"[Leopold] also indicated that a portion of the skin on the left shoulder was infiltrated. [I noticed this, just as he did, in spite of her dress.]…""In spite of her dress. This was in any case only an interpolation. We naturally used to examine the children in the hospital undressed: and this would be a contrast to the manner in which adult female patients have to be examined. I remembered that it was said of a celebrated clinician that he never made a physical examination of his patients except through their clothes. Further than this I could not see. Frankly, I had no desire to penetrate more deeply at this point.."
It’s the case history model, one familiar to psychotherapists who see one case in depth at a time. It’s the opposite of the evidence-based medicine model that finds confirmation in group characteristics and comparisons. Both models have their strengths and weaknesses. As we’ve seen, both can be jury-rigged to distraction. So how are things chosen as representative cases for an in·depth study? They sort of choose themselves. Freud’s dream is obvious. He was a first, and he put the dream out there in detail. Milton was the ranking mind of his era. Don Quixote was the first real novel and Cervantes the first real novelist. And so at last we arrive at my point – Paxil Study 329. It has obviously become the paradigmatic case of a clinical trial that was distorted for commercial gain. It’s the one that has Alison Bass’s book Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial], several published journal articles, too numerous to count blog posts, has curtailed the careers of some of the authors, has collected a library of subpoenaed documents. It helped launch Elliot Spitzer’s successful run for New York State governor, and resulted in legal settlements reaching into the Billions. It’s only eleven pages long with two figures and three tables, but it stands as the place·marker for a genre – a classic. It wasn’t the first industry influenced article by a long shot. But it was the first one really busted, and its target being children helped thrust it into the limelight where it remains.
When the Journal of the American Academy of Child and Adolescent Psychiatry [JAACAP] published study 329 in 2001, its editors could have had no idea that the paper would spark a controversy, not only about the use of the antidepressant paroxetine in children but also about secrecy in clinical trials. It is a controversy that rages to this day…
Q: Do you know why it took you until December 18, 1998 to prepare the first draft of this Study 329?A: NoQ: Okay, where did the data come from that ended up in this first draft?A: A clinical study report was provided to me.Q: Okay, who was that provided by?A: I don’t remember the person who sent it to me.Q: Okay, but it came from GSK?A: Yes• Murgatroyed then asks Laden if she received the entire clinical study report, which, he adds was "over 1400 pages."• Laden answers, "A clinical study report that STI would normally receive would probably be about 200 pages in length." She later adds, "I believe it’s considered a synopsis of the report rather than each individual patient’s data."
The date of that first draft [December 18, 1998] is less than a month after the date on the Full Study Report that’s posted on the Internet here [November 24, 1998]. That report is 528 pages long. The Narrative is 124 pages, and the remainder are printouts of the summary data used to generate it. The actual data is in a host of Appendices that run 5000 pages and would fill a shelf. There’s also a 9 page Synopsis posted. So what’s illuminating about this? Sally Laden wrote her draft from some version of a summary prepared by GSK [then SmithKline Beecham]. The take-home is that the jury rigging was prepackaged for her by the sponsor. If this were a CLUE game, it would be "the sponsor in the lounge" who done it, rather than "the ghost·writer in the study" or the "guest·author in the kitchen," at least that’s how it looks in this instance. But unlike the CLUE game, the "the ghost·writer in the study" and the "guest·author in the kitchen" are complicit accomplices [along with the "journal·editor in the conservatory"]. You don’t have to be a dream interpreter or a scholar to know why I’m drawn to the case history model. It’s what I did for a career. And it’s easy to see its weaknesses. You’d need a lot of instances from many other sponsors, drugs, articles, authors, etc. before you could generalize from this n=1 case. But they’re out there. Excerpta Medica turned out tons of articles like this for JNJ. There’s an editorial assistant, Jon Kilmer, signed on to most STAR*D articles. In fact, our literature is packed with loud hints that have yet to be fleshed out for us all to see, just waiting for those future scholars looking for something to study. I expect readers tire of people like Fiddaman and yours truly who perseverate on [go over and over] this case. We do it because it’s the one and it has its own growing database that can be explored. We can do more than just raise the questions and speculate, we can approximate actually finding the answers. And after so long in the wilderness, that’s compelling. The line between paranoia and insight can be mighty thin, and it often hinges on accumulated facts like the ones in Fid’s blog today.
"I’ve reviewed data analytic tables. I don’t recall how raw it was. Huge printouts. You know, that list items by item number. Item numbers and variable numbers. And don’t even have words on them. I tend not to look at those. I do better with words than I do with symbols."
Thanks Mikey. I have put 329 to bed on many occasions but I guess that’s what Laden, Keller et al want. Laden’s depo is fascinating, would love to get my hands on the video, if only to see Murgatroyed severely spank Glaxo lawyer Todd Davis.
Mickey.. you should write the book. You need a wider audience methinks. And society will benefit from it. Thanks for all your hard work on this.
Hear hear!
Why not go on and on about reboxetine instead http://blogs.scientificamerican.com/guest-blog/2010/11/30/the-antidepressant-reboxetine-a-headdesk-moment-in-science/
http://neuroskeptic.blogspot.com/2010/10/worst-antidepressant-ever.html
http://pipeline.corante.com/archives/2011/01/17/reboxetine_doesnt_work_but_thats_not_the_real_problem.php
And guess who was in the thick of it:
J Clin Psychiatry. 2000;61 Suppl 10:31-8.
Clinical efficacy of reboxetine in major depression.
Schatzberg AF.
Source
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Calif 94305-5717, USA.
Abstract http://www.ncbi.nlm.nih.gov/pubmed/10910015
The past decade has witnessed the advent of selective serotonin reuptake inhibitors (SSRIs) as first-line treatments for major depression. Still, there is considerable debate as to whether these agents are as effective or as potent as the first-generation tricyclic antidepressants (TCAs) or the mixed reuptake inhibitor, venlafaxine, all of which exert considerable effect on norepinephrine (NE) reuptake. Recently, reboxetine, a selective NE reuptake inhibitor (selective NRI), has been introduced in Europe. This drug has only a minimal affinity for muscarinic acetylcholine receptors and therefore causes less dry mouth, constipation, or other such effects than do the TCAs. Reboxetine does not block serotonin reuptake or alpha1 receptors and, thus, does not appear to produce significant nausea, diarrhea, or hypotension. Unlike other antidepressants, reboxetine appears to be nonsedating. Data on acute and long-term clinical efficacy and safety from double-blind, placebo-controlled, and active comparator studies with reboxetine are reviewed. These studies indicate that reboxetine is significantly more effective than placebo and as effective as fluoxetine in reducing depressive symptoms. Improvements in social adjustments were reported to be more favorable with reboxetine than with fluoxetine. Further, data from controlled clinical trials have shown that the side effect profile for reboxetine is relatively benign. The clinical implications of studies on reboxetine are discussed with an eye toward understanding the potential role NE reuptake blockers may play in the treatment of patients with major depression.
In art history, the term for those firsts is “prime object”. Prime objects are the beginning of a body of work that proceeds from prior work, but leaves a mark that separates it from previous work that had become prosaic. They are most often labeled as groundbreaking after the fact. Whether an object was to become a flash in the pan, or part of a movement was up to time to tell.
In one sense, Freud’s interpretation of his dream was typical of an industry rife with men who thought themselves to be scientific and therefore “objective”. Dogma has a way of thwarting recognition of phenomena that are in-your-face if you’re not convinced that you’re dealing with some profound truth about humans and/or the human mind.
The same happened with 329. It’s a prime object that took corruption in drug studies to dizzying new heights, especially in the field of psychiatry.
I’m curious to see if they can top themselves. Otherwise, for researchers and clinicians that want solid evidence, well-structured studies, and all the data; this study is a call to battle and a new age of openness and integrity in drug studies for the betterment of all but greedy and amoral executives and CEOs.