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...]

Archive for Modern Myths

Crusoe, We Say, Was Rescued

This is the Sixteenth Modern Myth featuring Crusoe. The Persecution series resumes next week with Brand Fascism.

The clinics were different now to what they had been.

Hands on fire

The woman walked in, glancing at her hands as she came. Crusoe already knew what she would say. In days gone by peripheral neuropathies were rare. You saw one a year, perhaps in older people – more often women than men. The books talked of stocking and glove problems – the person with a burning or other odd sensation in their hands or feet. The books linked the problems to alcohol which was odd as it seemed to happen more in women than men.

Lost on the Sea of Medicine

But now it was becoming common and seemed to affect any age – often quite young women – who presented with burning feet. These weren’t peripheral neuropathies strictly speaking but if the person was referred to a neurologist that was the diagnosis they would end up with.

Nobody knew what was going on or how to treat it. People on triptans for migraine came in with strange sensations across their upper body. Those on antidepressants or benzodiazepines had burning feet.

Those on antibiotics like Cipro and Levaquin had the worst problem – especially it seemed to her, the men who had prostatism. If the treatment was stopped quickly, they might be left with no more than tingling sensations in their hands or feet. This wasn’t trivial – nothing that lasts for years is trivial. But if the treatment went on for longer, the problems could be anywhere round the body and were often much worse than tingling. Sometimes the person was left in constant disabling pain.

Worse again, if really badly affected, the neurologist might run tests on their nerves and the test reports would say working normally. She had seen lots of people told it was all in their mind and they were given a prescription for antidepressants.

Is he alright doctor?

The next woman brought her baby in. He was eighteen months old. He seemed slower than her first child had been she said. Was there anything she should be worried about? A quick check on the computer showed she had been on antidepressant during pregnancy.

Here was a dilemma. Crusoe was trained was to see variation in children as normal – in her generation there were boys who were tiny till late adolescence who later became the tallest people in the class, girls who at first seemed slow in school who later got first place in class exams. Some babies seemed to live on nothing while others were just voracious but they all ended up the same size.

So did she just advise the mother to do nothing that everything would be okay or did she tell her there was a possibility that the antidepressant might have caused a problem? She was seeing more and more of these children and still hadn’t worked out what the right thing to say was.

She’d heard a Ministry official on the evening news the previous day, asked about some drug and its problems, say that the Benefit-Risk ratio was still favourable. As long as a drug was still on the market, this is what they always said but what did it mean? It seemed to mean that it was more than the bureaucrat’s life was worth to start asking questions.

Where art thou Romeo?

What bothered her as much as anything was a new problem that was linked to the disappearance of old one – there were fewer Romeos and Juliettes. There used to be a string of broken hearted adolescents looking for antidepressants. She tried her best to keep them off medications – you’re eighteen and in love – how do you expect to be feeling?

There still were some Romeos, but there was an increasing number of teenagers who seemed to have no interest in romance.  At first she thought that it was one of those swings of the pendulum to Puritanism. Perhaps some new Just Say No campaign in schools was having an impact.

But when she fished, the kids knew what she was talking about but told her that she was a sexual and they weren’t. They just accepted it. Didn’t bother them. They’d never known any different.

What didn’t bother them bothered her. It bothered her that the same few drugs came up in their mother’s pregnancy records or in the kids records before they hit puberty.

Years ago she had met a a man who desperately wanted a limb removed. I’ll feel more like me without my right leg, doctor. This was in the early days of the Internet, and using Google before the word googling came into use, she found communities of “apotemnophiliacs”. Some people had probably always had feelings like this but others looked more vulnerable, uncertain of their own identities, and at risk of getting sucked in by a group like this. What would happen when they had a leg removed?

She could believe there might have always been some Asexuals around waiting for the Internet to shine a light on them. But lots of the kids she was now seeing had never accessed any Asexual websites. And there just seemed to be too many of them.

Drifting out to sea

More and more she felt that if she voiced her suspicions to any of her colleagues, or even her friends, she would start feeling like an island unconnected to their mainland. Might be time to find a real island.

The woman with burning hands, the mother with the autistic baby or the asexual son, were in the same place as her – no-one wanted to know them. Was there any way to unite all these people, each marooned on their own island, this new Archipelago of the Shipwrecked?

The shortest novel in the English language, complete with its post-modernist twist, came to mind.

“Crusoe, we say, was rescued”.

Rescued?

Illustration: The Sea of Medicine, © 2014 created by Billiam James

Castel Gandolfo

This is the Fifteenth Modern Myth, featuring Crusoe. The rest can be accessed under the modern myth tag. There will be another next week. The Pharma Sub-Series of the Persecution Murder Mystery will resume in the first week of the New Year.

A strange man

It was a time when Crusoe managed to be in Europe in Septembers. In 1957, interested in the fuss surrounding the new tranquilizers, she dropped in to a World Congress of Psychiatry Meeting being held that year in Zurich. There was an extraordinary buzz – the excitement surrounding the discovery of chlorpromazine was growing not fading. It really did seem like a cure for schizophrenia or the harbinger of a cure that would arrive any day now.

The meeting was full of chatter about the next wonder drug about to appear and what it all meant. As one of the delegates put it, this was the only thing in the world besides football that would get the French and the Germans into the same room.

Needing a break from the razzmatazz, she slipped into a side room that looked quieter. There was a presentation just starting from an unusual man – older than the rest. He looked awkward and eccentric.  Spindly, waving his arms around, insisting on his points she felt when no-one was arguing. There was an unprecedented number of delegates at the meeting – well over a thousand, but there was almost no-one in this room. She counted twelve aside from the speaker. Not even company people were there.

But if you could get past the combination of country accent and school-master style what he was saying was surprising. This pill, G22355, was different. Starting in January 1956, he had given it to agitated and psychotically depressed patients, the kind that nothing else except Shock Treatment touched. They mostly recovered in a week. The first was Paula JF – difficult not to wonder if JF meant Jewish Female. She recovered after six days. He didn’t have a name for his drug – it wasn’t a tranquilizer he said, it wasn’t a stimulant. He emphasized that it was for severe depression but then seemed almost to contradict himself by saying he had had a homosexual patient change orientation on it.

In the train station when she was leaving Zurich that evening, she spotted a number of the delegates she had seen at the meeting heading into the Banquet Room. She stopped one of them – almost a White Rabbit she thought – and asked what was up.  He winked conspiratorially and said they were on their way to found a new Church. One dedicated to psychopharmacology. It was going to come into being over a meal in the Banquet Room.

The Miracle of the Chemical Cure

A strange scene

Maybe it was the reception a year later on September 9th at the Pope’s summer residence in Castel Gandolfo that did it, Crusoe mused.

Once it had been agreed that the first meeting of the New College would be in Rome, one of those in the train station had used his influence to get Pius to address the delegates on the moral framework of the new field – and to bless them.

The Pope stressed that it was observance of the moral order that conferred value and dignity on human activities. Hardly profound. Difficult to take seriously, given his silence in the shadow of the death camps.  But even though psychopharmacology was a Jewish thing. and the single largest section of the group listening to him were Jews, no-one questioned him.

Pius pointed to the risks that drugs like the new tranquilizers could be over-used. No hint here that the driver to over-use might come from industry.

People couldn’t be trusted. They had to be led. It was clear Pius saw himself as speaking to the leaders in the new field.

He said nothing about the visions, the spirituality, linked to Sandoz’s most famous drug – LSD – that along with chlorpromazine had created the New World.

This just didn’t feel like a message for the times, she thought.

It was openly accepted that the new College had been created by Sandoz, who had convened the Supper in Zurich. One delegate even joked that Sandoz’s boss, Rothlin, the President of the College, was the head of a new religion – a Pope. Rothlin though was a businessman – well maybe that’s what Pope’s were. Not someone anyone thought was likely to have had LSD himself.

Sandoz and other companies bankrolled the meeting, paid for the delegates to be there, and put on the coaches that took them from Rome to Castel Gandolfo. On other days, there were trips to Mussolini’s villa where the tour guides worked their way through the dictator’s mistresses.

She spotted the strange man from Zurich at the reception but when she looked for him later on the program he was nowhere to be found. There were others talking about his drug and calling it an antidepressant.

A few weeks later the front pages featured the death of Pius. The editorial writers wondered where the Church might go from there. None mentioned the fact that his brush with the new church of psychopharmacology had been one of his last engagements.

Going viral

Fifty years later the talk was all about how to get things to go viral. Was it the Supper with a select few that was key, or was it delivering a message few understood to an audience of Twelve that did it, she wondered.

Illustration: The Miracle of the Chemical Cure, © 2014 created by Billiam James

The Snow Queen

Crusoe and Hans grew up together. Crusoe’s father encouraged her to believe she could do anything she put her mind to. Han’s father, Peter, was a story-teller who delighted both children with his stories, especially during the long evenings at the onset of Winter. He told them about the Microbe Hunters who discovered the causes of diseases and laid the basis for new cures.

But their favourite was the story of the Snow Queen. So scarily did Peter tell this that both children were certain that some Winter, the Snow Queen would sweep down and take one of them away leaving the other behind with a Mission to save whichever of them now had a sliver of ice in their heart.

Fairy tales

The Heart of Medicine

But fairy tales are just that after all. Both went to University, and became doctors.

Medicine had just passed through a glorious Summer that had led to the greatest harvesting of the benefits of new treatments ever recorded in human history. Life expectancies increased dramatically. Where once almost every family was blighted by the death of a child, now almost no family had a child who died. In some countries the treatments conferred such obvious benefits that governments made them available for free. A tyranny of fear had been lifted.

After qualifying their paths diverged. Crusoe immersed herself in the problems patients brought to her. For her every patient was different.

Evidence based medicine

Hans gravitated toward the most exciting new discipline – evidence based medicine. What could be better than ensuring doctors stuck to treatments that had been proven to work and stopped doing things for which there was no evidence. Patients’ stories might be interesting, but the evidence allowed you to pull back the veil of stories and glimpse reality. Patient improvement might be only a placebo response. They and their doctors might think they knew what was happening but be wrong.

Even when there seemed to be cast iron proof that a drug did something useful in a laboratory or at a bedside, Hans insisted on the need to test it out in hundreds of patients. He was adept at reeling off instances when laboratory breakthroughs have proven to be a mirage. Hard-hearted though it might seem to dying patients, he insisted on a proper demonstration that treatments worked.

The snow queen

Unlike some of his colleagues, Hans was not a fundamentalist. There was a passion behind his approach born of a recognition that Medicine was up against the wiliest of adversaries – the pharmaceutical industry – who thought nothing of the deaths of children in pursuit of profits unless those deaths compromised a profit line.

Industry was truly villainous, and in an effort to contain its capacity to injure people Hans was to the forefront of ensuring that the latest evidence was built into guidelines to which doctors would have to adhere. Frustrated at the slow rate of progress, he was of the view this could only be explained by the fact that some doctors even those who were involved in writing the guidelines were on the take. He became a crusader for Sunlight – bringing all and any payments to doctors from industry into the chilly light of day.

His career took off. He moved to Boston. He hadn’t seen or heard from Crusoe for years. There was an ocean between them. He became dimly aware that she had become critical of guidelines. She seemed to have drifted into a position close to homeopathy quoting obscurantist nineteenth century philosophy about there being an Art to medicine in knowing when to give a drug but an even greater Art in knowing when not to treat.

Medicine clearly had to be one thing or the other – an Art or a Science. The idea that modern medicine could be an art he thought belonged to an era that believed in fairy tales.

The clinic

Not having heard from Hans for over a decade, when she found a trip took her through Boston, Crusoe decided to surprise him. She found from his secretary that he had a clinic on Tuesday afternoons and joined the queue in the waiting room planning to walk in as his last patient.

She was early but had her iPad. The string of patients ahead of her after their appointments came back to the room to pick up waiting relatives, friends and belongings. She registered the low muttering of these returns. She could only catch snatches of the stories but there was no missing the disappointment.

“He told me there is no evidence that there is a dependence on these drugs – that my difficulties must just be the illness coming back”.

“He said I should stop worrying about the drugs. If I stopped the treatment and the illness came back that would be much more likely to cause harm to any baby we might have. If he had his way, pills would come stamped with an image of a pregnant mother precisely to stop people like me from misinterpreting what we find on the internet”.

“He told me that my hunch that my pills were causing me to drink were typical alcoholic denial and unless I got to grips with my alcoholism there was nothing he could do for me”.

“He told me that my idea that the medication he put me on to stop me smoking had caused me to have epilepsy was bizarre. Epilepsy is genetic not drug induced”.

“He told me that my conviction that the drugs had caused Shane to commit suicide was becoming close to delusional. I think we should leave before he detains me in a psychiatric unit”.

Crusoe walked in less jauntily than she had planned. Had she not known it was Hans she might not have recognized him. Flinty was the word that came to mind.

A drink?

For a moment he had no idea who she was. Once he recognized her, he greeted her teasingly:

“What’s this I hear about you having gone over to the Dark Side?”

“Come out for a drink and a meal and I’ll tell you all about it”, she said.

He had a series of committee meetings he said but he could skip one and give her an hour – it was so good to see her. She really should have told him she was coming.

To win some, you have to lose some

Quizzing him over a drink on how his patients responded to him, he told her that he suspected that time would show he was wrong in some cases but even on cases that once worried him he’d stopped feeling a long time ago. If the patients had been injured by treatment they would suffer less if he denied a link to treatment.

If someone who had been injured came to doubt the system and think that their injury could have been avoided, or that the system was going to acknowledge the injustice, it might lead to despair and who knows even suicide.

If patients on treatment or still to enter treatment came to doubt the system it would be too appalling a vista to contemplate.

Better leave it to people like him to negotiate with regulators and drug companies dispassionately. He was now in a position to do just this – a position he would never have been appointed to had he been too outspoken. And the companies were slowly coming round – they are registering their trials and making more data than ever before available.

Through the looking glass

There was even talk of nominating Andrew Witty for a special award – Nobel Prize might be a step too far for some people to take but even that artificial barrier would have to fall sometime.

 “You do know that you’re killing more people than you’re saving”, she said.

“Don’t be silly”, he responded.

“Well life expectancies are falling, and drug induced death might even the leading cause of death now. That’s not because of the chemicals – the chemicals have always been risky. It’s because the information that makes it possible to use a chemical as a medicine has never been so toxic.

“Sorry”, she said, “that I didn’t get to Peter’s funeral. He was so pleased when you brought him over here to Boston.

“He got the best possible treatment,” he said.

“Oh I’m sure, given the treating team knew who you are, that he was being treated perfectly according to every guideline for diabetes and hypertension. But you know if you wrote a guideline for treating a Peter the first thing you’d have to put in is to half the number of whatever medicines he is on.  I hear he was on twenty-one when he died”.

“So what do we do – do we go back to the day when some doctor arbitrarily decides what to keep in and what to leave out?”, he asked.

“Well  when it all comes down to dust, you believe in placebos. You call them RCTs but they are really placebos – mumbo-jumbo. You force people to believe in a system rather than to question it and make it better”.

“And”?

said Crusoe’s partner afterwards.

“The Snow Queen is far more formidable and wilier than I ever suspected”, she said. “Maybe I should have dropped some anti-freeze in his glass of wine”.

Illustration: The Heart of Medicine, © 2013 created by Billiam James

The Medicine Maker

Editorial Note: This is based on the Finnish National Epic, the Kalevala. The image comes from the series painted by Axel Gallen to illustrate the Kalevala.

Crusoe spent years trying to make a Medicine Maker. She was finally successful at the end of a long Winter just as the first signs of growth appeared on the trees. Everyone for miles around came when they heard the news. People with oozing tubercular abscesses were given isoniazid and cured. Children with bacterial endocarditis were brought in on their deathbeds and after taking penicillin got up off their beds and walked. Epileptics in mid-convulsion were given diazepam and settled down and then stabilized on carbamazepine. There was no end to the wonders.

Everyone remembered it as the most glorious summer in the area about Turku.

News of these wonders came to Lilly in her Lapland fastness. She sent out messengers to confirm if this really was true – that there was such a wondrous Machine. Yes it was true each of her messengers told her. She must have it, she decided.

She summoned a trusty troupe and on Midsummer’s Night when everyone was busy partying but there was plenty of light for the raiding party to see what they were doing, she broke into Crusoe’s laboratory and stole the Machine.

The following day everyone woke late from the Midsummer festivities and it took time for them to realize the Medicine Maker was gone. There was consternation. No-one had any idea where it had gone. Summer turned into Autumn with still no clue.

But finally word leaked out from Lapland that Lilly had the Machine but could not make it work. Still she wouldn’t give it back.

Crusoe formed a plan. To ease the difficulties of travelling in mid-Winter, they would travel by boat up the Gulf of Bothnia to Lapland. After that they would travel overland to Lilly’s fortress and see whether they could retrieve the Medicine Maker.

Arriving in late December, they found the guards asleep at the fortress gate. Everyone inside was asleep. They found the Medicine Maker and made off with it.

When Lilly awoke some days later and found the Medicine Maker gone, she flew into a frightening rage. Summoning her Myrmidons she set off in pursuit. By this time Crusoe and her band had reached their boat on the shores of the Gulf of Bothnia. Placing the Medicine Maker in the bottom of the vessel, they set sail for the South.

They were gone three days, with home in sight, when the midday sky in the North behind them darkened ominously. The cloud approached rapidly dissolving into a flight of the most enormous vultures each with a warrior on its back. It swooped down on the boat and a tussle began between the Pharmers turned sailors and the vultures with Lilly’s troops on their backs.

In the struggle the Medicine Maker fell overboard into the Gulf.

Axel Gallén - the Kalevala

Lilly retreated.

Crusoe and her band who lived near the shore where the accident had happened sent repeated expeditions attempting to retrieve the Medicine Maker from the depths but to no avail. However they kept up the hunt because invariably each of these efforts led someone to come across a new medicine that had just popped to the surface liberated from the Machine beneath. There was not the plenty of before but there was enough to be grateful for.

Medystopia

Editorial Note: Crusoe has not been lying low since The Shipwreck of the Singular and The Girl who Wasn’t Heard When She Cried Wolf. Check these out for previous Crusoe posts. The AbbVie story calls for a decent myth. Here is a start.

Sink all vaccines to the bottom of the sea?

Crusoe was listening to Oliver give out. “They called me yesterday evening”, he said, “to tell me about the vaccination clinic on Thursday. Did I know how bad shingles were for an older man like me? I could even go blind if it affected the nerve that led to my eye. Yes I told them I knew all this”.

“So are you going to come along to the Zostavax clinic?”  “No, I have a meeting”, I told them. “What time does your meeting start?”  “At nine o’clock”. “The clinic opens at 8 AM”. “Ah but I have to prepare things before the meeting”.

“What time does your meeting end at?” “At 5 PM”. “The clinic is open till 6.30, you can make it”. “Well possibly not. The meeting ends at 5 PM but it’s highly likely I will have to spend time in fringe activities afterwards”.

“What about the following week?” They weren’t giving up. What if I’d been taking Humira – taking a live vaccination might be dangerous – they didn’t ask.

It’s getting to a stage where I think it might be better for mankind if all vaccines were sunk to the bottom of the sea, but worse for the fishes.

Looking out to sea…

Crusoe was day-dreaming at this point. She was in the Florida Keys looking out to sea.

“Out there are the leper colonies”, the boy said. “Really”, she asked. “Yes”, he said. “And what are lepers?” she asked. “Lepers are people who can’t take vaccines”, he said. “They can’t be let mix with normal people like us because they can contaminate us. So they have to spend their lives on those islands”.

“Do you know the name of the islands”, she asked. “Yes”, he said. “One is Cuba and the other is Haiti. And I know the names of their capital cities”, he said. “I know the names of every capital city on earth”. “Do you?, she asked. “Yes”, he said. “Port-au-Prince is Haiti and Humira is Cuba”.

“I think you’ve got Cuba wrong. Don’t you mean Havana?”

“No”, he said.

Humirastan

Puzzled she asked the barman later that evening – “Have they renamed Havana?”

“Yes”, he said, “several years ago. Humira. At first it was a joke, but it stuck. Everyone who is taking a Biologic drug now has to go there because as I’m sure you know they can’t take certain vaccines.

“There was a real fuss ten years ago when the vaccination program got into full swing. A hysteria developed about people who remained unvaccinated – they posed a threat to all the rest of us.

“It began in schools when some parents refused to let their children have the Flu Jab. The other children shunned them and made it impossible for a child to remain unvaccinated.

“The authorities couldn’t deny it because this was just what they had been saying to people in the first place to get them to accept the vaccines – it’s a duty you owe to others.

“Any way there was a big concern about all those taking Biologics. You don’t hear much about Humira now but it was the blockbuster then. The best-selling drug ever. And then it was finally decided that everyone taking a Biologic who couldn’t be vaccinated because their immune systems were compromised would have to relocate to Cuba.

“In the wake of the uprising that got rid of the last of the Castros, the Cubans were very keen to swap properties on the very generous terms the Federal Government offered – and that’s where people on Biologics went. They renamed Havana as a joke but it seems to have stuck. Humirastan didn’t”.

HIVictory

“And Haiti? Who’s on Haiti”, she asked.

“Oh that’s where they put people with HIV. They can’t take vaccines either. The rest of us have all had our vaccine against HIV and they figure that it will be eliminated completely from the US mainland within a matter of months.

“People are taking bets on the President having a photo op on an Aircraft Carrier with a sign behind him – HIVictory – apparently it’s a tradition that stems from something called the Gulf War – you remember the War with Cuba back in the last Millenium”.

Marilyn’s Curse

Editorial Note: This an unexpected eighth part to the Lasagna Trilogy that started with Not So Bad Pharma and runs through to Witty A: Report to the President.

Ondine

Ondine was a nymph whose lover swore that his every waking breath was a testimony to his love of her. Finding him unfaithful, she cursed him – should he fall asleep he would stop breathing.

Marilyn died of an overdose of barbiturate sleeping pills (Tragedy). A bystander, Lou Lasagna, noted she had been denied access to a sleeping pill that was safe in overdose, the first pill of any sort that had been proven to work and be safe in an RCT before it was marketed. She was denied by doctors who put more weight on uncontrolled clinical observations than RCT data. As she died, she uttered a curse. Life went on. At first Lou noticed nothing but over the years his horror grew (Empire 1Empire 2).

Put-Me-To-Sleep Pills

Fishers

In the Spring of 1926, Ronald Aylmer Fisher, a lifelong smoker and denier of the idea that smoking might cause lung cancer, undertook some studies on the effects of fertilizers on seed growth in some fields outside Cambridge. Many factors could confound the results of a fertilizer study from differences in soil drainage, to the angle of the incident sunlight, exposure to wind and a myriad of soil elements that could only be guessed at. Fisher hit on a way to control both known and unknown confounders – he randomized the fertilizer to alternate seed and soil patches. And so the randomized controlled trial (RCT) was borne.

Fisher tied significance testing to RCTs. If we got the same result every time, we had designed a good experiment. There was a Quod Erat Demonstrandum quality to this – shave a bit off one side of a coin and you can expect heads to come up nineteen times out of twenty. He was looking for something close to a Euclidean Theorem – if you understand something the results will almost always be the same. But this insight on what Fisher meant by statistical significance, like most things about RCTs, has been inverted or perverted.

In 1947, Bradford Hill applied Fisher’s randomization to testing whether claims made for the efficacy of streptomycin for tuberculosis held up. He didn’t discover that streptomycin worked – others had done that in laboratories and clinics. But against a background of desperation and false claims, he showed that this time the claims could not be dismissed.

The RCT tide came in quickly after that and by the mid-1960s Hill noted that drug company salesmen ironically were encouraging doctors to use our products based on RCT evidence. While believing RCTs had a place in medicine, Hill noted that if RCTs ever became the only way to evaluate drugs that the pendulum would not just have swung too far it would have come off its hook.

Pharmers

RCTs have since been fetishized – made into a Golden Calf. Few can see any problems with bringing the rating scales and other measuring tools linked to them into clinical care – to make it more scientific. But just as with Midas, the touch of Gold brings death not benefit.

The pendulum has not just come off its hook, Pharma has picked it up and is battering people and governments over the head with it. We have recently had the close to degrading spectacle of the UK government in a parliamentary committee touting for Pharma “clinical trial business” and being told by GSK and Roche that UK clinical practices are just not Pharma friendly enough.

In this battering of people and governments, Pharma’s most useful allies are the proponents of Evidence Based Medicine, who insist clinical trials are if not the only way forward then by far the most useful way. RCTs, they indicate, would be just perfect if trial design was taken out of Pharma’s hands, if we had a registry of all trials done, and if we were let have a Witty-style peek at the data from time to time. It’s this fetishing of trials by independent academics that gives Pharma its grip over US and European governments.

Mediculture or medicine?

For 80 years we have unthinkingly celebrated Fisher’s apparent managing of confounders. Many trumpet the ability of RCTs to demonstrate cause and effect. Few accept that these trials are simply association studies with a particular method for controlling confounders. Few guess that there are more disturbing problems.

Let’s return to whatever image an agricultural field outside Cambridge conjures up in your mind. Using her FishCam, Crusoe watched Fisher weed his patches of Rye, exclude all stones, meticulously ensure each of the A patches was the same size as the B patches and got the same amount of seed. After days of preparation, he allocated the fertilizer randomly and headed home to his pipe. (For more on Crusoe see The Girl who was not Heard). She saw him check the patches weekly and then on the night of June 1, just as the first plants were sprouting, she saw a Sprite arrive and sprinkle Pixie Dust on Fisher’s handiwork.

Some weeks later when there was clearly much more Rye growing on the A than on the B patches, and the Rye on B was moldy, she saw Fisher race out to invest in Company A shares.

Using her Sprite tracking App, Crusoe locates where the imp dwells and while he is out one night creating mischief, she sneaks into his tree-house, finds the bag containing the Pixie Dust, steals some and brings it home to analyse. And for good measure she borrows a pretty pink envelope lying beside it.

The Dust contains a mixture of MM Rye and MM mold. She opens the envelope and finds a message: If you chant these words on scattering the supercharged Rye will all land on the A patches and the mold on B:

‘Norma-Jeanne thou art, Marilyn thou wilt be, and Queen of Camelot hereafter’.

Crusoe concludes that this can never happen in agriculture and there is no need to warn Fisher he’s at risk of losing his money. But she sees that this can and must happen in medicine, and that it won’t be spotted because medicine is a much more desperate business than agriculture. Human beings and diseases are not an inert field that you sprinkle fertilizer on. In medicine you give poisons that have effects on both a person and a disease that no randomization can control for.

She concludes that RCTs will be of limited use for testing medical treatments but she recognizes that the idea of a simple solution has irresistible appeal to desperate people and the invention of this idea makes investment in pharmaceutical companies worthwhile – because it hands companies the perfect way to market Snake Oil.

Standing back and surveying the clinical domain over seven decades she sees the value of RCTs as a marketing tool for pharmaceutical companies steadily grow until it far outweighs the value of trials to doctors testing treatments in clinical conditions. As this happens she notices one group of clinicians – those with least contact with the pharmaceutical industry – develop a delusional belief in the invincibility of RCTs.

These believers try to update GSK Chesterton’s (and Gandhi’s) message that it is not Christianity that has failed, it is Christians, substituting RCTs for Christianity. She sees the annual Christmas solemnities of a people celebrating their control of confounders, and giving thanks to EBM, completely oblivious to the confounding produced by the Clinical Sprite that cannot be overcome.

The clinical sprite

Imipramine, the first antidepressant, was discovered in 1957, the year Fisher left England for Adelaide. It was launched in 1958 – not an RCT in sight. A year later in 1959, three years before Fisher died of cancer, and a few miles away from his patches of ground, a meeting of psychiatrists was convened in Cambridge to discuss its effects.

At this meeting, some doctors, mainly Danes, noted on the basis of the Christmas Tree lightbulb test that wonderful though it was for many of their patients imipramine could trigger suicidal and homicidal ideation in some (See Time to Abandon Evidence Based Medicine at 38 minutes et seq).

When Christmas Trees had old style light bulbs, after a year laid up there was an annual drama as the lights failed to work. Unscrewing them sequentially would finally lead to one which when unscrewed lit them up. Screwing that bulb back in turned them off again. Jettisoning this bulb fixed the problem, even more conclusively than Fishers nineteen heads out of twenty.

So imipramine causes suicide. But it is also a far more potent antidepressant than Prozac, or any subsequent antidepressant. It got people with melancholia well where later drugs don’t. Melancholic patients are 80 times more likely to commit suicide than mildly depressed patients – according to studies drug companies cite.

Accordingly comparing imipramine and placebo in an RCT would likely show less suicides and suicidal acts on imipramine than placebo. The relative risk might be 0.5. Imipramine protects against suicide.

Had an RCT been done showing no risk on imipramine, we cannot know for sure what effect it might have had on the doctors in Cambridge, celebrating imipramine’s benefits but acutely aware of its hazards.

But some hints come from an RCT four years earlier, in 1955, which found reserpine worked well for depression and caused no suicidality. The immediately preceding articles in the Lancet were Christmas Tree light bulb reports of it causing suicide from Geelong and Dunedin. Where? The field didn’t need an RCT to know that reserpine could be useful. In the face of an RCT from the most distinguished Institute in the world showing no problems, doctors still had no difficulty believing reserpine could cause suicide on the basis of light bulb reports from goodness only knew where. If asked what they made of these new-fangled RCTs, most clinicians would almost certainly have said “interesting but hardly clinically relevant”.

It took a political impasse about drug regulation in 1962 and the need to find something simple enough for bureaucrats to work with to produce the primacy that RCTs have now. Something signed into law by Marilyn’s lover, nine weeks after her death and ten weeks after Fisher’s, that put the lights out on the Christmas tree.

The sprite’s RCT

The findings of our imipramine thought experiment are represented in figure 1. These are the findings even though the drug causes suicide.

Imipramine in melancholia suicidal acts

Figure 2 shows the findings for suicides and suicidal acts in SSRI trials.

SSRIs in mild-mod depression suicidal acts

In these trials we get a relative risk that the drugs will cause suicide and suicidal acts of 2.0. This happens because SSRIs are much weaker than imipramine and so were tested in people who were mildly depressed at little or no risk of suicide. When the findings got to be statistically significant, the regulators seemingly felt obliged to agree that the SSRIs caused suicide and came out with a warning to that effect.

The regulators were wrong. The data in this SSRI population show the drugs produce an excess of suicides over lives saved. They say nothing about causality except in so far as there could not be an excess of suicides if the drugs didn’t cause suicide. In the case of the SSRIs and suicide, the evidence comes from Teicher’s 1990 Christmas Tree light bulb paper on Prozac and suicide – and earlier cases.

The first point to make is this is not confounding by indication.

The second is that despite mantras to the contrary, RCTs do not and cannot show cause and effect.

The third is that they do not even give useful data on frequency. We in principle cannot have any idea from RCT figures how often antidepressants trigger suicidality.

But here’s the real deal. This finding is not an inconvenience that stems from some oddity to do with antidepressants or suicide or drug companies. It is intrinsic to RCTs within medicine. It can be expected every time a treatment and an illness produce at least superficially similar outcomes – whether a benefit or a harm.

It happens to cardiac rhythm problems in trials of anti-arrhythmics given for cardiac arrhythmias, and to breathing difficulties in trials of anti-asthmatics given for asthma. It happens with vaccines. It happens to the benefits of treatments just as much as their harms.

It holds as true for completely independent RCTs with hard outcome measures, no surrogate outcomes, complete data access, and intention-to-treat analyses, in long duration or short duration studies, as it does for industry studies.

It means that notions of Numbers Needed to Treat (NNTs) or to Harm (NNH) or even treatment effect sizes are for the most part little more than empty statistical artefacts, except in so far as they apply to dead bodies.

Patients can in fact distinguish between depression induced and drug induced suicidality or between antidepressant induced and spontaneous recovery from depression – if we ask them. Patients can tell you if a drug is ‘working’ even if its not ‘working’ – as when they say this SSRI is producing a useful emotional numbing even though it’s not making much difference overall. It is only if you listen to the patient that you can know whether to add another Therapeutic Principle into the mix or whether you should stop the drug they are on and try another.

Having your ears stopped to what the patient says, with the poison of “this is anecdotal data”, is a way to turn your patients into ghosts who must wander abroad seeking someone to come to their aid.

Cardiologists can also distinguish between drug and illness induced arrhythmias.

But if we believe a patient’s answers or a cardiologist’s clinical experience, RCTs immediately shape shift from gold standard evaluation to gold-plated but often misleading association studies.

So, who does not asking patients suit most?

The only trials that the Clinical Sprite cannot confound are Drug Trials. These trials of a drug done in healthy volunteers reveal unconfounded drugs effects. But there is no register of these trials, and no access to their data even though there are no issues of clinical confidentiality involved.

The clinical pixie

The Clinical Sprite has a sister – the Clinical Pixie.

In the late 1980s, Eli Lilly undertook a trial of Prozac in a group of patients with recurrent brief depressive disorder (RBDD). In this trial placebo was sweepingly statistically superior to Prozac. The study was published four years later shorn of all key data.

In the early 1990s, SmithKline Beecham (GSK 2B) undertook study 106 of Paxil – Prozac’s sister SSRI in the same hospital centre, in the same RBDD patients, possibly with some of the same patients who had been in the Prozac trial. This second study terminated early. The results were never published. The rate of suicidal acts on Paxil (Paroxetine) was three-fold higher than on placebo.

Nevertheless a few years later GSK 2B undertook study 057 in a similar group of patients. Several different sets of results from this trial circulate, none of which support using Paxil in this group of patients.

In April 2006, GlaxoSmithKline (GSK Not 2B) issued a press release with the following figures for suicidal acts in the Paroxetine trials in Major Depressive Disorder.

Suicidal Acts in MDD Trials

 ParoxetinePlaceboRelative Risk
Suicidal Acts/
MDD Patients
11/
2943
0/
1671
Inf (1.3, inf)

The MDD patients show a significant increase in the suicidal act risk on Paroxetine. But even though the results of studies 106 and 057 were so bad, GSK Not 2B gleefully added them in to the mix – and when they did so Hey Presto the risk from Paxil vanished. It can even be made protective against suicidal acts (See Table 2).

Suicidal Acts in MDD & RBDD Trials

 ParoxetinePlaceboRelative Risk
Suicidal Acts/
MDD Patients
11/
2943
0/
1671
Inf (1.3, Inf)
Suicidal Acts/
RBDD Patients
32/
147
35/
151
0.9
Suicidal Acts/
MDD & RBDD Patients
43/
3090
35/
1822
0.7

We can dump lots more suicidal acts into the RBDD trials and still get the same magical outcome – see Table 3.

Suicidal Acts in MDD & RBDD Trials w Sprite

 ParoxetinePlaceboRelative Risk
Suicidal Acts/
MDD Patients
11/
2943
0/
1671
Inf (1.3, Inf)
Suicidal Acts/
RBDD Patients
48/
147
35/
151
1.4
Suicidal Acts/
MDD & RBDD Patients
59/
3090
35/
1822
0.99

This paradoxical outcome is not a funny quirk of antidepressants and suicide. It is totally predictable and obvious. I could have advised GSK-2B or Not 2B to do studies 106 and 057 to get this outcome. Knowing what a drug can do, you can often design studies that use a problem the drug causes to hide that very same problem.

Now the pillars of the EBM establishment, so used to dealing with the scurvy knaves from Pharma, look at this and say it is just bad meta-analytic technique – you shouldn’t mix studies like this. And you shouldn’t. There is a horrific scandal here – FDA, MHRA, and the luminaries of EBM have let GSK Not 2B get away with this without a peep of protest.

But there is a deeper problem. We can see what is going on here. But exactly the same thing can happen by accident in clinical trials done in every illness we don’t fully understand – from pain to Parkinson’s Disease.

RBDD patients can meet criteria for MDD easily. Provided there is more than one of them entered into MDD trials randomization will ensure these Pixie patients will hide some benefit or harm.

Unlike fertilizers, drugs have a hundred or more effects. When we Design an Experiment employing randomization to manage the unknown unknowns for one of these effects, we risk generating an ignorance about ignorance regarding most of what the drug in fact does, and sometimes even for the effect we are focused on. This is true for statins, antibiotics and all drugs – not just antidepressants.

Pharmagnosia

Generating ignorance about ignorance is a serious clinical problem – for which pharmagnosia seems a good term. If a good medicine is a chemical that comes with good information, then RCTs through pharmagnosia are leading to a systematic degradation of our medical arsenal.

All RCTs do harm. Some do good as well. Pharmagnosia is worth risking when there are grounds to think a claimed benefit does not hold water and if wrong vulnerable patients are likely to be harmed. If the drug doesn’t work, we don’t CReate Ignorance in MEdicine (CRIME).

The only way to get the result Fisher would have insisted on for the main effect of a drug rather than a fertilizer, that is the same outcome every time, is to understand the clinical condition you are treating and the agent you are using so that you produce a Quod Erat Demonstrandum – this treatment works every time or no it doesn’t work.

But if we understand the clinical population this well, RCTs come close to being irrelevant to moving decent medicine forward. Their main value lies in dealing with the claims of hucksters and charlatans.

The Clinical Pixie looks like Tinker-belle but she is a not a benign fairy. There are far more MDD patients that RBDD patients in this world. If you spot what she has done in this case, you can see that the results show the drug harms more people than not.

But if you don’t spot what she has done, she will beguile you if you are a public health official or regulator into supporting a treatment in front of the press saying it has a favorable risk benefit ratio by which you mean produces more benefit than harms on a population basis. You will do this although in fact the treatment is cripplingly bad for far more patients than it benefits.

At a rough guess, 90% of these pronouncements by regulators are wrong and 99% or more are lacking in appropriate supportive evidence.

One of the most egregious examples of this came recently in a Cochrane review of Statins that focusing exclusively on their lipid lowering effects, neglecting their effects on muscle, endocrine and cognitive function, concluded that the evidence supports their use (Cochrane Library 2013, Issue 1). Only time will tell which of the current blockbuster drugs will in the longer run take the title for the drug group that has caused the most damage but the statins are worth betting on.

In Elsinore

Within the walls of the Elsinore, the citizens of EBM remain at ease. As far as they can see the only Sprites that might confound clinical trial results are those scurvy knaves who work in the pharmaceutical industry. The citizens still believe that the suicide risks of antidepressants were discovered in clinical trials done in children, not knowing that trials were actively and likely deliberately used to hide an obvious link for fifteen years.

Within the Citadel, Claudius has decreed that anyone who seems to question the primacy of trials should never be engaged in public, can be attacked in ad hominem fashion, or failing all else should be consigned to the Antidepressants & Suicide Chamber, on the door of which there is a notice Here be Sprites.

Lethe, the river of forgetfulness runs through EBM. What need is there for History. Things could not have been better in the past. Fisher’s texts are revered as they lie sealed in a glass cabinet. No-one can find out that he was looking for a Christmas Tree light bulb equivalent. They don’t even know he was dealing with agriculture not medicine.

In the Real World, outside the Castle, the one foot on the ground world, RCTs can be seen to function in medicine primarily as a rhetorical device giving the impression that if a drug has passed through them, a patient will get the same beneficial outcome time after time, even when in fact in 80% of the trials the drug has performed worse than placebo.

Cut to the battlements of Elsinore, where a man stands paralyzed with fear by the approach of what his fevered imagination sees as a ghost. The ghost of a beautiful woman. Frozen with fear, he murmurs:

Let us go in together
And still your fingers on your lips, I pray
The time is out of joint, Oh Cursed Sprite
That ever I was born to set it right.

Inside, Crusoe takes off her white cloak.

“Dr Gotzsche I presume.

I’m thrilled you mistook me for Marilyn but her ghost walks elsewhere. It was the children crippled by thalidomide that led her to suicide. Another MM, Morton Mintz, broke the story in the US just three weeks before she overdosed. No, I’m here because Denmark is close to the worst place in the world for patients. Their ghosts seek rest. More SSRIs have come from here than anywhere else. We need to hoist the malignant Sprite responsible for this with his own petard.

Your trip to England with Rosendorous and Guildenacre, two good people, to demand access to clinical trial data could go badly wrong. More than anyone else, through your work on breast screening you have shown that good intentions do not prevent disasters. But if your wonderful efforts to get access to RCT data makes it seem that RCT’s are important rather than that the withholding of even cruddy data is a scandal, you just could make things much worse”.

Illustration: Put-Me-to-Sleep Pills, © 2013 created by Billiam James

The Girl Who Was Not Heard When She Cried Wolf

Crusoe was called to see Lisbeth. The girl – young woman was mute and catatonic by day but after she fell asleep she had nightmares when she wailed piteously, rent her nightdress, walked in her sleep muttering ‘the children, the children’ or other such phrases. It was a similar pattern each night, the parents said. The dreams seemed to repeat.

Crusoe came in the evening when the room was dark except for a scented candle flickering in the corner. Lisbeth lay on her bed, one arm stretched out over the side. Crusoe pulled up a chair beside her. The parents hovered anxiously in the background.

The doctor's nightmare (from Fildes)

To sleep perchance to dream

After she had been there for nearly an hour, the girl began to stir. She sat up and screamed, clutching her shoulders, looking at the place where her arms should be. Then her face grimaced and neck bent as though she had a severe pain in her chest. She jumped as if she had been cracked with a whip and felt for her Achilles’ tendons on either side.

She got up and walked to the bathroom. She bent down and stared at the rug for what seemed like an age. She came back and picking up a limp cloth doll from a bookshelf on the way placed it on her bed, knelt down beside the bed and began apparently sawing at where the doll’s breastbone might have been, after which she made to pull open the chest cavity as if to work on the heart inside.

Inception

When she finished this, Crusoe intervened, helped her back into bed, and moved closer. The girl was having waking dreams. Crusoe must some how have slipped into this one. Suddenly Lisbeth began talking: Dr. Crusoe, Dr. Crusoe it’s terrible, terrible. I see children born without arms or legs. I try to tell someone what is happening but no-one listens.

I went to a door marked FDA and someone looked out but couldn’t see me.

I thought it might be better in England and went to one marked MHRA. This had names on the door – Sir this and Sir that.  I thought Knights of the Round Table, ah good! But, they said, you think this drug has caused children to be born with shortened arms or legs, how do you know that the drug didn’t just prevent spontaneous miscarriages so that these children who would never have been born are now born?

I told them I thought the pain in my chest must be linked to the Plavix I was taking– it came every time I tried to stop it.  They said, they couldn’t be certain that I wasn’t aspirin resistant. When my tendons snapped, the pain was excruciating – I was certain it was the Cipro I was on but they stared at me blankly – don’t be silly an antibiotic couldn’t do that.

I told them I had seen Matt Miller, in his bright orange football gear, 13 years old. I can see him now – over there. I saw him put on Zoloft by his doctor when he was anxious in a new school. I followed him a week later when he went into the bathroom between his bedroom and his parents’ room and hung himself there. Are you sure they smirked that this wasn’t auto-erotic asphyxiation? You know what little boys are like! Perhaps he accidentally went too far. I watched a person from Pfizer check the carpet for seminal stains, she said, looking at Crusoe. I went and looked, but there were none there.

There are too many babies needing heart repairs, I can’t keep up, she said, and who is going to help all those children queuing up outside who have autism and learning disabilities.

When I was in America I picked up the phone and tried calling GSK, using the phone numbers on their adverts. Many of the numbers didn’t work. On others I got put through to a call centre, not a doctor. They told me not to tell them anything but to send my report to the FDA instead. This sounded good but when it got there, I saw FDA filed some reports and binned others.

There used to be a picture of the Pied Piper in my Grimm’s book of fairy tales years ago taking the children away. I can’t see him now but I can hear the tune that is leading women to take antidepressants just before they get pregnant. It goes round and round in my head. Can’t anyone stop it?

Can anyone hear me?

Can’t they see that when things go wrong, the AMA, and RCP, and ICP will line up to tell you it was your illness that caused the problem?

I see an endless line of mothers knock on doors. I see them in England where they get sent from the DoH to the GMC to the RCP, to MHRA to NICE. The Department of Health say it’s the General Medical Council’s job, who say it’s the Royal Colleges job, who say it’s the regulator who say it’s the people who make the guidelines, who say it’s the Department of Health. You’d have thought the Royals might have done something.

I see them in America where they get sent from the HHS, to the FDA to the IOM, to the AMA but the same message everywhere – “not us, lady”.

FBI, CIA, IRA, EMA, MI6, KGB – can anyone hear me?

Who dares wins

Lisbeth dreamt Crusoe held her and whispered: “When you wake, you and I will go to England to see the SAS. They don’t have them in America, but if they did I suppose they’d be called SEALs”.

SAS – Short –Arm-Squad
SEALs – thalidomide caused phocomelia – seal-like limbs

FDA – Food and Drugs Administration
MHRA – Medical and Healthcare Products Regulatory Agency
NICE – National Institute for Healthcare and Clinical Excellence
AMA – American Medical Association
RCP – Royal College of Physicians
ICP – Irish College of Psychiatrists
HHS – Health and Human Services
IOM – Institute of Medicine
EMA – European Medicines’ Agency
IRA – Irish Republican Army

SAS to Lisbeth

From [email protected]

I dreamt I saw Joe Hill last night,
Alive as you or me
Says I, “But Joe, you’re ten years dead,”
“I never died”, says he
“I never died”, says he

“In Salt Lake City”, Joe, says I
Him standing by my bed,
“They claimed you died from your disease
Says Joe, “I didn’t die”
Says Joe, “I didn’t die”

“The pharma bosses killed you, Joe
They pumped you full of drugs”,
“Takes more than drugs to kill a man”
Says Joe, “And I ain’t dead
Says Joe, “And I ain’t dead

And standing there as big as life
And smiling with his eyes
Joe says, “What they forgot to kill
Went on to organize
Went on to organize”

Illustration: The Doctor’s Nightmare (from Fildes), © 2012 Billiam James

The Shipwreck of the Singular

Crusoe’s first appearance was in The Creation of Psychopharmacology, where in recognition of the tensions inherent in medicine between the numerous who enter clinical trials and the single person being treated by a doctor, the book opened with a quote from George Oppen’s Of Being Numerous, in which he notes that: “Crusoe we say was rescued”.

Since Oppen wrote these lines, the idea of the perfect ultra-short story has caught the imagination of many. Competitions have been run in an attempt to equal or surpass Hemingway’s 6 words: “For sale: baby shoes, never worn.”

“Crusoe we say was saved” is only 5 words and is not just a story but one with a perfect post-modern twist.

Crusoe deals in ambiguity – how apparent progress can give rise to new problems or even new evils. You will hate her if you are the kind of person who thinks good intentions the most important thing there is. She lives in a world in which as Gandhi put it: “He who would do a great evil must first of all persuade himself he is doing a great good”.

Sometimes its better to be less certain. And here a mythic image can unite us in the way that holding hands in the dark can. To check out who you’re holding hands with, Crusoe appears in Watch where you wave that wandThe Oedipus EffectThe Tree must go and The Data Access Wars, but her spirit is also present in Randomized God, If Pharma made carsMay Fools’ Day and One Script to rule them all. She will appear again in a companion piece on January 1st – The girl who wasn’t heard when she cried wolf.

Shipwrecked by the cure

The pharmageddon three

Pharmageddon is about how three obviously good things we did to manage the pharmaceutical industry (for its own good of course) have given rise to the increasing threat that modern medicine poses to our safety and sanity.

1. Making clinical trials mandatory for regulatory purposes. This was supposed to keep us safe in heavenly health by forcing the financial camel that is the pharmaceutical industry to squeeze through the eye of a scientific needle. But harnessing trials for this purpose has transformed their role from one of puncturing therapeutic bubbles into one of providing the fuel for therapeutic bandwagons, and has degraded them from scientific experiments to a mechanical exercise adapted to the convenience of bureaucrats.

2. Prescription-only status for new drugs. This regulation aimed at bringing hazards to light and protecting vulnerable patients but is now a means whereby the major hazards of new drugs take 10-15 years to come to light and it is only after campaigns by injured patients that doctors ever concede there might be a problem. Doctors have become a risk-laundering system. Thalidomide might still be on the market if it had been prescription only.

3. Rewarding companies with product rather than process patents for drugs. We have, possibly accidentally, over-rewarded pharma. Or product patents may have been a deliberate move by the United States to capture the European pharmaceutical industry. At a time when medicine has been captured by pharma, and doctors have been hypnotized to focus on clinical processes rather than clinical outcomes, patents might ironically be the one place in medicine where the process should be the outcome.

Crusoe’s other conundrums

1. Eurordis. It sounds like a wonderful idea to form an organization for patients with rare diseases who would lobby Pharma to do something they didn’t want to do namely to focus on rare conditions for which the market returns might have seemed slim. But Eurordis and other rare disease organizations have now become one of Pharma’s most treasured conduits. These groups can be depended on to take Pharma’s side even though very little money changes hands – See Data Access Wars and Access to clinical trial data.

2. Ownership of clinical trial data. It might seem like a good idea to have patients own their own data but ownership in this sense is a Trojan Horse. If you own something you can sell it and this will kill science. Imagine someone coming along to a scientific experiment who was only willing to let their piece of apparatus be used to find out what the universe is made of if an appropriate fee is paid beforehand.

It is not clear who owns clinical trial data. If pharmaceutical companies do not own it, the only proper course of action is, companies will say, to make the patient the owner. This sounds almost benevolent except it will transform patients into livestock at an auction.

3. Eliminating chance through statistical significance testing – reliable analyses is what the pharmaceutical industry call this – sounds like a good idea. But rather than producing reliable knowledge, claiming we only know something when the findings are statistically significant in fact induces a psychosis, causing both doctors and patients to discount the evidence of their own eyes. A reverse Macbeth problem – “I see no weight gain or muscle wasting or heart attack before me”.

4. Quality improvement. We should monitor what doctors do – everyone can improve their performance. Having someone stand there with a tickbox to monitor what is happening in clinical care sounds like a good way to produce steady improvement. In fact in close to 100% of cases the process becomes the outcome. And as the quality of the process improves the quality of the outcomes deteriorates.

There is no better way than this to transform doctors into factory doctors. Set a target they should meet – screening 80% of patients who have asthma and pretty soon the relationship of doctor to patient will be changed from one in which you consult your doctor when you have a problem to one in which your doctor will summon you to be screened and tell you you have a problem even though you might feel perfectly well.

5. Outcome data. Doctors should monitor what in fact happens when they do things. Mortality should be low and there should be little variation between centres. But if the treatment is one that shouldn’t be done, as in the case of hysterectomies or giving statins for primary prevention of cardiovascular disorders you can have perfect mortality statistics and almost no variation across centres but a disastrous outcome.

The best example of this are recent approaches to mandatory vaccination for influenza and other disorders in which rather than count outcomes such as the number of living and dead in those vaccinated or not, quality services are determined by compliance with policy. If everyone is vaccinated the outcome is deemed good, whether or not there are more dead bodies.

6. Reporting adverse events to regulators. Companies increasingly encourage people and doctors to report adverse events to FDA. This sounds marvelous and something like turkeys voting for Xmas. But in fact companies advocate this deliberately because they have a legal obligation to follow up reports to see what happens to patients whereas FDA don’t. This demonstration of corporate responsibility is in other words a way to transform drug induced injuries into anecdotes with no legal or policy implications. Unbelievable though it sounds this is the most devious and best way ever devised to hide the data – as the American Woman story demonstrates.

7. Drawing up standards of care – guidelines – will help shield us from rogue doctors. In fact guidelines – especially the most independent guidelines – have become the greatest marketing tool for the pharmaceutical industry who have learnt how selective publication and creating new disease indications can capture a guideline completely. Guidelines then become a threat to the future employment of doctors practicing a medical care that is at odds with what pharmaceutical companies wish. In the United States at present, certainly within the mental health field, they have produced an extraordinary fear and paranoia with doctors unable to contemplate reducing medication in either number of different medications or dose.

There are two ways in which guidelines might work. One is a set of guidelines that outline treatments that should not be given. The other is a set of guidelines that outline where data is missing – that outline what we do not know rather than outline what it is pretended we do know. The Data Based Medicine Guidelines on dopamine agonists, antidepressants and mood stabilizers attempt to do this.

8. In clinical trials, we should protect patient privacy and confidentiality. This sounds wonderful until placed in informed consent forms where it means, pharmaceutical companies will hide your data for ever.

9. Medical staff should undertake ongoing educational assessment to remain up to date, and should demonstrate this openly to the public. The intention here is that doctors should have a real and continuing engagement with science. But this is not measurable. The outcome will be a series of boxes to be ticked that get in the way of doctors asking real questions. Because industry do box ticking better than anyone else, this is guaranteed to hand healthcare professionals over to the marketing departments of pharmaceutical companies or their surrogates.

10. Doctors should stick to what FDA approve and should not prescribe off-label. If my roofer put an unapproved material on my roof I would be furious. But the so called approval process for drugs is about approving the wording of advertisements – it is not about setting standards for treatments that work nor is it about regulating the practice of medicine. The most effective treatments in medicine are off-label. SSRIs are much more effective for premature ejaculation than for depression.

Forcing doctors to prescribe on-label would hand over medicine to the pharmaceutical industry. As it is doctors are increasingly scared to prescribe off-label – as they come more and more under the control of Sauron’s Eye. As Tom Laughren might have said but didn’t quite, doctors need to Man Up.

11. Everything would be okay if doctors just declared their conflicts of interest. The trouble here is we want doctors to be biased toward treatments that work and the best possible evidence. Someone with no conflicts of interest might be nice to go and talk to but if I need something done this kind of person is not going to be much use to me. The problem with doctors and conflicts is that they have lost sight of the fact that they can’t prescribe the best rather than the latest and the fashionable if they don’t have access to the data, and if they can’t stand up to pharmaceutical companies they have no brand value. They are like salt that has lost its bite. (Model doctors, Scaremongers of the world unite, So long and thanks for all the fish).

12. The Mencken paradox. Most of these perversions arise from efforts to find solutions to problems – which suggests that the insoluble problem is our need to have solutions. Solutions end up being problems.

To adapt HL Mencken; “Every complex problem has many simple solutions – all of them wrong”.

Chuang Tzu

Or as Chuang Tzu put it in 323 BC;

“For security against robbers who snatch purses, rifle luggage, and crack safes, one must fasten all property with ropes, lock it up with locks, bolt it with bolts. This is elementary good sense. But when a strong thief comes along he picks up the whole lot, puts it on his back, and goes on his way with only one fear; that ropes, locks and bolts may give way.”

On Fridays

The unsolvable problem medicine faces is that each of us is shipwrecked in the singular. When on a Friday running from a threat to our life we seek refuge in Crusoe’s clinic, we have to hope that a basic humanity asserts itself. We have to hope that Crusoe has not been trussed in guidelines, and quality improvement programs, and that she is not being slowly cooked in a management pot. We have to hope that she is not part of a system in which cruelty has been normalized – as Ann Clwyd put it so devastatingly a few weeks ago.

We have to hope that Crusoe has not been saved. If snatched away, those of us who turn up on Friday will have to mount the mission to rescue her.

Illustration: Shipwrecked by the Cure, © 2012 Billiam James

The Data Access Wars

This is the first of three Crusoe posts. For background on Crusoe, see Watch where you wave that wandThe Oedipus EffectThe Tree must go.

What does your doctor know about your medicines?

Beta Centauri was unquestionably a long way from Massachusetts. Somewhat to her surprise Crusoe found breathing no problem, and the temperature seemed just about right. The scenery as they’d come in was not unlike that of a temperate zone on earth.

Walking around, she had begun to wonder if there were clinics there when she spotted the entrance to what was unquestionably a medical facility. Going in, she found a procedure in progress. It seemed sophisticated – no anaesthesia. Wounds from battle or other encounters seemed to heal under the touch of a vibrating instrument passed slowly over them. In other cases apparently normal limbs turned out to be quite artificial, and repairing them was entirely bloodless. This was a new frontier.

But it was another building that ultimately drew her attention. Where only those in obvious need of care for something like a severed limb went to what she would have called a clinic, everyone came to this other building at some point. Here the staff administered a supply of some substance. The same for everyone. Crusoe took some. She noticed no effect.

What was it? She didn’t want to ask as who knew what would happen if the Centaurians realized she didn’t need what it seemed they did. It was only in one of the taverns in town, after a few drinks, that she was able without raising suspicions to get someone to tell her what went on in the building.

Some decades earlier, faced they were told with a looming pandemic, the entire population of the Economy was vaccinated. This was done compulsorily. The Corporation was the only body who held supplies of the right vaccine. While treatment may have saved them from something, there was a side effect.

This was not spotted at first – at least this was how Centaurian history recorded it. The vaccine knocked out a gene and all children borne after that were short of a protein – alpha-nucleositol, without which life was impossible. Fortunately very few children died, as when the problem declared itself in the first few children, the Corporation rushed out supplies of alpha-nucleositol and supplied it to everyone. Provided they took it, everything was okay. It came free of charge but with a requirement for annual screening.

No-one knew quite what was being screened for. But there were rumors. Some said that if the screening revealed that the subject held aberrant views on the Economy or the merits of the Corporation, the person’s supply of alpha-nucleositol was terminated. Everyone, including bioethicists and others with no links to the Economy or the Corporation, justified this on the basis that the Economy couldn’t be expected to support the continued existence of those who disagreed with its principles.

Every so often small groups it was rumored escaped with a supply of alpha-nucleositol, and headed it was said for some planet on the outer limits of galaxy, where it was rumored that someone had synthesized a gene for alpha-nucleositol.

What Crusoe needed she realized was information on where they were going and someone she could trust to get her there. Where’s Harrison Ford when you need him?

Eurordis

This take on Star Wars is not as remote as it seems. It’s happening on the planet right here beneath our feet.

Quite innocently some decades ago a network was set up by Silvio Garattini among others to investigate rare diseases. This later gave rise to Eurordis, an organization to speak on behalf of patients with rare diseases.

An organization of patients and by patients and for patients sounds like a wonderful thing but far from being a sanetocracy it has turned out to be an insanetocracy.

As it happens as of 2011 Eurordis took funds from 38 different pharmaceutical companies. These only amounted however to 22% of their income. Financial conflicts are not really the issue – they could survive without the money. It’s something else that keeps them tied to the Corporation. This is the patient group for whom pharmaceutical solutions are a lifeline. They are more committed to the interests of the pharmaceutical industry than are any of the employees of any of the pharmaceutical companies.

They can be absolutely depended upon to read the runes right and come out with a strong industry position, making it possible for industry representatives to sound relatively accommodating to others in contrast – as they did at the European Medicines’ Agency meeting on access to clinical trial data in November.

Eurordis don’t want anyone to know about any planet where you might get your gene transplant and they want us to ban anyone who is not a certified pilot or who might be flying some battered old jalopy. Han Solo and Indiana Jones not welcome.

Illustration: Data Wars, 2012 © Billiam James

The Tree Must Go

tree in the countryside

Crusoe had a chance to view the new facility – the brainchild of one of the world’s wealthiest men, who had made his name in a race to sequence the genetic code. He had famously used his own DNA in the process. He later went on to create synthetic life and it was from synthetic biology He made his fortune.

The inspiration to recreate Eden came from watching an old movie, The Truman Show, in which Truman Burbank, played by JC, is cocooned in a world in which everyone else is an extra in his life and everything is stage-managed.

Why not do it properly with real people? They could be designed free of genetic disorders. Their main use for drugs would then be for psychedelic or hallucinogen purposes where every dose produces a different outcome in contrast to the numbing uniformity of twenty-first century drugs.

A range of projects in a number of different countries had shown how to create self-contained environments. Curiosity’s trip to Mars in 2012 had confirmed the presence of extensive subterranean water, making all else possible. The new facility was set up. Unlike the Truman Show, its occupants were unlikely to come into contact with outsiders for several centuries, perhaps millennia.

Synthetic biology had made it possible to design species to fit the new ecosystem. No-one of course could know beforehand what in fact would happen when these species began to interact. In other words, the place would almost instantly begin to have a history, and slip out of control. Whether He realized this or not was less clear. Maybe He had a fantasy about being able to intervene.

The most important moment was designing the woman to take control of the Garden. The man came from stem cells retrieved from the marrow in one of her ribs.The first couple were just about to be woken up in the Garden, when Crusoe arrived. She was in time to see the final check that everything was in order. One last round for Health and Safety. It was then they noticed the tree, growing on a slope. A firstborn son out climbing who slipped could have a dangerous drop on the downhill side. The tree must go they said.

The New World had a history. Ultra-short story writing became its dominant art form. The form developed when someone dreamt one night of the following: “For sale, baby shoes, never worn“. The shortest was “Crusoe, we say, was saved”.