Thursday, 26 July 2007

The Life and Times of Martin B Keller, MD - Part V: Ghost in the Machine

The first four parts of my little homage to the great genius that is Dr Keller are to be found on Bob Fiddaman's Seroxat Sufferers, under "Matthew Holford rant". However, this one's my personal favourite, and I couldn't help but reproduce it, here.

Ghost in the Machine

It is from Gilbert Ryles' critique of Descartes' view of dualism that I have taken the title of Part V. It is a play on words, though, because this little offering is about ghostwriters within the medical establishment. One particular ghostwriter, in fact, and one particular ghostwriting incident. Having said that, whilst conducting the research on this piece, my colleagues and I have, perhaps, clarified something that is potentially more valuable.

However, as an opening gambit, I would like to observe that mind/body dualism is not an original theory, by any means, and I would like to do this, because I can't conceive that I can make the subject matter of this piece any more bizarre than it already is by doing so. Once again, Classical Antiquity appears to witness the first recorded instance of this idea being discussed. Consider Plato's Concept of Forms, whereby universal concepts (ideas) permit us to understand the world. The intellect, then, may not be attributed to any particular organ of the body. Presumably this holds true of corporate persons, as well as natural persons. More recently, Descartes believed that the immaterial mind causally interacted with the material body, and vice versa.

Presumably, this means that body language is capable of being read: the mind will cause the body to behave in a particular way (I'm a fan of the practical benefits of theoretical discourse, as you may have gathered). If the understanding of a person was sufficiently subtle, this might even be done with precision, given that the eye takes in more information than any other organ of the senses, I'm told. This is fine, as long as mind, body and verbal communication are fully congruent. That doesn't happen very often, though, in my experience: people tend to modify their verbal language, in accordance with what is socially acceptable, for example, or to gain an advantage (lie, in other words).

This issue becomes significant, when the "incongruent person" insists that the verbal communication represents a truth. Consider the stiff body language of politicians, for example, when judging the value of this suggestion. Are people subconsciously aware that their body language communicates more than they would like it to, and attempt to suppress it?

I will leave the gentle reader to ponder that particular question as I return to the issue at hand. Now, we should, perhaps, recall that Study 329 was a cluster fuck, as far as SmithKline Beecham ("SKB") was concerned (my succinct appraisal of its position). The data suggested that the drug was dangerous and inefficacious in the target demographic (minors), by the Company's own admission. We should recall that the Company engaged a PR company, Scientific Therapeutics Information, Inc. ("STI"), to prepare a piece for publication in a peer-reviewed journal, JAACAP, and that Dr Martin Keller seemingly was chosen to endorse this piece, because he was perceived to be a key opinion leader, whatever that might be. Although, in the words of Drs Keller and Ryan, it seems that anybody who wanted to put their name to it, should feel free to do so, according to their draft letter to the Editor of JAACAP, Dr Mina Dulcan. I suppose that's one way to bulk out one's CV. Next, the piece, written by one Sally Laden, I am reliably informed, who no longer works for STI, received some stiff criticism from reviewers, if I may understate it like that, before having marketing authorizations refused in both the UK and US, although, as far as I am aware, none of the criticism was ever acted upon. Amusingly, in the draft letter to Dulcan, Keller and Ryan argue that if a trial fails to demonstrate efficacy, then the regulator will refuse to license. I was similarly amused by the additional detail that Keller and Ryan read into Drs Jureidini and Tonkin's critique. By extension, anybody who agrees with Drs Keller and Ryan will be as intellectually and morally superior, as they are, in their view.

Anyway, I don't like to dish dirt, so you can Google Laden's name, for yourself. Actually, no. Here's one perspective on the Cyberonics business, in the Write Stuff. And here's another, from the Alliance for Human Research. Make of that what you will, although I would note that Cyberonics is not directly concerned with ghostwriting, and so doesn't fit my theme as well as I would have liked, because, per Laden's own words, as quoted by Bloomberg News, she was just a facilitator (ie, she made things easier, presumably). A ghostwriter, as in the 329 case, will always be anonymous.

Now, I've tried to restrict myself to the bare facts, without engaging in histrionics, supposition or hyperbole, but I have to say, in my opinion as a compliance professional, the whole 329/JAACAP thing doesn't look good. And yet, because I have access to some very talented people, aside from my own skills and experience, I understand that this is by no means a complete picture of the process that was followed in order to transform Seroxat/Paxil from a dubious-looking piece of chemistry into a product that was "generally well tolerated and effective for major depression in adolescents."

So, who is the ghost in the machine, today? Is it Sally Laden? Was she given SKB's "disappointing" data, and then took to spinning it for the benefit of Dr Keller and his co-authors? Well, one of my good friends and colleagues (a pathologist) has rejected that possibility, and I'm inclined to agree with him. It seems that the likely scenario was that a SKB statistician was given the data, and, how shall I put this most delicately, was led or led him/herself to understand what was required? This re-jigged data would then have been presented, most likely in the form of a statistical report, to Sally Laden, who would have proceeded to base her view on that, possibly in complete ignorance of the true position. So taken were we by this theory that we decided to test it, and the upshot is that somebody else, aside from the statistician, is the ghost, so we're still looking, but it's only a matter of time.

Now, at the time that 329's numbers were being crunched, Rosemary Oakes was a senior statistician at SKB, or is that "Senior Statistician"? The person who managed and directed the US-based phase four (whatever that means) Paxil clinical trials was a chap by the name of James McCafferty, per his deposition made pursuant to several actions brought against SKB in various states, in 2006. This deposition is concerned with a discussion of primary endpoints and covariant analyses, which a dumbass like me isn't going to pretend to understand, although I found it quite amusing, because McCafferty doesn't appear to understand it, either. Now, Oakes and McCafferty were concerned with the generation of data from 329, as evidenced by this exchange, taken from Oakes' deposition, and, presumably, with the generation of the statistical report that most likely would have been presented to Laden.

"So, what?", I hear you ask, and quite rightly. Well, we know that in October, 1998, SKB believed that it had a turkey on its hands. And quite rightly. And yet, in March, 1999, we have Oakes and McCafferty's 'mail to Laden, which is appended, here, which is of greater interest to me, just now. McCafferty, then, was apparently Laden's primary contact at SKB. Given the juxtaposition between these various communications, one might also lead oneself to understand that the document that Oakes and McCafferty are working on is an early draft of Laden's finest work. It is also in this exchange that we see the first appearance of Dr Marty Keller (remember him?), and it is clear that McCafferty is in direct contact with both him and Ryan, which may or may not be an issue.

Moving on to July, 1999, and McCafferty is now in contact with Laden, here. He has noticed the incongruence between the claims made as to the drug's safety in Laden's latest draft, as against the admission in the same draft of significant reports of adverse events. He also expresses his concern that the editors (of JAACAP, or just generally?) will rumble this inconsistency, which I find quite amusing, given that Dulcan's failure to do so was, by exension, what Drs Jureidini and Tonkin were complaining of, so Keller tells us. In the words of Michael Stipe the "shit's so thick, you could stir it with a stick." Even SKB had noticed the stench. Two days later, McCafferty again contacts Laden, apparently this time to suggest a solution to the issue raised in his mail of 19 July, here.

Now, being the nitpicker that I am, I am not satisfied that this demonstrates that Laden had seen the original 329 trial data, particularly given that Oakes was still crunching 329 data eight months after the trial ended, according to that deposition. I am not even sure that this crunching of data means that Oakes was arranging for a "biased" statistical report to be made available to Laden. However, given McCafferty's comments with respect to suggested amendments to Laden's draft, she might have come to the conclusion that a rigorous appraisal of the data that was made available to her was not what was required, although I say this as a compliance professional, and not a medical writer. As to Dr Keller, being an honourable man, I don't doubt that he would be appalled to have a piece of work such as this on his CV.

Matthew Holford (c) 2007

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