Martha Rosenberg calls the reanalysis of Paxil and Study 329 “a victory for safety activists, medical reporters, the public and freedom of the press.” But, she warns, “many pro-pill doctors continue to fight evidence of Paxil’s suicide risks and similar SSRIs.”
The strongest evidence we have as to whether a drug causes a problem does not come from RCTs or any other controlled study but rather from good clinical accounts. Even if RCTs were done by angels, so there was no hiding, no miscoding, nothing untoward, RCTs can still hide adverse events. The onus is on large and powerful corporations who have a lot of resources to pinpoint the populations where the benefit is likely to exceed the risk, if they want to continue to make money out of vulnerable people.
In 2004, the FDA added a black-box warning to SSRI antidepressants on the increased risk of suicide among children taking these drugs. A new study suggests that this warning has increased the proportion of children who begin an antidepressant on a low dose, but the majority are still receiving higher than recommended doses.
Study 329 seems to fit the classic picture: It has Big Pharma ghostwriting articles, hiding data, corrupting the scientific process and leaving a trail of death, disability and grieving relatives in its wake. But is it at fault alone? Both Big Pharma and Big Risk (the insurance industry) were once our allies in keeping our hopes alive – in keeping our children alive and well. They are now a threat. And of the two – Big Risk is the bigger threat.
Nobody has retracted or apologized for a study that was an academic disgrace—but a marketing coup for GSK—which may well have caused untold numbers of deaths, suicide attempts and irreversible anguish to myriad families. Can we stand idly by when we’re told that it “accurately reflects the honestly-held views of the clinical investigator authors who do not agree that the article is false, fraudulent or misleading.”? What is the current market value of the honestly-held views of people who tell lies?
While making money from the publication of pharmaceutical company trials, and in the face of a complete failure by industry to adhere to basic scientific norms and make data available, BMJ and other journals — although BMJ in particular — have run a series of articles on supposed Academic Fraud. These articles feature instances of fraud sometimes as bizarre as researcher claiming he cannot show the data as it was eaten by termites. The universal feature is that these are academic studies, and academic fraud is an issue in academia.
The UK Times reports that pharmaceutical companies are actively lobbying to limit the release of clinical trial data to the public. Rather than limiting results and data to medical journals, new transparency initiatives are pushing for making the information publically available. The push for transparency comes in the wake of the reanalysis of the Study 329 data on paroxetine (marketed as Seroxat and Paxil), which found that the industry study had misconstrued its results.
Access to data is more important than access to information about conflicts of interest. It is only when there is access to the data that we can see if interests are conflicting and take that into account. Problems don’t get solved unless someone is motivated for some reason. We need the bias that pharmaceutical companies bring to bear in their defense of a product, along with the bias of those who might have been injured by a treatment. Both of these biases can distort the picture but it’s when people with differing points of view agree on what is right in front of their noses that we can begin to have some confidence about what we have.
The Scientific American reports on a new analysis of antidepressant trials revealing that the vast majority of meta-analyses have industry links and suppress negative results.
The BMJ states that it takes on average eight weeks from submission of an article to publication. The review process for Restoring Study 329 took a year, with a three-month review process involving six reviewers to begin with, and then a further four reviews in a four-month process, leading to a provisional acceptance in March that was withdrawn.
By 2002 GlaxoSmithKline had done 3 studies in children who were depressed and described all three to FDA as negative. As an old post on Bob Fiddaman’s blog reproduced here outlines, several years later they undertook another study in children in Japan. (Editor's note: This is a re-print, by David Healy, of a post by Bob Fiddaman)
The controversy over “Study 329” on the effects of Paxil in teen depression has raised questions about the state of ALL medical research. I decided to look at the research for the most recent psychiatric drug approved by the FDA, a new antipsychotic called cariprazine or Vraylar. I located twenty studies of Vraylar on www.ClinicalTrials.gov, the U.S. government-sponsored registry for clinical trials. Three were still in process, and seventeen were completed. Not one had shared its results on the government website, a supposedly mandatory step.
The antidepressant Paxil has been linked to birth defects. "An Ohio federal judge on Wednesday ruled that GlaxoSmithKline must face a product liability suit brought by a woman whose child was born with heart defects after she took the antidepressant Paxil during her pregnancy, ruling that she had successfully pled fraud."
It can be difficult to pinpoint transitions. The Rubicon that led from a Medical Republic to a Pharmaceutical Empire was crossed in 1962 with the passage of the Amendments to the Food and Drugs Act. This act put in place an apparatus of controlled trials, prescription-only status and disease indications that laid the basis for a global pharmaceutical hegemony, although the drift to Empire could still have been stopped at this point.
Writing for the Atlantic, David Dobbs examines how much harm has been done in the 14 years since Paxil was wrongly determined to be safe and effective. “Study 329, as it became known, helped spur a huge increase in Paxil prescriptions,” Dobbs writes. “In 2002 alone, over 2 million prescriptions were written for children and teens, and many more for adults.” “Thousands of children, teens, and young adults attempted or committed suicide while on Paxil,” and the reanalysis of Study 329 in BMJ makes it seem “more likely than ever” that many did because of the drug.
In May 2014, the RIAT team asked GSK what the children who became suicidal in the course of Study 329 have since been told. The consent form says that anyone entering the study would be treated just the way they would be in normal clinical practice. In Study 329, the children taking imipramine were by design force titrated upwards to doses of the order of 300 mg, which is close to double the dose of imipramine given in adult trials by GSK or in normal clinical practice. In normal clinical practice it would be usual to inform somebody who had become suicidal on an SSRI that the treatment had caused their problem.
It is appropriate to hold a company or doctors who may be aiming to make money out of vulnerable people to a high standard when it comes to efficacy, but for those interested to advance the treatment of patients with any medical condition it is not appropriate to deny the likely existence of harms on the basis of a failure to reach a significance threshold that the very process of conducting an RCT will mean cannot be met, as investigators' attention is systematically diverted elsewhere.
The authors of Study 329 began recruiting adolescents for a comparative study of Paxil, imipramine and placebo in 1994 and finished their investigations in 1997. They dropped a large number of their original cohort, so the randomness element in the study must be open to question. Late in 1998, SmithKline Beecham, the marketers of Paxil, acknowledged in an internal document that the study had shown that Paxil didn’t work for adolescents in terms of the two primary and six secondary outcomes they had established at the start of the study. In a nutshell, Study 329 was negative for efficacy and positive for harm, contrary to their succinct upbeat conclusion.
If someone were to ask the surviving authors of Study 329 the question: “Knowing what you know now, if you had to do it over, would you agree to participate in that study again?”, many would probably say no. Study 329’s problems started to surface right after it was published. Several doctors wrote letters to the JAACAP Editor with probing questions, mostly centred on the psychiatric side effects of paroxetine, and the measures used to claim its efficacy in treating adolescents. The authors responded and the questioners did not pursue their concerns further. Except one. Next week, fourteen years and two months after it was published, it is about to take yet another hit, when the Restored version is published.
In addition to hosting the Panorama programs and The Famous Grouse history of Study 329, Study329.org has a comprehensive timeline on the origins of concerns about the SSRIs and the risk of suicide, initially with Prozac and subsequently with Paxil/Seroxat. The hope is to provide a comprehensive repository for anyone who wants to study SSRIs, RCTs, and Study 329 in particular.
The buzz in academic publishing right now is the story about how several hundred open access journals accepted a fake research paper. Of much more concern is that there are top-tier medical journals which have published clinical trials, that were read by thousands of people, that influenced clinical decisions, that we now know were bogus, but have never been retracted.
For the past several years whenever a critical essay has come along examining the work of Irving Kirsch and his colleagues I have made an effort to examine the validity of the proposed arguments. Kirsch and his colleagues used the Freedom of Information Act to gain access to the unpublished trials of antidepressants and then pooled the clinical trial data – both published and unpublished ─ and analyzed it as a single data set. It is common for pharmaceutical companies to only publish those studies that find their products effective, and to withhold the negative studies, making it difficult to reach accurate conclusions by examining only the published data. Kirsch and his colleagues have reported that in the company sponsored clinical trials, the SSRIs only marginally outperform placebo, with the difference being statistically different but not clinically significant.
Did scientists recently discover that the Serotonin Theory of Depression is false? Or has this been known for decades? We investigate.
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