This post follows on from Science, Kansas and Pancakes. Peter is doing a good job spreading word of this article on the Prozac studies in children and featuring other aspects of this extraordinary story. This post focusses in on one revelatory feature.
A window with the view on the details of how drug approval proceeds. Very informative and helpful for understanding mechanisms of drugs (and vaccines!!) launching on the market.
This review – see Kansas and Pancakes – points readers to a section of the discussion called comment on context, which is laid out below. The results section and earlier Comment on the Results indicate that fluoxetine doesn’t work for children and is hazardous. The Comment on Context draws back the curtain on the Wizard of Washington. Almost no words in this are changed from the version in the article, but slides are added and some words to help readers for whom all this is new.
Given FDA recognition of a lack of efficacy on primary endpoints and significant safety hazards of fluoxetine, the results of this paper raise as many questions about the company, Eli Lilly, and the regulatory situation around 2002, as they do about fluoxetine use for minors. Aspects of the context in which these trials took place may shed a light on these company and regulatory issues.
Prior to the development of the SSRIs, there had been 15 randomised trials of tricyclic and related antidepressants in children and adolescents, all negative. An initial trial of fluoxetine was also negative. None of these were high quality trials. There was hope a well-done trial might demonstrate a benefit.
There was also, however, a clinical consensus and literature that children did not get endogenous depression. They might be miserable and unhappy, but this was situational and would respond to supportive interventions. Linked to this, there were almost no child psychiatrists with expertise in psychopharmacology.
A further feature of SSRIs at that time is that they were not effective in any age group for endogenous depression (melancholia). They had an anxiolytic, or serenic, action. The SSRIs became antidepressants in part to skirt around clinical concerns that any new anxiolytic would necessarily produce dependence as the benzodiazepines had. The RCTs done in children support the point that they are essentially anxiolytic rather than antidepressant.
Setting aside concerns about how companies did these trials, there appears to be better evidence for efficacy in conditions like obsessive-compulsive disorder (OCD) than for depression, although similar safety issues warrant concern about widespread use.
In 2008, in a now famous study, Erick Turner, who had previously worked in FDA, noted that of adult trials done as part of a licensing application for SSRIs and related antidepressants, 31% of trials viewed by FDA as negative were published as positive.
These positive publications are what make sertraline one of the antidepressants that guidelines recommend and that Andrea Cipriani has extolled to high heaven saying this is the drug people should be using – see Infection Super-Spreaders, Hengartner, Cipriani and Frontiers.
FDA made no comment about these publications, or about the later Emslie fluoxetine publications.
In 1997, the year X065 (the first Emslie Prozac in children study) completed, Congress offered half a year of patent extension to companies who submitted trials done in children to FDA. The studies did not need to be positive; the stated intention was to help establish the safety profile in children.
Two trials are needed for a license and Lilly immediately began study HCJE (a second Emslie study of Prozac in childhood depression). Both studies were submitted to FDA in support of a patent extension FDA supported this and also licensed claims that fluoxetine could be used to treat depressed children, as did other regulators that year.
Internally FDA had concluded that these two studies were negative.
After licensing the fluoxetine claim, based on studies negative on their primary endpoint, in October 2002 FDA issued an approvable letter for paroxetine in the treatment of children and adolescents who were depressed. The approvable letter is on Study329.org.
FDA’s letter agreed with GlaxoSmithKline (GSK) that all three trials they submitted (protocols 329, 377 and 701) in the application were negative as regards efficacy (letter available on study329.org). FDA also noted:
“Given the fact that negative trials are frequently seen, even for antidepressant drugs that we know are effective, we agree that it would not be useful to describe these negative trials in labelling.”
In the initial 2001 publication of study 329, a trial of paroxetine in depressed minors, GSK claimed paroxetine was safe and effective. The study (Study 329) was not dissimilar to the Emslie studies in terms of safety and efficacy. An internal GSK document from 1998, however, made it clear that the company knew the study demonstrated its drug to be ineffective but that it would be commercially unacceptable to publish this. This document also available on Study329.org states that
“the good bits of the study would be published”.
Based on this information, in 2004 New York State’s Attorney General lodged a fraud action against GSK. The settlement of this action made it possible to access data on study 329 and restore it in a manner that demonstrated paroxetine’s lack of efficacy and a trebling of suicidal events acts compared with the original publication.
This was published in 2015 in the BMJ – Restoring Study 329.
This information also triggered a crisis centered on the use of antidepressants for children. FDA convened a Psychopharmacologic Drugs Advisory Committee meeting in February 2004. It and other regulators published papers on 15 trials that had then been undertaken in depressed children and adolescents. The publications, including the Prozac ones, all claimed the drugs worked. The regulators at this hearing decided none of these trials (bar fluoxetine) demonstrated efficacy. There was a strong safety signal, a doubling of the risk of suicidal events, but FDA played for time and deferred action on this to a later hearing in September.
By then GSK had agreed to resolve their New York Fraud case and offered to make their clinical trial data public. This, and several reviews which returned figures for a doubling of the suicide event rate on antidepressants compared to placebo, led to an acceptance of the need for a Black Box Warning, in part because of the accepted lack of efficacy for antidepressants in this age group.
The licensing of paroxetine and other drugs was aborted but the approval of fluoxetine was not rolled back. All regulators, then and since, and medical authorities continue to claim that fluoxetine has been is effective in this age group.
To this day, the major media outlets like the BBC or medical journals like the NEJM are scared to say anthing other than this. See In the Name of the BMJ and In the Name of the BBC. Witnessing just how Lilly-Livered well-placed figures of the establishment can be has been astonishing. It is not as though the evidence they refuse to go near is hidden away – it lies there in the broad light of day.
The material available to us in respect of X065 (Emslie 1) and HCJE (Emslie 2) was less comprehensive than that for study 329 but our re-analysis makes clear there was no basis for claims for efficacy or safety. It can also be noted that Lilly and other companies have used fluoxetine as a comparator in subsequent antidepressant trials in this age group and that none of these studies demonstrated efficacy or safety for fluoxetine.
There has been one independent trial of fluoxetine, the National Institutes of Health’s Treatment of Adolescent Depression Study (TADS). This claimed efficacy and safety for fluoxetine, but efficacy was minimal and there were 34 suicidal events on fluoxetine compared with 3 on placebo. In none of 15 articles about this study between 2004 and 2010, written by senior figures linked to child psychiatry, published after the Black Box Warnings on these drugs, have these fluoxetine suicide data been addressed.
Duke University where the trial data was lodged has refused to hand over serious adverse event forms from the trial that might permit a restoration of this study – see link to Jon Jureidini video on Post-Truth and Science in Science Kansas and Pancakes.
The dataset from X065 and HCJE on QT intervals also has a regulatory context. At the time these trials were being reviewed by FDA, Lilly had submitted a license application for R-fluoxetine, which was ultimately withdrawn in part because of QTc interval problems. QT interval problems are clearly an issue with fluoxetine in adults, as they are with all SSRIs (The Reverse Dodo Effect).
There were marked changes to cardiac QTc intervals in these Prozac pediatric trials. In response to FDA concerns, Lilly argued that the statistically significant increase in mean QTc found with the initial analysis was the product of random variability. FDA’s reviewer responded that, with a P-value of 0.009, the result was, by definition, unlikely to be produced by random variability.
Despite telling Lilly publicly they were crazy, and despite Lilly withdrawing R-fluoxetine because it causes cardiac problems, FDA did nothing else about this problem.
Erick Turner’s article is famous for two slides. The one further up the page shows how wonderfully well these drugs work. Who could resist prescribing them.
The second slide, here, shows what FDA saw and was perhaps even told by companies, as GSK told them in their children’s studies – the drugs don’t work in these trials, but agreed not to tell the world. These adult trials were done in th 1990s – before the trials in children.
Had FDA stated in the label for paroxetine given to children that study 329 was negative, it now appears they would have opened GSK up to a fraud action and a large settlement fine. This is exactly what happened when the internal company document came to light.
GSK and all companies are likely to have been aware of this when in discussions with FDA. It is not the job of drug regulators to police the medical literature but, if the medical literature limits a regulator’s freedom of movement, and forces them not to say things that we really should be told – both doctors prescribing and the rest of us taking – we have a nexus of issues that likely leaves everyone feeling uncomfortable.
If they play their cards right it looks like companies can almost force regulators to approve drugs on the back of negative trials.
When Emslie 1 and Emslie 2 were run, there was an expectation that many unhappy children could be helped with support. Support is still a good option. The approval of fluoxetine for depression in children and adolescents and the publication of many articles since, some of which have been shown to be ghost written, claiming efficacy for a number of SSRIs swept away the idea of relying on support and paved the way for a rapid increase in the use of antidepressants in children and teenagers.
Antidepressant drugs are now among the most commonly used drugs by adolescent females and among women of child-bearing years even though they double the rates of miscarriage, birth defects and behavioural abnormalities in their offspring. The figures for usage are as high in part because once started these drugs can be difficult to stop.
This is a public health emergency. FDA’s willingness to license Eli Lilly claims that fluoxetine is an antidepressant in paediatric populations was a key step in the evolution of this situation. The divide between what the academic literature on these drugs says and what the data when accessible shows is the greatest known divide in medicine. How this came about may need to be understood if we are to prevent comparable situations in future.
Several women, Shelley Jofre, working on BBC’s Panorama, and Cindy Hall, working at the Baum-Hedlund law firm, and Rose Firestein, working in the office of the Attorney General in New York, made the difference in this story. They rather than any academics, doctors or medical journals dug up the documents that brought a shocking scandal to light and derailed companies and regulators.
They ripped back the curtain that kept the Wizard of Washington concealed, revealing a pathetic old dude that we should not depend on to keep the system working or keep us safe.
The expectation many had at the time was that, given the scale of the scandal revealed, the system would be shamed into reform. Far from it. The Lancet, the Cochrane Collaboration and others we might think we could trust led the way in sweeping the scandal under the carpet.
Things are worse for children now, many of whom are on multiple psychotropic drugs. They are worse for the rest of us, an increasing number of whom are on drug cocktails that are shortening our lives and leading to evident falls in life expectancies in Western countries.
The regulatory apparatus has become an unlocked door against which companies or the Department of Defense can breeze through unimpeded. There are always some who think that this time the scandal is so shocking – as with Aduhelm or recent gene therapies – that things must now change. The system is inured to such scandals. Each shocking event makes it less likely there will be any change.
We’re off to see the Shrink,
The wonderful Chemical Shrink
We hear he is a whiz of a Shrink if ever a Shrink there was.
If ever, oh ever, a Shrink there was,
The Chemical Shrink is one becoz, becoz, becoz, becoz, becoz, becoz,
Becoz of the wonderful pills he gives
We’re off to see the Shrink,
The wonderful Chemical Shrink
Swallow the yellow-green pill,
Swallow the yellow-green pill,
Swallow, swallow, swallow, swallow, swallow the yellow-green pill.
Swallow the promise in the pill,
Swallow the capsule well or ill,
Swallow, swallow, swallow, swallow,
Swallow the yellow-green pill.
Apologies for the unscientific tone of this post. I must have caught a disorder from Peter Goetzsche.
To be continued next week.
RxISK acknowledges that the experiences of those who have been harmed by medical treatments are the cornerstone on which it is built, and believes this should be the case for all of medicine.
See Black Robe, White Coat for more detail on this people acknowledgement