  decided it was an improvement over just having the published paper because of its structure, but was far short of having the raw data itself  [see eyes wide shut open I…, eyes wide shut open II…, eyes wide shut open III…, and eyes wide shut open IV…]. This report from last week documents the extent of the problem [medicine-wide]:
by Anderson ML, Chiswell K, Peterson ED, Tasneem A, Topping J, and Califf RM
The New England Journal of Medicine. 2015 372[11]:1031-1039.

BACKGROUND: The Food and Drug Administration Amendments Act [FDAAA] mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.
METHODS:Using an algorithm based on input from the National Library of Medicine, we identified trials that were likely to be subject to FDAAA provisions [highly likely applicable clinical trials, or HLACTs] from 2008 through 2013. We determined the proportion of HLACTs that reported results within the 12-month interval mandated by the FDAAA or at any time during the 5-year study period. We used regression models to examine characteristics associated with reporting at 12 months and throughout the 5-year study period.
RESULTS: From all the trials at ClinicalTrials.gov, we identified 13,327 HLACTs that were terminated or completed from January 1, 2008, through August 31, 2012. Of these trials, 77.4% were classified as drug trials. A total of 36.9% of the trials were phase 2 studies, and 23.4% were phase 3 studies; 65.6% were funded by industry. Only 13.4% of trials reported summary results within 12 months after trial completion, whereas 38.3% reported results at any time up to September 27, 2013. Timely reporting was independently associated with factors such as FDA oversight, a later trial phase, and industry funding. A sample review suggested that 45% of industry-funded trials were not required to report results, as compared with 6% of trials funded by the National Institutes of Health [NIH] and 9% of trials that were funded by other government or academic institutions.
CONCLUSIONS: Despite ethical and legal obligations to disclose findings promptly, most HLACTs did not report results to ClinicalTrials.gov in a timely fashion during the study period. Industry-funded trials adhered to legal obligations more often than did trials funded by the NIH or other government or academic institutions.
[Funded by the Clinical Trials Transformation Initiative and the NIH.]
I’m not even going to bother with the excuses people make for not filling it out. Those are speculations. It’s totally simple to do, compared to other hoops people are asked to jump through. So my working hypothesis is that it’s straighforward and doesn’t have all the play one has in a published article to make things look better than [or not as bad as] they are. Whatever the reason, the compliance record is pitiful!

Just this week, I had an example of how useful the Results Database of ClinicalTrials.gov can be [see inertia…]. I was looking at the Clinical Trials for Saphris® [Asenapine] that was submitted for its FDA Approval [NCT01244815 and NCT01349907]. There’s no published paper, but I happened to notice that the Results of these Clinical Trials were already posted – a miracle all on its own!  And they had something of an answer to an open question. In the first trial, they gave Saphris® for three weeks to kids diagnosed with a Manic episode:

Acute: Measured Values after 3 Weeks

  Placebo Asenapine
2.5 mg BID
5.0 mg BID
10.0 mg BID
Participants 79 88 87 81
Change in Y-MRS
Mean ± SD
-9.6 ± 7.8 -12.3 ± 9.0 -15.1 ± 9.5 -15.9 ± 9.1
P Value   =0.008 <0.001 <0.001

There’s no surprise here – that one can knock down an agitated state with an antipsychotic. But these drugs have been used long term in these patients. What about that? In the extension study, things didn’t look so rosy:

Maintenance: After 50 Weeks of Asenapine

Acute Asenapine/Asenapine Placebo/Asenapine
Participants 241 80
With Adverse Event 197 74
Completed Study 102 38

I guess they were looking for a maintenance selling point in the extension phase of the study, but they sure didn’t find it – quite the opposite. One way to not deal with that finding would be to not publish it [publication bias]. Requiring a completed Results Database in ClinicalTrials.gov blocks that solution deception – instead it adds yet another piece of evidence that maintenance Atypical Antipsychotics are fraught with problems.

The Results Database in ClinicalTrials.gov may be only Data Transparency lite, but given the recent past, it’s going in the right direction. ClinicalTrials.gov, indeed the whole idea of requiring Clinical Trials themselves, was a reform move intended to give me access to the best evidence for the efficacy and safety for the drugs I prescribe. But the pharmaceutical industry has systematically used them as ways to deceive me [us] – engaging physicians in high places to collude with them in the process. This may be only one of the holes in the system that keeps me up to date on medications, but it’s time to put a cork in it and move on to the next leaky spot in the dyke…
    Sandra Steingard
    March 19, 2015 | 9:47 PM

    If you see this-
    I missed an opportunity to comment yesterday. I appreciate reading your contributions to this important discussion as I have in the past.

    berit bryn jensen
    March 20, 2015 | 8:00 AM

    As Sandra Steingard I appreciate your comments, and hope to be able to read more from you, on this most excellent blog by dr Nardo, which, ever so often, is marred by arrogance and incivility, not by dr Nardo, but by less sensitive men. They can be skipped. I usually do. Au revoir!

    March 20, 2015 | 7:11 PM


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