I first ran across a paper by Cosgrove et al in February [Under the Influence: The Interplay among Industry, Publishing, and Drug Regulation] and have talked about it frequently. I think it’s an important article for a number of reasons:
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It’s about a contemporary medication, Vortioxetine [Brintellix® now Trintellix®]. Our Paxil Study 329 article and the recent article about Karen Dineen Wagner et al’s Citalopram in Adolescents article are important windows into the deceitful publication practices in clinical trials of psychoactive drugs, but they’re about old studies [2001 & 2004] about drugs now long off-patent. No apologies about that. It took that long to get the information necessary to get to the bottom of things. But Cosgrove et al are writing about a drug that’s new and in-patent – a drug being detailed widely to doctors right now.
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They didn’t have access to any special information like the other two articles [raw data & subpoenaed documents]. They were able to show how the published articles were misleading using available information from regulators etc., showing that with enough stick-to-it-ness, these RTCs can be vetted effectively. While we long for data transparency, as we learned with the 329 effort, there’s a lot of work involved in a reanalysis. Cosgrove et al show us that with another version of a-lot-of-work, even without special access, these tainted articles can be evaluated.
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Their article doesn’t stop with demonstrating some of the methodology of the misreporting illustrated in the articles, but goes on to make suggestions about problems in the system and pathways to change. While you might not completely agree with all of them, they’re all valuable food for thought. That’s what academic publication is supposed to be about.
There’s another reason for focusing on this article. It’s a class act, yet it’s not published in a journal that has a wide readership, or as wide a readership as it deserves [journal and paper alike].
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So the article brings up another issue: how hard it is to get a controversial or contrarian article published in the medical literature. With Paxil Study 329, even with a willing journal, we went through a prolonged review. While it was difficult, in the end I’m for that. I wish the original paper we were reporting on had been looked at anywhere near as closely as our submission and conflicts of interest as closely scrutinized. With the Citalopram in adolescents study, the authors gave us a narrative of the difficulties they encountered [background notes].
You’d think as much as I’ve said about these articles already, that I’d shut up about them. But there’s a reason I haven’t. Reading blog posts from a boring old man can’t possibly do strong articles like these justice. They need to be read in person rather than in summary. And I found out that Cosgrove et al is finally available full-text on-line so it can [and should be] read by all. Here are the three articles with their full text links, and a fourth similarly important recent clarifying meta-analysis thrown in for good measure:Summer Reading List
We are finally seeing articles published about the other side of the coin – evidence-based analyses of Clinical Trials that reveal the kind of bias and deceit that has come to characterize too much of our medical literature. These clarifying papers are still uncommon, published with much blood, sweat, and tears – sometimes in remote corners of the medical literature. It’s important to make sure we’ve read them [and spread them]. We can’t expect hard working clinicians to run across them, so pass them along. The time for simply decrying what’s wrong has passed. It’s time for reparative action, and there’s no stronger stimulus than articles like these that document the scientific misbehavior behind the original publications…
Thiis is cash that can be use ffor tuition, for a home
mortgage, and ven ffor daycare.
I read no.2. on the summer reading list – the whole thing line by line and followed the references and internal documents and emails. As a long term consumer of medication targeting anxiety and depression (including paroextine which added paranoi to my list of symptoms) it is a really sobering and sad read. Im scratching my head trying to work out how there could be such a massive gap in trust and just ordinary care and empathy for people that are broken and hurting. When you visit your Doctor or your psychiatrist or a mental health facility you are relying on (and trusting) that they will give you medication that is scientifically proven to increase your chances of recovery…and boy would you want it to , because the trade off – the side effects of some of those medications, almost require you to get additional therapy to cope with them!
The most surprising thing in reading no.2 was the internal company emails that made it quite obvious to even an ordinary person with no science or statistics background, that the drug they were going ahead with promoting didn’t even work , and they were marketing it to kids and adolescents…..that’s really difficult for me.
What wasn’t surprising to me was the “feeling” that modern psychiatry and medication (or however I should phrase that) has lots its way and its effectiveness due to a whole complex mix of reasons. I felt this loss when in my own country the Health service cut back on its list of visiting specialists and psychiatrists and transferred me from an empathetic, engaged, listening psychiatrist (who actually let me tell my story and chat about my feelings and thoughts each visit – how radical!) to a psychiatrist who might be the product of the pharma food chain. No chats, no feelings, no room for thoughts or ramblings – just an increased dose of medication because clearly my current medication wasn’t working. My first psychiatrist would talk with me 45 – 50mins. I remember him saying in one appointment ” if you want to just talk ‘free association’ and tell me what’s in your head this visit that’s fine. The second psychiatrist – I made it to about 12 minutes one time (new record!) and remember telling my wife how I had succeeded in getting him to talk and listen. It felt like a prison compared to the first.
I know there would be lots of great, highly skilled, caring and empathic psychiatrists (like yourself Mickey) who would read your blog from time to time – you guys and gals are truly awesome and keep up the listening and empathy. The impact of having somewhere care and listen (really listen) was in my case much greater than the impact of any medication and I really miss my “old style” and incredibly skilled psychiatrist.
Apologies for the length of this “consumer rant” post. Once I started it was hard to stop.
MIckey,
Please correct me if I am wrong, but after reading the Cosgrove article it appears that as long as one of the doses used in an RCT shows a positive effect then the study is considered positive for purposes of approving the medication. Is that true? If so, then if an RCT uses 4 doses it is really 4 trials not 1 and if only 1 of the 4 needs to be positive that makes it even easier for an ineffective medicine to get approved. I appreciate it you can clarify for me. Thanks.
Courtesy of Twitter:
http://frog.gatech.edu/Pubs/How-to-Publish-a-Scientific-Comment-in-123-Easy-Steps.pdf
And… to illustrate that overselling hand waving is not unique to medication based interventions:
https://www.psychologytoday.com/blog/fulfillment-any-age/201507/psychotherapy-vs-medications-the-verdict-is-in
Contains a link part way down “majority of studies on therapy effectiveness showing the advantages of skipping drugs altogether.” That takes one to another post that states “estimates of psychotherapy’s effectiveness, based on hundreds of empirical studies, are that it works apprpximately 75-80% of the time. That’s a pretty impressive figure.”
In the word of Neuroskeptic:
Hmmmmmmm.
Also, there is that reference to the pesky “file drawer” effect for pharmaceutical interventions. But it’s nothing but hundreds of empirical studies and blue skies for psychotherapy interventions.
Please forgive the tone, but the whole “Team Pharma” “Team Therapy” dichotomous crap just gets frustrating after a while.
Exit interviews with RCT subjects, conducted by an impartial agency, would do much to help us judge the usefulness of RCTs. There’s something fishy the size of a whale shark going on with vortioxetine.
There are two kinds of crazyboards members for whom Br/Trintellix works. One is those who also take Vyvanse or Wellbutrin, and the other is an odd breed of newcomer who announces herself as a newbie, describes her terrible pharma history, says how she got her guts up to try Br/Trintellix, applies some lip service to initial side effects, says it works great, and adds that no one should give up hope. Their posts are all about the same length. The user makes 1 or 2 posts and is not heard from again. (Apparent marketing posts, in other words.)
Maybe a pharmacological type can explain the apparent symbiosis between Wellbutrin or Vyvanse and Trintellix.
For everyone else, it’s vomiting, headaches that go one for days or weeks, itching, crying jags, anxiety to the point of agoraphobia, or most recently, a three-hour fit of anger on Day 1.
Comparing the crazyboards reports to the RCTs’ stated adverse effects makes it seem like people in the RCTs were not taking the right drug. I’ve never read about a drug making as many people as blasted sick as vortioxetine does. (Maybe nefazadone, in a keller/nemeroff/etc study.) The topic might be the longest topic on crazyboards. It started in December 2013. Much hope and optimism back in 2013.
A close look at the raw data is most definitely in order.
http://www.crazyboards.org/forums/index.php?/topic/68311-brintellix-is-anyone-else-actually-taking-this/&page=1