"There is only one difference between a bad economist and a good one: the bad economist confines himself to the visible effect; the good economist takes into account both the effect that can be seen and those effects that must be foreseen…"
French Journalist/Economist Frédéric Bastiat
The Law of Unintended Consequences is an all too frequent force in the best laid plans of mice and men – derailing the most well meant reforms. It’s like an unseen ghost, lurking behind every tree just waiting to pop out when you least expect it. At the risk of a mundane example, the Kudzu on the sides of some of our Southern byways was actively imported by TVA in its early days to control erosion, but lingers in perpetuity choking everything in its path.
Back in 2001 when Paxil Study 329 was first published, it was a genuine shock to discover that it was ghost-written by professional medical writer, Sally Laden, who created the first draft of that article and oversaw the the subsequent revisions [and other paperwork]:
Children’s Hospital of Philadelphia [Dr. Weller]; North America Medical Affairs, GlaxoSmithKIine, Collegeville, PA [Ms. Oakes, Mr. McCafferty]. This study was supported by a grant from GlaxoSmithKline, Collegeville. PA. Children’s Hospital of Philadelphia [Dr. Weller]; North America Medical Affairs, ClaxoSmithKIine, Collegeville, PA [Ms. Oakes, Mr. McCafferty]. This study was supported by a grant from GlaxoSmithKline, Collegeville. PA. The authors acknowledge the contributions of the following individuals; Jill M. Abbott, Ellen Basian Ph.D.. Carolyn Boulos, M.D., Elyse Dubo, M.D., Mary A. Fristad. Ph.D., Joan Hebeler. M.D.. Kevin Kelly. Ph.D.. Sharon Reiter. M.D.. and Ronald A. Weller. M.D. Editorial assistance was provided by Sally K. Laden. MS.
By then, the funding source and the authors who were company employees were also being regularly acknowledged, though the COIs of the authors weren’t mentioned; ClinicalTrials.gov for trial registration was in its infancy; and Propublica/Sunshine Act declarations were just a dream in the minds of a few:
In olden days, a glimpse of stocking
Was looked on as something shocking.
Now heaven knows,
Anything goes…
Good authors too who once knew better words
Now only use four-letter words
Writing prose.
Anything goes…
Was looked on as something shocking.
Now heaven knows,
Anything goes…
Good authors too who once knew better words
Now only use four-letter words
Writing prose.
Anything goes…
Cole Porter 1934
But have the required declarations made a difference? I’m sure they have made some difference, but like the statistical differences in many of our Clinical Trials, is it enough of a difference to really matter? Has it had the desired effect? I’m actually beginning to think that the old Law of Unintended Consequences is operating here, and that the insistance on declaring conflicts of interest may have had a paradoxical effect and increased our tolerance for Conflicts of Interest and industry involvement in scientific/academic matters. It’s a hypothesis I don’t care much for. For example, the recent Clinical Trials of the late-coming Atypical Antipsychotic, Brexpiprazole [the spice must flow…, how many stars?…]:
by Correll CU, Skuban A, Ouyang J, Hobart M, Pfister S, McQuade RD, Nyilas M, Carson WH, Sanchez R, and Eriksson H.American Journal of Psychiatry. 2015 172[9]:820-821.From the Zucker Hillside Hospital, Glen Oaks, N.Y.; Otsuka Pharmaceutical Development & Commercialization, Princeton, N.J.; and H. Lundbeck A/S, Valby, Copenhagen, Denmark.Funded by Otsuka Pharmaceutical Development & Commercialization, Inc., and H. Lundbeck A/S. Jennifer Stewart, M.Sc. [QXV Communications, Macclesfield, U.K.] provided writing support that was funded by Otsuka Pharmaceutical Development & Commercialization, Inc., and H. Lundbeck A/S.
Dr. Correll has been a consultant and/or advisor to or has received honoraria from Actelion, Alexza, American Academy of Child and Adolescent Psychiatry, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, National Institute of Mental Health, Janssen/J&J, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda; he has received grant support from Bristol-Myers Squibb, Feinstein Institute for Medical Research, Janssen/J&J, National Institute of Mental Health, NARSAD, and Otsuka; and he has been a Data Safety Monitoring Board member for Cephalon, Eli Lilly, Janssen, Lundbeck, Pfizer, Takeda, and Teva. Drs. Skuban, Ouyang, Hobart, McQuade, Nyilas, Carson, and Sanchez and Ms. Pfister are employees of Otsuka Pharmaceutical Development & Commercialization, Inc. Dr. Eriksson is an employee of, and owns stock in, H. Lundbeck A/S.
by Kane JM, Skuban, Ouyang, Hobart, Pfister, McQuade, Nyilas, Carson, Sanchez, and Eriksson.Schizophrenia Research. 2015 164[1-3]:127-35.Contributors: Drs Kane, Skuban, Youakim, Hobart, Pfister, McQuade, Nyilas, Carson and Sanchez designed the study and wrote the protocol. Drs Kane, Skuban, McQuade and Eriksson contributed to interpretation of the data, and Dr Ouyang performed the statistical analysis. All authors contributed to and have approved the final manuscript. Ruth Steer, PhD, [QXV Communications, Macclesfield, UK] provided writing support, which was funded by Otsuka Pharmaceutical Development & Commercialization, Inc. [Princeton, USA] and H. Lundbeck A/S [Valby, Denmark].Conflict of interest Dr Kane has been a consultant for Amgen, Alkermes, Bristol-Meyers Squibb, Eli Lilly, EnVivo Pharmaceuticals [Forum] Genentech, H. Lundbeck. Intracellular Therapeutics, Janssen Pharmaceutica, Johnson and Johnson, Merck, Novartis, Otsuka, Pierre Fabre, Proteus, Reviva, Roche and Sunovion. Dr Kane has been on the Speakers Bureaus for Bristol-Meyers Squibb, Eli Lilly, Janssen, Genentech and Otsuka, and is a shareholder in MedAvante, Inc. Drs Skuban, Ouyang, Hobart, Pfister, McQuade, Nyilas, Carson and Sanchez are employees of Otsuka Pharmaceutical Development & Commercialization, Inc. Dr Eriksson is an employee of H. Lundbeck A/S.
And, as I mentioned in the spice must flow…, there is only one academic author for each article, and both authors are at the Feinstein Institute for Medical Research. Both articles say:
From the Zucker Hillside Hospital, Glen Oaks, N.Y.; Otsuka Pharmaceutical Development & Commercialization, Princeton, N.J.; and H. Lundbeck A/S, Valby, Copenhagen, Denmark.
So like Cole Porter said:
Now heaven knows,
Anything goes…
Anything goes…
I think if we had seen this much openly declared industry imprint back in 2001 [the days of Study 329], there would have been a loud general outcry [rather than just this complaint on my little blog here on the edge of the galaxy]. These articles are openly industry productions with all but two authors employed directly by industry. Both studies used 60 [!] sites [for rapidity] all over the world. They’re both ghost-written and the sole academic authors are from the same department and themselves heavily loaded with COI. We should be up in arms that two first-line journals published such obviously tainted articles. But unless I missed it, nobody has had much to say. So, as to that Law of Unintended Consequences, I’m wondering if our insistence in demanding these disclosures hasn’t sent the message that this kind of publication is fine. And that what was intended to be a check on tainted Clinical Trials has turned into a tolerance – a permission to publish them in this form. It damn sure hasn’t put a stop to them…
They are hiding in plain sight, and that has become the new normal.
Over ten years ago, reviewing Sheldon Krimsky’s book Science in the Private Interest, Lancet editor Richard Horton commented: “… a high proportion of researchers (now) have ties to the industries whose products they are investigating. Many have argued and some no doubt believe that money could never influence their scientific independence. But Krimsky makes a telling comparison of journalists and public officials, two groups for whom monetary conflicts of interest, now endemic in science, are anathema to their professional ethics. Instead, and this is surely a remarkable double standard, scientists absolve themselves from the dangers of often deep financial conflicts (such as company directorships, equity ownership, research grants, honoraria, and travel costs) by the simple means of disclosure. Reporting a payment, a gift, or other interest has become a panacea, especially in medical journals, allowing scientists to wash their hands of criticism.
….
Even scientific journals, supposedly the neutral arbiters of quality by virtue of their much-vaunted process of critical peer review, are owned by publishers and scientific societies that derive and demand huge earnings from advertising by drug companies and from the sale of commercially valuable content. The pressure on editors to adopt positions that favor these industries is yet another example of the bias that has infiltrated academic exchange. As editor of The Lancet I have attended medical conferences at which I have been urged to publish more favorable views of the pharmaceutical industry. For Krimsky, “the idea that public risk (that is, publicly supported research) should be turned into private wealth is a perversion of the capitalist ethic.” ”
Beyond the cosmetics, little has changed since 2004.
Well, it isn’t like no one has been sounding alarms. I took a closer look at the slides (available on-line) David Healy used in his lecture: “Global Business Masquerading as Science” (2004). I was floored by the reviews from academic psychiatry to Dr. Joseph Glenmullen’s book “Prozac Backlash” (2000)
From the slides, a few excerpts:
John Griest, Professor of Psychiatry, Univ. of Wisconsin Medical School says:
” Glenmullen is a master of textual exegesis, quoting fragments from other physicians that distort their larger meanings. Use of his and others’ personal testimonies is a reminder of medicine’s authoritarian past…The alternative is the scientific method where hypotheses tested in randomized clinical trials lead to incremental advances in knowledge.”
Surely, Dr. Healy corrected this misperception in his 2004 lecture, and this one:
Anthony J. Rothchild, Prof. of Psychiatry University of Massachusetts. claims:
” Dr. G. is creating a great disservice by claiming that SSRIs are over-used and often misused when in fact millions of people have taken and deprived benefit from these medications. further, the very medications Dr. G. claims are over used are well studied, scrutinized and closely regulated.”
Glenmullen’s outcries were silenced by pharma’s academics (2000), proven valid and worthy of grave concern by Healy (2004) — just one example of the futility of crying out—
Just a week to count down to the publicizing of the report on study 329 . We will all be able to see how critical the access to raw clinical data from this trial — really was. Will this generate a loud outcry for full disclosure of all clinical data from every RCT , from all pharmaceutical companies? Will there be a louder cry for accountability aimed at academic psychiatry, regulatory agencies, editors of the most prestigious psychiatric professional journals? Are there enough members of the psychiatric profession, who are not Pharma’s frontmen, to make a noise that can be heard? For clinical trial data to be disclosed, the answer is probably, yes… Accountability? Not likely.
We have new agencies who vow to keep an eye on Pharma, appearing coincidentally while the RIAT review of Paxil Study 329 was being conducted. Looks like the smoke and mirrors strategy is in full swing– and meanwhile, the more crucial issue of RCTs themselves will escape notice. But, it’s not like someone hasn’t sounded an alarm on this ruse- See: David Healy’s blog post trilogy on Sense about Science/All Trials.
I have lost faith in the medical community and it’s multi billion dollar industrial empire. Moral bankruptcy fed by greed, notwithstanding, there doesn’t seem to be more than a hand full of MDs who can grasp that they have not been practicing medicine, much less how the wool was pulled over their eyes.
And it isn’t like no one has devoted tireless efforts to evoke a loud general outcry. Maybe you have over-estimated the capacity of your audience?
Correction: Rothchild’s quote, should read “derived”, NOT “deprived” benefit–
Freudian slip, no doubt.
Ah, but then there are Healy’s undeclared conflicts of interest in promoting ineffective and often dangerous reboxetine?
https://dl.dropboxusercontent.com/u/23608059/martyrdom%20of%20healy.pdf
Who can you trust?
And then there’s this from David Healy’s blog:
http://davidhealy.org/harassment-rolf-harris-to-james-coyne-to-doctor-who/
“I was referred to GMC some 8 years ago. Then the referral came from David Nutt and Guy Goodwin, professors of psychiatry in Bristol and Oxford, who as the basis of the complaint used an article by James Coyne, a psychologist in Philadelphia, raising concerns about Healy.
Coyne had become or perhaps saw himself as an unofficial spokesperson for the University of Toronto in the Healy Affair in 2001 – a scandal precipitated by the possibly self-styled Boss of Bosses, Charlie Nemeroff leaning on the University to get rid of Healy. JC spent years afterwards ranting and raving to anyone who would listen about Healy’s conflicts of interest, lack of academic heft, and general sliminess. But he didn’t turn up to debates that were scheduled and wouldn’t engage on the issues.”
Who can you believe?
I’ve long been concerned that disclosure of COI may not make much difference, or could even be subtly counterproductive.
speaking of “medical writing assistance”, check out http://www.nature.com/npp/journal/vaop/naam/abs/npp2015275a.html
Katie Tierney Higgins RN >>>>> Well spoken, accountability must become standard, from medicine to politics. My naive idea was that this was allready in Place.
Medicine and Healthcare in America is business, but I naively thought it wasn’t here in Europe.
And don’t bother about that Coyne, he has an obvious “flip-side” towards DH.
It just looks strange when a person tries to find faults in a better person.
No-one is flawless, but if you make an effort to improve yourself and things around you, you get the “high ground”. DH has a mountain to stand on.
On the issue of David Healy and reboxetine … what I’ve seen of his record has made me more inclined to trust him not less.
His basic theory was that it might work better than an SSRI for people with symptoms and personality traits of a certain type. In other words, a minority of people complaining of depression. That was not the message the industry wanted to hear. They wanted a Blockbuster Story: Reboxetine for everyone, Reboxetine in the water! Healy’s theory may have been closer to the truth but it wasn’t profitable enough.
He was also just as interested in questioning the Gospel of Serotonin as in promoting a non-serotonin-stimulating drug. Another line of research not likely to thrill the sponsors. His study of 20 normal volunteers on Zoloft and reboxetine was aimed at testing his “different strokes for different folks” theory. He wasn’t trying to study drug-induced suicidal impulses, which he thought were real but very rare. Both he and his university would have been scared to death to try any such thing. But when 2 of 20 volunteers became suicidal on Zoloft, he realized that was the most important result — not his theory.
Actually, the theory came out looking pretty damn good. Everyone in the study had rather liked one drug and disliked the other, pretty much as he thought. In fact, there were more “Zoloft fans” than “Reboxetine fans.” Healy never tried to cover that up, either.
Awfully weird behavior for a supposed “hired gun for Reboxetine” as Coyle would have us see him …