Where is the outrage?


https://www.bmj.com/content/362/bmj.k3948/rr-1

Pandemrix and narcolepsy

Where is the outrage? GlaxoSmithKline suppressed clear danger signals from vaccination with Pandemrix. The result, to begin with, was the suffering of a large number of children and adolescents who developed narcolepsy. Peter Doshi is to be commended for dispassionate reporting of the facts, but I am frustrated by his cool rhetoric in the face of what I believe are acts of greed and cruelty.

The facts reported by Doshi are new, but the pattern of behavior is not. The manufacturers and their professional surrogates are past masters at doing research that shows short-term vaccine efficacy but that does not reveal serious adverse effects. They always end up saying, as in this case, that “there is no proof of a causal association.” Such behavior might be forgiven if influenza vaccines were real lifesavers, but we still do not know if they have done more good than harm in the long run. I am not alone in making this assertion.

Not long ago Gaffney and Lexchin said that US and Canadian pharmaceutical systems, “…are dysfunctional. Costs are exorbitant, commercial goals distort drug development, misleading promotion fosters misuse, and medications are too often unaffordable for patients.” (BMJ 2018;361:k1039) Much the same can be said for the development and promotion of vaccines in the last 10-15 years.

I get frustrated and angry about the promotion of some drugs and vaccines, but I am saved from despair by the efforts of professionals like Doshi and his colleagues who keep plugging away at the facts.

Allan S. Cunningham

Competing interests: No competing interests

24 September 2018
Allan S. Cunningham
Retired pediatrician
Cooperstown NY 13326, USA
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But Of Course They Would..


https://www.fiercepharma.com/vaccines/ema-mhra-and-glaxosmithkline-blast-bmj-s-flawed-pandemic-flu-vaccine-safety-report

 

EMA, MHRA and GlaxoSmithKline blast BMJ’s ‘flawed’ pandemic flu vaccine safety report

 

“…European drug regulatory bodies and GlaxoSmithKline have quickly rallied their rebuttals to a BMJ report that questioned the safety profile of GSK’s now-unavailable pandemic flu vaccine Pandemrix, as well as the lack of transparency over drug information.

In a report based on GSK-made internal safety reports, The BMJ found that during the 2009-2010 H1N1 flu pandemic, GSK had received 5,069 serious adverse event reports for Pandemrix in about six months. It represents a rate of 72 cases per million doses—seven times the rate for two other GSK pandemic flu vaccines combined. The report also criticized the drugmaker and health authorities for not making the information public.

By Wednesday, the European Medicines Agency (EMA), the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) and GSK had raised their issues with the article, lambasting its “scientifically inappropriate” methodology and what they saw as an “incorrect” accusation regarding transparency….”

GSK’s Pandemrix vaccine: why was the public not told of early warning signs?


Because we’re all just Glaxo’s guinea pigs aren’t we?

 

 

From the BMJ-

https://www.bmj.com/content/362/bmj.k3948


Eight years after the pandemic influenza outbreak, a lawsuit alleging that GlaxoSmithKline’s Pandemrix vaccine caused narcolepsy has unearthed internal reports suggesting problems with the vaccine’s safety. Peter Doshi asks what this means for the future of transparency during public health emergencies

In October 2009, the US National Institutes of Health infectious diseases chief, Anthony Fauci, appeared on YouTube to reassure Americans about the safety of the “swine flu” vaccine. “The track record for serious adverse events is very good. It’s very, very, very rare that you ever see anything that’s associated with the vaccine that’s a serious event,”1 he said.

Four months earlier, the World Health Organization had declared H1N1 influenza a pandemic, and by October 2009 the new vaccines were being rolled out across the world. A similar story was playing out in the UK, with prominent organisations, including the Department of Health, British Medical Association, and Royal Colleges of General Practitioners, working hard to convince a reluctant NHS workforce to get vaccinated.2 “We fully support the swine flu vaccination programme … The vaccine has been thoroughly tested,” they declared in a joint statement.3

Except, it hadn’t. Anticipating a severe influenza pandemic, governments around the world had made various logistical and legal arrangements to shorten the time between recognition of a pandemic virus and the production of a vaccine and administration of that vaccine in the population. In Europe, one element of those plans was an agreement to grant licences to pandemic vaccines based on data from pre-pandemic “mock-up” vaccines produced using a different virus (H5N1 influenza). Another element, adopted by countries such as Canada, the US, UK, France, and Germany, was to provide vaccine manufacturers indemnity from liability for wrongdoing, thereby reducing the risk of a lawsuit stemming from vaccine related injury.45

In an interview with The BMJ, Liam Donaldson, England’s chief medical officer at the time, recalled the situation around the October 2009 roll-out: “The UK had worked for several years on its pandemic influenza plans, as part of a globally coordinated approach. This included, well in advance, establishing the process for developing and introducing a vaccine in such a public health emergency.

“Faced with an emerging pandemic of unknown severity, the process was initiated. The national scientific committee for vaccines (the JCVI) and the statutory medicines regulatory authorities were fully engaged in the procedural steps that led to the introduction and use of the vaccine. This was not a policy decision taken in the absence of such expertise,” he said.

Controversy

Vaccines against influenza are arguably the only vaccines that a notable portion of healthcare professionals decline despite recommendations.6 And in late 2009, vaccines against the H1N1 swine flu—which was turning out to be a far milder pandemic than officials had predicted—were even more controversial than normal.

In Germany, senior physicians expressed doubts about GlaxoSmithKline’s Pandemrix vaccine. They were concerned about potential side effects triggered by the AS03 adjuvant, an oil-in-water emulsion that it contained to boost effectiveness.7 Then controversy erupted when the German newspaper Der Spiegel reported that top politicians and government employees were going to receive Celvapan, Baxter’s unadjuvanted H1N1 vaccine, not Pandemrix.7

The concerns, it seems, were prescient. A year later, signs of a problem with Pandemrix were emerging through postmarket reports of narcolepsy, predominantly among children and adolescents in Sweden and Finland.8 Multiple academic and government led studies subsequently judged that the relation between Pandemrix and narcolepsy was likely to be causal.91011 Over 1300 people are estimated to have been affected among the roughly 30 million vaccinated across Europe,12 including around 100 families in the UK.13

However, GSK and the European Medicines Agency, which licensed Pandemrix, have not accepted that the association with narcolepsy has been proved to be causal, and research on the topic continues.14 GSK told The BMJ that “further research is needed to confirm what role Pandemrix may have played in the development of narcolepsy among those affected.”

Claims for compensation followed, with many still being fought in the courts.15

Now, eight years after the outbreak, new information is emerging from one of the lawsuits that, months before the narcolepsy cases were reported, the manufacturer and public health officials were aware of other serious adverse events logged in relation to Pandemrix.

Undisclosed problem

In documents obtained through the pretrial discovery process (see supplementary data on bmj.com), prosecutors suing the Irish Minister of Health, Health Service Executive, Health Products Regulatory Authority, and GSK have found a string of GSK postmarketing safety reports that show a striking difference in the number and frequency of adverse events reported for three GSK pandemic vaccines approved and used across the world: Pandemrix, Arepanrix, a similar H1N1 vaccine that also contained AS03 adjuvant, and an H1N1 vaccine without adjuvant (no brand name is given).

The BMJ learnt of the reports from my colleague Tom Jefferson, a medically trained epidemiologist who was hired as an expert witness by the solicitors representing Aoife Bennett, an Irish woman who developed narcolepsy after vaccination with Pandemrix in 2009. Jefferson took on the case in 2015, and last year the lawyers received a copy of the GSK safety reports that had been emailed within the company and to at least one regulator (Ireland). Adverse event tables embedded in nine reports spanning the four months between December 2009 and March 2010 offer a glimpse into the vaccines’ safety profiles.

“When I saw those tables, I just fell off the chair. A consumer can figure out what’s going on here,” Jefferson told me (table 1).

Table 1

Reproduction of table of adverse event reports from internal GSK report dated 2 December 2009*

Jefferson immediately calculated the adverse event rates for each vaccine, which showed large differences between Pandemrix and Arepanrix. Any real differences between the vaccines would be especially alarming because Pandemrix and Arepanrix are, broadly speaking, the same vaccine manufactured in different facilities and used in different countries. Divergent rates of adverse events might implicate a manufacturing problem.

“The odds ratios, the point estimates, are all high. And some of them are significantly high—5.39 [95% confidence interval 3.70 to 7.85] for deaths [for Pandemrix v the other vaccines],” Jefferson said.

“The thing that struck me was not just that the odds ratios were high, but the fact that nobody had tabulated and analysed them,” he said, pointing out that the GSK reports provided numerator and denominator data sufficient to calculate the odds ratios but did not actually contain those calculations.

The BMJ conducted its own analysis of the adverse events, most of which seem to have been reported spontaneously to GSK (figs 1 and 2). For a range of concerning adverse events, reports were coming in for Pandemrix at a consistently higher rate than for the other two GSK pandemic vaccines–four times the rate of facial palsy, eight times the rate of serious adverse events, nine times the rate of convulsions. Overall, Pandemrix had, proportionally, five times more adverse events reported than Arepanrix and the unadjuvanted vaccine.


Fig 1

Adverse event reports (number/million doses) for GSK pandemic influenza vaccines up to 2 December 2009 (GSK reports number of doses for Arepanrix and the non-adjuvant vaccine together)

“>Fig 1

Fig 1

Adverse event reports (number/million doses) for GSK pandemic influenza vaccines up to 2 December 2009 (GSK reports number of doses for Arepanrix and the non-adjuvant vaccine together)

“>Fig 2

Fig 2

Cumulative rate of adverse events (number/million doses) for pandemic influenza vaccines over time, December 2009 to March 2010

And the raw numbers of adverse events were not small. Although it is often said that perhaps only up to 10% of adverse events are reported to national reporting systems,16 by late November, GSK had received 1138 serious adverse event reports for Pandemrix—a rate of 76 per million doses administered. By mid-December, there had been 3280 serious adverse event reports (68/million doses). The last report seen by The BMJ, dated 31 March 2010, shows 5069 serious adverse events for Pandemrix (72/million doses), seven times the rate for Arepanrix and the unadjuvanted vaccine combined.

The data are insufficient to draw conclusions about cause and effect, but for Gillian O’Connor, the solicitor representing Bennett, they raise serious questions about transparency. The disparity, she wrote in an affidavit filed in court, was “of such striking difference that any person contemplating taking the Pandemrix vaccine would be likely, if in receipt of this information, not to choose to have the Pandemrix vaccination.”

Alarm bells that never rang

But neither GSK nor the health authorities seem to have made the information public—nor is it clear that the disparity was investigated. This is in contrast to the reaction to narcolepsy, which quickly made news headlines and was the subject of a GSK press release and investigation17 in a matter of weeks after the first reports from Sweden and Finland.

In many of the GSK reports, the company briefly mentions having conducted “safety reviews”—for example, with respect to anaphylaxis, facial palsy, and Guillain-Barré syndrome. The BMJ asked GSK for a copy of those reviews but it did not provide them.

In a statement, GSK wrote: “After the introduction of Pandemrix, GSK continuously evaluated all available safety data and shared the data with the EMA and other regulatory authorities where the vaccine was licensed so that the authorities could conduct their own independent assessments. EMA made weekly summaries of the data provided by GSK and other manufacturers publicly accessible and they remain accessible through the EMA’s website.”

The BMJ asked GSK whether it ever undertook any investigations to understand the discrepancy in adverse event reporting between Pandemrix and Arepanrix, whether it notified healthcare providers about the discrepancies, whether it considered pulling Pandemrix from the market, or considered recommending Arepanrix or another company’s vaccine. But GSK declined to answer these and all of The BMJ’s questions, citing ongoing litigation.

The BMJ asked the UK Department of Health why it recommended Pandemrix over Baxter’s Celvapan, but the department also declined to comment, calling the question “quite technical” and suggesting we submit a freedom of information request for an answer.

In December 2009 demonstrators in Scotland took to the streets to challenge the government’s swine flu vaccine campaign arguing it was out of step with the mild pandemic.18

“Avoidable catastrophe”

The vaccination programme continued in Ireland as well. “The Irish government kept inviting people to get vaccinated,” Jefferson observed. “This was when it was quite clear that the pandemic was on the wane and it was nowhere near the catastrophe portrayed by influenza researchers, governments, industry, and the media.”

Clare Daly, a member of the Irish parliament, called the adverse events after Pandemrix a “completely avoidable catastrophe,” and has been demanding answers for over a year.19 In the Irish National Assembly last year, she told the then prime minister, Enda Kenny, “The Health Service Executive (HSE) decided to purchase Pandemrix and continued to distribute it even after they knew it was dangerous and untested, and before most of the public in Ireland received it.”20 In response, the Taoiseach said that concerns about the safety of Pandemrix and actions by GSK deserve “immediate analysis.” The BMJ requested an update on the investigation from the Irish Department of Health but did not receive a direct answer.

What EMA knew—or could have known—about the comparative safety of GSK’s pandemic vaccines is hard to discern. It told The BMJ that “EMA does not perform comparative benefit and risk evaluations between products approved in the EU, or between EU products and products approved or used outside the EU.”

But, had it wanted to, did the agency have the data to conduct such an analysis? Despite the similarity between the two vaccines, Arepanrix was not authorised in the EU until March 2010, late in the pandemic, and data reporting requirements for the two vaccines differed.

“While it might have been possible to estimate reporting rates based on usage data, which are difficult to obtain during a pandemic, EMA does not have a methodology to compare reporting rates between two products (note that the pandemic influenza pharmacovigilance updates included number of reports, not rates),” an EMA spokesperson said.

Jefferson was uncompelled. “What is the purpose of pharmacovigilance if nobody is acting on the information? This information took eight years to come to light through academic work and litigation. Is this acceptable? If the information at our disposal is partial, that is the direct consequence of secrecy, which should not surround any public health intervention.”

Pandemrix and Arepanrix were designed for a pandemic and were removed from global markets after the pandemic. Whatever adverse events they may have caused, they are vaccines of the past. But the events of 2009-10 raise fundamental questions about the transparency of information. When do public health officials have a duty to warn the public over possible harms of vaccines detected through pharmacovigilance? How much detail should the public be provided with, who should provide it, and should the provision of such information be proactive or passive?

If history were to repeat itself, does the public have a right to know?

Footnotes

  • This article was amended on 21 September 2018 to correct the date in the legend to figure 1 from 2 October to 2 December.

  • Competing interests: I have read and understood BMJ policy on declaration of interests and declare I am a colleague of Tom Jefferson, quoted in this story.

  • Provenance and peer review: Commissioned; externally peer reviewed.

References

 

View Abstract

Peter C Gøtzsche : Antidepressants increase the risk of suicide, violence and homicide at all ages


http://www.bmj.com/content/358/bmj.j3697/rr-4
Feature Medicine and the Media

Antidepressants and murder: case not closed

BMJ 2017; 358 doi: https://doi.org/10.1136/bmj.j3697 (Published 02 August 2017) Cite this as: BMJ 2017;358:j3697

Antidepressants increase the risk of suicide, violence and homicide at all ages

The FDA admitted in 2007 that SSRIs can cause madness at all ages and that the drugs are very dangerous; otherwise daily monitoring wouldn’t be needed: “Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt” … “All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants” (1).

Such daily monitoring is, however, a fake fix. People cannot be monitored every minute and many have committed SSRI-induced suicide or homicide within a few hours after everyone thought they were perfectly okay.

As the published trial literature related to suicidality and aggression on antidepressants is unreliable, we looked at 64,381 pages of clinical study reports (70 trials) we got from the European Medicines Agency. We showed for the first time that SSRIs in comparison with placebo increase aggression in children and adolescents, odds ratio 2.79 (95% CI 1.62 to 4.81) (2). This is an important finding considering the many school shootings where the killers were on SSRIs.

In a systematic review of placebo-controlled trials in adult healthy volunteers, we showed that antidepressants double the occurrence of events that the FDA has defined as possible precursors to suicide and violence, odds ratio 1.85 (95% CI 1.11 to 3.08)(3). The number needed to treat to harm one healthy adult person was only 16 (95% CI 8 to 100).

Based on the clinical study reports, we showed that adverse effects that increase the risk of suicide and violence were 4-5 times more common with duloxetine than with placebo in trials in middle-aged women with stress urinary incontinence (4). There were also more women on duloxetine who experienced a core or potential psychotic event, relative risk RR 2.25 (95% CI 1.06 to 4.81). The number needed to harm was only seven. It would have been quite impossible to demonstrate how dangerous duloxetine is, if we had only had access to published research. In accordance with our findings, the FDA has previously announced that women who were treated with duloxetine for incontinence in the open-label extension phase of the clinical studies had 2.6 times more suicide attempts than other women of the same age (5).

Looking at precursor events to suicide and violence is just like looking at prognostic factors for heart disease. We say that increased cholesterol, smoking and inactivity increase the risk of heart attacks and heart deaths and therefore recommend people to do something about it. Psychiatric leaders, however, routinely try to get away with untenable arguments. Many say, for example, that antidepressants can be given safely to children arguing that there were no more suicides in the trials, only more suicidal events, as if there was no relation between the two, although we all know that a suicide starts with suicidal thoughts, followed by preparations and one or more attempts. The same can be said about homicide. It can no longer be doubted that antidepressants are dangerous and can cause suicide and homicide at any age (5-7). It is absurd to use drugs for depression that increase the risk of suicide and homicide when we know that cognitive behavioural therapy can halve the risk of suicide in patients who have been admitted after a suicide attempt (8) and when psychotherapy does not increase the risk of murder.

References

1. FDA. Antidepressant use in children, adolescents, and adults. http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm096273.htm.
2. Sharma T, Guski LS, Freund N, Gøtzsche PC. Suicidality and aggression during antidepressant treatment: systematic review and meta-analyses based on clinical study reports. BMJ 2016;352:i65.
3. Bielefeldt AØ, Danborg PB, Gøtzsche PC. Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers. J R Soc Med 2016;109:381-392.
4. Maund E, Guski LS, Gøtzsche PC. Considering benefits and harms of duloxetine for treatment of stress urinary incontinence: a meta-analysis of clinical study reports. CMAJ 2017;189:E194-203.
5. Gøtzsche PC. Deadly psychiatry and organised denial. Copenhagen: People’s Press; 2015.
6. Healy D. Let them eat Prozac. New York: New York University Press; 2004.
7. Breggin P. Medication madness. New York: St. Martin’s Griffin; 2008.
8. Gøtzsche PC, Gøtzsche PK. Cognitive behavioural therapy halves the risk of repeated suicide attempts: systematic review. J R Soc Med 2017 (in press).

Competing interests: No competing interests

BMJ: US drug regulators should consider adding adults to SSRI suicide warning, says campaigner


http://www.bmj.com/content/357/bmj.j2050
News

US drug regulators should consider adding adults to SSRI suicide warning, says campaigner

BMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2050 (Published 25 April 2017) Cite this as: BMJ 2017;357:j2050

  1. Ed Silverman

Author affiliations

A British doctor who campaigned for the public to be warned about increased suicide risk in young people taking antidepressants has said that US drug regulators should consider including adults in warnings.

David Healy, a psychiatry professor at Bangor University, called for the warnings after GlaxoSmithKline (GSK) was ordered to pay $3m (£2.34m; €2.75m) to the widow of a US man who killed himself shortly after starting generic paroxetine.

The jury in the case of Stewart Dolin, a 57 year old attorney, concluded that GSK had failed to properly warn the public about the increased risk of suicide when taking paroxetine. The jury reached its verdict after lawyers for Dolin’s widow, Wendy, presented evidence in the Chicago federal court suggesting that GSK knew that paroxetine posed a risk to adults but had concealed or manipulated data.

Dolin stepped in front of a train in July 2010 shortly after starting a generic version of paroxetine that was sold by Mylan Pharmaceuticals. Mylan was originally named in the lawsuit but was later dismissed because of regulations and a Supreme Court ruling that a generic company cannot be sued if the brand name company does not first change product labelling.

Warnings about the increased risk of suicidal thoughts and behaviour in children and young adults were added to the labels of antidepressants in the US and Europe more than a decade ago.1 In the US, however, labels do not warn of these risks for anyone over 24 years old.

Many consumers have tried to hold drug makers responsible for suicides in adults without success. But the legal team representing Wendy Dolin argued that GSK had artificially inflated the number of suicides and suicide attempts that occurred among people who were given a placebo during clinical trials of paroxetine. They said that this alleged move made the antidepressant look better by comparison, since it appeared to minimise the risk of suicide associated with the drug.

The lawyers also argued that GSK had used averages for all selective serotonin reuptake inhibitors (SSRIs) to demonstrate that paroxetine did not raise the risk of suicide in adults aged over 24. Court documents also indicated that paroxetine displayed a much higher risk than all but one of the SSRI drugs.

Wendy Dolin declared the verdict “a great day for consumers.” After the verdict she told the Chicago Tribune, “This for me has not just been about the money. This has always been about awareness [of] a health issue, and the public has to be aware of this.”

Healy, who spearheaded the campaign to upgrade suicide warnings on antidepressants and testified as an expert witness on behalf of Wendy Dolin, said that the findings in the case should prompt the US drug regulator to review the evidence on SSRIs and suicide risk in adults.

“When it becomes so clear cut that a jury finds there is a problem, it suggests the evidence is strong enough to look at the issue,” Healy told The BMJ. “If it’s that clear to the average man on the street, and the FDA [the US Food and Drug Administration] doesn’t do something about it, we have an odd situation.”

GSK, which markets paroxetine under the brand name Paxil in the US, has said that it will appeal the verdict. “GSK maintains that because it did not manufacture or market the medicine ingested by Mr Dolin, it should not be liable,” it said in a statement. “Additionally, the Paxil label provided complete and adequate warnings during the time period relevant to this lawsuit.”

GSK added, “The scientific evidence does not establish that paroxetine causes suicide, suicide attempts, self-harm, or suicidal thinking in adult patients. In 2007, FDA revised the labelling for the entire class of SSRI drugs (including generic paroxetine and Paxil). The label includes statements that studies did not show an increased risk of suicidality (attempts or ideation) in adults over the age of 24, and that there appeared to be a protective effect in adults over 64.”

References

Doctor Ben Goldacre Knows Best…


Page_1

Note to Ben Goldacre (from me):



“….Missing data poisons the well for everybody. If proper trials are never done, if trials with negative results are withheld, then we simply cannot know the true effects of the treatments we use. Evidence in medicine is not an abstract academic preoccupation. When we are fed bad data, we make the wrong decisions, inflicting unnecessary pain and suffering, and death, on people just like us….”

Ben Goldacre 2012

http://www.bibliotecapleyades.net/ciencia/ciencia_industrybigpharma105.htm


“…As one of the authors of the RIAT restoration of Paxil Study 329 who was around for the whole process, I don’t actually know the answer to Leonie’s question about why it was so hard to get our paper published.

I don’t know if a Conflict of Interest had anything to do with that, but in a way, that’s the whole point – when there’s a significant Conflict of Interest, you can’t ever really know.

It’s a variable that can’t be evaluated.

So her question stands whether it can be answered or not. Should the original Study 329 report be retracted?

That’s not in our hands.

My choice would be that it should never have been published in the first place..”

(Comment by Mickey Nardo one of the authors of the BMJ published- RIAT Study on GSK’s Study 329 for Paroxetine in Adolescents on “Club 329”– David Healy’s Blog- ).



There is a fascinating debate happening over on Dr David Healy’s blog about a lecture which  Dr Ben Goldacre gave in Dublin’s Royal College of Surgeons last week. It all started when (patient activist, and blogger) Leonie Fennell (an attendee of the lecture)- published her opinion of Ben’s talk in a post on Dr Healy’s blog (titled ‘Club 329‘). The post seems to be sparking some very interesting reactions, not least from Ben Goldacre himself (who  incidentally has already accused Dr. Healy of misrepresenting his views because the post is published on Healy’s web-page).

Personally I don’t think that Leonie misrepresented Ben at all, and ironically, Ben claims that the audio of the lecture itself confirms this misrepresentation, when in fact- it does the opposite: it upholds, and confirms Leonie’s views.

You can listen to the audio here:

https://soundcloud.com/truthman-thirty/bg-11-06-2016-1333https://soundcloud.com/truthman-thirty/bg-11-06-2016-1333

Ben released it on Twitter, and I thought it might be helpful (for clarity) to cut it to the exact parts which are under debate.

The following is Leonie’s full blog post, on Dr Healy’s blog.

I will follow underneath it with some commentary.


http://davidhealy.org/club-329-part-1/#comments

Club 329: Part 1

June, 7, 2016 | 24 Comments

 


https://seroxatsecrets.wordpress.com/2012/09/22/the-drugs-dont-work-a-modern-medical-scandal-by-dr-ben-goldacre/

The doctors prescribing the drugs don’t know they don’t do what they’re meant to. Nor do their patients. The manufacturers know full well, but they’re not telling. Drugs are tested by their manufacturers, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that exaggerate the benefits.

Reboxetine is a drug I have prescribed. Other drugs had done nothing for my patient, so we wanted to try something new. I’d read the trial data before I wrote the prescription, and found only well-designed, fair tests, with overwhelmingly positive results. Reboxetine was better than a placebo, and as good as any other antidepressant in head-to-head comparisons. It’s approved for use by the Medicines and Healthcare products Regulatory Agency (the MHRA), which governs all drugs in the UK. Millions of doses are prescribed every year, around the world. Reboxetine was clearly a safe and effective treatment. The patient and I discussed the evidence briefly, and agreed it was the right treatment to try next. I signed a prescription.

But we had both been misled. In October 2010, a group of researchers was finally able to bring together all the data that had ever been collected on reboxetine, both from trials that were published and from those that had never appeared in academic papers. When all this trial data was put together, it produced a shocking picture. Seven trials had been conducted comparing reboxetine against a placebo. Only one, conducted in 254 patients, had a neat, positive result, and that one was published in an academic journal, for doctors and researchers to read. But six more trials were conducted, in almost 10 times as many patients. All of them showed that reboxetine was no better than a dummy sugar pill. None of these trials was published. I had no idea they existed.

It got worse. The trials comparing reboxetine against other drugs showed exactly the same picture: three small studies, 507 patients in total, showed that reboxetine was just as good as any other drug. They were all published. But 1,657 patients’ worth of data was left unpublished, and this unpublished data showed that patients on reboxetine did worse than those on other drugs. If all this wasn’t bad enough, there was also the side-effects data. The drug looked fine in the trials that appeared in the academic literature; but when we saw the unpublished studies, it turned out that patients were more likely to have side-effects, more likely to drop out of taking the drug and more likely to withdraw from the trial because of side-effects, if they were taking reboxetine rather than one of its competitors.

I did everything a doctor is supposed to do. I read all the papers, I critically appraised them, I understood them, I discussed them with the patient and we made a decision together, based on the evidence. In the published data, reboxetine was a safe and effective drug. In reality, it was no better than a sugar pill and, worse, it does more harm than good. As a doctor, I did something that, on the balance of all the evidence, harmed my patient, simply because unflattering data was left unpublished.

Nobody broke any law in that situation, reboxetine is still on the market and the system that allowed all this to happen is still in play, for all drugs, in all countries in the world. Negative data goes missing, for all treatments, in all areas of science. The regulators and professional bodies we would reasonably expect to stamp out such practices have failed us. These problems have been protected from public scrutiny because they’re too complex to capture in a soundbite. This is why they’ve gone unfixed by politicians, at least to some extent; but it’s also why it takes detail to explain. The people you should have been able to trust to fix these problems have failed you, and because you have to understand a problem properly in order to fix it, there are some things you need to know.

Drugs are tested by the people who manufacture them, in poorly designed trials, on hopelessly small numbers of weird, unrepresentative patients, and analysed using techniques that are flawed by design, in such a way that they exaggerate the benefits of treatments. Unsurprisingly, these trials tend to produce results that favour the manufacturer. When trials throw up results that companies don’t like, they are perfectly entitled to hide them from doctors and patients, so we only ever see a distorted picture of any drug’s true effects. Regulators see most of the trial data, but only from early on in a drug’s life, and even then they don’t give this data to doctors or patients, or even to other parts of government. This distorted evidence is then communicated and applied in a distorted fashion.

In their 40 years of practice after leaving medical school, doctors hear about what works ad hoc, from sales reps, colleagues and journals. But those colleagues can be in the pay of drug companies – often undisclosed – and the journals are, too. And so are the patient groups. And finally, academic papers, which everyone thinks of as objective, are often covertly planned and written by people who work directly for the companies, without disclosure. Sometimes whole academic journals are owned outright by one drug company. Aside from all this, for several of the most important and enduring problems in medicine, we have no idea what the best treatment is, because it’s not in anyone’s financial interest to conduct any trials at all.

Now, on to the details.

In 2010, researchers from Harvard and Toronto found all the trials looking at five major classes of drug – antidepressants, ulcer drugs and so on – then measured two key features: were they positive, and were they funded by industry? They found more than 500 trials in total: 85% of the industry-funded studies were positive, but only 50% of the government-funded trials were. In 2007, researchers looked at every published trial that set out to explore the benefits of a statin. These cholesterol-lowering drugs reduce your risk of having a heart attack and are prescribed in very large quantities. This study found 192 trials in total, either comparing one statin against another, or comparing a statin against a different kind of treatment. They found that industry-funded trials were 20 times more likely to give results favouring the test drug.

These are frightening results, but they come from individual studies. So let’s consider systematic reviews into this area. In 2003, two were published. They took all the studies ever published that looked at whether industry funding is associated with pro-industry results, and both found that industry-funded trials were, overall, about four times more likely to report positive results. A further review in 2007 looked at the new studies in the intervening four years: it found 20 more pieces of work, and all but two showed that industry-sponsored trials were more likely to report flattering results.

It turns out that this pattern persists even when you move away from published academic papers and look instead at trial reports from academic conferences. James Fries and Eswar Krishnan, at the Stanford University School of Medicine in California, studied all the research abstracts presented at the 2001 American College of Rheumatology meetings which reported any kind of trial and acknowledged industry sponsorship, in order to find out what proportion had results that favoured the sponsor’s drug.

In general, the results section of an academic paper is extensive: the raw numbers are given for each outcome, and for each possible causal factor, but not just as raw figures. The “ranges” are given, subgroups are explored, statistical tests conducted, and each detail is described in table form, and in shorter narrative form in the text. This lengthy process is usually spread over several pages. In Fries and Krishnan (2004), this level of detail was unnecessary. The results section is a single, simple and – I like to imagine – fairly passive-aggressive sentence:

“The results from every randomised controlled trial (45 out of 45) favoured the drug of the sponsor.”

How does this happen? How do industry-sponsored trials almost always manage to get a positive result? Sometimes trials are flawed by design. You can compare your new drug with something you know to be rubbish – an existing drug at an inadequate dose, perhaps, or a placebo sugar pill that does almost nothing. You can choose your patients very carefully, so they are more likely to get better on your treatment. You can peek at the results halfway through, and stop your trial early if they look good. But after all these methodological quirks comes one very simple insult to the integrity of the data. Sometimes, drug companies conduct lots of trials, and when they see that the results are unflattering, they simply fail to publish them.

Because researchers are free to bury any result they please, patients are exposed to harm on a staggering scale throughout the whole of medicine. Doctors can have no idea about the true effects of the treatments they give. Does this drug really work best, or have I simply been deprived of half the data? No one can tell. Is this expensive drug worth the money, or has the data simply been massaged? No one can tell. Will this drug kill patients? Is there any evidence that it’s dangerous? No one can tell. This is a bizarre situation to arise in medicine, a discipline in which everything is supposed to be based on evidence.

And this data is withheld from everyone in medicine, from top to bottom. Nice, for example, is the National Institute for Health and Clinical Excellence, created by the British government to conduct careful, unbiased summaries of all the evidence on new treatments. It is unable either to identify or to access data on a drug’s effectiveness that’s been withheld by researchers or companies: Nice has no more legal right to that data than you or I do, even though it is making decisions about effectiveness, and cost-effectiveness, on behalf of the NHS, for millions of people.

In any sensible world, when researchers are conducting trials on a new tablet for a drug company, for example, we’d expect universal contracts, making it clear that all researchers are obliged to publish their results, and that industry sponsors – which have a huge interest in positive results – must have no control over the data. But, despite everything we know about industry-funded research being systematically biased, this does not happen. In fact, the opposite is true: it is entirely normal for researchers and academics conducting industry-funded trials to sign contracts subjecting them to gagging clauses that forbid them to publish, discuss or analyse data from their trials without the permission of the funder.

This is such a secretive and shameful situation that even trying to document it in public can be a fraught business. In 2006, a paper was published in the Journal of the American Medical Association (Jama), one of the biggest medical journals in the world, describing how common it was for researchers doing industry-funded trials to have these kinds of constraints placed on their right to publish the results. The study was conducted by the Nordic Cochrane Centre and it looked at all the trials given approval to go ahead in Copenhagen and Frederiksberg. (If you’re wondering why these two cities were chosen, it was simply a matter of practicality: the researchers applied elsewhere without success, and were specifically refused access to data in the UK.) These trials were overwhelmingly sponsored by the pharmaceutical industry (98%) and the rules governing the management of the results tell a story that walks the now familiar line between frightening and absurd.

For 16 of the 44 trials, the sponsoring company got to see the data as it accumulated, and in a further 16 it had the right to stop the trial at any time, for any reason. This means that a company can see if a trial is going against it, and can interfere as it progresses, distorting the results. Even if the study was allowed to finish, the data could still be suppressed: there were constraints on publication rights in 40 of the 44 trials, and in half of them the contracts specifically stated that the sponsor either owned the data outright (what about the patients, you might say?), or needed to approve the final publication, or both. None of these restrictions was mentioned in any of the published papers.

When the paper describing this situation was published in Jama, Lif, the Danish pharmaceutical industry association, responded by announcing, in the Journal of the Danish Medical Association, that it was “both shaken and enraged about the criticism, that could not be recognised”. It demanded an investigation of the scientists, though it failed to say by whom or of what. Lif then wrote to the Danish Committee on Scientific Dishonesty, accusing the Cochrane researchers of scientific misconduct. We can’t see the letter, but the researchers say the allegations were extremely serious – they were accused of deliberately distorting the data – but vague, and without documents or evidence to back them up.

Nonetheless, the investigation went on for a year. Peter Gøtzsche, director of the Cochrane Centre, told the British Medical Journal that only Lif’s third letter, 10 months into this process, made specific allegations that could be investigated by the committee. Two months after that, the charges were dismissed. The Cochrane researchers had done nothing wrong. But before they were cleared, Lif copied the letters alleging scientific dishonesty to the hospital where four of them worked, and to the management organisation running that hospital, and sent similar letters to the Danish medical association, the ministry of health, the ministry of science and so on. Gøtzsche and his colleagues felt “intimidated and harassed” by Lif’s behaviour. Lif continued to insist that the researchers were guilty of misconduct even after the investigation was completed.

Paroxetine is a commonly used antidepressant, from the class of drugs known as selective serotonin reuptake inhibitors or SSRIs. It’s also a good example of how companies have exploited our long-standing permissiveness about missing trials, and found loopholes in our inadequate regulations on trial disclosure.

To understand why, we first need to go through a quirk of the licensing process. Drugs do not simply come on to the market for use in all medical conditions: for any specific use of any drug, in any specific disease, you need a separate marketing authorisation. So a drug might be licensed to treat ovarian cancer, for example, but not breast cancer. That doesn’t mean the drug doesn’t work in breast cancer. There might well be some evidence that it’s great for treating that disease, too, but maybe the company hasn’t gone to the trouble and expense of getting a formal marketing authorisation for that specific use. Doctors can still go ahead and prescribe it for breast cancer, if they want, because the drug is available for prescription, it probably works, and there are boxes of it sitting in pharmacies waiting to go out. In this situation, the doctor will be prescribing the drug legally, but “off-label”.

Now, it turns out that the use of a drug in children is treated as a separate marketing authorisation from its use in adults. This makes sense in many cases, because children can respond to drugs in very different ways and so research needs to be done in children separately. But getting a licence for a specific use is an arduous business, requiring lots of paperwork and some specific studies. Often, this will be so expensive that companies will not bother to get a licence specifically to market a drug for use in children, because that market is usually much smaller.

So it is not unusual for a drug to be licensed for use in adults but then prescribed for children. Regulators have recognised that this is a problem, so recently they have started to offer incentives for companies to conduct more research and formally seek these licences.

When GlaxoSmithKline applied for a marketing authorisation in children for paroxetine, an extraordinary situation came to light, triggering the longest investigation in the history of UK drugs regulation. Between 1994 and 2002, GSK conducted nine trials of paroxetine in children. The first two failed to show any benefit, but the company made no attempt to inform anyone of this by changing the “drug label” that is sent to all doctors and patients. In fact, after these trials were completed, an internal company management document stated: “It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.” In the year after this secret internal memo, 32,000 prescriptions were issued to children for paroxetine in the UK alone: so, while the company knew the drug didn’t work in children, it was in no hurry to tell doctors that, despite knowing that large numbers of children were taking it. More trials were conducted over the coming years – nine in total – and none showed that the drug was effective at treating depression in children.

It gets much worse than that. These children weren’t simply receiving a drug that the company knew to be ineffective for them; they were also being exposed to side-effects. This should be self-evident, since any effective treatment will have some side-effects, and doctors factor this in, alongside the benefits (which in this case were nonexistent). But nobody knew how bad these side-effects were, because the company didn’t tell doctors, or patients, or even the regulator about the worrying safety data from its trials. This was because of a loophole: you have to tell the regulator only about side-effects reported in studies looking at the specific uses for which the drug has a marketing authorisation. Because the use of paroxetine in children was “off-label”, GSK had no legal obligation to tell anyone about what it had found.

People had worried for a long time that paroxetine might increase the risk of suicide, though that is quite a difficult side-effect to detect in an antidepressant. In February 2003, GSK spontaneously sent the MHRA a package of information on the risk of suicide on paroxetine, containing some analyses done in 2002 from adverse-event data in trials the company had held, going back a decade. This analysis showed that there was no increased risk of suicide. But it was misleading: although it was unclear at the time, data from trials in children had been mixed in with data from trials in adults, which had vastly greater numbers of participants. As a result, any sign of increased suicide risk among children on paroxetine had been completely diluted away.

Later in 2003, GSK had a meeting with the MHRA to discuss another issue involving paroxetine. At the end of this meeting, the GSK representatives gave out a briefing document, explaining that the company was planning to apply later that year for a specific marketing authorisation to use paroxetine in children. They mentioned, while handing out the document, that the MHRA might wish to bear in mind a safety concern the company had noted: an increased risk of suicide among children with depression who received paroxetine, compared with those on dummy placebo pills.

This was vitally important side-effect data, being presented, after an astonishing delay, casually, through an entirely inappropriate and unofficial channel. Although the data was given to completely the wrong team, the MHRA staff present at this meeting had the wit to spot that this was an important new problem. A flurry of activity followed: analyses were done, and within one month a letter was sent to all doctors advising them not to prescribe paroxetine to patients under the age of 18.

How is it possible that our systems for getting data from companies are so poor, they can simply withhold vitally important information showing that a drug is not only ineffective, but actively dangerous? Because the regulations contain ridiculous loopholes, and it’s dismal to see how GSK cheerfully exploited them: when the investigation was published in 2008, it concluded that what the company had done – withholding important data about safety and effectiveness that doctors and patients clearly needed to see – was plainly unethical, and put children around the world at risk; but our laws are so weak that GSK could not be charged with any crime.

After this episode, the MHRA and EU changed some of their regulations, though not adequately. They created an obligation for companies to hand over safety data for uses of a drug outside its marketing authorisation; but ridiculously, for example, trials conducted outside the EU were still exempt. Some of the trials GSK conducted were published in part, but that is obviously not enough: we already know that if we see only a biased sample of the data, we are misled. But we also need all the data for the more simple reason that we need lots of data: safety signals are often weak, subtle and difficult to detect. In the case of paroxetine, the dangers became apparent only when the adverse events from all of the trials were pooled and analysed together.

That leads us to the second obvious flaw in the current system: the results of these trials are given in secret to the regulator, which then sits and quietly makes a decision. This is the opposite of science, which is reliable only because everyone shows their working, explains how they know that something is effective or safe, shares their methods and results, and allows others to decide if they agree with the way in which the data was processed and analysed. Yet for the safety and efficacy of drugs, we allow it to happen behind closed doors, because drug companies have decided that they want to share their trial results discretely with the regulators. So the most important job in evidence-based medicine is carried out alone and in secret. And regulators are not infallible, as we shall see.

Rosiglitazone was first marketed in 1999. In that first year, Dr John Buse from the University of North Carolina discussed an increased risk of heart problems at a pair of academic meetings. The drug’s manufacturer, GSK, made direct contact in an attempt to silence him, then moved on to his head of department. Buse felt pressured to sign various legal documents. To cut a long story short, after wading through documents for several months, in 2007 the US Senate committee on finance released a report describing the treatment of Buse as “intimidation”.

But we are more concerned with the safety and efficacy data. In 2003 the Uppsala drug monitoring group of the World Health Organisation contacted GSK about an unusually large number of spontaneous reports associating rosiglitazone with heart problems. GSK conducted two internal meta-analyses of its own data on this, in 2005 and 2006. These showed that the risk was real, but although both GSK and the FDA had these results, neither made any public statement about them, and they were not published until 2008.

During this delay, vast numbers of patients were exposed to the drug, but doctors and patients learned about this serious problem only in 2007, when cardiologist Professor Steve Nissen and colleagues published a landmark meta-analysis. This showed a 43% increase in the risk of heart problems in patients on rosiglitazone. Since people with diabetes are already at increased risk of heart problems, and the whole point of treating diabetes is to reduce this risk, that finding was big potatoes. Nissen’s findings were confirmed in later work, and in 2010 the drug was either taken off the market or restricted, all around the world.

Now, my argument is not that this drug should have been banned sooner because, as perverse as it sounds, doctors do often need inferior drugs for use as a last resort. For example, a patient may develop idiosyncratic side-effects on the most effective pills and be unable to take them any longer. Once this has happened, it may be worth trying a less effective drug if it is at least better than nothing.

The concern is that these discussions happened with the data locked behind closed doors, visible only to regulators. In fact, Nissen’s analysis could only be done at all because of a very unusual court judgment. In 2004, when GSK was caught out withholding data showing evidence of serious side-effects from paroxetine in children, their bad behaviour resulted in a US court case over allegations of fraud, the settlement of which, alongside a significant payout, required GSK to commit to posting clinical trial results on a public website.

Nissen used the rosiglitazone data, when it became available, and found worrying signs of harm, which they then published to doctors – something the regulators had never done, despite having the information years earlier. If this information had all been freely available from the start, regulators might have felt a little more anxious about their decisions but, crucially, doctors and patients could have disagreed with them and made informed choices. This is why we need wider access to all trial reports, for all medicines.

Missing data poisons the well for everybody. If proper trials are never done, if trials with negative results are withheld, then we simply cannot know the true effects of the treatments we use. Evidence in medicine is not an abstract academic preoccupation. When we are fed bad data, we make the wrong decisions, inflicting unnecessary pain and suffering, and death, on people just like us.

Dr David Healy’s Blog : Restoring Study 329: Letter to BMJ


http://davidhealy.org/restoring-study-329-letter-to-bmj/

Restoring Study 329: Letter to BMJ

May, 2, 2016 | Reply

In The BMJ: Nurse Explains The Devastating Consequences Of Being Prescribed Seroxat (Paxil) At Age 20…


What’s the difference between an 18 year old and a 20 year old in terms of side effects of Seroxat? (Seroxat is banned for under-18’s but that didn’t stop GSK from pushing it, nor did it stop them from pushing it in adults).
I was 21 when I was prescribed Seroxat, and I was upped my dose to 40mg at one point..
This nurse was zombified on 5mg after a few weeks…
Try it for years.. how do you imagine that would turn out?
GSK have literally been poisoning people to death with Seroxat..
It’s a disgrace…

http://www.bmj.com/content/351/bmj.h4629/rr-1

Feature Research Conduct

No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility

BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h4629 (Published 16 September 2015) Cite this as: BMJ 2015;351:h4629

Paroxetine trial reanalysis raises questions about institutional responsibility

I wanted to say thank you for publishing this article. I was once on Paxil myself, as a newly 20 year old, for panic disorder without agoraphobia. While taking just 1/4 of the normal starting dose (5mg was my dose), I displayed flat affect and a “zombie” like appearance. This was within several weeks, about two. I then became suicidal.

For something that is supposed to be an ANTI-depressant, I’m amazed at how PRO mental disorder it truly was.

I’m a very happy woman, and was always a happy teenager. This was not normal. The small, sane part of my brain told me I needed to tell someone I was feeling this way, but I didn’t want to – they would try to stop me if I did tell someone. I will never forget what that feeling was like, and I truly wonder if I am a PTSD patient now because of it.

In the end, I did try to hurt myself. I was very lucky to have my mother and a very close friend stop me and take me to the doctor. They pulled me off Paxil completely and switched me to another SSRI and a benzodiazepine to ease the withdrawal side effects from the Paxil. I’ve been on this SSRI ever since, and it has now been about 10 years.

Everytime I see an article like this, my heart breaks. I truly hope that this research saves other adolescents from experiencing what I went through. I wouldn’t wish it on my worst enemy.

Competing interests: No competing interests

Some Interesting Responses On The BMJ Site About The Restoration Of Paroxetine Study 329


http://www.bmj.com/content/351/bmj.h4629/rapid-responses

Re: No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility

It is refreshing to see the BMJ publish an article highlighting the corruption, collusion and dangerously unethical behaviors among the pharmaceutical and psychiatric industries, university medical departments and government “regulators.” I’d like to tell my teen-aged daughter all about the “retraction.” Unfortunately, she died from SSRI-induced akathisia, Serotonin Toxicity and prescribed suicidality. When she was experiencing life-threatening SSRI-induced side effects, her doctor did what many misguided doctors incompetently do: increased the toxin. Sadly, her death-and the deaths of hundreds of thousands of other innocent children, is not retractable.

Perhaps lawmakers might some day pass universal Informed Consent laws so that parents can be accurately informed prior to prescribing. Doing so would help better protect children from the torture and deaths that occur when profits are valued more than people…

Competing interests: No competing interests

18 September 2015
Kristina K. Gehrki
Educator & Advocate
None
Fairfax, VA 22030

Re: No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility

Thanks to Peter Doshi for his thorough overview of how the bastions of psychiatry and a top university ignored shoddy science, rampant conflicts of interest, ghostwriting, and the interests of children’s health (in my opinion) from the notorious study 329. Note the study and those involved played prominent roles in Boston Globe reporter Alison Bass’ 2008 book, Side Effects, “A richly detailed account of the disgraceful self-serving ties between drug companies and the psychiatric profession,” as described by former New England Journal of Medicine editor Arnold Relman.

Competing interests: No competing interests

17 September 2015
Susan Molchan
psychiatrist
Bethesda, MD

Paroxetine trial reanalysis raises questions about institutional responsibility

I wanted to say thank you for publishing this article. I was once on Paxil myself, as a newly 20 year old, for panic disorder without agoraphobia. While taking just 1/4 of the normal starting dose (5mg was my dose), I displayed flat affect and a “zombie” like appearance. This was within several weeks, about two. I then became suicidal.

For something that is supposed to be an ANTI-depressant, I’m amazed at how PRO mental disorder it truly was.

I’m a very happy woman, and was always a happy teenager. This was not normal. The small, sane part of my brain told me I needed to tell someone I was feeling this way, but I didn’t want to – they would try to stop me if I did tell someone. I will never forget what that feeling was like, and I truly wonder if I am a PTSD patient now because of it.

In the end, I did try to hurt myself. I was very lucky to have my mother and a very close friend stop me and take me to the doctor. They pulled me off Paxil completely and switched me to another SSRI and a benzodiazepine to ease the withdrawal side effects from the Paxil. I’ve been on this SSRI ever since, and it has now been about 10 years.

Everytime I see an article like this, my heart breaks. I truly hope that this research saves other adolescents from experiencing what I went through. I wouldn’t wish it on my worst enemy.

Competing interests: No competing interests

17 September 2015
Tracy Eisen
Student Nurse
Phoenix, AZ

No correction, no retraction, no apology, no comment = No science

Peter Doshi’s incisive commentary on the reactions to the RIAT re-analysis of Study 329 by its authors and the institutions, organizations, and corporations that stand behind them should be required reading for all mental health trainees — and, indeed, for all health care trainees.

Study 329 nicely illustrates the dangers that Marcia Angell pointed out in her 2004 volume, The Truth About the Drug Companies: How They Deceive Us and What to Do About It.

We all should be skeptics regarding hyped-up claims of efficacy — whether the agent is Paxil or CBT or psychoanalysis. We are only just beginning to understand the ways in which “body” and “mind” interact. New neuro-imaging techniques yield wonderful “pictures” of the brain . . . but these pictures might be usefully compared to what we see when we train a telescope on the night sky. Our vision is enhanced by a hundred-fold . . . but we still do not see more than the tiniest slice of what is really “out there.” The fact that we now can see so much more should not make us think that we now see the whole picture.

We also shouldn’t fall victim to another common error. The fact that an intervention is aimed at a specific target does not mean that the intervention affects only the target. [This is as true for psychoanalysis as it is for Paxil.] Our interventions always affect people in many unintended ways as well as those we intend.

Pharmaceutical advertisements usually give the impression that drugs affect a specific part of the body; they close their eyes to the fact that the drugs are disseminated throughout the body, with many unintended effects. [If they are mentioned, these “side effects” are put in small print, thus magically reducing their importance.]

Interventions aimed at affecting the mind are prone to the same error — but helping a person to “change their mind” often (or USUALLY) affects their life (and their relationships with others) in many unintended ways, too.

“Evidence-based medicine” or “empirically supported treatments” are put forth as a kind of gold standard these days. But “Restoring Study 329” demonstrates that we shouldn’t mistake iron pyrite (“fool’s gold”) for the real item, especially when someone has a vested interest in keeping a good bit of the evidence hidden from view. If we’re going to endorse “evidence-based medicine” we’d better be sure that we’ve got all the evidence and not just a cherry-picked subset.

Competing interests: No competing interests

17 September 2015
Paul M Brinich
Psychoanalyst. Clinical Professor (Emeritus) of Psychology and Psychiatry
University of North Carolina at Chapel Hill
Chapel Hill, NC 27516 USA

GSK ambiguity

Dr Doshi’s article might give the impression that an independent FDA review of the Study 329 data came to a different conclusion to GSK’s claims the trial had shown paroxetine worked. But in fact an approvable letter from FDA to GSK states: ” we agree that the results from … Study 329… failed to demonstrate the efficacy of Paxil in pediatric populations with MDD”. [but] “we agree that it would not be useful to describe these negative trials in the labeling”.[1]

In the media flurry surrounding these articles yesterday and today, GSK seem to lay the blame for a positive write up of the data on Keller and colleagues, while Keller and colleagues hint that GSK involvement compromised them. None of us – journals, regulators, academics, or doctors – come out of this with much credit.

1 http://2spl8q29vbqd3lm23j2qv8ck.wpengine.netdna-cdn.com/wp-content/uploa…

Competing interests: An author on Restoring Study 329, a founder member of RxISK.org and an expert witness in psychotropic cases both pro and con drug induced harms.

17 September 2015
David Healy
Doctor
Hergest Unit, Bangor

Seroxat (Paxil) Study 329 Is Restored And Published In The BMJ at 11.30pm 16th Sept 2015


BMJ Press Release and Materials

Reanalysis of antidepressant trial finds popular drug ineffective and unsafe for adolescents
BMJ Press Release: 16 September 2015
Results contradict original findings and have important implications for research and practice

Restoring Study 329
BMJ Paper: Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence

Liberating the data from clinical trials
BMJ Editorial: David Henry, Professor, Tiffany Fitzpatrick, Meta-Data Specialist
Liberated trial data have enduring potential to benefit patients, prevent harm, and correct misleading research

No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility
BMJ Feature: Peter Doshi, Associate Editor, The BMJ
As a new data analysis adds weight to calls for retraction of a paper on paroxetine in adolescents, Peter Doshi examines the resistance to action of a professional society, its journal, and an Ivy League university

BMJ Video of Jon Jureidini on Restoring Study 329
Features Dr. Jon Jureidini, Clinical Professor, Critical and Ethical Mental Health Research Group, University of Adelaide, Adelaide, Australia who provides an overview of Restoring Study 329 and its differences with the conclusions of the original Study 329.

BMJ Press Briefing Audio
14 September 2015


Bob Fiddaman’s perspective:

http://fiddaman.blogspot.ie/2015/09/reanalysis-of-glaxos-329-study-goes.html

Wednesday, September 16, 2015

Reanalysis of Glaxo’s 329 Study Goes Public

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It’s been a long time coming, 14 years give or take.

Today sees the publication of a damning reanalysis of GlaxoSmithKline’s infamous Study 329, a study, or a review of which, that was first published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in 2001.

BACKGROUND

The study made claims that paroxetine (Paxil, Seroxat, Aropax) was a safe and effective medication for treating major depression in adolescents and has, for the past 14 years, been widely cited in the medical literature, providing physicians with assurances about the usefulness, and safety, of paroxetine in this patient population.

Despite many calls for its retraction it remains unretracted and still provides false and misleading information to physicians and, in many cases, parents, who read it.

Let’s take a look at the findings of the original study…

“Paroxetine is generally well tolerated and effective for major depression in adolescents.”

 

Initially, the study looked plausible, after all, it had the backing of high ranking child psychiatrists who had, so we were led to believe, trawled through the data and supported the claim that paroxetine was safe and effective for children and adolescents.**

The new groundbreaking study published today shows how the claims and subsequent support of the claims were misleading and, in actual fact, false.

The reanalysis, Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence Joanna Le Noury (Lead author), John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude, concludes that…

“Neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.”

More on this new study and commentary from me, further down this post of mine.

With an initial study that made claims of safety and efficacy doctors and patients were led to believe that there would be no problems ingesting paroxetine and that it would make a lot of troubled children and teenagers well. Behind the scenes the pediatric Paxil machine was turning its wheels. GlaxoSmithKline, the company that sponsored the original study and manufactured the pill, had learned, some three years previous to the original publication, that the study did not show efficacy in this patient population but they had spent a lot of time and money trying to gain a licence in children and unfavourable results would mean losing out to a lucrative market.  Internal company memos, sent to senior management set the stall. It showed how they, with silence and denial could convince doctors and journals to play along with the claim that Paxil was safe and effective.

One has to ask why they would do this. One can only arrive at the answer that Glaxo did it for the profit, nothing more, nothing less. In fact, it’s a good question to ask Glaxo officials – Why did they claim a study drug was safe and effective when they knew that it wasn’t?

How do we know this?

Well, a company email surfaced via litigation in the US. It was dated Oct 14, 1998 and told senior management that…

“As you will know, the results of the studies were disappointing in that we did not reach statistical significance on the primary end points and thus the data do not support a label claim for the treatment of Adolescent Depression.”

So, how did we get from this to this?

 “This ‘cutting edge,’ landmark study is the first to compare efficacy of an SSRI and a TCA with placebo in the treatment of major depression in adolescents. Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression.”

Well, it has to do with not being fruitful with the truth. The study results were sent to a PR firm who, after reading through them came to the conclusion that paroxetine was indeed safe and effective. Here’s the rub though, Glaxo only provided the PR firm with a summary of the study, roughly 200 pages. The actual study results (raw data) was over 77,000 pages long. Neither the PR firm or the authors who added their names to the study actually saw the raw data, more importantly, nae bizarrely, neither the PR firm or the original study authors asked to see the raw data. One has to ask why?

Glaxo didn’t want the negative results leaking out to doctors, the public or their sales staff so they, once again internally, sent out the following to senior management..

“TARGET
To effectively manage the dissemination of these data in order to minimize any potential negative commercial impact…. It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.”

It worked as some two million American children and adolescents have been prescribed Paxil. That figure is America only – add to it the number of children and adolescents elsewhere in the world that have been prescribed it and you will see why this was a lucrative market for GlaxoSmithKline.

The subsequent marketing of Paxil by its sales representatives to physicians is discussed on pages 11-12. United States of America Vs GlaxoSmithKline.


RESTORING STUDY 329

In as much as proving that the original 329 study was deeply flawed and misleading, the restoration (reanalysis) shows severe problems with the way studies are accepted by medical journals and also highlights how study authors merely put their names to ghostwritten reviews, in this case Glaxo hired a PR firm (1 & 2) to draft the misleading evidence that Paroxetine was generally well tolerated and effective for major depression in adolescents, despite evidence to the contrary, evidence that, allegedly, the PR firm did not see.

The “authors” of the original review, unlike the authors of  ‘Restoring Study 329’ didn’t actually get to see the raw data and signed off the review (passed it off as their own clinical findings) – it’s akin to structural engineer inspectors taking it as gospel that a building is safe because the builders told them so.

Restoring Study 329 also showed significant increases in the paroxetine and imipramine arms, including serious, severe, and suicide related adverse events, all of which became apparent when the data were made available for reanalysis.

One has to ask some serious questions here about the original 329 authors, all of whom have, over the past 14 years, refused to retract their names from the study.

In an accompanying feature in the British Medical Journal (BMJ) Peter Doshi associate editor, The BMJ, writes…

“The first draft of the manuscript ultimately published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) was not written by any of the 22 named authors but by an outside medical writer hired by GSK. And the paper’s lead author, Brown University’s chief of psychiatry, Martin Keller, had been the focus of a front page investigation in the Boston Globe in 1999 that documented his under-reporting of financial ties to drug companies.

“But for those who have been calling for a retraction of the Keller paper for many years, the system has failed. None of the paper’s 22 mostly academic university authors, nor the journal’s editors, nor the academic and professional institutions they belong to, have intervened to correct the record. The paper remains without so much as an erratum, and none of its authors, many of whom are educators and prominent members of their respective professional societies, have been disciplined.”

Doshi also picks up on Karen Wagner who was one of the original 329 study authors. He writes…

Karen Wagner, is a coauthor of the JAACAP paper. Wagner, a psychiatrist at the University of Texas, is also named eight times in the 2011 US Department of Justice complaint against GSK. According to the complaint, Wagner promoted paroxetine at a 1999 GSK sales force event. A GSK newsletter cited in the complaint quotes Wagner as telling the sales force that major depression was “a lethal disorder and it requires treatment.” Based on the results of Study 329, which were at the time still unpublished, “Dr Wagner said: ‘We can say that paroxetine has both efficacy and safety data for treating depression in adolescents.’”

At a telephone press conference (BMJ kindly invited me to participate) on Monday (14th Sept) Doshi spoke about the two studies. “What we have here is one paper published in 2001 saying that paroxetine is safe and effective and a new analysis that says that the drug is unsafe and ineffective, different conclusions and I think the RIAT authors have it right.” (RIAT is the name given to the restoration authors – restoring invisible and abandoned trials)

On answering if criminal charges may be brought against any of those connected with the original study, Fiona Godlee, editor in chief of the BMJ, said, “I think there are movements, and this debate is ongoing, about the extent to which research and misconduct, which I think we can all agree, seems to have happened here and certainly many other instances could be the subject of criminal proceedings.”

GlaxoSmithKline have had a copy of the RIAT findings since March. I asked one of the co-authors, David Healy, who was also part of the teleconference, if Glaxo had responded to it. He told me, “Not to us, that we’re aware of.”

RIAT author, Jon Jureidini, a child psychiatrist, also spoke of the study. “You will see from our paper that the harms associated with this drug in this trial were quite striking – twice the severe adverse events, four times the psychiatric events and high levels of suicide (events) and self harm, all of which were unclear in the previous publication.” The high levels of suicide that Jureidini spoke of are  shocking. There were 11 suicidal patients in the paroxetine group compared to just one in the placebo group.

In an accompanying video (link at foot of this post) Jureidini shows how the RIAT team found more adverse events than the FDA and how Martin Keller, the lead author in the original study, under reported events, even though they had been identified by GlaxoSmithKline.



COMMENTARY

It’s ‘take a bow’ time for the restoration study authors, Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, and Elia Abi-Jaoude.

This is a significant piece of history and the British Medical Journal should be applauded too for finally showing some common sense and for not bowing down to pressure from British pharmaceutical giant, GlaxoSmithKline.

I don’t expect for one minute that we will get any form of apology from either GlaxoSmithKline, the original study authors or, indeed, the Journal of the American Academy of Child and Adolescent Psychiatry. They have had nigh on 14 years to make retractions to the fraudulent study and they have each, individually declined. Today’s publication of the reanalysis should, however, shake the boots of the authors. What they have done here is become part of Glaxo’s murky history and hopefully every single one of the authors (22 in all) will, at some point in the future, come under scrutiny from law enforcers. Fraud is fraud, whatever way you slice it and each of the 22 have, knowingly or unknowingly, been part of that fraud, a fraud that put children and adolescents at risk, a fraud that has for 14 years been part of the reason why Paxil, this non-efficacious and unsafe antidepressant with side-effects such as suicidal thinking, has found its way into the mouths of children and adolescents.

For their part in this lack of care and duty to children they will have to face tough questions from family, friends and the media. Pleading ignorance just won’t cut the mustard anymore.

The universities who have stood behind these authors also need to feel shame today, they have also been part of the reason why so many kids have been put at great risk and, arguably, many kids who have gone on to complete suicide induced by Paxil.

The original study, given the thumbs up by the original 329 review authors, was also taken as gospel by doctors who referred to it when checking to see if it was safe to prescribe kids Paxil off-label. Had Glaxo had been truthful then kids such as Sara Carlin, Sharise Gatchell and Adrian Keegan, to name but a few, would probably still be alive today. The same can be said for the authors, had they had asked to see the raw data then they would have drawn the same conclusion as the restoration authors, had they had called for the study to be retracted then kids who are now in the ground would, more than likely, be above the ground and enjoying their young lives. The JAACAP also needs to hold up its hand here as do the Universities who have, it appears, backed the authors associated with them.

There are different degrees of murder and manslaughter, someone, if not all, should be held accountable here. No better place to start than the current CEO of GlaxoSmithKline, Andrew Witty. Failing a murder or manslaughter charge then why not bring those responsible to trial under The Federal Child Abuse Prevention and Treatment Act, child neglect under this law states, “An act or failure to act which presents an imminent risk of serious harm.”. I think the risks have been clearly proven, don’t you?  Am I wrong to suggest that those responsible should face criminal charges? Ironically, in England, the National Society for the Prevention of Cruelty to Children (NSPCC) use the tagline, “Every Childhood Is Worth Fighting For,” yet I cannot find one single piece of legislation that protects children from unsafe prescription drugs, or those that market and promote these drugs. This needs to change!


GSK BOXING CLEVER

On April 26, 2013, RIAT team member, Jon Jureidini, sent Andrew Witty a letter calling for the retraction of the JAACAP 329 article (fig 1). In a cleverly drafted response (fig 2) from GSK’s Head of Governance, John E. Kraus, GSK told Jureidini that they did not agree that the journal article was false and misleading, they added that the article, “accurately reflects the honestly held views of the clinical investigator authors.” In essence, GSK are correct, and it is yet another example of GSK’s spin.

What GSK are saying here is that the article (not the actual study) stands up to scrutiny. Of course it does! The JACCAP article was based on a summary of the actual study and the findings of the PR firm hired to write the findings of that summary. Remember, GSK omitted negative findings in the summary sent to the PR firm and ghostwriter, Sally K. Laden. (Letters obtained from http://study329.org/)

FIG 1
FIG 2

I really can’t find words to describe GlaxoSmithKline’s attitude. I am, for the first time since the conception of this blog, utterly dumbfounded by GlaxoSmithKline’s ‘shrug of the shoulders’ and lack of respect for those harmed by their product approach. Glaxo will argue until they are blue in the face that it has never been proven that Sara Carlin, Sharise Gatchell, Adrian Keegan and many more killed themselves because of paroxetine induced suicide. They can say this with confidence because no subject in the original trial, as far as we know, went on to complete suicide. The truth of the matter is, since its launch, paroxetine has been implicated in many suicides. In Britain alone there have been 65 reported suicides associated with paroxetine, these are just reports sent in to the British drug regulator when family members or doctors suspect that paroxetine may have been attributed to the individual suicides. Many more are not sent in – and herein lies the problem of the original study. If a patient kills themselves whilst on paroxetine the treating physician may once again refer to the original 329 review, and what will they see?

“Paroxetine is generally well tolerated and effective for major depression in adolescents.”

No mention of a suicide threat, so any of the subsequent articles about Paxil related suicides and black box warnings will be largely ignored because, at the end of the day, a doctor is going to believe the word of 22 academics rather than a tabloid newspaper or documentary.

The study published today highlights the suicide threats in the original study, the subjects who, remember were just children and adolescents, who felt suicidal whilst in the trial. Many more were self harming, a precursor to suicidal thinking – GlaxoSmithKline did not label these subjects as suicidal, instead they opted for the term “emotional lability.” A code they used, one can only assume, to prevent questions being asked – to me, a layperson, the term “emotional labilty” just means the subject was unstable. In fact, the medical dictionary defines it as “a condition of excessive emotional reactions and frequent mood changes.” Glaxo will, once again, argue that suicidal thinking could fall into this definition but to actually label an adverse reaction as a suicidal thought would have probably meant that the original study would not have been published and hailed as a landmark study in the treatment of depression in children and adolescents.

I guess the results of the restoration study will show the world just how abhorrent this British company are when it comes to the welfare of children and adolescents. It’s not the intention of the study to show that, it’s just my view. It will also show how the whole process of clinical trials are deeply flawed and one sided and how paying highly respected child psychiatrists to endorse a drug takes precedence over actually allowing those same highly respected child psychiatrists to see the actual raw data.

Two studies, two opposite outcomes…and a whole bunch of internal company memos that show how this one company knowingly managed the dissemination of the negative study results so perfectly, making a huge profit as a result and, at the same time, putting children and adolescents at risk.

Clinical trials should be about science and about rigorously checking raw data. Restoring 329 is, I believe, the very first study that has used these models.

I anticipate that  Le Noury, Nardo, Healy, Jureidini, Raven, Tufanaru, Abi-Jaoude and the BMJ will now fall under the radar of GSK and the mud-slinging will begin. That’s how Glaxo operate. They do it with reps who bring it to the attention of senior management that illegal activities are occurring within the company, they do it with expert witnesses who offer evidence against their products in court rooms, an example of this can be seen here, they do it with anyone who basically questions their ethics.

The RIAT team need to be applauded, it’s not been easy to wade through 77,000 pages of raw data, a task made even harder by GlaxoSmithKline when the study authors learned that they could not simply save information off Glaxo’s database, they had to painstakingly do it the old-fashioned way, by using a pen and paper.

Many others need to be applauded for their efforts over the years too. Leemon McHenry and Shelley Jofre spring to mind, the LA based law firm, Baum Hedlund have also been instrumental in getting the information out as have the infinite amount of bloggers, not forgetting, of course, the Healthy Skepticism team and the Citizen’s Commission on Human Rights.

It will be interesting to see, over the coming weeks and months if any of the original authors reject the findings of the restoration study – chances are they will, likelihood is that they won’t be able to tell you why they reject these new findings. Science, particularly where raw data is used, cannot be argued.

For the record, the 22 authors of the original study are:

Martin B. Keller (lead author), Neal D. Ryan, Michael Strobber, Rachel G. Klein, Stan P. Kutcher, Boris Birmaher, Owen R. Hagino, Harold Koplewicz, Gabrielle A. Carlson, Gregory N. Clarke, Graham J. Emslie, David Feinberg, Barbara Geller, Vivek Kusumakar, George Papatheodorou, William H. Sack, Michael Sweeney, Karen Dineen Wagner, Elizabeth B. Weller, Nancy C. Winters, Rosemary Oakes, and James P. McCafferty.

As for GlaxoSmithKline, they will do everything to minimize the fallout of this study, after all they have shareholders whom they wish to continue buying their shares. If those same shareholders had any morals they would disassociate themselves with a company who knowingly put profit before the safety of children and adolescents – then again, money blinds people – the original 329 study is crystal clear evidence of that.

Make a habit of two things: to help; or at least to do no harm. – Hippocrates




Bob Fiddaman.





** I use the term ‘children and adolescents’ because, to me at least, there is no definitive cross-over when a child becomes an adolescent.

Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence (BMJ 2015)  –  Joanna Le Noury, John M Nardo, David Healy, Jon Jureidini, Melissa Raven, Catalin Tufanaru, Elia Abi-Jaoude

No correction, no retraction, no apology, no comment: paroxetine trial reanalysis raises questions about institutional responsibility (BMJ 2015) – Peter Doshi associate editor, The BMJ

Restoring Study 329 Website

Link to author video

Related news: Glaxo go to trial in the UK within the next 12 months where they will defend allegations that Paxil (known as Seroxat in the UK) caused severe withdrawal issues and dependency in a number of people who were prescribed it.