latter day RCTs – the re in re·search

Posted on Monday 26 January 2015

I sometimes refer to the years since 1980 as the age of antidepressants or the age of psychopharmacology, but I would be closer to the mark if I called it the age of clinical trials. Not only were the pharmaceutical companies turning them out, the NIMH [then under Director Steven Hyman] was regularly funding them. Here are some of the big ones from that time period:


STEP-BD Systematic Treatment Enhancement Program – Bipolar Disorder NCT00012558
CATIE Clinical Antipsychotic Trials of Intervention Effectiveness NCT00014001
STAR*D Sequenced Treatment Alternatives to Relieve Depression NCT00021528
TORDIA Treatment of SSRI-Resistant Depression In Adolescents NCT00018902
TADS Treatment for Adolescents with Depression Study NCT00006286

In the last two posts [latter day STAR*D I…, latter day STAR*D II…], I was looking at several independent studies using data from the STAR*D trial to address issues not central to the study itself. I expect that there’s a lot more mileage in that approach, plus, in some cases, a much needed re-analysis of the original research question [see significant III… for an example]. But the number of NIMH sponsored trials pales in the face of the industry run and funded clinical trials – and the same points apply in terms of both re-purposing and re-analyzing that data.

In back on track… I was arguing that it’s the legacy RCTs that actually need to be included in the Data Transparency programs because the out-of-patent drugs are going to be in use for a very long time, and much of what we think we know about them is suspect. The argument about Commercially Confidential Information obviously falls by the wayside with out-of-patent drugs. And the more I think about it, so does the argument about patient confidentiality for reasons I’ve already mentioned. I would suggest that the Institute of Medicine, the NIH, the EMA, the FDA, etc. begin to have committees and meetings looking into how to effectively anonymize the data rather than succumbing to the industry’s co-opting medical confidentiality as an excuse for continued secrecy. There’s a wealth of important medical information locked away in file drawers that needs inspecting, harvesting.

I don’t think we [psychiatrists] knew a lot about RCTs in those medicalizing days. I sure didn’t. And by the 1990s, our journals were filled with RCTs. It seems in retrospect that they quickly became the currency of the land, fitting right in with the emphasis on biomedical treatment and psychiatry’s new preoccupation with evidence-based medicine. I doubt that it ever occurred to me or many of us that they were financed by PHARMA, conducted by contract Clinical Research Organizations, or that the authors on the byline didn’t do the study, the analyses, even the writing. I only thought about those things a decade or more after the fact. I expect most of us looked at the graphs of rating scale scores like they were precise chemical measurements rather than results from subjective questionnaires or raters opinions. We looked at p rather than NNT or Effect Sizes. In the process of medicalizing, we took on the trappings of medical science too quickly without getting in up to our elbows and evaluating the instruments that were directing us. My point is that we were naive, gullible, ill-prepared to critically review what we were reading – and it showed in our performance.

So, at least in psychiatry, there’s more at stake than just the individual RTCs from the last thirty years. We need to re·search these studies to learn how to critically evaluate their content and find their place in making good clinical decisions. In my mind, that’s another strong reason we need for Data Transparency to include access to the raw data from those studies we’ve been reading about in our journals all these years. At least in our specialty, having independent teams re-evaluating that information is an important piece of our path to learning what we needed to know in the first place about the ins and outs of medical science [but didn’t]. We drank the Kool-Ade…
    January 27, 2015 | 3:11 PM

    Consider this little truism taught to me while I spent two years in Pharmacy School prior to going to Med School:

    Medications/drugs follow the 4 P’s of pharmacology,
    promise, panacea, placebo, and poison.
    All have gone down this path, and fairly much all have finally rested somewhere in which they survived, but rarely if ever thrived for a long period. Why is that? Because there is no sole cure for an illness or malady, but, a medicinal product can open doors and options that can provide solutions from multiple sources.

    My point to this is the placebo portion to the equation: while I don’t view it as purely placebo, the “new and improved meds” end up being no better than their predecessors in the same class or pharmaceutical category for which such new drug was formulated originally to impact in treating. And yet when we learned the poisons to the predecessor and seemed to figure out how to minimize or even avoid such poisons, we either conveniently, or more so cluelessly, ignore or justify the new drug’s poisons until it appears the poison is as disruptive as the initial promise seemed to be.

    But, as we watch in awe and annoyance, we don’t pay attention to history, to the given course to chemistry, and we certainly have no tolerance to have to endure hardship and hassle when a new product comes to the shelf. No, we get to that same part in the path to healing with that inevitable pothole and either trip over it or come to a screeching halt and then risk the person behind us crashing in and the mayhem ensues.

    As I wrote earlier in a post here last week, maybe we maxed out with genuine possible benefits with the early SSRIs and the newer first generation antipsychotics that followed Haldol and thorazine, and these “improved versions of Serotonin and Dopamine agents” have just muddled the waters, and when there is buck to be made, well, those poisons aren’t so bad.

    Just as long as the profiteer isn’t having to ingest his product, eh?

    Amazing, isn’t it, that we won’t accept truisms if they don’t benefit the narrative, the agenda, the business goal. Thus why much of medicine is going down the crapper grabbing the toilet paper, not the life line.

    James O'Brien, M.D.
    January 27, 2015 | 8:36 PM

    OMG, Dr. Hassman, did you just write “t___t paper”? That is so deeply offensive. I’m having an episode of the vapors as we speak. Please page Dr. Charcot or one of these 19th century experts in hysteria, as I feel a seizure coming on too. This kind of thing is why the First Amendment should be revoked. John Milton is turning over in his grave. (sorry major inside joke here)

    January 27, 2015 | 10:27 PM

    Freudian slip there about the “toilet paper”, actually, a double play of words here with the sentence. Those most passionate in defending the indefensible efforts to reinforce meds only approaches to psychiatry, most of them once Freudian die hard supporters, I’ll bet.

    Confused readers see my post linked below and the second link in that post per the Psychiatric Times column by an entrenched supporter of “defend the assailants”, and you might understand the point both of us are making.

    Although my initial use of toilet paper was truly to the point of my above comment of swirling down the commode…

    Sorry for the distraction to Dr Nardo’s point here in his post.

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