Making medicines safer for all of us

Adverse drug events are now the fourth leading cause of death in hospitals.

It’s a reasonable bet they are an even greater cause of death in non-hospital settings where there is no one to monitor things going wrong and no one to intervene to save a life. In mental health, for instance, drug-induced problems are the leading cause of death — and these deaths happen in community rather than hospital settings.

There is also another drug crisis — we are failing to discover new drugs. [Read more...]

Author Archive for David Healy

Go Figure: A Geek Tragedy

ddt1

In 1939, in the laboratories of Geigy pharmaceuticals, Paul Mueller discovered that DichloroDiphenylTrichlorethane DDT killed insects more effectively that anything else then available.

Robert Domenjoz, the later creator of imipramine, had the job of evaluating it. He did the testing on lice that was to make DDT one of the best-selling pharmaceuticals in the world. He asked the Salvation Army to bring him two of the paupers who slept there and he bought their shirts – for their lice. He put the lice in small boxes which could be sealed with a sieve so that the lice could breathe. He attached the boxes to his arms so that they could live off his blood. Over weeks, they multiplied. When he had enough, they started testing DDT on them. It worked a treat.

Lice carried typhus, which killed more people in wars since Napoleon than the actual wars had killed. Domenjoz headed straight to the Swiss army who started using it and then presented the results at the American embassy in Bern. When the Americans invaded Italy soon after, the troops were all sprayed with DDT and pretty soon everyone who was liberated from the Germans was liberated from lice also.

After the war was over

ddt2

After the War it became common to spray the public in cinema queues and at football games across Europe and America for instance as the photo shows. Mueller won the Nobel Prize in 1948. Domenjoz might have thought at the time he should have shared it.

As almost every ghostwritten article about all of the drugs in current use now says, DDT was very clearly safe and effective.

The use of DDT spread. The images most of us have now is of planes dusting crops with plumes trailing behind them.

Then in the early 1960s the wheels came off the bandwagon. By the time Rachel Carson’s Silent Spring was published, DDT was on the road to oblivion, with most of us thankful we had been saved from oblivion. DDT it became clear accumulated in the food chain, with small doses in some insects and crops, ending up as larger doses in the predators living on them,and larger and lethal doses in the birds, fish and other mammals living on them, or in their eggs or milk. And larger doses in us.

We had learnt that the acute effects of a drug given in a particular way might be dramatically different to the effect that came with chronic exposures or from unexpected routes of administration.

Wasn’t this what we learnt?

Geek tragedy

Controlled trials (RCTs) are all about establishing the acute effects of a drug given in a standardized way by drug companies who hope the verdict will be their chemical is safe and effective so that they can head out and put it in the drinking water (metaphorically). People will end up on these chemicals chronically and they will be mixed with lots of other chemicals in ways never imagined when the drug was first tested.

The result is biphosphonate drugs marketed to reduce the risk of fractures which increase the risk of serious fractures. Antidepressants marketed to reduce suicide risk, alcoholism, substance misuse, marriage breakdown etc which increase the risk of all these things, as well as causing Autistic Spectrum Disorder and birth defects. Statins marketed to reduce risks linked to diabetes which increase rates of diabetes, and to reduce the cognitive problems stemming from strokes but causing cognitive problems in their own right. RCTs miss all of these things – and when they don’t miss them as in the case of the antidepressants and suicide the data is fudged, sometimes fraudulently.

Far from recognizing the role of RCTs in producing a new Silent Sprint, RCT enthusiasts are spreading the word that we need more of them. No-one should be on a treatment who isn’t in an RCT. This is the script for a Geek Tragedy.

RCTs do more than miss the long term injuries a drug might do us. They get used to build standards of care to which doctors are obliged to adhere. Anyone who figures it might not be wise to add a sixth drug into the mix a person is on, or that thinks that maybe adolescent crises are not something that need medicating, will find themselves up against these standards of care facing managers who ask Who are you to go against the Standard of Care? Sorry we have to let you go.

Part of the tragedy is that we would in fact save vast amounts of money by giving the pharmaceutical companies 10 times the inflated prices they currently receive for drugs as part of a bargain where their marketing ensures that only 10% of those currently taking lipid-lowering drugs, antidepressants, biphosphonate and other drugs end up on them – and perhaps slightly higher proportions for hypoglycemic drugs, antihypertensives and antibiotics. The savings would come from shutting down osteoporosis screening services. From the savings on not having to treat treatment induced disabilities. From Elective patients (patients on cancer chemotherapy) not having their bed blocked by an antidepressant induced suicide attempt or biphosphonate triggered fracture of the femur, or a hypoglycemic episode (the biggest cause of brain damage) triggered by the use of extra hypogylcemic drugs being used to lower blood sugars elevated by the use of Statins that current standards of care mandate in diabetes.

Most of us thankfully won’t get tangled up in these elements of the tragedy – the final scenes where as in King Lear the corpses are strewn around the stage. For most of us the ending will more like the ending of a play by Samuel Beckett – The Algorithm will See You Now.

Go Figure on Perversity

Chloracne

In 1936, three workers at the Halowax Corporation in New York State, who had been working with chlorinated naphthalenes, developed chloracne – a skin condition that Viktor Yushenko’s face brought dramatically to world attention in 2004, when he was standing as the pro-Western candidate for the presidency of Ukraine.

Chloracne can be caused by many chlorinated compounds from vinyl chloride, through polyvinyl chloride (PVC) and polychlorinated biphenyls (PCBs). Many medicines are chlorinated. I have no idea if this chlorination, as in Zyprexa, olanzapine, for instance can be a problem but Zyprexa and other compounds can certainly give rise to chloracne.

The three workers went on to develop jaundice and then liver failure and died. Halowax had shortly beforehand increased the strength of the chlorinated compounds that went into their halowaxes, which were used as insulators for electrical wires.

The company called in Cecil Drinker, then the dean of Harvard School of Public Health. Drinker and colleagues had helped create industrial hygiene. In this case, the approach involved taking air samples and then testing the chemicals found in the air on laboratory animals – chlorinated naphthalenes and biphenyls. The new more intensely chlorinated compounds were in fact more likely to cause liver damage than the older mixes. The trick then was to find the dose that could cause this problem in rats, half the dose, set this new dose as the maximal exposure permitted, and then recommend ventilation and related measures that would ensure the factory milieu never reached these levels.

There was a tacit understanding that industrial hygienists would not recommend safe levels too difficult for factories to reach. Having undertaken work to manage the issues, factories were well placed in the case of litigation to show they had acted responsibly.

Your point being?

The problem was these tests measured the acute effects of chlorinated compounds – six weeks. They assumed the problems arose from inhalation. And they measured the average effects. This leaves no room for an unusual sensitivity to a chemical, or chronic exposure or exposure that arises from chlorides or related compounds absorbed in unexpected ways.

Vinyl Chlorides can be very safe if used acutely and with discrimination. They are among the materials of choice for dominatrix outfits – as in the featured image.

The vinyl chlorides however also give rise to dioxins. Viktor Yanushenko’s chloracne likely came from dioxin levels that were at 4000 times the safe level in his body. He survived this apparently very acute exposure, which is widely thought to have been a poisoning.

But the cancers that lots of other people have developed since have come not from poisoning by political opponents, or from Sexual Games even those that until recently might have been seen as perverse (longer than usual exposure, variations on the norm and… ), but from chronic exposure to much lower doses than were in the Halowax air in the form of dioxins that have ended up in the food chain.

Dioxin

Without any conspiracy involved, the best science of the day, stamped with a Harvard imprimatur, completely missed the problem. But it did give industry great cover, and helped create the Harvard Department of Public Health and now Global Health.

To be continued.

Go Figure: Digging for the Truth of Injuries

Quarry men

Editorial Note: In her comment, reproduced below,Sally was the person who best got to grips with what I was struggling with in last week’s post and this week’s and for the next few weeks. Drug induced injury is one sphere in which we get injured. Turning to other spheres may give us some ideas about how to handle the dilemma of a treatment induced injury – how to avoid being singled out the system, how to build a community that can resist and seek redress.

The Silver Lining Clouds the View outlined how working with mercury can cause a distinct psychosis or tremor or confusion that clears when the person leaves work.

But what about when a worker gets an illness like tuberculosis? This is not a specific industrial injury.

For fifty years around 1900, North Wales had the biggest slate quarries in the world. At a time when deaths from tuberculosis were falling in Britain, these quarries had increasing rates of tuberculosis and deaths. Repeated enquiries reviewed all options. Quarrying gave the workers silicosis. Did silicosis make tuberculosis more likely?

Local doctors said no. The problem was down to poor diet. The modern housewife spent too much time at school and her only domestic skill was the ability to use a tin opener. These medical views passed muster as the considered judgments of scientifically trained men.

Silicosis does predispose to TB. But, just as the mirror workers in Furth fifty years earlier took their chances with mercury, so too the quarrymen kept quiet about their chest problems. They steered clear of doctors. There was no other employment in the area if they were signed off. Both workers and employers knew that jobs in the mines were dying out.

You don’t have to silver a mirror or go down a mine to appreciate the psychology and politics at play here. You just have to take a medicine. Drugs come with risks. Even when things go wrong on treatment, short of being invalided, most people opt to cope with it, often silently, rather than own up. Owning up, especially if there is no treatment, makes you a loser, and the herd leaves losers behind. The injured worker or patient is like a dog barking at the passing caravan.

Your point being?

Sometimes truth is not something you dig for.

The link between treatment and injury may be a social one. The entire community may know what is going on. But the doctor will see a picture where it is not proven what causes what, and one of his options is to take your moral failings into account. This is often the most convenient option – for him, especially if you’re a woman.

This is a delicate world, a world in which there are no accidents if by accident we mean random events. An unexpected or unintended event is not an accident – although we use the word that way when we are knocked down by a car, and lawyers advertise their expertise in accidents. But Road Traffic Accidents, no less than Drug Traffic Accidents are rarely Acts of God.

An Act of God is when a cow jumps over a ditch and onto your car. In Road Traffic Accidents or Drug Traffic Accidents, someone has always been careless. It may be like the carelessness that started with the American Civil War when rifles that could hit a target at long range replaced muskets that couldn’t and all of a sudden troops could be picked off by a sniper. Being picked off by a sniper sounds almost random, but after the first time it happens, the military top brass are responsible for your death if, having seen what can happen, they do nothing to prevent it happening again.

If the event is not random, the question of responsibility comes into play. Before 1800 roughly we used to be able to attribute misfortune to God or Fate. It is now down to us. If I didn’t intend to hurt you, I am unlikely to concede that something I did in fact did hurt you. The bystanders, those with a superficial knowledge, will side with the likely winner rather than the likely loser, unless forced to delve deeper. Everybody takes steps to avoid being the person responsible, or on the side of the person responsible.

In nurseries for 4 year olds now if a mother brings in a cake on her son’s birthday, the staff will not let other children have a piece because they cannot validate her cake-making. A piece of cake will be put in a take home bag for the children, whose parents can let them have it, if the parents take responsibility.

For the loser in games like this, beyond the injury an identity is destroyed, as surely as if acid has been thrown in a face. I am now marked as a loser and the only people who can understand that are those marked in the same way. But no-one, not even a loser, likes the company of losers. The loser in the lottery of life will also likely lose any contest about what has happened her.

In the world of treatment induced injuries, God fails as an explanation. The modern replacement for God, Science, also fails. We are Shipwrecked and on our own.

Go Figure: The Silver Lining Clouds the View

The Mad Hatter

Editorial Note: Sally’s first Go Figure post with its 100 comments outlines the basic dilemma facing RxISK – how can anyone who has been injured by treatment get people who have not yet been injured to wake up. The next 5 – 10 posts will pick up various ways this dilemma has been answered over the last century. All comments welcome along with any posts – something more than a comment – anyone figures they have.

In 1861, the Furth Provincial Medical Association reported on mercury poisoning among mirror workers in the Furth-Nuremberg area. Along with Venice, Nuremberg was a center of the European mirror industry. The first Guild for Mirror Makers opened here in 1373. The craftsmen were using a technique developed in Venice of silvering the backs of mirrors with a mercury tin amalgam to improve the reflection.

The workers were suffering. Few complained. Their problems were only detected when they came to the doctor with other issues or if some new treatment, such as electrotherapy appeared, that some workers figured might be worth getting the doctor to try to manage the problems they were having.

The workers could see in the mirror exactly what mercury was causing when doctors hadn’t – a flush, tremors, irritability, and madness. It caused their feet to burn or go numb.

But against these risks, the only cure was to stop working which brought the certainty of pauperism and maybe death. So the workers lied to their doctors out of fear of losing their jobs. Besides pay was tied to risk – make the job safer and the rates of pay were likely to drop. Did they want a safer job or more pay? The factory owners denied the link.

Mercury had been causing problems for centuries. It was used in felt hats and caused confusion and disorientation to hatters, leading to the phrase Mad as a Hatter and to the Mad Hatter in Alice in Wonderland in 1865.

Administered as a paste for syphilitic sores from 1600 onwards it seemed to help them heal. This led to its use internally and after 1780 to the use of the stronger form – mercuric chloride or Calomel. Soon after this began to be used widely, dementia paralytica appeared, a psychotic disorder commonly put down to syphilis but which only happened where mercuric chloride was used in its treatment. The combination of syphilis and mercury likely did for Mozart (kidney disease), Beethoven and Schubert. See The Day the Music Died.

But in 1861 the link between mercury and health problems, always known at one level but persistently denied, didn’t go away. Adolf Kussmaul, a university physician, agreed with the link the Furth “general practitioners” were proposing.

There was another factor. Chemistry was flourishing and Justus Liebig and others came up with alternate ways to silver mirrors. Mercury was no longer needed and in 1886 its use for silvering was banned.

Your point being?

Faced with a plague, many of us emigrate, a smaller number stay and resist, but most of us get on the train. It is only if there are options that anything else happens. In Furth there were options in terms of new ways to make a living and perhaps some unusual doctors.

In 1848, revolutions across Europe led to changes of government. Doctors played a big part in these uprisings as they had in Paris in 1790. Two of the revolutionaries in Germany, Rudolf Virchow and Karl Marx, had an enduring impact on politics and healthcare politics. Virchow saw doctors as a revolutionary class, where Marx saw workers.

Industrial health issues, exactly like those the Furth mirror workers demonstrated, triggered the formation of a German Workers Association in 1863. A German Socialist party appeared in 1869. There was a growing number of strikes. In 1869, the response from Bismarck, the German Chancellor, was a Factory Act that left owners free of obligations other than those they voluntarily took on. Factories were regarded as private property – not part of the public realm, and not subject to inspections.

In 1875, the Worker’s Association and Socialist party merged to form the Socialist Workers Party, later the Social Democrats. The socialists accepted the validity of the state and the need to work with its institutions to bring about change – workers health and safety were a critical testing ground for whether this was possible.

Industry argued that technology was so diverse and growing so rapidly that it was not possible to legislate in a way that would work. Bismarck again accepted the employers’ argument that money put into health and safety was a tax on jobs and at a time of growing international competition this was not in the national interest.

In 1878, he enacted a set of punitive Anti-Socialist laws.

But he also took another step. Just as the Republican President Dwight Eisenhower put in place a program of interstate highway construction in the United States in the 1950s as a form of state socialism, so in the 1880s Bismarck put State sponsored health insurance schemes on the table as a means to stave off revolution:

“A duty of a state preserving policy should be to cultivate the conception among the non-propertied classes which form at once the most numerous and the least instructed part of the population that the state is not merely a necessary but a beneficent institution”.

The certification or not of workers as sick was a new role that opened up for doctors, a source of income. But it also made them part of the apparatus of the State. They “matured”. As Adolph Beyer in a lecture to the German Association for Public Health in 1877 put it:

“Precisely in this field, prudence and caution are necessary and one should not try to support a safety which risks or neglects the main priority, the securing of the daily bread. That is why it is necessary to openly oppose those immoderate demands which hide behind their pleasant mask of safety and humanitarian ends quite different aims. One should not let emotions reign, but considerations and experience”.

Go Figure: Sally’s Problem with Whinging about Medicines

99 percent

Two weeks ago in response to the last post in the Study 329 series, Sally MacGregor added the comment – that features as a post below. It’s spot on. The problem is how to avoid being marginalized, becoming part of a 1%. How to capture the attention of the 99% for whom the meds work just fine thanks. There will be more on this theme over the next few posts.

The whole point about the revisited Study 329 for me was that it was so meticulously and scrupulously carried out by a team of researchers, in a way that left no wriggle-room for it to be dismissed as ‘bad science’. (Even though some have tried). So it stands as a solid, irrefutable, excellent piece of science, which will be cited in the literature, and, crucially, is likely to pop up on Google. It’s kind of embedded now, which seems to me to be its lasting legacy. That it concerned GSK and paroxetine is secondary – Eli Lilly were just as murderously and indifferently mendacious – and in the UK get much, much less publicity for their callously commercial behavior.

The difficulties in getting through the hoops to the BMJ must have been incredibly frustrating, but – is anyone outside the ‘Study 329’ inner circle, or people who suffered from paroxetine, truly interested in the fact that someone’s husband was related to someone else who might have hindered the path to publication. It GOT published – which is the really important thing.

No one I know, service users included, had even heard of Study 329 – although several friends were very interested in the RIAT paper – mainly as a concrete example of meretricious Big Pharma mendacity. Hell – I’d never heard of Study 329 until 2013.

I’m playing devil’s advocate to a degree but sometimes I think we have to get real about life outside, where the chemical imbalance theory still reigns supreme, and if the public perceive any problem at all with antidepressants it is far more likely to be along the lines of ‘well he/she wasn’t taking their medication, that’s why they went berserk’.

No one will like me saying this – but I am sometimes reluctant to point people in the direction of David’s blog and Rxisk because, coming at it from a newcomer’s perspective, people don’t understand why AllTrials is suspect, (no one ever slows down and explains, for one reason) what on earth the BMJ did wrong, why Fiona Godlee is Nurse Ratchett, or what on earth is the point of laboriously transcribing an exchange between Goldacre just to show he’s an unreliable twat… And those new visitors will probably never repeat the experience.

Drawing new people in, from places other than those (like me) who’ve been dreadfully harmed is really important: doctors, researchers, scientists, our children, relatives, neighbours, philosophers, writers, journalists. We honestly HAVE to broaden the debate otherwise it simply becomes an incestuous gathering of victims and activists, who already know all there is to know about the damage. If visitors from outside don’t feel welcome, or just don’t understand what everyone’s going on about, then what on earth is the point?

Believe me, I’ve tried getting people to engage with Rxisk and David’s blog but it hasn’t worked – for all the reasons I’ve just stated. But they are surely the truly important people to get on board? Otherwise both forums just end up with ‘I am a victim’ hand-wringing on a big scale which does nothing to spread the message…no one apart from Johanna offered me any help with my ‘Take a Rxisk report to your GP’ request – and that was a challenge thrown out by David, which I didn’t especially want to do, but was willing to give it a go.

Similarly, with the Complex Withdrawal site (which I’m deeply interested in, as it might just offer some hope in the future for people like me) – I asked around, as requested, got some small bits of information from my hairdresser and a friend who’s a beautician– but there is no where sensible to put it, and the comments section has (yet again) been mainly co-opted by people offering well meaning but probably useless dietary advice or repeating, yet again, their stories. Surely the challenge was to GET MORE AND DIFFERENT people involved in collecting information?

It seems to me that every single attempt to move forward just dies – because no one slows down long enough to consolidate the practical ideas which might just make a difference to future victims. It’s too late for me, but I’d like to do my best to see that help is there for all those still to come. We can carry on preaching to the converted till the cows come home, but seems to me far more important to educate, persuade, chip away at societal views about antidepressants (non addictive, no such thing as withdrawal etc etc) without making people who take them feel alienated and ashamed.

I’m fed up with bashing away and for anyone who wants to reply ‘I did not like this comment’ – go figure.

Why Do People Sing?

Under African Skies

In 1989, BBC ran a program Under African Skies covering the music of the continent. The program and music from it captured on Cassette and later Record became widely known.

On Side 2 of 4 sides of cassette, there is a brief snippet of 4 children at St Joseph’s Music School in Harare answering their teacher’s question – Why do People Sing?

Peter: People sing to pass a message to others through music

Tom: People sing because they want to forget their problem

Terra: People sing because they want to get even

Art: People sing because they want to entertain others.

The soundtrack is Here.

Its worth listening to just to get the music of the childrens’ voices but it would also be great if someone can decipher what Terra says – the current suggestion is “because they want to get even” and the name of the last boy – seems like Art.

This is an introduction to a new series of posts. More once the reasons why people sing are filled in. Readers are welcome to offer more reasons for singing.

Club 329: Part 4

Leonie

Editorial Note: This post perhaps should be called: There’s Something about Leonie. The image above is of a Rapid Response she submitted to a BMJ editorial by Richard Smith and Fiona Godlee that BMJ published and unpublished and republished and re-unpublished. The full story is here. It again hinges around Study 329.

The full transcript of her exchanges with Ben G is below. It’s important. It suggests AllTrials see the side effects of drugs as irrelevant.

Leonie

Hi, this is to do with, specifically to do with Study 329. The BMJ took a year to publish the Restoring Study 329, the reanalysis of Study 329. I was just wondering what you thought of the fact that, would it be a factor that the BMJ clinical editor is married to a partner in Ropes and Gray, the same law-firm that GSK paid to defend them in the US department of justice action?

Ben Goldacre

I don’t know – also I don’t care. Honestly, conflict of interest, it happens – and it is clearly problematic. I don’t find it interesting, in the same way as I don’t find fraud interesting. So, I’m not saying that it’s not important.  I’m just saying, it’s not my thing. Conflict of interest is also what people who don’t understand trial design talk about, and it’s kind-of all that we talk about. So, all of the, almost all of the popular discourse around problems in research in medicine that you see mentioned it’s almost all about financial conflict of interests and I just feel like that’s really, that’s all we talk about, it’s well covered by the .. but it’s not, it’s doesn’t set me on fire.

I don’t think you can honestly say the BMJ are the bad guys in the world of suppressing medical research, and if anything, they’ve got a reputation of being, a kind of sanctimonious obsessives about research integrity.

And when you say it’s been a year to publish the reanalysis of Study 329, But firstly, I don’t think we needed a reanalysis of Study 329, honestly – it was a rhetorical act. It was interesting that someone went out and did it. But we knew that within six months of the trial being published, that the trial was crap. We knew within six months of the trial being published that it had been misreported and all of the stuff that I had showed you on that slide that Study 329 misreported it’s from a paper by Jureidini that came out almost as soon as Study 329 did. So we already knew, we already knew Study 329 was crap and study 329 was published 20 years ago.

I’m glad that someone did a reanalysis of the underlying data, to show, yet again, that it was dodgy and I’m glad that they got some media coverage, for showing, yet again, that Study 329 was dodgy, and showing that people switch outcomes. But actually, I’m more interested in the fact that there has now been 29 cohort studies, showing that on average about a third to a half of all trials switch main outcomes. It’s not about Study 329, it’s about these endemic structural problems throughout the whole of healthcare that we can fix. And I don’t know what fix you’ve got in mind, cos the fix that I’ve got in mind in the misreporting of outcomes, is, we need to hold journals to account when they misreport outcomes, and we need to stop then doing that bad stuff.  But I don’t know what you do about, I don’t know who ?? person is.. but I don’t know what we should do about that?

Leonie

But it’s still unretracted?

Ben Goldacre

Study 329? You think the BMJ should retract Study 329?

Leonie

I think it should be done by somebody.

Ben Goldacre

But the BMJ didn’t publish Study 329.

Leonie

No, but, GSK then.  Whoever, whoever wrote it.

Ben Goldacre

Yeah, I mean I think it should probably be retracted. BUT, again, what’s the purpose of a retraction, because anybody switched on knows that Study 329 was crap – and, also are we going to retract the tens, possibly hundreds of thousands of clinical trials that also switched their main outcomes?  I mean, maybe we should, but that’s a really big piece of work and why would we, why would we be more interested in Study 329, than the tens or hundreds of thousands of trials which we know switched outcome?  I mean this is a systemic structural problem. I mean Study 329 has rhetorical value for getting the media interested and engaged. But why are we trying to retract that one trial, rather than a hundred thousand trials that also switched outcome?

Unknown Male

I just want to ask a similar question, about Study 329 as well. Is outomce switching not basically fraud then? Is it not fraud, switching?

Ben Goldacre

Fraud?

Guy

Would you call it fraud?

Ben Goldacre

So, it’s really interesting isn’t it.  I think, it’s very, very interesting how the lines have been drawn between fabricating your data, actually going into the spreadsheet in excel and deleting the number that’s there, for the, for the patient’s blood-pressure, and typing in a new one. That’s fraud.

But, all of these different design shortcomings, which we know, are associated with over exaggerating treatment benefits and downplaying side-effects. That’s not regarded as fraud. I think that’s really, really interesting and it’s not a, it’s not a position that I’m sure, that I think I can respect. Because what I think is when you get the wrong answer you hurt people, and it’s your job to get the right answer.

Guy

In the case of 329, wasn’t there a lot of teenagers damaged? Young people were prescribed the drug on the basis of it.

Ben Goldacre

Yeah, but, like, why are you talking about teenagers and Paroxetine? We’re talking about the whole of medicine. Like, so what’s special about 329? What’s special about ..

Guy

Is it not the canary in the coal mine, no?

Ben Goldacre

Is it what?
Guy

Like, it’s the most publicised example of a corrupt study?

Ben Goldacre

Emm, yeah. It is this year, yeah.

Guy

Sorry. Why is it not important?

Ben Goldacre

Why is study.. No,  Study 329 is important but I don’t understand why you’re so interested in Study 329, when we’re talking about structural problems throughout the whole of health.

Guy

Well it’s just one of your examples, that you had in your slides.

Ben Goldacre

Yeah, I’m happy – I’m totally fine with that but I think, I think it’s a real strategic error and a backward step, to be preoccupied with one study, when you’ve identified structural problems throughout the whole information architecture of evidence based medicine. When you’ve identified a problem that hits, like a third of all trials, then I’m not sure that I care about ..

Guy

Can I just ask another question, because I find it this stuff interesting. You’re talking about antipsychotics and antidepressants, and you know, the dodginess of some of the trials, but, do you not think the medicalizing human distress is also the bigger problem?

Ben Goldacre

That’s about informed choice. So I get a sense of, that maybe you’re coming from a particular standpoint in mental health and that’s a partial view but I think with, with any treatment the right thing to do is to say, look, for the problems that you have, there is very good evidence, that this is a medicine which exists, which is been invented, which is available on prescription. From the best evidence we have, overall it looks like it has the following benefits and the following harms and it’s for you to choose whether you’d like to take it.

Now that works really well for most treatments, except it’s not done properly. So first of all you need to get better at disseminating information, not just to doctors but to patients, as I said… That would be my funding priority for a whole year to get better shared decision making between doctors and patients and then you can say, well look, with this statin, you get the following objective benefit with the risk of the following side-effects, you make your own choice.

And the thing that we know, from all the research on decision making, is that different people make different choices. So some people when they’re offered Statins say “ ..I don’t want to be medicalized… Even if the does overall reduce my chances of heart-attack, stroke and death, by two percent over the next ten years, I’m not interested”. But, some people will say “Yeah, I definitely want that drug, are you insane? Why wouldn’t I take that drug – I want to live?” So different people make different choices on the basis of the same information and I don’t know if it’s for me, to bring my own personal views and prejudices, which are actually, between you and I, and the room, more aligned to yours, than to most of the psychiatric profession, but I don’t think it’s for me to bring my own prejudices to bear on that. I think it’s for me to help my patients make an informed choice on the basis of the best currently available evidence and if they want to take an antidepressant, where the best currently available evidence shows that it will reduce your Beck Depression Inventory score by 2 out of 30 points, which is a modest, but nonetheless true benefit – then, that’s a choice for them to make, it’s not for me to bring my prejudices about medicalization of society to bear on that. That, that’s a choice for them.

Lady asks a question (edited out)

Ben Goldacre

But I really want to know what you think about?

Guy

I just think when you’re saying about informed choice, a lot of people were prescribed antidepressants 15 years ago, maybe 20 years ago in the 90’s or whatever – they didn’t have informed choice, the side effects only came out when the general population of millions of people were prescribed them. So you’re talking informed choice now, but there wasn’t then… so.. so

Ben

Yeah, I agree, it’s really shit isn’t it

That’s what we want to fix with proper trials and proper side effect monitoring and all of that but that’s very different than the broader, sort of cultural view you seem to have of medicalizing human distress.

Guy

I think the pharmaceutical industry have medicalized human distress, yeah.

Ben

There’s no doubt that people have marketed pharmaceutical products for medical problems for medical treatment. But nonetheless if this treatment will knock two points off your..

Guy

But you’re talking about scales and stuff that’s not applicable to people’s subjective experiences of these emotional problems.

Ben

Well it’s not perfect but it’s the best that there is and an informed patient will make an informed choice, they will look at their depression metric and they’ll know what those questions are and they’ll look at at and see well we can knock two points off that- and they can look at that and go well what would that actually mean? Yeah you’re right actually that could just mean just not waking up in the morning two days a week..

Guy

It’s all subjective…

Ben

So people can make an informed choice, and if they don’t make an informed choice, well that’s their decision too, and people throughout society on all treatments vary hugely on whether they want to be involved in shared decision making, and that’s their right…

Guy

It doesn’t happen in reality though. Well certainly not in Ireland- maybe in the UK, but in Ireland it’s not happening.

Ben

Well that’s what we want to happen. But also you have to be really careful about imposing your prejudices on other people.

Guy

I’m not imposing my prejudices on other people.

Club 329: Part 3

Shane Clancy

Editorial Note: This post by Leonie Fennel carries on from parts 1 and 2 in this series. There will be one more post.

I dreamt I met my son Shane last night – in a jewelry shop, of all places. I was admiring the beautiful costume jewelry, when I overturned the dainty display and went clambering to pick up all the pieces. It seems I don’t escape my klutziness in the land of my dreams (or my love of all things bling).

The shop doorbell tinkled and in walked Shane who had been gone for so, so long, as handsome and animated as ever. All thoughts of scattered jewels were instantly forgotten while I launched myself at him. Shane’s younger brothers and sister appeared behind me (it is a dream after all) and he laughed happily while telling them stories of what he’d been up to. They all looked on, transfixed, fascinated as always by their big brother – listening attentively for once. All the while my arms were wrapped around him, with my head buried in his chest, clinging on for dear life, crying happy tears and feeling a joy in my heart that somehow seemed so alien.

Then I woke up and cried all over again when I realized it just a silly, silly dream and my lovely Shane was still dead – it’s ‘Marbh’ in Irish but means the same, deceased, dead, unadulterated and irrevocably dead.

Seven years and I’m still haunted. Haunted by the ‘what ifs’. What if I hadn’t insisted that Shane see a doctor? What if the doctor had not believed in the biological model of treating heartache? What if we had insisted on knowing all the facts BEFORE he took an SSRI, not afterwards? What if we had known Study 329 was a crap trial before 2009, not afterwards? What if Shane’s arms around me were actually real, not just a dream? ENOUGH. Back to a modicum of normality. I don’t know why I shared that with you, apart from the fact that the feeling of Shane is burned into my mind today.

Pandora

As this is my second post, I should point out that my previous one effectively opened a virtual Pandora’s box, by annoying Ben Goldacre. He said I misrepresented his talk in Dublin – which of course I didn’t. He also said that David Healy was ‘fully responsible’, presumably for publishing the post on his website – have to be careful of misrepresentation here but I’m a little offended at the suggestion that I’m not entirely responsible for myself. To be perfectly honest, I’m not quite sure what all the fuss was about – but it seemed to have had a Streisand effect, which I suppose is a good thing. I think I’ll leave Drs Healy and Goldacre to debate the finer details, although I’d love to see them debating in the same room. Wonder if I’d get an invite if I promised to take a responsible adult as a chaperone, although Dr Dishy has now officially disowned me!

Moving on

Tragedies similar to Shane’s are increasing every year, largely due to the increase in the prescribing of psychotropic drugs. Last week, very near to where I live, we heard police cars racing past with their sirens blaring and helicopters flying around overhead. It turned out that a man who lived nearby had tried to strangle his four children. Thankfully they all survived, but it was a close call, with two of the children being airlifted to hospital. Reports suggest that this man is a nice guy who loves his children dearly, so how do we marry these two opposing images? Every year we see the same tragedies, filicides, siblicides and infanticide, all with the same SSRI-induced hallmarks – yet very few ‘get it’.

When I hear of awful incidents like this latest one in Wicklow, the first thought that goes through my head is “Please, let these kids survive”. The second is “I wonder if this poor man was recently prescribed an SSRI or was he in withdrawal?” That most medics wrongly believe that psychiatric drugs are not addictive only exacerbates the problem. Hence, this latest incident is all too similar to many previous ones in Ireland, where the outcomes were not always as fortunate.

Despite the FDA and EMA warnings, on the rare occasions when medication is implicated, medical professionals will spout ‘autonomy’ and ‘informed consent’ – as if this is an actual possibility. Tell me, what medic tells a patient presenting with distress, that the proposed treatment may cause suicide, violence, emotional blunting, akathisia and among many other awful effects? Oh yeah, let us not forget the sexual dysfunction. Who will tell a vulnerable patient that the most dangerous time with psychiatric drugs is upon starting, changing dose (up or down) or discontinuation? Tragically, in the case of withdrawal, many healthcare professionals will justify these incidents by saying it’s the ‘mental illness’ returning – stating that If these people took their meds as prescribed, there wouldn’t be a problem. Thus, was this Wicklow native and his family given even the tiniest degree of informed consent? If this ‘out of the blue’ case turns out to be yet another instance of prescripticide, I can only hope that this man’s family, who know him better than anybody, will understand that these drugs can be the catalyst.

Lastly, the opinion of a lone member of the Irish Police force “There is only one thing I know that enables a parent to want to kill their children, SSRI antidepressants”. Whether this latest case is SSRI-induced, we will just have to wait and see. I’ll keep you posted.

Club 329: Part 2

Untitled

Following last week’s post, Club 329: Part 1, Ben Goldacre went into orbit claiming his views on medicalization and Study 329 had been misrepresented. He offered a SoundCloud as evidence. The link can be found in the comments after the last post. Seems to me Leonie got the content of the Q & A right.

In the course of listening to the BG SoundCloud though something else came into view. Leonie began questioning him about the links between one of the BMJ editors and the law firm Ropes and Gray who had represented GSK in the Department of Justice case that led to a $3 Billion fine for GSK. This didn’t seem to worry Ben. He’s not worried about Conflict of Interest – nor am I. His view on Fraud is unclear.

There was something else in the recording that caught my interest. BG didn’t figure the question of BMJ taking over a year to publish Study 329 was an issue. You couldn’t possibly make out that BMJ are the bad guys in the business of suppressing good science, he said. If anything they have a reputation for being too sanctimoniously obsessive about research integrity.

As BG says people react differently to things. If you and he were both facing a course of treatment, some piece of trial data about a drug might speak to him and not you and vice-versa. Maybe the Study 329 story doesn’t speak to him and others of you out there – doesn’t give you a feel for GSK or BMJ.

Perhaps a completely different story will work for those of you to whom Restoring Study 329 doesn’t speak.

A curious development

Six months into a tortured year long review process for Restoring Study 329, something odd happened. On February 9 2015, I was approached by the BMJ:

I’ve long been interested in the controversy over the role of serotonin in mental illness and wonder if you would like to write an editorial for us on: “What is the evidence that serotonin plays a role in depression?”

I replied:

More than happy to think about doing this for you. But I probably need to make something of a pre-conflict of interest conflict of interest statement, which you will need to consider.

The idea of serotonin in depression is inextricably linked to the marketing of the SSRIs. There is vanishingly little evidence that serotonin is involved in depression – but I can probably put more evidence on the table for its role than almost anyone can.

The idea of a role for serotonin in depression has been an extraordinary marketing trope – one that is critical to perceptions when it comes to the way the role of SSRIs in suicidality and birth defects is viewed. Because of this latter aspect and my role in some of these debates many people viewing an editorial by me would probably have a blood boiling moment. That’s just viewing the existence of an editorial – might not be too bad if they read it.

BMJ decided to run with it, but then seemed to have a crisis. They got back to me with an extensive conflict of interest declaration and there was a considerable delay after I got this back to them before anything else happened. Given all the fuss BMJ were making about Conflicts of Interest on Restoring Study 329, it was difficult not to think there was some link.

Finally they ran with the editorial but had difficulties with the title. So, So Long and Thanks for all the Serotonin became Serotonin and Depression. The Marketing of a Myth. It did well in terms of impact factor despite the fact that Sense about Science, with which Ben Goldacre is closely linked and which kicked off AllTrials with him, mobilized to get dissing comments about it from the Royal College of Psychiatrists and others.

Sense about Science spends a good deal of time mobilizing responses to material that might seem not supportive of corporate interests – see the Sense about Science series of posts to which BG also took exception.

Curiouser and curiouser

But there is a more interesting story behind this one that I only know about by accident.

A short while before the BMJ approached me, I had been sent an article – on the Myth and Marketing of Serotonin. It was a very good read. At least as good as mine if not better. One of the authors asked what I thought about the possibility of BMJ being interested. I said I thought it was unlikely.

Despite my advice, the authors went ahead and submitted anyway – on February 7 2015. They got a quick reply.

We are in the process of commissioning an editorial for The BMJ, looking specifically at the role of serotonin in depression, and so you will be able to send in a rapid response to that directly.

When dealing with BMJ you can get the feeling they (the editors) are using authors to run their own agenda. You might get in touch with a draft article on Access to Clinical Trial Data and they get back saying “sorry we’ve just had something else from someone else on this topic”. The something else when it appears a good deal later turns out to be a neutered version of what needs to be said.

Many people figure journals shouldn’t have an agenda. In fact the first medical journal, the Lancet, began with an agenda – against food adulteration. The later appearing BMJ ran its own campaign against nostrums – around 1900. These campaigns put these journals at considerable risk of reprisals. BMJ sees itself under its current editor as on a mission. It’s more recent campaigns, far from putting the journal at risk, have been for Evidence Based Medicine and Against Overdiagnosis, along with AllTrials to which pharma has signed up.

Whatever the BMJ mission its not a mission to tackle adverse events – the modern equivalent of adulteration or nostrums. It was close to paralyzed in the case of Study 329 by having to conceded a drug might have a side effect.

The educational articles BMJ runs on most drugs contain little or no mention of adverse events. While it published Restoring Study 329 after a gun was put to its head, its educational articles on antidepressants play down any risk of suicide, are comfortable with giving antidepressants to children, never mention withdrawal, and deny links to birth defects.

But here’s the rub. The article that was better written than mine was written by Leonie Fennel and Maria Bradshaw – neither of whom have healthcare or neuroscience backgrounds. Both write like angels. Leonie was a hairdresser before a family tragedy mobilized her to find out more about the drugs that led to the death of her son and others. The latest version can be accessed on ResearchGate and an earlier version is attached here.

You’d have to think BMJ couldn’t cope with the idea of a hairdresser joining the club. Only credentialed nerds need apply.

Leonie’s input along with that of people like Anne Marie Kelly who have done so much to establish the role of SSRIs in promoting alcoholism proves again and again – and is the inspiration behind RxISK.org – that motivation counts for more than expertise.

When my article came out, Sense about Sense mobilized against it – having been sent a copy by BMJ, with whom they, BG and GSK are part of an AllTrials coalition.

Parts 3 and 4 to come.

Club 329: Part 1

Ben Goldacre

Editorial Note: This post is by Leonie Fennel. It’s one of two involving Leonie.

Last week, Dr Ben Goldacre gave a public lecture in the Royal College of Surgeons in Dublin (organised by the 3U Partnership and the very lovely Dr Ruth Davis). Dr Goldacre is a doctor, academic, campaigner and writer; he is also a psychiatrist and self-professed nerd. I was eager to hear what he had to say, not least as the subject-matter was ‘Bad Trials’ – so off I toddled to Stephen’s Green with a friend in tow, a psychotherapist. He, like me, has a personal interest – he has witnessed first-hand the devastation that can be caused by nothing more than a GP’s farraginous prescribing. He is also a very kind, funny, charming companion, so I was delighted to have any excuse to meet up with him. I’d also say he’s a handsome chap but the husband I abandoned for the day wouldn’t be too impressed.

Having read Goldacre’s ‘Bad Pharma’ book, we were both curious to hear what he had to say. Incidentally, he once called my English friend Fid a ‘Smeary Conspiracy Theorist’ – so apart from guaranteed entertainment, I wasn’t too sure what else to expect. In fact, his talk was fast-paced and as excitable as he is – he hops around like a Duracell bunny on speed and lets out intermittent roars, which effectively kick-starts the heartbeats of anyone not paying attention. Nevertheless, he attempts to make data and statistics fun, a nigh-on impossible task.

Needless to say, as the subject concerned ‘bad-trials’, he specifically mentioned GlaxoSmithKline’s notorious Study 329, although bizarrely managed to do so without mention of GSK (usually both are referenced synonymously). He seemed like an amicable chap and was quite happy to answer questions afterwards in the Q & A session.

I was interested to explore his views on Study 329 and asked his opinion on why the BMJ took a year (of much wrangling) to publish Le Noury et al’s reanalysis of it – and did he think it had anything to do with the BMJ’s clinical editor being married to a partner in Ropes and Gray, the same law-firm hired by GSK to defend the action brought by the US Dept. of Justice, where Study 329 was a central element.

Goldacre said that he didn’t know and didn’t care – that fraud and Conflicts of Interest were not of interest to him. He asked what the fixation with Study 329 was, as it was just one of the many trials where data was misrepresented?

He expressed the opinion that everyone knew from early on that the original study 329 was flawed and nobody really relied on it. I sincerely doubt that the authors would agree with him on that, but he is entitled to his opinion. The oddity as the photo shows he was talking about outcome switching which is what happened in this originally well-designed trial.

He went on to say that the reanalysis (Restoring Study 329: efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence) was nothing new. It only did what had largely been done before and confirmed what everyone actually already knew.

Expressing my concerns that Study 329 was still not retracted, he asked what I wanted to happen, that all papers that are re-analysed and found wanting, be retracted? Erm, yes!

My friend, the dishy therapist, then said that wasn’t the crucial point being that 329 harmed so many children? Ben said once people have informed consent, they can make their own choices – like this is a common practice. He pushed Ben on the now-common practice of problematizing distress, with Ben suggesting that people need to be careful not to push their own biases onto others.

It struck me as odd that BG seemed disturbed by the discussion turning to study 329 – yet he had specifically brought it up himself. I thought it even odder that he didn’t give the re-analysis by Le Noury et al any credit at all. I got the distinct impression that while his forte may be in data and stats, the enormous numbers harmed by these fraudulent trials were given little consideration.

How can anyone say that people can make an autonomous choice to take a drug, when the (usually ghost-written) studies are manipulated to give positive results, while hiding serious harms?

The mammoth undertaking by Le Noury et al deserves huge recognition for exposing just this – that truly informed consent is impossible unless the full facts are provided.

Editor’s Note: Ben Goldacre has taken exception to this characterization. He comments below. His tweets on the issue can be found BG tweets