Is Giving Anti-Depressants To Teens A bad Idea ?


“..The study looked at the average effect of anti-depressants rather than how they worked for individuals, and the researchers said the findings might not apply to use of the drugs over the longer term…”

 

Great documentary from the acclaimed ‘the doctor who gave up drugs’ series (see below), about the dangers of anti-depressants in kids. It has been established for a long time now that SSRI anti-depressants are unsafe for kids, but what about their use in the adult population?

Interesting segment from David Healy discussing the raw data on Seroxat in teens (see first video below). It was because of the actions of people like David Healy that Seroxat was never officially approved for use in teens in the UK. If Glaxo had gotten their way, it’s possible that Glaxo would have pushed Seroxat for a licence for kids in the UK. This would have meant more SSRI induced teen suicides.

The most interesting segment for me was the part with Andrea Cipriani, the researcher who recently analyzed a meta-analysis of studies on SSRI’s, which made waves in the media not too long ago.

Back in February, Cipriani (see second video down) said that ‘anti-depressants are effective for moderate to severe major depression in adults’. However as Dr David Healy points out, the studies that Cipriani made his analysis on, were mostly ghost written articles.

Cipriani did not study the raw data, therefore his analysis is inherently skewed. He doesn’t mention this in the many media articles he appeared in to promote this study.; he only addresses it because David Healy brought it up. It seems to me that doctors like Cipriani are merely agents of PR for psychiatry (and indeed by default then- the drug companies) than patient advocates. Every few years psychiatry needs to re-establish its dominance of the mental health paradigm.

It’s just marketing.

Why do academics like Cipriani not demand to see the raw data from the drug companies?

Why do they mislead the public?

Why does Cipriani (and indeed Carmine Pariante) not mention also that his analysis was based on very short term studies (and that these studies are not raw data studies), and that safety and effectiveness in long term use in adults has not been established? (This despite the fact that people end up on these drugs for years, sometimes decades).

I feel also that any time Carmine Pariante is interviewed on TV he should be forced to mention his links to drug companies:

His links to GSK  alone are shameful considering GSK’s vast criminality and harm to consumers and patients over the decades.

“…Dr Carmine Pariante has received Funds for a member of staff and funds for research. Professor Pariante’s research on depression and inflammation is supported by: the grants ‘Persistent Fatigue Induced by Interferon alpha: A New Immunological Model for Chronic Fatigue Syndrome’ (MR/J002739/1) and ‘Immunopsychiatry: a consortium to test the opportunity for immunotherapeutics in psychiatry’ (MR/L014815/1; together with GSK), from the Medical Research Council (UK); the National Institute for HealthResearch (NIHR) Mental Health Biomedical Research Centre in Mental Health at South London and Maudsley NHS Foundati on Trust and King’s College London; by Johnson & Johnson as part of a programme of research on depression and inflammation; and by a Wellcome Trust led consortium that also include Johnson & Johnson, GSK and Lundbeck…”

 

I don’t trust Andrea Cipriani, I don’t think he is being honest.

I also don’t trust Carmine Pariante either, however I think he is more misguided than anything else.

Anti-depressants don’t save lives.

Doctors like David Healy save lives.

Doctors like Pariante and Cipriani help drug companies to extinguish them..

 

 

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Pandemonium And Pandemrix


Seroxat/Paxil, Avandia, Myodil, Pluserix, Lotronex, Cervarix, Tafenoquine….All GSK Drugs Not Adequately Tested Before Harming Consumers.. Pandemrix Is Just Another Of A Long Line Of GSK’s Dodgy Drugs…

https://davidhealy.org/pandemonium-and-pandemrix/

Pandemonium and Pandemrix

November, 27, 2017 | 2 Comments

Watch The Full Panorama Documentary ‘A Prescription For Murder’ Here…


Is it possible that a pill prescribed by your doctor can turn you into a killer? Over 40 million prescriptions for SSRI anti-depressants were handed out by doctors last year in the UK. Panorama reveals the devastating side effects on a tiny minority that can lead to psychosis, violence, possibly even murder. With exclusive access to psychiatric reports, court footage and drug company data, reporter Shelley Jofre investigates the mass killings at the 2012 midnight premiere of a Batman movie in Aurora, Colorado. Twenty-four-year-old PhD student James Holmes, who had no record of violence or gun ownership, murdered 12 and injured 70. Did the SSRI anti-depressant he had been prescribed play a part in the killings? Panorama has uncovered other cases of murder and extreme violence which could be linked to psychosis developed after the taking of SSRIs – including a father who strangled his 11-year-old son. Panorama asks if enough is known about this rare side effect, and if doctors are unwittingly prescribing what could be a prescription for murder.

13 Ways That GSK Hid The Seroxat/Paxil Suicide Signal…


Seroxat/Paxil/Aropax (Paroxetine) : The Anti-Depressant that makes you want to kill yourself!..

 


https://davidhealy.org/change-in-chicago-whose-problem/

Change in Chicago: Whose Problem?

May, 24, 2017 | Reply

Stewart Dolin’s Doctor Says (about Paxil) : ““I don’t trust the labeling,” he said. “I don’t trust the company, to be honest.”…


And why would he?

Why would anybody trust GSK? Would you trust a felon?

The Dolin trial opened a can of worms about Paxil/Seroxat, suicidality and akathisia which GSK would rather remained tightly in the can. It’s too late now though, the worms are already out…

See Dr. David Healy’s excellent new post about wider implications of the Stewart Dolin Paxil induced suicide trial.


“……The regulatory history of Paxil and the other SSRI’s was almost Byzantine.   For years they carried no warnings of a risk for suicide.  In 2004, after thousands of troubling reports, a Black Box warning was finally issued for children and adolescents.  A number of medical experts felt the warning should apply with equal urgency to adults.

However, in 2007, the FDA decided on a uniform warning for all antidepressants, old and new.  This was the “24 and under” label attached to both brand-name and generic Paxil in 2010.  This suited GSK just fine.  The FDA invited the company to discuss whether additional warnings were needed for Paxil, but GSK never took them up on it.

More importantly, it never fully shared with the FDA—and still less with doctors in the community—what it knew about the real risks of its product.  In fact, GSK had known since 1989 that its drug could trigger akathisia, an agonizing combination of physical restlessness and emotional turmoil that could lead to suicide.  The risk applied to both teenagers and adults; at least twenty suicides had occurred in patients on Paxil in clinical trials, the majority of them in people over age thirty…..”


https://davidhealy.org/change-in-chicago-dr-welby-on-the-witness-stand/

Change in Chicago:  Dr. Welby on the Witness Stand

May, 15, 2017 | 8 Comments

Editorial Note: This is part three in the Change in Chicago series covering the Dolin trial and its implications.  Like part 1 it is written by  Johanna Ryan – The Dolin Verdict and Playing Go

By twenty-first century American standards, Stu Dolin’s medical care was close to ideal.  That’s a hard idea to swallow, given what happened to him in the end, but it’s true.  The real paradox is why it wasn’t enough to save him – and how his doctor became a victim as well.

In June 2010, while taking a generic version of the antidepressant Paxil, Dolin jumped in front of an oncoming subway train in downtown Chicago.  His family was convinced that the medication had caused his suicide.  Last month, a federal jury agreed.  They found GlaxoSmithKline (GSK) liable for Dolin’s death, and awarded $3 million to his widow Wendy – two million for her own loss, and one million for Stu Dolin’s own suffering in his last week of life.

Few people succeed in suing the drug company when a loved one dies from the effects of his medication.  It’s far more common to sue the prescribing doctor.  Plenty of lawyers are willing to take on a malpractice insurer with limited loyalty to the doctor, and a lively interest in a reasonable settlement.  To face off against a multinational corporation with an unlimited war chest, which will fight like hell for the reputation of its product, is something else entirely.

An even bigger barrier is something called the Learned Intermediary Doctrine.  Under American law, drug companies have no obligation to level with you, the patient, about the potential hazards of the drug.  Their only obligation is to tell your doctor about those risks.  He or she is then expected to function as a “learned intermediary” – a sort of educated bodyguard who will tell you what you need to know, in language you can understand, and see to it that no harm comes to you.   The drug’s official label (that enormous, technical document folded up and stuffed into the drug package) is written with your doctor, not you, in mind.

But what if that official label does not tell the whole truth about the drug’s hazards?  That was the situation faced by Martin Sachman, M.D., Stu Dolin’s family doctor, who became a key witness in the Dolin lawsuit.

Marcus Welby M.D. – the old-school family doctor

That’s not Martin Sachman in the picture at the top of today’s blog – it’s Robert Young in the title role of Marcus Welby, M.D., the popular prime-time TV drama from the 1970’s.  To most of us, Dr. Welby represents the family doctor we wish we could have – the one our parents had in the good old days.  He was a settled presence in the neighborhood; he’d known you and your family for years.  You could go to him for advice on just about anything, and you tended to trust what he told you.

For Dolin, Marty Sachman was that kind of doctor.  Since about 2005, Sachman has had what’s known as a “concierge” practice.  For an annual fee of about $2,000 (over and above their usual insurance costs), patients can get something close to a Marcus Welby level of care from a doctor of this type.  They can be reached on weekends, may even make house calls from time to time, and you’re almost never limited to a ten-minute appointment.

Sachman had been Stu Dolin’s doctor for at least ten years. He was also a close personal friend.  (That’s unusual enough these days that attorneys rushed to assure the jury there was nothing “unethical” about it.  A generation or two ago it was fairly common, especially in small towns.)   Often, faced with a difficult medical decision, there’s one question we really want to ask the doctor: Would you give the same advice to a loved one or a best friend, if they were in my shoes?  Mostly, we don’t have the nerve to ask.  Stu Dolin was lucky enough to know the answer would be yes.

A Job For A General Practitioner

Most family doctors take that Learned Intermediary business fairly seriously.  It’s one reason why they refrain from handling “specialty” drugs for complex or serious conditions, which may require expert management.  Chemotherapy for cancer; biologic drugs for Crohn’s disease, MS and other autoimmune disorders – those are best left to specialists.

When he began practicing medicine in the 1980’s, Sachman explained, antidepressants were in that category.  The older ones were more problematic, with more side effects, and were reserved for people with relatively severe symptoms.  Rather than try to treat such patients  himself, he’d refer them to a psychiatrist.

This changed when Paxil, Prozac and the other SSRI drugs came out in the early 1990’s.  They were depicted as being safe enough to be handled by general practitioners, and a reasonable option for patients whose troubles didn’t warrant seeing a psychiatrist.  By the mid-2000’s, this had become the first-line option for dealing with both depression and anxiety.

As Dr. Sachman saw it, if a patient had mild to moderate depression in response to some trouble or stress in his life that was a “reactive” depression for which he could prescribe SSRI’s.  If they had serious problems with sleep and appetite, a slowed-down or unusually agitated appearance, and an inability to function in daily life, that was true “clinical depression,” and they should see a psychiatrist.

Dr. Sachman knew Stu Dolin well, and the anxiety he complained of in June 2010 did not alarm him.  Stu was just going through “one of his stress periods, on account of his work responsibilities.  He seemed to be getting through it like he did the other times.”  Dr. Sachman’s diagnosis was situational anxiety.  A drug like Paxil could help people get through a rough period like this.  The condition was fairly benign—and like the overwhelming majority of his colleagues, he considered Paxil to be a fairly benign drug.

A “Warning Label” that failed to warn

By 2010, the official label for Paxil gave physicians no reason to doubt that assessment – at least for adult patients.  It warned that any antidepressant could trigger agitation and suicidal impulses in children and youth up to the age of 24.  However, it also stated that “short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24,” and showed lowered suicidality in those over 65.

The warning added two more crucial sentences:

“Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.   Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behavior.”

As psychiatrist Joseph Glenmullen told the jury, this label effectively blinded doctors to the risks faced by adults:  “What this tells me as a practicing psychiatrist is that if I’m treating a 57-year-old patient, and I put them on Paxil, Paxil couldn’t make them worse.  Paxil couldn’t make them suicidal.”  If they did feel worse, said Glenmullen, “it would be, and it says explicitly, their depression or other underlying psychiatric condition.”

Worst of all, he said, “if the patient gets worse and it might be the drug, what do you do?  You take them off the drug to see.  If they get worse and it couldn’t be the drug but it’s the depression, what do you do?  You increase the drug, which is going to worsen the risk.  So it’s very dangerous.”

The regulatory history of Paxil and the other SSRI’s was almost Byzantine.   For years they carried no warnings of a risk for suicide.  In 2004, after thousands of troubling reports, a Black Box warning was finally issued for children and adolescents.  A number of medical experts felt the warning should apply with equal urgency to adults.

However, in 2007, the FDA decided on a uniform warning for all antidepressants, old and new.  This was the “24 and under” label attached to both brand-name and generic Paxil in 2010.  This suited GSK just fine.  The FDA invited the company to discuss whether additional warnings were needed for Paxil, but GSK never took them up on it.

More importantly, it never fully shared with the FDA—and still less with doctors in the community—what it knew about the real risks of its product.  In fact, GSK had known since 1989 that its drug could trigger akathisia, an agonizing combination of physical restlessness and emotional turmoil that could lead to suicide.  The risk applied to both teenagers and adults; at least twenty suicides had occurred in patients on Paxil in clinical trials, the majority of them in people over age thirty.

A Doctor Taken Hostage

Thanks to GSK, that information never reached Marty Sachman.  If it had, he testified, he would never have prescribed Paxil for Stu Dolin.  There were plenty of other options—other drugs, and non-drug strategies – for treating situational anxiety.  Because of the warning label, he said, he had never prescribed Paxil to a patient under 25; the benefits didn’t seem worth the risk.  He had a few adult patients who seemed to do well on Paxil; if they had been on it for several years and wanted to continue, he would refill it.  However, in the seven years since Stu Dolin’s death he had not written a single new Paxil script:  “I don’t trust the labeling,” he said.  “I don’t trust the company, to be honest.”

Marty Sachman’s anguish—and his sense of betrayal—was apparent to everyone in the courtroom.  Physicians like himself, he said, “rely on truth and honesty from pharmaceutical companies, and to falsify information or hold back information is totally criminal. How can we treat people effectively and safely if we can’t depend on that?”  They couldn’t.  Instead, he had prescribed a drug, and a patient had died.  That alone would have been traumatic for any honest doctor; that the patient was his best friend made it devastating.  It was not like being a Learned Intermediary; it was more like being a hostage.

So what about the average Joe?

Dr. Sachman never got the chance for a follow-up visit with Stu Dolin; within six days of starting Paxil, he was dead.  If he had, it’s just possible he could have spotted his longtime patient’s real problem. Maybe even stopped the Paxil.  We’ll never know.

In 2010, the year Stu Dolin died, doctors wrote 259 million antidepressant prescriptions.  For most patients, who don’t have access to anyone remotely resembling Dr. Welby, the situation is even scarier.  They may get a script for an SSRI in a ten-minute encounter with an overworked stranger, based on a checklist left in the waiting room so that every patient can be “screened” for depression.  The potential number of doctors taken hostage – and patients tossed overboard – is hard to imagine.

I have to think genial old Marcus Welby, M.D. wouldn’t stand for it.  What about us?

Dr David Healy Blogs About The Stewart Dolin Trial Verdict… (well worth reading)


https://davidhealy.org/change-in-chicago-the-dolin-verdict/

Change in Chicago: The Dolin Verdict

May, 1, 2017 | Reply

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

The Dolin Trial..


Roy Strom, The Am Law Daily March 22, 2017    | 0 Comments

Photo: Diego M. Radzinschi/ALM

The bad blood between Dr. David Healy and GlaxoSmithKline plc brewed up long before the psychiatrist took the stand in a Chicago federal court last week to testify that the pharmaceutical giant hid the risk of suicide in its blockbuster antidepressant Paxil.

Healy’s testimony is the bedrock of a claim brought by the widow of a Reed Smith partner who committed suicide in 2010 while taking a generic version of Paxil. GSK argues that Stewart Dolin’s death was the result of stress from a diminished role at the firm following a 2007 merger. Dolin’s widow, who claims her husband died from an adverse reaction to Paxil, is seeking $12 million from GSK.

All GSK has wanted is for the fast-talking psychiatrist to stop testifying.

Healy, a professor at a British university and a practicing physician in Toronto, has been a thorn in the pharmaceutical giant’s side since about 1999, when he wrote “The Antidepressant Era” and first began raising concerns about GSK’s clinical trials related to antidepressants known as SSRIs, or selective serotonin reuptake inhibitors. In 2005, The New York Times profiled Healy, noting that he was “internationally known as both a scholar and a pariah.”

“You don’t really know who you can trust,” Healy told the paper.

Healy has been a longtime expert witness in cases against GSK. His all-day direct examination in Chicago last Thursday was followed by a six-hour cross-examination this week. Healy said he had testified in more than 10 cases against GSK, something the company’s lawyers at Dentons and King & Spalding made a spirited effort to prevent in the Dolin case.

Healy’s testimony, for instance, was admitted in a suit in the Southern District of Indiana involving the sister of a priest who committed suicide after taking paroxetine, the trade name for Paxil. That case appears to have settled in 2011. And in 2015, Healy was an author of a new review of clinical Paxil trials on teenagers, which led to headlines that the drug was unsafe for teens.

The heart of Healy’s testimony contends that GSK artificially inflated the number of suicides and suicide attempts committed by members of the placebo group during clinical trials for Paxil. That had the effect of minimizing the risk of suicide associated with the antidepressant, meaning there was no warning of suicide risks on the drug’s label.

In the Dolin case, GSK’s lawyers filed a motion to exclude Healy’s testimony in the Dolin case, writing a 46-page memorandum with 70 attached exhibits arguing that Healy was a financially biased witness with an axe to grind against GSK.

The filing asserts that the lead plaintiff lawyer in the Chicago case, Michael Baum, a senior managing partner of Los Angeles-based Baum, Hedlund, Aristei & Goldman, is an investor in a company founded by Healy. That company runs a website, RxISK.org, which GSK’s lawyers said helps promote suits against the pharmaceutical industry. The filing also said Healy’s personal blog showed his bias against GSK, including his purported belief that the company helped get him fired from a previous professor position and may have been behind an investigation that could have led to his medical license being revoked in the U.K.

U.S. District Judge James Zagel ruled that Healy (pictured right) could testify in the Dolin case. But at the trial, presided over by U.S. District Judge William Hart, lawyers could not ask Healy about his blog or his personal relationship with GSK.

King & Spalding life sciences and health care litigation co-chair Andrew Bayman asked Healy if his website was intended to make it easier for the public to file suits and to garner work for himself as an expert. Healy testified that he bills $750 an hour to testify and $400 an hour to review cases.

But as was the case with many of the points that Bayman tried to pin Healy down on, the psychiatrist was prepared with a response to that charge in court Monday.

The website “has nothing to do with supporting lawsuits. This is all about minimizing the problem so there won’t be lawsuits,” Healy said, adding that Baum’s investment in his company, “would probably put him out of business.”

Proceedings in the Dolin case are continuing this week in Chicago. Some of his former Reed Smith partners are expected to take the stand.

Dr Healy’s New Blog Post..


Psychiatrist Peter Kramer’s new book ‘Ordinarily Well: The Case for Antidepressants (2016)’ is reviewed by Dr David Healy on his blog (see below).

Whilst it does not surprise me that a psychiatrist like Kramer would publish a pro-anti-depressant book, it does disturb me how he got it published without mentioning the side effects, and the many controversies, surrounding the drugs- over the years.

Surely this is promoting ‘misinformed consent’?

Psychiatrists like Kramer put patients lives at risk.

We are lucky to have psychiatrists like Healy, to counter the balance.

Healy’s review decimates Kramer..

and rightly so…


https://davidhealy.org/venomagnosia/

Venomagnosia

January, 30, 2017 | 11 Comments

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.

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