Header picture by Ken Teegardin
Trying to make sense of nonsense
The Saga of Seroxat
October 15, 2012Posted by on
“My name is Gail Griffith and I serve as the patient representative on this committee, and I would just like to take this opportunity to say why I am here. First, I am not a medical professional; I am a consumer. I have suffered from major depression since I was a teen. Second, I have a son who suffers from major depression and three years ago, at age 17, after he was diagnosed and placed on a regimen of antidepressants he attempted suicide by overdosing intentionally on all his medications. He nearly died. So, I know this illness. I know what it does to adolescents.
“For the record, I would simply like to state that I have no professional ties to any advocacy group or any patient constituency. I also wish to affirm that I have no ties to any pharmaceutical company, nor do I hold any investments in pharmaceutical manufacturers. My sole responsibility is to ensure that the interests of concerned parents and families are represented”
If you have read Dr Ben Goldacre’s Bad Pharma, you may have been surprised at how the pharmaceutical industry has been able to distort the evidence for the effectiveness of medicines in their favour. As about 1/3 of my PhD focuses on antidepressant use in children, I have been a bit less surprised. Throughout the two years I’ve been looking into this particular topic, I’ve been finding out about the industry’s (and regulators’ and academics’) transgressions on an almost weekly basis. Even more so when I started reading the FDA’s seemingly endless meeting reports as I had some problems falling asleep. Surely, these would be the perfect long dry reads I needed to combat my insomnia? Well, to cut a long story short, they didn’t. But in order to get to the particular meeting Ms Griffith was introducing herself to above, we need to step back to the ’80s.
In the ’80s, Eli Lilly was trying very hard to get a market authorisation for their new antidepressant fluoxetine. It was a revolutionising drug as it was the first in a whole new class, the selective serotonin reuptake inhibitors or SSRIs, to go on the market (though not the first to be discovered). But before their drug becomes available to doctors to prescribe to patients, Eli Lilly had to get approval from the national regulators. In this case, the German Bundesgesundheitsamt (BGA for short) was chosen for a first attempt. Eli Lilly submitted their trial data and on 25 May 1984 their received a damning fax telling them the BGA did not intend to approve their drug.
The main reason for the BGA labelling fluoxetine ‘totally unsuitable for the treatment of depression’ was that they found that 16 people taking the drug in trials had attempted suicide, 2 of whom successfully. You might think at this point that a drug like this would never make it past the regulators. You would be wrong. After being rejected again by the BGA in 1988, it finally made it onto the market in 1991. By that time fluoxetine had already made a name for itself in most of the rest of the world. You might know it better by it’s other name: Prozac.
Soon after Prozac started being prescribed to people, doctors started to worry. Some noticed that some patients they prescribed the drug to became aggressive or suicidal, which they hadn’t been before1. In response to this, the FDA got together the experts in the field to discuss the matter, and concluded that it wasn’t the drug, but the depression that the drug was trying to treat that caused the excess in suicidal behaviour. Prozac remained on the market, and no warnings were given out.
As Prozac, and other ‘me-too’ SSRIs started to make billions for pharmaceutical companies, trials were started to see whether they were effective for treating depression in teenagers as well. GSK ran three trials between 1995 and 2001 on their SSRI paroxetine. “The results of the studies were disappointing. The possibility of obtaining a safety statement from this data was considered but rejected,” read an internal email referring to the studies. Nonetheless, an article appeared in 2001, in the Journal of American Academy of Child and Adolescent Psychiatry (that’s a pretty good journal to be published in), showing that paroxetine was indeed very effective in treating depression in children2. At the same time, GSK organised meetings where they told GPs that paroxetine “demonstrates remarkable efficacy and safety in the treatment of adolescent depression.”
Academics wrote to the journal criticising the paper, drawing the attention of Shelley Jofre, a journalist for BBC’s Panorama. From 2002 to 2007 she made 4 documentaries focussing on Seroxat, as paroxetine is sold in the UK, and how GSK had distorted and hidden data on this drug. The last documentary in the series forms a nice half hour summary of, as one person in the documentary puts it, ‘the despicable actions of GSK’. I’d very much recommend watching it, but just to give a bit of an idea: GSK held back the data from two trials that showed paroxetine was no better than placebo and distorted the evidence in the study that it did publish. In the peer-reviewed study the primary outcome had changed (when using the original primary outcome paroxetine was no better than placebo or the best available treatment at the time), and as it turned out, the study was ghostwritten (Professor Martin Keller, first ‘author’ on the published paper, admits never having seen the raw data, just neatly prepared summary tables).
But most worryingly of all: the serious adverse effects (suicidal behaviour as it turns out) had been downplayed. In the trial, 11 teenagers taking paroxetine experienced serious adverse events, compared to only five for imipramine (the ‘active’ control – imipramine is a different type of antidepressant), and two for placebo; the group sizes were equal. Serious side effects are the kind that lands you in hospital. However, in the article, only 1 case (out of 11) was deemed to be related to paroxetine. When the study was later reanalysed, it turned out 10 of the 92 teenagers in the paroxetine group had experienced a potential suicidal reaction. None of this was mentioned in the article. The study, which should be retracted on the basis of distortion, is still available on the journal’s website and has been cited 475 times as of 11 October 2012.
Almost every single issue raised in Bad Pharma seems to have happened in the saga of Seroxat. In June 2003, the MHRA (after being informally told by GSK that there might be an issue with suicidal behaviour in patients taking their drug Seroxat) issued a warning, stating that paroxetine shouldn’t be prescribed in people under the age of 18. A larger investigation into all antidepressant followed, and at the end of the same year, the MHRA extended their warning to all other SSRIs, with the exception of fluoxetine.
Enter the meeting this story started with. On 13 September 2004, in a Holiday Inn in Bethesda, Maryland, the FDA held a meeting to discuss similar worries antidepressants might increase the risk of teenagers committing or attempting suicide. Gail Griffith, whose son had attempted suicide by taking an overdose of his antidepressants three and a half years before, attended this meeting as a patient representative. As the only member of the public in a meeting with 37 academics and medics, it must have been intimidating.
The meeting took two whole days, and concluded all antidepressants should carry a black box warning (a warning on the patient information leaflet in each box of medicine, emphasised by a black box surrounding the message), warning these drugs might increase the risk of ‘suicidality’ in children. Don’t know what that word, ‘suicidality’, means? Don’t worry, neither does the FDA:
“Dr. Irwin (committee member): Is there a word ‘suicidality’?
Dr. Goodman (committee chairman): Every time I write it in Word, it gets red underlined.
Dr. Irwin: It seems to me, I mean to me, I am not certain anyone really knows what it is that we are saying and what you are voting on, or, to me, I would like to know what suicidality is.
Dr. Goodman: I don’t think it is in an Oxford Dictionary either.
Ms. Griffith (patient representative): It is not in Webster’s.
Dr. Irwin: In a sense, it confounds things by, you know, the front page of the paper today [The Wall Street Journal carried a story stating that SSRIs had caused children to commit suicide], I think may lead to kind of a misrepresentation.
Dr. Pollock (committee member): Can’t we just use the explicit language?
Dr. Goodman: That is, in part, what I would favor, is that if we use it, I think we need to at least parenthetically define what we mean when we are answering the question.
Dr. Temple (FDA associate director for medical policy): Yes, that is what we do. I think that is what we actually did in labeling. Whether we should coin a new word is debatable, obviously, but it means suicidal behaviour plus suicidal ideation. That is what we use it to mean as those items.
Dr. Goodman: Would it be fair for us to slightly modify the question, or do we have to take
it as it is, because what I would say, if we could use the definition that corresponds to Outcome 3, I would feel most comfortable, because that corresponds to the reclassification and the way you approach the dataset. So, suicidality, suicide attempt, preparatory action/or suicidal ideation.
Dr. Katz (FDA Supv. Medical Officer and Director of Division of Neuropharmacological Drug Products): Yes, you can certain amend the question. We called it suicidal behavior and ideation, but it is clearly what is embodied in Codes 1, 2, and 6.
Dr Goodman: ‘I think we have a clarification on that and hopefully, the public will understand what we mean, too, and that, I think we will leave it to the press to do their job in trying to best define what we mean and don’t mean by that term, specifically, that we are not talking about actual completed suicide if we are restricting our deliberations to the clinical trials, because there weren’t any instances.’”
So this is where our story ends, for now. The confusing warnings by the MHRA (no SSRIs apart from Prozac for children), the FDA (no antidepressants at all for people under the age of 25) and the EMA (no SSRIs, but other antidepressants are kind of okay for children) still stand, and are supposedly based on exactly the same evidence. Initially, in the UK, GPs seemed to adhere the MHRA’s advice3 (yup, that’s my study). However, the change didn’t last long: from 2005 rates for SSRI prescription in teenagers have been on the increase again. And more than that: research comparing the Netherlands and the UK suggests that the negative media attention (which mostly only happened in the UK) and regulatory warnings overall didn’t have much effect on the increasing trends in SSRI prescriptions4. Even more worrying: apart from not knowing whether antidepressants are safe for children, we also don’t know whether they work at relieving their depression. The Cochrane Library has two separate reviews looking at whether the older tricyclic antidepressants and the newer SSRIs work, but the results aren’t too comforting to say the least5,6.
Please don’t think GSK is the only the company in the wrong. It just so happens that because of their $3 billion fine earlier this year (partly because they marketed paroxetine to children) a lot of the evidence used in this piece was uprooted. It can all be found on the US Department of Justice’s website.
(Quotes from Ms Gail Griffith and the discussion on ‘suicidality’ are directly taken from transcripts of the Joint meeting of the Psychopharmacologic Drugs Advisory Committee and the Pediatric Advisory Committee on 13/14 September 2004 – excerpt 1 from page 12-13 from 13 September meeting, and excerpt 2 from page 213-16 from the 14 September meeting. Both can be found on the FDA’s CDER 2004 Meeting Documents page – I won’t link directly to the PDF’s as they’re quite big)
1) Teicher MH, Glod C, Cole JO: Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990; 147(2):207-10
2) Keller MB, Ryan ND, Strober M, et al: Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry 2001; 40(7):762-72
3) Wijlaars LPMM, Nazareth I, Petersen I (2012) Trends in Depression and Antidepressant Prescribing in Children and Adolescents: A Cohort Study in The Health Improvement Network (THIN). PLoS ONE 7(3): e33181. doi:10.1371/journal.pone.0033181
4) Hernandez JF, Mantel-Teeuwisse AK, van Thiel GJMW, Belitser SV, Warmerdam J, et al. (2012) A 10-Year Analysis of the Effects of Media Coverage of Regulatory Warnings on Antidepressant Use in The Netherlands and UK. PLoS ONE 7(9): e45515. doi:10.1371/journal.pone.0045515
5) Hetrick SE, Merry SN, McKenzie J, et al. (2009) Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. The Cochrane Library
6) Hazell P, O’Connell D, Heathcote D, et al. (2010) Tricyclic drugs fro depression in children and adolescents. The Cochrane Library