To the Sounds of a Drum © Nina Otulakowski November 2022
This letter, which has had no response, needs to be read in conjunction with Can you Hear the Suzerain Call?
Dear Drs Roberts and Ms. Nebhrajani
I wrote to your predecessors Dr Haslam and Mr. Dillon just under 3 years ago about the issues of ghostwriting in clinical trials along with lack of access to trial data – the material on which NICE base their Guidelines. Mr. Dillon replied, acknowledging the issue, but adding it was difficult to see what NICE could do (1).
Over a decade earlier in 2004, with NICE in the middle of writing Guidelines on the treatment of paediatric depression, a crisis blew up centred on the ghostwriting of clinical trials and lack of access to trial data. Evidence of a deliberate intention to mislead doctors and the public in the case of a ghostwritten publication of Study 329, a study of paroxetine in adolescent depression, led New York State to take a fraud action against GlaxoSmithKline (GSK). Study 329 also had a part in a later Department of Justice action against GSK that was resolved for $3 Billion.
This crisis, in addition, produced evidence of a doubling of suicidal event rates in adolescents on active treatment compared to placebo. Around 2004-2006, pretty well the entire literature on paediatric depression was company written and constituted the greatest known divide, to me at least, in any branch of science between what the published literature said and what the data from trials, when accessed, indicated.
These events led to a celebrated Lancet editorial in June 2004 – Depressing Research (2). Between the lines, this editorial appeared to ask if it was possible, against the backdrop of a comprehensively ghostwritten literature at odds with the data it purported to represent, to write any guidelines for anything.
The NICE Guideline writers involved in the Lancet editorial appear to have been advised to adopt a more politically mature position. NICE, presented with an opportunity to advance the health of all, continued to do as it had previously done – basing its Guidelines on a dodgy literature, making them essentially a free marketing tool for pharmaceutical companies.
I mentioned these points at a House of Commons Health Select Committee in 2004. Richard Horton, Lancet Editor, and Iain Chalmers, Cochrane Collaboration Founder, rushed in to assure the committee that these problems were rare and only applied to peripheral journals – the New England Journal of Medicine has been one of the lead offenders for over a decade.
Cochrane also opted for political maturity and continued to view company studies as valid evidence. When following a complaint to the European Ombudsman Professor Peter Gøtzsche secured access through EMA to company Clinical Study Reports, Cochrane continued to prefer ghostwritten articles. This arguably contributed a little over a decade later to a collapse of Cochrane’s reputation in many quarters.
FDA and MHRA, who had approved fluoxetine for depressed minors before the 2004 crisis blew up, rushed to assure the world that doctors could use it. The two published fluoxetine trials underpinning approval were company written and claimed efficacy, where FDA reviews report them as negative on their primary outcome.
Peter Gøtzsche and I have recently written an article, linked below, reanalyzing the data from the original fluoxetine trials in children and young people (3). It details the suicidal events, as well as cardiac and other problems found hidden in those trials, problems that kill children, in addition to confirming that fluoxetine is ineffectual.
You should know that in 2002 FDA issued an approvable letter for paroxetine, on the basis of 3 negative trials. This approval was aborted when the 2004 crisis blew up, but it was too much it seems for regulators to admit to a prior mistake in the case of fluoxetine.
FDA also agreed with GSK not to mention these negative trials in the label of paroxetine. It seems likely that GSK and other companies were acutely aware they could get sued for fraud if the label mentioned Study 329 was negative given their published claims that it demonstrated paroxetine worked well and was safe.
In a 2008 article, Erick Turner, who had formerly worked in FDA, along with colleagues showed that one third of negative trials done in adults with antidepressants then on the market were published as positive – just as Study 329 had been, with no mention of this in the label of these drugs. FDA have never commented on any of these articles.
Meta-analyses, by Cipriani and others, have since argued we should think of using sertraline as a first line antidepressant. This makes some sense when looking at Turner’s table of published results. Looking at Turner’s table of FDA reviews, sertraline is the last drug anyone would use.
There is one study of fluoxetine in adolescents, run under the auspices of the NIH, but run on Lilly headed forms and rating scales. This has 34 suicidal events on fluoxetine compared to 3 on placebo, something the 7 publications on this trial side-step. Duke University, listed as holding the trial data, claim the adverse event data has all been destroyed.
As long ago as 2016, Jeremy Hunt, when Minister for Health said:
“Children’s mental health is possibly the biggest single area of weakness in NHS provision at the moment” (4).
An outcome like this is surely to be expected when services are trying to operate on the basis of a published literature and guidelines that assure them of one set of outcomes, when the inaccessible data suggest exactly the opposite will happen. Guidelines that palter with us in a double sense – that keep the word of promise to our ears but break it to our hope.
Things have got worse since with the National Institute of Health and Care Research suggesting that doctors, in the habit of dishing out these medicines to minors, are paying little heed to NICE Guidelines (5). The NICE Guidelines recommend referring to psychotherapy for milder cases, unaware that psychotherapists commonly recommend antidepressants. The recommendation to reserve these drugs for severer cases of depression, likely suggests to many that if they work for severer cases, they will work for milder cases. Exactly this principle has underpinned pharmaceutical company marketing strategies for drugs like alprazolam.
Many children given these drugs, while on waiting lists, will present to mental health services with much more disorganized behaviour than if left untreated. They present to clinicians who have no training in how to assess or manage such consequences and who are likely to prescribe further medicines. This situation has recently led the New York Times to write a feature on adolescents, primarily women, who end up on up to ten psychotropic drugs simultaneously with no obvious benefit (6). The same is happening in Europe (7).
The NIHR research makes clear that the UK is not spared. This year’s Office of National Statistics (ONS) figures show a recent increase in suicides in females under the age of 24 in the UK, a sufficiently clear cut change to attract a specific ONS editorial comment (8).
Greta Thunberg’s generation who are doing so much to draw our attention to the polluting effects of an excessive use of chemicals on the outer environment are having their inner environment polluted to a greater extent than ever before.
The BMJ have just published a piece on the need to combat the infodemic of misinformation we have seen with COVID and its vaccines (9). There is no better example of a misinformation infodemic than the trials of antidepressants in adolescents. There are few, if any, anti-vaxx groups, with the resources to match pharmaceutical company capacities to create a mismatch between reality and propaganda.
I am copying MHRA, BMJ and other professional bodies in to this letter. When initially drafting this, I had little hope that any of you are likely to do anything, let alone collaborate to solve this problem. I think I have even less hope now with the establishment of the Vaccine Taskforce Model to tackle Health Challenges (10). Regretfully, writing is more a case of letting the public see that nothing is being done or likely to be done about a problem outlined here that all parties acknowledge is happening. The situation seems more likely to get worse.
David Healy MD FRCPsych
MHRA: J Raine
BMJ: K Abbasi. M McKee
Royal Coll Psychiatrists: A James
Royal Coll Paediatrics: C Kingdon firstname.lastname@example.org
British Medical Association: P Banfield. M McKee
Minister for Health UK: S Barclay
Minister for Mental Health Scotland: K Stewart
See Can You Hear the Call of the Suzerain? for the significance of these images.