Making medicines safer for all of us

When it comes to branded and generic drugs, the listing of key issues in this image misses a trick. The labels are identical.

This lack of difference is a consequence of the 1984 Hatch-Waxman Act which after two decades of dispute staked out a boundary between generic and branded pharmaceutical companies, part of which in the case of their drugs required the generic companies to take over the label of the branded drug when they entered the market.

The Cost of Drugs

The issue of branded and generic took shape in the 1950s.  Before then the primary way companies controlled drug niches – monopolized on the sale of profitable drugs – was through branding rather than patents. This meant there were a lot of branded generics and a lot of companies who manufactured drugs for other companies who branded and marketed.

The branding and marketing cost money and was the major component of a drug’s price – that and profit taking. If consumers could access “raw” medicines the same way they can access unbranded other products, they would be able to save money. And driving down the price of drugs was the main goal of Estes Kefauver’s hearings on the pharmaceutical industry that led to the 1962 Amendments to the Food and Drugs Act.

Kefauver failed in his goal of containing prices.  Other changes his amendments introduced, such as the need to prove a drug worked before marketing and the use of controlled trials to achieve this, drove the price of drugs up. As prices rose during the 1960s, for a variety of reasons support for the idea of increasing the flow of generic drugs began to grow.

The main block to the use of generics was legal.  Most American states for instance had anti-substitution laws, meaning that, if a doctor wrote a script for a branded drug, a pharmacist could not substitute a cheaper generic drug.

Battle lines were drawn between the consumer movement, a relatively powerful lobby in the 1960s, and the branded industry who for the most part were operating behind a shield of doctors.

The push to repeal anti-substitution laws and greater use of generics was portrayed as a push for socialized medicine and an infringement of the sacred relationship between doctor and patient. Do you want your doctor to give you the best or the cheapest drug?

Pharmacists were warned about the risks of being sued by patients if they were to intervene and swap drugs and something then went wrong.

Staring in 1974 with Kentucky a trickle of states repealed their anti-substitution laws, while Oklahoma refused to do so.  The key moment came in 1978 when New York opted to allow substitution.  This was key because where other states had lists allowing twenty or thirty drugs to be substituted, using cloak and dagger methods Bill Haddad in New York had created a list of 800 FDA supported substitutions.  It was this rather than Haddad’s later involvement with Orrin Hatch and Henry Waxman that brought generics into play.

Tidying Up?

Hatch-Waxman tidied up the loose ends.  It gave the branded industry a modest amount of patent extension and streamlined the process for generic drugs to enter the market.

A central element of the deal involved the label generic companies would run.  Generic companies can make chemicals but the branded companies run the trials and collect the early data on a drug that makes the label and transforms a chemical into a medicine. The best deal seemed to be for generic companies to take over the branded label lock stock and barrel.

When the Supreme Court ruled in 2011 that generic companies could not be sued in a failure to warn case, because they had not done the warning, this set up a predictable clash.  In 2001 when Prozac went off patent and Barr Laboratories brought out a generic fluoxetine, it was clear that at some point the question of suicide on a generic SSRI would become an issues.

The Dolin case is where the rubber hits the road. Some higher court will have to decide on the merits of allowing GlaxoSmithKline to be sued when Stewart Dolin committed suicide while taking generic paroxetine rather than Paxil.  This may take some years to sort out, with every iteration in the legal process cementing Stewart Dolin’s name in legal history.

Boomerang

Meanwhile, the cost of branded drugs around 1962 was less than $10 Billion per year.  In 1984, the year of Hatch-Waxman, it was slightly over $20 Billion per year.  It is now a $1,200 Billion per year operation.

Somehow every action in the pharmaceutical sphere has a way of turning out exactly the opposite of what its promoter intended.

Courts are not a place you can make jokes. I started off with a confident pitch:

If you owe a bank a million pounds, you have a problem but if you owe the bank a billion …

I didn’t get much further.  It felt like several GSK lawyers popped up, addressing the judge with words to the effect that he’s talking about banking your honor, this is not his area of expertise. The judge accepted their objections and I didn’t get to complete the analogy.

Nobody knew what I was talking about anyway – pounds?  What are pounds?

Judge Hart also ruled out the following image.  So the jury never got to see it.

A lot of my testimony centered on working through each of the ways to hide the data listed here. The exhibit couldn’t be shown but this is what was covered – in some ways too well. There were documents showing correspondence between GSK and FDA on many of these points leaving the jury wondering whether GSK or FDA were more to blame.

Many of the things that were done were shocking. GSK and other companies dumped withdrawal related suicidal acts into the placebo arm of trials, inflating the risks of placebo and breaching FDA regulations in the process. A good deal of this was so blatant that the jury must have been left wondering whether FDA reviewers were asleep or out to lunch.

Suicidal events were coded under the heading of emotional lability.  When a journalist and lawyers independently spotted  this coding trick and it became a public issue,  emails circulated within FDA asking what emotional lability actually was, and where it had come from.  But Andy Bayman for GSK could show the jury the documents sent into FDA which showed suicidal events clearly coded as emotional lability. This naturally cast doubt on whether FDA could have been as ignorant of what was going on as FDA head honchos later claimed to be.

Another egregious trick was the use of patient exposure years.  This gives rise to the Space Shuttle fallacy.  If you calculate lives lost per miles traveled the Space Shuttle may be the safest means of transport in the universe. But it takes a brave person to go on one.

This is because in terms of exit from and entry to earth’s atmosphere the shuttle is highly risky – just like antidepressants where its the starting and stopping that are the problem.  GSK and other companies continued some people who were happy as clams on their paroxetine for lengthy periods of time and mixed these with the patients having difficulties to dilute the problem.  All of sudden, per year on treatment, the antidepressants looked safe. This is a legitimate approach for some problems but not for this one.

Another trick was putting suicidal events in a neurological category that also included dizziness and headache. These happen so commonly they drown out the signal from suicidal events.

Every time a maneuver like this was exposed, GSK looked bad.  They looked like they owed the jury and the public money – a million dollars.  The problem is though, they hold all the data.  No one could give the jury the data from these GSK trials and say “here you are – its not rocket science – you work out what this data shows”.

While this is the case GSK effectively owe us Billions and its us who have the problem.  They own us. And don’t seem to be under any onus to stop owning us.

But GSK interrupted my efforts to lighten the jury’s day by making this remark. A Court is not a place for this kind of thing.

Editorial Note: This is a second post in the Change in Chicago Series looking at the Dolin trial and its verdict.  There will be two more in the series. 

Being cross-examined in a legal case involving Pharma is rarely fun.  The lawyers will have done their homework in spades.  As one of them put it to me once: Dr Healy, I have read everything you have ever written. Looking straight at him, I was quite prepared to believe this included every email I’d ever written. Between raking over an expert’s financial affairs, and private lives and any view ever expressed on anything, the assault on the expert can take any shape and rarely involves an engagement with the “science” of the issue. The results can be bloody.

In a deposition in the Dolin case two years previously that was supposed to be about the science of paroxetine, after a quick hour on the science, Dr Tamar Halpern and Bob Glanville for GSK spent nine hours instead picking over my relations with Betsi Cadwaladr University Health Board,  my dealings with all sorts of people before finally producing several large binders containing every post on this and on the RxISK blog – something like 800,000 words and 500 blog posts, fishing fro statements to snag me on.

At trial, Andy Bayman, GSK’s lead lawyer made a show of presenting me with two huge binders of prior depositions and testimony.  I didn’t have the wit to count up all the words and pages and hours of testimony but it was likely 10,000 plus pages, a million plus words and over 3000 hours worth of being grilled under oath.  The usual tactic is to pick out a phrase deep in the folder and triumphantly present that to the Court as representative of “your views Dr Healy”.

This is where any prior use of irony, or jokes, or effort to take the views of those who have an opposite point of view to mine into account can become a liability.

One trick is just to ask: “Did I read that correctly Dr Healy” – and move quickly on. In Dolin I had what I thought was a minor triumph when Andy Bayman tried this and I had the wit to respond “No”. This was something he didn’t expect, particularly as he had all the words correct. I explained that he’d missed the note of irony.

Overall the cross in Dolin didn’t seem to be too bad.  Mr Bayman was more than averagely pleasant – it seemed. He didn’t argue too much when I seemed to score points – as I thought. At the end some of those on the plaintiff’s team congratulated me on having done a good job – but they probably say that to all witnesses. Several people reading the transcript later commented on a job well done but they were supporters to begin with.

So, after the trial was over, I turned to the closing arguments from both sides with interest. What would Andy Bayman say?  I was a little surprised to begin with.  Surprise turned to consternation. What was this – it seemed like someone called David Healy was the prize witness for GSK.  Again and again they quoted that nice Dr Healy as saying FDA knew of the problem decades previously.  Dr Healy showed you that FDA saw exactly what GSK had done and you didn’t hear him mention any quibbles.

A lot of the points I thought I had scored with looked like own goals. No wonder Andy Bayman didn’t contest some of what I thought were my most effective shots.  No wonder he was so nice.

The full transcripts and exhibits are available on the Baum Hedlund website and will be on SSRI stories.

In trials like the Dolin trial, the plaintiff’s team try to make sure the jury blames GSK rather than the man himself or his doctor.  At the end of this trial, they thought they had done a good job and the jury might not be out for much more than a few hours.  The jury was out for days. And when they came back it became clear they were wrestling on the issue of who to blame. But Stewart Dolin wasn’t in the frame. Nor was his doctor. The dilemma was whether FDA were more culpable than GSK.

This was like playing Go, where it can look like the black counters on the board have white encircled until white puts down one more piece and all of a sudden it wins.

As someone who knows Andy Bayman, I was interested to see what Andy Vickery would make of what had happened. Vickery is a Houston lawyer who in 2001 won the Tobin case – a first ever verdict against a pharmaceutical company for a behavioral effect of one of their drugs – which should have led to a Black Box Warning for Adults on Antidepressants.   He might say he was “just a lil ol’ country lawyer, but momma Vickery didn’t raise no fools …  But it would be tongue in cheek if he did. 

In the end, the Jury got it right. They usually do. The citizens who decided the Dolin Paxil suicide case in Chicago last week held GSK accountable for the wrongful death of Stewart Dolin, by all accounts a very good man. And, although the verdict was only a fraction of the daily profits that GSK garnered from Paxil during its lengthy monopoly money patent protected marketing days, the verdict still holds the company that made those billions of dollars in profits — the company that had both the legal authority and moral responsibility to change the label — liable for damages.

But it was not easy. By all appearances, the Jury struggled at length with the beguiling arguments of GSK’s very talented lead counsel, Andy Bayman. He told them that the FDA were a “neutral group of scientists” who did not have a “dog in this fight.” And that the FDA had “spoken loudly” on the issue of SSRI induced suicide. It was excellent advocacy, but a sleight of hand.

The truth is that the FDA stuck its head in the sand on this issue when it was first raised regarding Prozac in 1990, and, with the exception of a minor nod for the protection of pediatric patients in 2004, it has kept its head in the sand. In this respect, I share Mr. Bayman’s perspective that the FDA has, indeed, “spoken through its silence.” The FDA’s abysmal abdication of its duty to protect patients was, indeed, another “proximate cause” of Stewart Dolin’s death. Its “silence” killed Stewart Dolin.

BUT, the FDA is immune from suit. To be sure, the FDA could argue that one of the reasons that it was silent is that GSK “cooked the books” on Paxil suicidality. There is ample evidence to support that. But the “whole truth” is that the FDA had plenty of information which should have caused it to act proactively and to protect the American populace, and it willfully neglected its duty to do so.

The issue first arose in 1989 in the wake of a scientific study by two highly credentialed Harvard neuropsychopharmacologists. They cited 6 cases in which Prozac was the likely precipitating cause in adult suicide attempts, and they posited a “biologically plausible” explanation for how and why that happened.

In response, the FDA assembled an ostensible “blue ribbon” panel to advise it. It was a total farce. Several of the panel members had to obtain “waivers” of their extensive ties to Big Pharma in order to serve at all, and the Chairman of the Committee wore a bullet-proof vest at the public hearing because he feared a family member of an SSRI suicide victim might shoot him!

When a citizen’s group petitioned the FDA to take action, to require warnings, it said, not now, but if ever there is a “court judgment” we will sit up and take notice. Our law firm provided that verdict in June of 2001 in the Tobin case in Wyoming. After hearing all of the scientific evidence from both sides, the Jury specifically found that “Paxil can cause some people to commit homicide and/or suicide,” that it had caused the four deaths in issue there, and that damages for those deaths were $8MM. Our principal expert was Dr. David Healy (who also testified on behalf of Mrs. Dolin, and who has been grossly and unfairly maligned by GSK for years).

In the wake of our 2001 verdict, the FDA could and should have required full, robust warnings. But they did not. Three years later they required “Black Box” warnings for pediatric patients, but, although the adult data was almost exactly the same, they permitted the drug companies to phrase the warnings as if to appear that they did not apply to adults over the age of 24.

Stewart Dolin was 57. And Mr. Bayman used the FDA’s “silence” and its pathetic endorsement of the “pediatric” only warning to good purpose. He argued effectively that the FDA has “never said” that Paxil causes suicide and that it had taken “no action” for the last 10 years (since it finally received all of the adult data regarding SSRI suicidality). In this, he was right. The FDA has taken “no action.” Shame on them! Andy Bayman was also on target when he said that Dr. Healy “laid the blame at the FDA’s feet.” He did so because the FDA was wrong all along!

Many, many good people have died because the FDA stuck its head in the sand on this issue. It should now pull its head out of the sand, and hang it in total shame.

Editorial: This series of posts on Stewart Dolin’s death interrupts a series on how to bring about change . This is not inappropriate as law suits are one of the few ways to bring about change. This post in the series is by a Chicagoan – Johanna Ryan who has been tracking the case since it was filed first. 

How a Chicago jury got it right

On April 20, a federal jury in Chicago awarded $3 million to the widow of a man who threw himself in front of a downtown subway train seven years ago.  Stewart Dolin’s suicide, they concluded, was not the result of depression, anxiety or the stresses of his job as a corporate lawyer.   Rather, it was his medication that had led to his death: a generic version of paroxetine or Paxil, the blockbuster antidepressant made by GlaxoSmithKline (GSK).

Paxil is one of a class of antidepressant drugs known as selective serotonin reuptake inhibitors or SSRI’s.  These have become some of the most commonly prescribed drugs in America and worldwide, offered to treat a wide range of emotional ills from grief to social anxiety.   But while many people find them helpful, they have long been known to make some patients irritable and anxious.

In extreme cases, this can advance to a state known as akathisia – an intense emotional turmoil and physical restlessness that can be so unbearable as to trigger suicide in those who suffer from it.  That’s what Wendy Dolin, Stewart’s wife, insisted had happened to her husband.  After listening to the evidence for six weeks, the jury agreed.

They also agreed that GSK had known all about the risks of akathisia and suicide posed by Paxil, but had failed to warn prescribers.  As Dolin lawyer Michael Baum put it: “GSK has known for two decades that Paxil can cause people of all ages to commit suicide … GSK not only hid the risk, but stuck its head in the sand and ignored countless suicides that occurred in its clinical trials.”

Generic drugs and the Catch-22

Wendy Dolin’s victory also challenges an enormous Catch-22 in the current state of the law.  A 2011 decision of the U.S. Supreme Court had barred consumers from suing the manufacturer of any generic drug for failure to warn of its hazards.  That’s because by law, the generic pill must not only contain the same ingredients as the brand-name version – it must also carry the same warning label issued by the drug’s original brand-name developer.   Yet because they do not produce the generic tablets, GSK and other drug companies have insisted they can’t be liable for any harm done on account of a false or misleading label.

However, in 2014 the Chicago court ruled that this would leave patients without any legal protection, and allowed Wendy Dolin to pursue a case against GSK.  The entire pharmaceutical industry will be keenly interested in GSK’s appeal.

What happened to Stu Dolin?

At 57, Stu Dolin had been a corporate lawyer for over thirty years.  He had risen to the rank of senior partner in the multinational firm of Reed Smith. He and Wendy had been together since their senior year in high school and were still inseparable; their two adult children were both doing well and close to their father.  Stu Dolin worked hard but also loved travel, sports and hanging out with his family and a circle of close friends.  He seemed anything but depressed.

At 57, Dolin was also not supposed to be at risk for problems related to Paxil.  In 2004, the FDA had imposed a Black Box warning label on Paxil and other SSRI’s, alerting doctors to a risk of suicide in children and teens.  The warning was later applied to all antidepressants and extended to patients up to age 24.  However, based on the evidence submitted by GSK and other drug manufacturers, no warning was issued for adults.

In the summer of 2010 Stu Dolin began seeing a counselor for anxiety linked to job stress.  He had sought help for similar problems once or twice before.  Two years into the Great Recession, there was plenty of stress to go around in Chicago’s financial district.  However, a fellow Reed Smith partner and longtime friend testified that Dolin’s anxiety was nothing all that out of the ordinary.   His counselor worked with him on relaxation and problem-solving techniques; she did not see him as a man at risk of suicide.

His family doctor, another old friend, prescribed Paxil.  Dr. Sachmann didn’t think Stu  needed to see a psychiatrist; it was a garden-variety case of stress.  However, within two days of beginning the Paxil, those who knew Stu Dolin saw unsettling changes.  His moods swung from happy and confident one moment, to agitated or weepy the next.  His wife Wendy recalled that he didn’t seem like himself.  For the first time, he asked his counselor for an emergency session; she was concerned enough to call him the next morning and urge him to ask Dr. Sachmann for some tranquilizers to calm him down.   That same day, after a business lunch, he walked down to the Blue Line subway station where a fellow passenger noticed him pacing back and forth in an agitated manner.  When the train arrived, he threw himself in front of it.

The Dolin jury and the March for Science

If Paxil really posed that kind of danger, argued GSK attorney Andrew Bayman, why hadn’t anyone spoken out?   His implication was clear:  This was an established drug, a staple of modern medicine.   Surely it must have been vetted by reputable scientific experts.  If the jury couldn’t see that, perhaps they were just blind to the science.

Two days after the verdict, on Earth Day, 40,000 people rallied in downtown Chicago against what they saw as attacks on science itself by the new team in Washington: dismissing global warming as a Chinese hoax, blaming autism on the measles-mumps-rubella vaccine, and taking aim at public science budgets from the EPA to the National Institutes of Health.  Clearly, nothing might garner more sympathy for GSK than to paint itself as another victim of “anti-science hysteria.”

More than a few Americans, long urged to blame the nation’s woes on other people’s frivolous lawsuits, might buy that claim.  “Sorry for the woman’s loss but this is truly an example of when juries go bad,” commented one Chicago Tribune reader.  “We all suffer with giant health premiums and drug costs because of ignorant juries and greedy lawyers,” another wrote.  “Wonder why he was so depressed?”

They might be surprised to learn that the jury’s verdict was based less on the speeches of hyperventilating trial lawyers than on a six-week immersion in the science of clinical trials, antidepressants, statistical significance and drug regulation.  If anything, the jurors’ efforts could have earned them a place on the podium at the March for Science.

They heard Dr. David Ross, a former senior regulatory scientist with the Food and Drug Administration (FDA) testify that “GSK was not upfront” with FDA reviewers about Paxil’s suicide risks.  Dr. Ross explained that the FDA does not test new drugs on its own, but relies on studies conducted by the companies themselves: “We only know what we are shown.”  GSK’s analysis of its own clinical trials pointed to 8.9 times the rate of suicidal behavior in depressed patients on Paxil compared to those taking a placebo. However, Dr. Ross testified, the company had misrepresented the results so that the increased odds of suicidal acts on Paxil appeared to be just 1.8, which reassured FDA that the difference was not significant.

They heard Dr. David Healy, an expert on the SSRI class of drugs from the UK, explain that psychiatry had known for fifty years that antidepressants could cause agitation and suicide in some patients.  SSRI’s carried higher risks than older drugs, with violent suicidal acts being noticeably more frequent.  Based on his own experience conducting clinical trials, Healy showed jurors the methods GSK had used to conceal the suicide risk – in particular, inflating the number of suicides and suicide attempts in trial subjects taking placebos, which made Paxil look safer by comparison than it actually was.  He also explained how clearly suicidal behavior could be coded under misleading terms such as “emotional lability.”

They heard Dr. Joseph Glenmullen, a clinical psychiatry professor at Harvard Medical School who reviewed Dolin’s treatment records, testify that his original anxiety symptoms were quite different from the drug-induced akathisia he had shown in the days before his suicide.  Glenmullen testified that he was 100% certain that Paxil, not job stress, had caused Dolin’s suicide – but the drug’s labeling would have led his doctor to believe that this could not occur in a middle-aged man.

GSK’s own experts may have sealed its fate

Certainly GSK was not cheated of its own opportunity to bring on the science.  Yet time and again its own employees and retained experts were forced to concede the Dolin team’s main points.  Dr. Anthony Rothschild, a purported expert in “psychological autopsies,” was unable to convince jurors that Stu Dolin’s suicide was due to his underlying mental illness.  He did, however, inform them that he had testified for GSK in about 20-30 prior Paxil death cases – he had lost count of the exact number.

Dr. John Kraus, a senior GSK scientist, and Dr. Geoffrey Dunbar, its former CEO, both admitted that the company’s misclassifying of “placebo suicides” had made its Paxil safety data misleading.  Yet both men had published the data in medical journals which had never been corrected, along with submitting it to the FDA.  Finally, faced with the twenty known and two possible suicides on Paxil during clinical trials, Dr. Kraus reluctantly conceded that 80% of the victims were over thirty.   Whatever they had told the FDA, the risks of Paxil could not be confined to adolescents – and GSK knew it.

What happened to Stu Dolin, attorney David Rapaport told the jury, could have happened to anyone.   The tragedy was that it could have been prevented, if Dolin and his doctor had been told of the potential risks.   After six weeks of testimony, the jury was convinced: The science should have mandated a warning.

Where will Wendy Dolin’s victory lead?

Four years ago the Dolin family founded MISS-D: the Medication-Induced Suicide Foundation in Memory of Stewart Dolin.  They plan to step up the great educational work they’ve already begun to make sure that other families don’t suffer the same fate. “None of us here are anti-drug. That’s not the issue,” she told the press. “But we are patient advocates and we hope that people will start asking better questions.”

For David Healy, the time has come for the FDA and other regulators to consider changing that label to extend the suicide warning to adults.  “If it’s that clear to the average man on the street, and the FDA doesn’t do something about it, we have an odd situation.”  Considering that as many as one in five American adults may take these drugs, “odd” is putting it mildly.

Editorial Note: This is the third part of a talk giving to the BNPA on February 22.  It follows on from Tweeting While Psychiatry Burns and Tweeting While Medicine Burns.  The final group of slides are HERE. 

The talk you have just heard was first given in Toronto on Thursday November 30 2000 to mark the 75 anniversary of the University Dept and 150 anniversary of the Queen Street Mental Hospital (Slide 1).  The Chads were still hanging in Florida while the Supreme Court tried to decide whether Bush or Gore had won.

I had recently been hired by the University of Toronto and I and a number of others had been invited to contribute to a meeting to celebrate the occasions.

I led off the program with the talk pretty much as you’ve heard it.  The word for word original is HERE.

One of the other speakers was this dude – Charles Nemeroff.  Nemeroff was quite happy at this point in time to be featured as the Boss of Bosses (Slide 2).  He wasn’t the boss of bosses because of any scientific or clinical contribution of which there was none.

In line with these Mafia connotations, at the meeting Nemeroff approached one of the key people involved in my hiring and suggested they get rid of Healy.  According to Nemeroff later, this individual wet his pants. The University later claimed my colleagues were disturbed by the talk and would have found it difficult to work with me.  They also claimed Healy had said Antidepressants cause Suicide which was like crying Fire in a crowded theater.

The talk was as you’ve heard it.  It was a talk about lack of access to data not about antidepressants and suicide. It was the plot of a book then in press – The Creation of Psychopharmacology (Slide 3).  Harvard University Press don’t do wild or off the wall.

My talk received the highest rating on the day by the audience which seems at odds with later university claims.  Nemeroff was the lowest (Slide 4). His talk was largely an advert for paroxetine (Paxil – Seroxat) and how it was more of an SNRI than people thought which didn’t seem particularly appropriate for the occasion, but perhaps interesting in that he seemed to be thinking about being an expert for GSK in the forthcoming Tobin trial.

Escape to New York

Nemeroff flew to New York that Thursday night.  The following morning, Friday, at a Suicide Prevention meeting he told colleagues that Healy had lost his job.

Unaware of any of this, I flew to New York on Friday morning and that afternoon was a few blocks away from Nemeroff.  Neither he nor I knew this.  I was in Pfizer’s archives where even the loo paper was marked confidential. Articles in the public domain for years were stamped confidential.

But extraordinarily this document wasn’t (Slide 5).  This page comes from a portfolio of articles on Pfizer’s Zoloft. covering the writing of articles on Zoloft for ingrown toenails, for anxiety, for the elderly, for the young and how it was cheaper than older treatments that cost only a fraction of its price.  This page shows you that there were two articles on PTSD being ghostwritten for leading journals.  The articles were written, the journals selected, the company just had to decide on who the authors were going to be.  TBD stands for To Be Determined.

Based on this portfolio of articles we were later able to show that heading toward 100% of articles in the peer reviewed literature on on-patent drugs are ghostwritten. In 100% of cases there is lack of access to the data.  This is true across medicine.  It applies to respiratory, neurology and cardiac medicine as much as to psychiatry.

What it means is that for instance the NICE guidelines which are based on these articles are Junk. Complete and utter junk. But increasingly our trainees and everyone else are trapped by Guidelines like these. We will lose our jobs if we don’t adhere to them.  This is what has led to the opioid epidemic in the US.

Tweeting

A few days after I gave this talk, I was informed that I had lost my job – I wasn’t a good fit and the department would lose money.

Over the last sixteen years when visiting the US, I have been struck at what can only be called a Medical McCathyism. Everyone in healthcare is scared to open their mouths.  While the average American is probably still prepared to stand up for themselves than the average European, when it comes to doctors at times it feels like the land of the craven and the home of the slave.  Just last week, however, the President of Royal College of Surgeons in Britain made a case that medicine in Britain is heading exactly the same way.

Pretty soon after this talk, the worry has to be most of us in the US, UK and Europe are going to lose our jobs – at least going to lose the kind of jobs many of us thought we were taking up when we entered the field.

If the drugs are as effective as we are told and as free from side effects as we are told, you can replace high cost prescribers with nurses, pharmacists and pretty soon with robots.  This is in fact happening quite rapidly.

In the 16 years from 1952 to 1968 the world changed in astonishing ways.  In the 16 years since I first gave this talk, it seems to have changed almost as much again.

So when some future historian in a very few years from now, looks back at this period and wonders about the senior figures in the field – the Jean Delays (Slide 6) – in the UK they will have Sir before their name – will say they say it was a time when the field’s significant figures tweeted while psychiatry burned?

Note

The slides here changed from the original 2000 slides at two points.  The weighing scales slide is now in color. In 2000 it was black and white.  And the Risk Hammer now replaces a Hamburger – hamburgers were scary images in 2000 with BSE.

The original words are HERE.

Later on Monday, the day of posting, Barney Carroll emailed this comment and the article that goes with the photo of the Boss.

I stumbled upon this photograph on Twitter today, courtesy of David Healy. It’s a pair with the classic fawning article about Nemeroff, which I will attach as well. The article is written by James LaRossa who bought the rights to Psychopharmacology Bulletin in the mid to late 1990s and then hired Nemeroff to turn it into a vehicle for infomercials. These bring back such fine memories!

Boss of Bosses  Charles B Nemeroff, MD, PhD

Charlie Nemeroff is sitting quietly at the speaker’s table, ignoring the bustle going on around him. His face betrays nothing – neither boredom, nor interest, or apprehension. Only the blinking of his eyes distinguish him from a statue. When he hears his name he rises very slowly, and begins to move to the lectern with deliberate strides, gathering speed as he goes, brightening now. He breaks into a grin and begins speaking the minute he approaches the microphone and, before the hush of the room takes hold, he has won the crowd with a disarming and deliberate manner that cuts simply to the heart of the most complex issues in neuropsychiatry.

Charles B Nemeroff, MD, PhD, chairman of the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine in Atlanta, finds himself addressing a room of crowded colleagues hundreds of times each year. Even in the ultra-competitive world of medicine and academia, Nemeroff is admittedly the most coveted academic speaker in psychiatry in the United States. His prolific authorship (he has published 600 research reports and reviews) along with a sheer enormity of research grants, awards, and scientific board appointments, has afforded him unprecedented celebrity within the psychiatric community.

Nemeroff’s academic and intellectual largess translates to a small and influential group of close friends, including fellow department chairmen Alan Schatzberg (Stanford), Marty Keller (Brown), Dwight Evans (U. Penn), Bob Hirschfeld (U. of Texas, Galveston) and NIMH heavyweight Dennis Charney, all of whom spend a great deal of professional and personal time together. Psychiatry is a highly charged topic these days, and these six thought leaders walk a fine line between controversy and political correctness, often made possible by their strong allegiances both to topics and to one another.

The ethics surrounding the implementation of placebo-control trials is one of psychiatry’s most supercharged political issues, as is addressed in more detail in this issue of TEN. “From a scientific point of view, the best data on efficacy of any treatment is best derived from placebo-controlled trials,” Nemeroff says. But with diseases like cancer and stroke, placebo trials become unethical. Thus, “the FDA in most cases has allowed for comparison between novel treatments for devastating disorders with traditional already-approved treatments.” If a novel agent proves efficacious against an existing agent, it gets approved. But “that has not been the case in psychiatry. And we have to raise questions about the use of placebo in conditions like mania, where patients are terribly ill. [In these cases] one wonders why it isn’t sufficient to have evaluation based on ‘just-as-good-as’ or ‘better-than’ currently available treatments and better side effect profile.”

Nemeroff is among the most coveted advisors to the pharmaceutical industry. Predictably, rumors about his alliances, or lack thereof, abound. It is safe to say that his views are expressed in a forceful manner he is a passionate person ­ and he fully expects to lead the corporate strategy of those he advises. Those who do not heed his advice are often recipients of his wrath. Consequently, Nemeroff is often in favor with the most successful drug makers, since those firms are doing the lion’s share of research, which he often directs.

Privately, Nemeroff is circumspect about the role between private and public funding. Working with industry can “be a win-win. There is a shared vision but also separate mission. The university mission is a troika: research, teaching, clinical service; whereas the pharmaceutical industry [mission is to] discover new drugs and to market them effectively. Sometimes those goals are simpatico and sometimes they’re not.” As an example of a situation where industry funding works to the benefit of the scientific community, Nemeroff recounts a new teaching council that he started recently with a grant from Janssen called The Young Faculty Development Program, where young professors get the opportunity to learn about clinical issues and academic life. And he talks also about the differences he sees between today’s young clinicians and those of his generation. ”In the past, there was a clear schism between psychoanalytically oriented psychiatrists and so-called biological psychiatrists. Today, this mindframe dualism seems silly… Patients of course have both minds and brains.” The fact of the matter is that psychosocial factors… can certainly affect how the brain functions and we also   know that the brain itself changes. The nature/nurture controversy is really no controversy, as we’ve improved our understanding of the brain.”

The Bronx-NY-born Nemeroff is most content being both a researcher and a physician. As an example, he recounts a part of the very day of this phone interview. “[Earlier today] I saw four patients, one on emergency consult; at the same time, I was dealing with a number of issues related to an NIMH grant of the psychobiology of early trauma. What can be better than being a teacher and a researcher and a physician?”

James La Rossa Jr. & Genevieve Romano

Editorial Note: This is part 2 of a 3 part lecture given on February 22 that began with Tweeting while Psychiatry Burns.  The text and slides continue from last week. The slides for this part are Here. The numbering continues from last week. 

When his office was ransacked, Delay’s world was turned upside down but psychiatry and doctors are still here – so we won, didn’t we?

Corporate Medicine

We didn’t win. Both psychiatry and anti-psychiatry were swept away and replaced by a new corporate psychiatry. In 1967, the year before Delay was upended, JK Galbraith argued we no longer have free markets with companies making products we need.  Instead corporations now shape our needs to meet their products (Slide 12).  It works for cars, oil, and everything else, why would it not work for medicine? Prescription only status makes medicine easier than any other market – a comparatively few hearts and minds need to be won.

Within psychiatry, two factors played a part.  One was the emergence of Big Science. This graph from 1974 (Slide 13) shows the correlation between affinity for D-2 receptors and the clinical potency of antipsychotics.  It was one of the most famous images in modern psychiatry until replaced by fMRI scan images.

The image remains as accurate today as when it was first published.  But these binding data introduce something else as well, for which neither Seeman nor Snyder, nor others who developed radiolabeled techniques can be held responsible.  They introduced a new language, a language of Big Science.  Where previously psychiatrists and antipsychiatrists and patients were using the same language, this no longer applied after 1974.  After 1974, to get into the debate you had to have a manifold filter and a scintillation counter.

This as it turned out was not a science that worked in the interests of patients. No longer answerable it seems to how the patients in front of us actually looked, following the science, we moved on to megadose regimes of antipsychotics that may have harmed as many brains as were ever injured with psychosurgery.  Science won’t necessarily save us, it must be applied with wisdom.  We have moved into an era when we depend on our experts in a new way – we depend on them to be genuine. Conflict of interest began to play as an issue.

Big Risk

Another factor stems from figures like Rene Descartes (Slide 14), Blaise Pascal and others, who were behind the development of statistics and probability theory. This laid the basis for the Enlightenment.

Statistics initially referred to government statistics – a process of mapping peoples rather than just the land. This led on to the notion of the rule of the people by the people, the creation of social science and epidemiology, along with public health and insurance.

The same forces led around 1900 to the first attempts to map the human individual, their attitudes and abilities, personality, or intelligence.  Sales such as the IQ scale led to new concepts of norms and deviations from those norms and psychologists emerged to take a place in the educational system, the legal system, and in the government of ourselves – it was this that underpinned the psychodynamic revolution (Slide 15).

This was not just the replacement of theology and philosophy – the qualitative sciences – by a new set of quantitative sciences.  The new sciences set up something else.  They set up a market in futures.  A market in risks.  We were on our way to becoming a Risk Society (Slide 16).  In the case of the IQ test for instance, deviations from the norm were now something that predicted problems in the future.  Parents sought out psychologists in order to improve the futures for their children.  This was how we would govern ourselves in the future.  Through the marketplace.

Drugs entered this new market in many different ways.  The oral contraceptives for instance are clearly not for the treatment of disease.  They were a means of managing risks.  Where once, the risks of eternal damnation had been those that concerned people, now it was a much more immediate set of risks – we switched one set of future risks for another (Slide 17).

The best selling drugs in modern medicine don’t treat disease.  They manage risks.  This holds for the antihypertensives, the statins to lower lipids and other drugs (Slide 18). It holds for antidepressants, which have been sold on the back of efforts to reduce risks of suicide (Slide 19).

All the Evidence that’s Fit to Print

The development of probability theory also gave rise to clinical trials.  We are now in an “Evidence Based Medicine” era. What can go wrong if we have clinical trial evidence to demonstrate what works and what doesn’t (Slide 20)?

But clinical trials in psychiatry have never shown that anything worked.  Penicillin eradicated a major psychiatric disease without any clinical trial to show that it worked.  Chlorpromazine and the antidepressants were all discovered without clinical trials.  You don’t need a trial to show something works.  Haloperidol and other agents worked for delirium and no one ever thought to do a clinical trial to support this.  Anesthetics work without trials to show the point.  Analgesics work and clinical trials aren’t needed to show this.  Clinical trials nearly got in the way of us getting fluoxetine and sertraline.

Trials demonstrate treatment effects.  In some cases, these effects are minimal.  The majority of trials for sertraline and for fluoxetine failed to detect any treatment effect.  In clinical practice many of us are under no doubt that these drugs do work.  But if our drugs really worked, we shouldn’t have 3 times the number of patients detained now compared with before, 15 times the number of admissions and lengthier service bed stays for mood and other disorders that we have now.  This isn’t what happened in the case of a treatment that works, such as penicillin for GPI.

Aside from this, professors of psychiatry have been jailed for inventing patients, much of the scientific literature is now ghost written, many trials are not reported if the results don’t suit the companies sponsoring the study, while other trials are multiply reported making it difficult to work out how many trials there have been. Within the studies that are reported, data such as quality of life scales on antidepressants have been almost uniformly suppressed.  More generally there is no access to the data. To call this science is misleading.

Medical Robots

But these are not the most important consequences for medicine of clinical trials. The critical development is contained in the following quote from Max Hamilton in 1972 about his rating scale:

“it may be that we are witnessing a change as revolutionary as was the introduction of standardization and mass production in manufacture.  Both have their positive and negative sides” (Slide 21).

Anyone who has used the Hamilton Rating Scale for Depression will wonder what is this man talking about when he talks about a revolutionary aspect to using a checklist like this.  Maybe as a communist, he was sensitive to things that we are not sensitive to now.

Rating Scales have been such feature of psychiatric trials so long now that it is perhaps difficult to see that there are revolutionary aspects to what happened.  We use these checklists in all walks of life from sexual behavior, to children’s behavior. Where once there was life’s rich variety, now our children fall outside all sorts of norms when checked against these lists.  And when they do parents desperately want to bring their children back inside appropriate norms.  We bring them to psychologists and to doctors.

The figures on treatment effects from rating scales used in our clinical trials have set up a new market.  When you consider that as far back as 2000 we were treating children from the ages of 1 to 4 with “Prozac” and “Ritalin”, you realize that we are not treating diseases here (Slide 22).  Pharma makes markets but until recently they have not sold psychotropic drugs to children.  The explosion of drug use in children is a manifestation of the force that fills the sails of pharma marketing.  It comes from us. What parent could not want to minimize future risks for their child?

Anorexia offers an analogy for what is involved (Slide 23).   Clearly people have starved themselves for millennia for all kinds of reasons. But Anorexia nervosa emerged in 1873 a few years after the first weighing scales.  Eating disorders increased in frequency in the 1920s when weighing scales migrated into drug stores complete with a plate featuring norms for ideal weight.  In the 1960s, the frequency increased yet again with new variants mushrooming – as we all bought portable scales for our bathrooms.

Competing theories have focused on the possible psychodynamics of the problem, the biology of the problem, or socio-political aspects of the problems.  None of these recognize the role of scales and norms for weight and deviations from the norm and an awareness that deviations in the direction of what had formerly been thought to be healthy and beautiful carried risks.

This problem applies to any situation in which we have a datastream frm one area of our life but not others.  It applies to figures for GDP which run the risk of seriously distorting society in general.  The problems seem likely to get worse with the proliferation of Health Apps.

But there is another consequence for medicine itself. Figures like scores on a Hamilton Scale set up algorithms – If X, then do Y.  The figures drive the prescription of drugs.  But the use of checklists like this looks scientific to managers who run health systems.  They want staff to stick to checklist questions in clinical encounters rather than have doctors or nurses talk to patients.  Its scientific after all in a way that conversations are not.  And doing things this way means doctors can be replaced by nurses and pharmacists and everyone in the near future will be replaceable by robots.

Serial Killing

Harold Shipman (Slide 24) was one of the greatest serial killers ever. He killed over 200 people with opioids.  Shipman’s case illustrates that situations where trust is important can provide the conditions for extraordinary abuses.

One of the conditions where trust applies is in prescription only arrangements.  This arrangement was introduced to restrict bad drugs but now applies exclusively to the good drugs.  Since 1951, the idea is physicians would quarry information out of pharmaceutical companies on behalf of their patients and would provide the counter-balancing wisdom to market forces.

Since 1951, pharmaceutical companies have grown to be the most profitable on the planet.  There has been a change from companies run by physicians and chemists to companies run by business managers who rotate in from Big Oil or Big Tobacco, advised by the same lawyers who advise Big Oil and Big Tobacco.

In the case of tobacco industry, it now seems clear the advice was not to research the hazards of smoking, as to do so would increase the legal liabilities of the corporations involved (Slide 25).  Similar advice given to the managers of our pharmaceutical corporations would be completely incompatible with prescription-only arrangements.  Advice like this converts prescription-only arrangements into a vehicle to deliver adverse medical consequences with legal impunity.

Prescription only opioids are now linked to 30,000 deaths per year in the USA. This happens because clinical trials have been cleverly built into guidelines to mandate the use of opioids for minor pains where wisdom would say this was a bad idea. These trap doctors because their managers will now sack them if they don’t keep to guidelines. We have institutionalized Shipman.

I happen to believe that Prozac and other SSRIs can lead to suicide.  These drugs may have been responsible for 1 death for every day that “Prozac” has been on the market in North America.  Many of you will probably not agree with me on this – but you haven’t seen the information that I have seen.  However we can all agree that there has been a controversy and since the controversy blew up, there has not been a single trial carried out to answer the questions of whether “Prozac” does cause suicide or not.  Designed yes, carried out – no.

Fake Science

With the mapping of the human genome, we have the possibilities of creating new markets (Slide 26).  We need this data and the data from clinical trials to govern ourselves.  The genetic data will tell us about some of the underpinnings to our beliefs – why we believe some of the things we do in the religious and political domains. But the products of this research along with trial data will belong almost exclusively to pharmaceutical corporations, and at present this democratically important data is being deployed against the interests of democracy.

It is also increasingly been managed through organizations like Sense about Science who run Science Media Centers to ensure we are all fed the interpretation of the latest science that best suits corporate interests.

In Slide 27 you see another image of the future. In the course of the last 70 years, plastic surgery evolved into cosmetic surgery.  Plastic surgery began as a set of reconstruction procedures aimed at restoring a person to their place in the social order.  It evolved into cosmetic surgery when the reliability with which certain procedures could be carried out passed a certain quality threshold.

The word “quality” is pervasive in healthcare today.  Quality in modern healthcare however does not refer to genunine interactions between two people as it did in the 1960s.  Quality nowadays is used in an industrial sense to refer to the reproducibility of certain outcomes.  Big Mac hamburgers are quality hamburgers in this sense — they are the same every time.

Viagra gives good indication of what will happen when we get to this stage.  Viagra is a drug that produces quality outcomes – reproducible outcomes.  When this happens, it becomes possible to abandon the disease concept.  Pharma talks openly instead about lifestyle agents.  This is the world that lies in store for us.  It is not the world of traditional medicine, where drugs treat diseases to restore the social order.  It is a world in which medical interventions will potentially change that order.

But cosmetic also suggests fake – that behind the appearances things might be rotting. The boxes that proliferate in healthcare today are being ticked ever more faithfully but behind the appearances our services are disintegrating.

1952 – 2000

This returns us to the picture of Delay and his colleagues (Slide 28).  If some relatively minor person from the UK or US – a white man visited Delay with a research proposal – Pichot and Deniker would be summoned and might be left standing behind Delay for an hour while he discussed matters with the visitor – Pichot on the right and Deniker on the left.

This was not an experience that Deniker or Pichot experienced as some exquisite form of torture or as a humiliation.  It was a different time.  Honor and loyalty counted for more then than the search for individual authenticity we now have.  The hierarchy and the collective was something these men believed in.

What this shows is that there are forces at play that can change not only the kinds of drugs we give, not only the conditions we think we are treating, but our very selves who are doing the giving.  These forces can change us just as profoundly as we can be changed by a handful of LSD containing dust.

to be continued..