Making medicines safer for all of us

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

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

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

Author Archive for David Healy

Study 329: Big Risk

Light bulb hit by hammer

Editorial Note: This is the Fourth Crusoe Report.

“Death waits for these things like a cement floor waits for a dropping light bulb”

Big pharma

Study 329 seems to fit the classic picture. It has Big Pharma ghostwriting articles, hiding data, corrupting the scientific process and leaving a trail of death, disability and grieving relatives in its wake.

Pharma began in the middle years of the nineteenth century when advances in the chemical and biological sciences underpinned the development of analgesics and antipyretics and later antibiotics. Within medicine, these were the first drugs that reliably worked. Within business, they led to developments in patenting and trade-marking, big profits and the emergence of an industrial-scientific complex.

The Second World War put a premium on pharmaceuticals. The development of Atabrine for malaria and Penicillin for everything else helped win the War – a lesson not lost on Governments. Pharma had become a strategic industry.

Government investment led to a cornucopia of new treatments in the 1950s and 1960s that transformed medicine. Lives were saved that would have otherwise been lost, research flourished, and the specter of premature death began to lift

Previously drugs had been developed in the pharmaceutical divisions of chemical companies. These divisions were now hived off as independent companies (Little Pharma) and these new companies rapidly became the most profitable on the planet.

In the late 1960s and early 1970s, Little Pharma called in management consultants in a bid to keep the goose laying the golden eggs. These outfits advocated outsourcing clinical trials to Clinical Research Organizations (CROs) and medical writing to Ghost Writing Agencies. They also advocated having businessmen and marketers as CEOs of the company rather than chemists or scientists or medics. They insisted on five year development plans that put a premium on the selling and reselling of popular diseases where even less effective products could be made into blockbusters rather than developing medicines for conditions that had no treatments. If the company was in the business of making profits, this switch in focus was a no brainer.

This advice created the very model of a modern major pharmaceutical – out of which came Big Pharma and Study 329.

But is this the whole story?

Big risk

The nineteenth century also gave rise to another profitable industry – the linsurance industry which is now a broader risk management industry.

The collection of data by the first life insurance companies in the eighteenth century led in the nineteenth century to the creation of public health and the idea of preventive medicine. (This will come as an extraordinary claim to many, but the underpinnings of this can be seen in books like The Creation of Psychopharmacology).

The interests of the insurance industry to manage risks laid the basis for epidemiology and an interest in numbers in health. It led to calls to eradicate filth even before the germ theory had established what it might be about filth that caused problems. Today the preventive impulse in public health medicine leads to calls to eliminate poverty – which brings medicine into politics and politics into medicine.

The first public health physicians in the early nineteenth century were called Hygienists or Sanatarians. In addition to campaigning against filth, and the adulteration of food, and for temperance, the Hygienists in Germany and Britain advocated strongly for pensions as a public health measure which in turn furthered the growth of the insurance industry. And ultimately healthcare today worldwide is (or will be with the latest Trade Treaties) delivered through insurance schemes of one sort or the other.

In the second half of the nineteenth century, therefore, the growth of the economy and of the modern world got a huge boost from both the emerging biomedical and epidemiological sciences and their linked industries.

We celebrate the gains that medicine made in the 1950s that stemmed from the discovery and production of new drugs. We miss the transformation of medicine that data from yearly insurance check-ups produced in the 1960s. These data created the notion of risk factors such as hypertension, raised cholesterol levels and raised blood sugar. From a risk management point of view the data put a premium on treating risk factors – giving drugs to people the vast majority of whom had nothing wrong with them. This was not a Pharma plot – or not solely a Pharma plot. The story has been told in Jeremy Greene’s Prescribing by Numbers.

And just as the dynamics of modern corporations transformed pharmaceutical companies from companies at the forefront of an effort to discover drugs that treat the disorders that need treating for which we have no treatments into companies that focus on the production of drugs that make a profit, so also these dynamics changed the insurance industry. It changed from an industry that viewed the environment as risky and aimed to ensure our safety from these threats and to provide our families with a safety net in the event of our death, into an industry that located risks within us and wanted to protect itself from us. Big Risk will refuse to cover anyone who is in fact risky.

The marriage of pharma and risk

The pharmaceutical and insurance industries were initially not perfect bedfellows. The insurance industry was hostile to individual doctors doing whatever they liked such as using the latest drug. But most doctors believed that medicine cannot be practiced by numbers – that the duty of the doctor is to the patient in front of her rather than to the population.

But still the early interplay between science and business within the health domain and between preventive medicine and biomedicine worked to the advantage of all. New drugs liberated us from the specters of disease. Insurance highlighted things we could do to safeguard ourselves, our families and communities.

But the situation became more ambiguous as the twentieth century went on. With the virtual elimination of mortality linked to bacterial infections some of the greatest hazards to health came from pollution linked to other new industries such as the lead and tobacco industries. Tackling the health problems that stem from industries that are important to the economy and jobs cannot expect to mobilize the same degree of community or political support, as fighting Tuberculosis or Ebola can.

In addition, the links industry developed with science in the nineteenth century left it well placed, and financially more able than academia, to mount epidemiological studies in the twentieth century. This awareness of the benefits of research along with greater resources to sponsor studies was deployed to great effect for instance in the defense of tobacco smoking and lead where industry demonstrated it had learnt to exploit the radical doubt that drives science.

There is also the tricky balance of working out where politics ends and medicine begins. There were vicious disputes in the nineteenth century between biomedicine and public health over filth. Mainstream medicine didn’t see it as its job to clear up filth. Public health insisted it was. Mainstream medicine discovered germs and embraced the elimination of germs as a legitimate medical contribution. Many in public health held out against the germ theory.

Is eliminating poverty (the modern equivalent of filth) a medical task? Or should medicine make its contribution by recognizing that many poor (a.k.a. non-white) children live in slums that still have lead in their paint and that lead poisoning knocks several points off a child’s IQ and is associated with criminality and that the medical contribution is to flag this up and find ways to eliminate lead poisoning in the face of determined efforts by a powerful industry to block them – leaving poverty to politicians?


The shipwreck of the singular

Whatever balance you opt for in the above disputes, today, as has ever been the case, when you take a problem to a doctor for help, both you and she expect to be able to draw on the best evidence to solve your problems.

In 1990 at the start of the Big Pharma era, you and your doctor lived in a world where medical issues were found in journals, textbooks and a small number of popular books. Today there is likely to be a health story on the front page of the newspaper, with an entire section inside devoted to health. The amount of health related material on the Web is second only to pornography and even pornography is grist to the medical grind.

The political has become personal in an extraordinary fashion.

Unlike any time in medicine hitherto, when you go to a doctor today you will have to take your place in a queue of people, many of whom have been summoned to a consultation by a clinic screening for a wide range of things none of which bother the people who have been summoned. They will come to the clinic unaware of any problem but will leave with diagnoses and on medication. The doctors call them in not out of concern for them but because the doctors have targets to meet in order to get reimbursed – targets set by Big Risk.

Big Pharma play on this pitch but it’s Big Risk that draws the lines and sets up the goalposts.

When you do get in to see the doctor, you’ll find someone who adheres to Guidelines. She will do so in good faith, figuring this the way to bring the best evidence to bear on your case. She will not recognize she is being guided to see problems in certain ways and to deliver on patent treatments. She will not be treating you according to the Guideline for Treating You. If there were such a Guideline, the first point would be pay little if any heed to Guidelines for treating diabetes, or hypertension or depression or the menopause. (See The Macbeth Test).

If the problem is a mental health one, both you and your doctor are likely to be aware of conversations denigrating biological reductionism claiming that it risks dehumanizing clinical encounters. In practice however biology contributes almost nothing to clinical encounters about nervous problems.

These encounters are being dehumanized but the problem lies with an informational reductionism linked to the use of rating scales and operational criteria.

Within the mental health domain, a great deal of public discourse claims the medical model is inappropriate, diagnosis unhelpful, and the word “patient” to be abjured along with an increasingly long string of politically correct replacements. But in practice patients seek diagnoses, and the appeal of the language of chemical imbalances lay in the fact it was destigmatizing. The allure of biomedicine lies in its promise of treatments that work.

But for the first time in a century, today’s first line treatments are likely to be less effective than yesterdays.

In all of medicine, one of the greatest sources of morbidity and mortality – perhaps the greatest – now stems from the treatments patients have been put on, the multiplication of hazards by polypharmacy and the denial of the possibility of risks by corporations whose own health depends on the continuing consumption of the greatest possible number of medications by the greatest possible number of patients from the earliest possible age.

In most of the medical and lay media, Big Pharma is the only whipping boy for these evils. But is it?

Epidemiological methods are used to deny these treatment related risks. RCTs come from Big Risk not Big Pharma. When they were introduced first they were a way to contain the pharmaceutical industry. Pharma lobbied vigorously against them. They began as a Risk Management Tool but have become the gold-standard way to hide risks – as Study 329 shows so dramatically.

Economically you might have thought it was in Big Risk’s interests to map out the epidemiology of treatment induced morbidity – the problems treatments cause. But it doesn’t do this. Big Risk’s traditional methods of prevention – Guidelines and RCTs – don’t work for treatment induced problems. And why solve a problem that generates more turnover?

Meanwhile so uncertain has Big Risk made access to care – so shredded has the safety net become – that any suggestions that consuming fewer drugs might be healthier are drowned out for most people by concerns about access to medicines. The ACLU for instance will not take up the issue of whether treatment induced violence might have led to inappropriate incarceration for fear it might complicate their efforts to ensure that prisoners have access to healthcare.

Just as a balance in drug development has tipped so that it no longer serves medical treatment, so also a balance within prevention has been perverted.

Big Risk should make it impossible for Big Pharma to take separate patents on drugs as similar as two drops of water by refusing to reimburse the second drop of water. It should make it impossible to ghost write over 90% of the literature for on-patent drugs and to sequester the data from clinical trials, in contravention of the fundamental norm of empirical science – but it doesn’t do any of these things.

Big Risk underpins a comprehensive failure to diagnose and treat in the face of morbidity and mortality on an epidemic scale. Before blaming Capitalism, the problem is the market isn’t working. It’s Big Risk that should make the market work and they aren’t. What we are looking at is the behavior of Corporations. This behavior is shaped by Rules and at the moment the Rules are not working for us.

Medicine is no longer what it was. Your doctor needs to relearn the skills of listening to, seeing and touching you. She will have to engage with a biology that recognizes the brain as a social organ rather than with the biobabble that stems from Pharma marketing. She will have to ignore an epidemiology that figures you can design authoritative RCTs without understanding the biology being investigated (most RCTs).

Both Big Pharma and Big Risk justify the status quo by saying they don’t want to impinge on the sanctity of the doctor patient relationship. So she will have to be able to take the dynamics of industrial power into account and Industry will have to figure she is made of the Right Stuff – unless we can find a way to rescue her from the pot in which she is now stewing.

Until such treatment becomes possible, we are all shipwrecked. We are all Crusoe.

Death waits


“This generation thinks that nothing faithful, vulnerable, fragile can be durable or have any true power. Death waits for these things as a cement floor waits for a dropping light bulb. The brittle shell of glass loses its tiny vacuum. This is how we teach metaphysics on each other”.

The quote is from Saul Bellow’s Herzog. In Bellow’s imagery, the vacuum in the dropping light bulb contains our hopes, our aspirations, our fears. Big Pharma and Big Risk were once our allies in keeping our hopes alive – in keeping our children alive and well. They are now a threat. And of the two – Big Risk is the bigger threat.

Study 329: BMJ Transparency


Two weeks ago The BMJ ran an editorial by Richard Smith (former editor) and Fiona Godlee (current editor) on the retraction of a 1989 article by R K Chandra under the heading of A Major Failure of Scientific Governance.

While making money from the publication of pharmaceutical company trials, and in the face of a complete failure by industry to adhere to basic scientific norms and make data available, BMJ and other journals, although BMJ in particular, have run a series of articles on supposed Academic Fraud. These articles feature instances of fraud sometimes as bizarre as researcher claiming he cannot show the data as it was eaten by termites. A common theme, as with Chandra, is the academic community are held back from tackling the issue by fear the dude will sue. The universal feature is that these are academic studies and academic fraud is an issue in academia. Talks on this topic are often given by representatives of pharma such as Frank Wells for the Association of the British Pharmaceutical Industry (ABPI).

A day after the editorial appeared, Leonie Fennell submitted a Rabid Response (RR) to the editorial that used several of the words of the editorial itself. This RR was posted. Then the response disappeared. A while later it was re-posted. This time it was there long enough for someone to like it and for the screenshot above to be taken. But establishing its reality by liking it was apparently not enough. It was removed again, and has not reappeared since.

This is a comment in limbo. Until recently many Irish believed that stillborn babies went to limbo and the vague promise their parents held on to was their children would be saved on the Last Day.

“To err is human, to cover up is unforgivable, and to fail to learn is inexcusable”. I agree with both BMJ editors (past and present) on the latter, yet I still have some concerns. Surely if the BMJ had actually learned from this, it would have been more proactive with Study 329, where scientific fraud has so obviously once again prevailed. Is the BMJ, as David Healy suggests, terrified when publishing anything that might make a pharmaceutical company uncomfortable? It’s interesting that an earlier article regarding Study 329 was reviewed and turned down by the BMJ (reviewers included the former editor in chief, Richard Smith).

The findings of Study 329, that Paroxetine was ‘safe and effective for adolescents’ led to the widespread medicating of children with Selective Serotonin ReUptake Inhibitors, subsequently causing many deaths. Saying that universities, authorities and the world of science have a chance to learn from the Chandra case is all well and good, but what have the BMJ actually done to right this latest, very evident wrong? Brown University, GSK and Keller et al are digging their heels in. The BMJ need to act now while there is still has time to put its own house in order. ‘Good men doing nothing’ is just not good enough. The BMJ’s current reputation as one of the leading medical journals is at stake here”.

Study 329: 50 Shades of Gray


Editorial Note:  None of these posts about Study 329 should be taken as representative of a RIAT view, especially this one. See Study 329: Conflicting Interests for a prequel to this post and to make sense of the last comment.

Fiona Godlee to RIAT July 6 2015
Re: Study 329

Dear Dr Jureidini,

“Many thanks for your letter. I quite understand you concerns. You are right to say that there are few or no precedents against which to compare this article. We ourselves are feeling our way, both with the RIAT process since this is the first full RIAT research paper we will publish, and with the specific challenges posed by this particular study and you as the paper’s authors. I want to stress that we are proceeding in good faith with the clear aim of publishing the article as soon as possible provided we can do so safely”. …

All best wishes

Fiona Godlee FRCP
Editor-in-Chief The BMJ

In utero

The editor dealing with Study 329 through its year-long gestation in the belly of the BMJ was Elizabeth Loder. The paper improved considerably during this time but there was almost nothing constructive from BMJ that led to any of these improvements – readers can examine for themselves the various letters, reviews and revisions, bearing in mind that from our side the correspondence is written under constraint . Indeed almost all inputs from BMJ produced outcomes that likely made the editorial staff ever more uncomfortable.

As the features of Study 329 took shape in the BMJ womb, the New England Journal of Medicine (NEJM) had a series of articles suggesting that concerns about Conflict of Interest had gone too far.  Some journals, NEJM said, were in a state of moral panic; they were hunting for witches. They should have run their articles at Halloween.

The BMJ in an editorial by Elizabeth Loder and Fiona Godlee led the way in responding with outrage to the NEJM, suggesting that this was not the time to step back from seeking transparency on conflicting interests.  Ideally we need to go further and find ways to bring non-financial conflicts of interest into the frame.  The medical literature is clearly still a mess and this can only be because we have not been zealous enough about conflicting interests.

The alternate view, not popular with some “progressives” who don’t do science, is that access to data is more important than access to information about conflicts of interest.  It is only when there is access to the data that we can see if interests are conflicting and take that into account.  Science needs conflicting interests – financial and non-financial. Problems don’t get solved unless someone is motivated for some reason. We need the bias that pharmaceutical companies bring to bear in their defense of a product, along with the bias of those who might have been injured by a treatment.  Both of these biases can distort the picture but it’s when people with differing points of view agree on what is right in front of their noses that we can begin to have some confidence about what we have.

Outsiders have conflicts; Insiders don’t

Sixteen years ago I sent a paper to BMJ based on Lilly documents that had come into the public domain because of a Court Case.  BMJ’s initial response was that they should perhaps publish given that they had published a Lilly article, the Beasley et al 1991 article, that had done a good deal to create the antidepressant and suicide problem. But Richard Smith resiled from this position. In later correspondence, he stated BMJ would never publish anything from me on this topic.

The real issue was that BMJ were lily-livered and were prepared to cite my supposed conflicts as their escape route even though the data was fully in the public domain and publishing would have laid bare whether my judgments were unduly conflicted.  Another journal took the paper promptly.

At the time of the July 6 email above, BMJ stated they were thinking about sending parts of our material out to a third party to review. In fact they had already sent the material out for review when they told us they were thinking about doing so.  We objected and made it clear that this was unacceptable and when the reviews came back, we paid little heed to them.

On July 8,  we emailed BMJ raising issues covered below.

A headache

Some of the drama in Restoring Study 329 centered on headaches. GSK coded headaches and dizziness one way in the original Study Report and a different way in the Keller et al paper.  Headaches and dizziness were so common that moving them from Body as a Whole to Nervous System laundered out the signal not just from suicide events (coded as emotional lability) but from pretty well all psychiatric events.

We were less interested in the question of where exactly headaches and dizziness should be placed and much more interested to make sure readers of the article were aware that it was possible to move them around and in so doing to “re-author” the findings.  Our concern wasn’t to show that deception had happened but rather to show how people might be misled – perhaps inadvertently.

Elizabeth Loder was upset.  She might have regarded our approach as cavalier or she might have missed the point because of a conflicting interest.

EL is a professor of neurology and a migraine expert based in Boston. She has several books on headaches – something we hadn’t thought to check before July 6.

She has been the President of and serves on the Board of the American Headache Society which runs an influential journal. She serves on the Executive Council of the International Headache Society, and the Board of the Headache Cooperative of New England. She has helped write all manner of guidelines for treatment of migraines, and has chaired the “Choosing Wisely Committee” of neurologists.

Knowing this might have affected how we worded things.

Dr Loder has been with BMJ since 2006 and declares that she has no links to pharmaceutical companies since then. She declares she has previously been a speaker, received grant support, or been a consultant for: OrthoMcNeil, Endo, AstraZeneca, GlaxoSmithKline, Pfizer, and Allergan – a list of companies that overlaps with one that formed part of my conflict of interest statement as of that point in time.

Before moving to BMJ, in a 2003 paper she co-wrote about how we don’t need to be so afraid of using triptans, it says both authors have gotten research grants and done speaking on behalf of various migraine medicine manufacturers including GSK.

Imitrex – sumatriptan – is GlaxoSmithKline’s triptan. With Imitrex off patent, GSK turned to Treximet, a combination of sumatriptan and an NSAID that was approved for migraine in children over 12 in May this year.

Sumatriptan comes with a suicide problem.  Robert Gibbons has been enlisted to pooh-pooh this.

In a recent Washington Post article Dr Loder answers readers’ questions about migraine. She says:

“you haven’t failed sumatriptan till you’ve failed to respond to a full dose of injectable sumatriptan given early in the migraine. That’s my mantra!”

She squeezes in that “there’s evidence it’s more effective when taken with an NSAID” – just before Treximet came out.

While Dr Loder’s name is not listed in OpenPayments or Dollars for Docs, a regular partner on much of her work is Stephen Silberstein.  They are on all the same Influential Committees.  Dr. Silberstein comes close to being the KOL’s KOL in the headache field.  Here is a recent Disclosure Statement.

Meanwhile, her hospital, Brigham & Women’s, got $15-20 million from GSK in 2014.

50 shades of gray

Meanwhile in addition to helping articulate BMJ’s position on conflicts of interest, Dr Loder was involved in a Lown Institute Twitter Chat in July on conflicts of interest, where she makes clear we need to find out more about non-financial COI’s.

Her BMJ COI statement refers to her husband’s position in a law firm but she states that he does not have a healthcare involvement.

His law firm is the Boston based Ropes and Gray.

John M Loder is not in the Healthcare division of Ropes and Gray.  He is in Hedge Funds, Investment Advisors, SEC compliance.  Attorneys from Mergers & Acquisitions, Government Enforcement, and White Collar Defense divisions likely work with GSK every day of the week.

Central to the work Ropes and Gray do is a First Amendment commitment that horrifies those who are usually most vocal about conflict of interest.  This company is one of the main supporters of off-label marketing, on the basis that to prohibit it would be an interference with free speech.  They have achieved some success in these areas. Their position makes a certain amount of sense to me.

The irony was that BMJ were using a close to monopoly position to abuse our First Amendment rights in respect of Restoring Study 329. If we had the money, the perfect people to have hired to fight our case against BMJ would have been Ropes and Gray.

But more to the point Ropes and Gray are currently GSK’s lead attorneys on company fraud matters in China. Their ties to GSK are close enough that journalists describe them as “GSK’s law firm in Hong Kong”.

And for several years they were also central to defending GSK in the Department of Justice and related investigations that led to a $3 billion fine for GSK in 2012.  A key element to the charge against GSK lay in their handling of Study 329.

Colleen Conry and Brien O’Connor, co-leaders of the Ropes & Gray government enforcement practice, were successful in winning an acquittal for former GlaxoSmithKline associate general counsel Lauren Stevens in the U.S. District Court for the District of Maryland back in 2011.

As they say on their website:

Companies and individuals worldwide turn to Ropes & Gray’s leading government enforcement practice to guide them through all manner of investigations, enforcement actions, and compliance issues. Our attorneys understand business and regulation and help our clients pre-empt, resolve or mitigate the impact of government investigations and enforcement actions.

A radical suggestion

Around the time of Fiona Godlee’s July 6 email, BMJ suggested that the entire data from the study be re-analyzed by a third party who had no prior contact with the issues. This would likely have taken a further year at the very least.

This was plain bizarre.

Intriguingly, Elizabeth Loder and I had both attended a Selling Sickness conference in Washington in February 2013, and in her account of the meeting in BMJ a few weeks later she floated a very similar proposal.

How medical journals can help stop disease mongering

“It would be hard to collect a more fascinating bunch of topics or people in a hotel conference room. The 2013 Selling Sickness conference recently held in Washington, DC was among the most thought provoking and just plain interesting conferences I’ve been to in a long while, and I go to a lot of conferences. This third conference in a string of international conferences was characterised by its organizers as part of “a global reform movement” against the “marketization of health, the corporatization of healthcare, and the hijacking of patient and consumer language to disguise market interests.” Opening speaker Shannon Brownlee identified “the different heads of the hydra” as “disease-mongering, conflict of interest, and overdiagnosis.” In her view, the challenge of this meeting was to identify these aspects of selling sickness and “weave them together in a systemic movement that promotes systemic changes.”

“I participated in a roundtable discussion charged with examining the news and communication perspective on disease-mongering, and was joined on the journal side by Jocalyn Clark of PLoS MedicineModerator Gary Schwitzer of HealthNews Review and panelist Nancy Shute considered the problem from the vantage of medical journalists. When it came time to examine how medical journals might address their role in selling sickness and disease mongering, I suggested two possible strategies.

“First, why not quarantine apparently ground breaking studies about new treatments or interventions in a special journal until the findings are replicated and long term consequences explored? Print copies of the journal would arrive in plain brown wrappers which undone would show the journal’s cover logo of a skull and crossbones. During quarantine, any news stories or summaries of research from this journal would travel with a sternly worded disclaimer, along the lines of those that accompany investment company advertisements. Something like the following would do nicely:

Warning! Taking any action on the basis of this research could result in injury or death. The results described in this study have not been replicated and the long term effects of this treatment are unknown. Past performance is no guarantee of future results. When subjected to further investigation, most published research findings turn out to be false.

“To fill the void, medical journals deprived of these sensational research studies could instead devote themselves to the promotion and prioritization of the less glamorous medical research that really matters: replication studies, comparative effectiveness trials, and long term pharmacosurveillance and safety studies.

“My second suggestion was that several parts of a typical research paper are too important to be written by the researchers or anyone else with a vested interest in the outcome of the research. These include the portions where “spin” is mostly likely to enter into the paper, namely the title, abstract, results, and conclusion sections, and any summary or “what this study adds” statements that authors are now sometimes asked to supply. These portions of research papers should instead be written by disinterested parties with subject matter expertise.

“I have no illusion that these things will come to pass but I can dream, can’t I?

“During the question and answer session fellow panelist Nancy Shute turned to me and said “I’m impressed by your radicalism.” I’ll take that as a compliment!”


One can wonder if Dr Loder ever suggested anything like this for any of Dr Silberstein’s articles, or GSK linked articles involving treatments for migraine.

While a suggestion like this didn’t appear formally in the correspondence between RIAT and BMJ, it was raised in behind the scenes negotiations.

Access to the data

On July 8, RIAT sent an email to Fiona Godlee outlining some of the points made above.  There was no response.

Have conflicting interests had an effect in this case?  There are data that can be consulted.

When finally published Restoring Study 329 came with a number of tabs, one of which is labeled Reviews.  As of this year it is BMJ’s policy to publish the reviews of articles along with the article.

One of the first Rapid Responses to the article was from Elizabeth Wager, a medical writer who has previously had close links with BMJ and who had reviewed previous articles about Study 329 submitted to BMJ that did not get published.  She asked where the Reviews were.  There was no response from BMJ.  I submitted a response to her letter indicating that the reviews were available in their entirety on  BMJ did not publish my response.

RIAT re-sent the July 8 letter to Fiona Godlee on September 30.  We have had no response.

My impression is that most people reading the entire correspondence on between RIAT and BMJ (mostly Elizabeth Loder) will agree that it shows an extraordinary level of difficulty. At several points the RIAT team came close to reaching the end of the line. The correspondence makes clear that some of us seriously entertained the view that BMJ did not want to publish.  By July 6 we were exploring publication options with other journals.

In my opinion very few people will think BMJ were not biased by something. You don’t have to trust me – you can access the data and make your own mind up. Against this background, Elizabeth Loder’s competing interests will raise eyebrows for some.

Not tonight. I have a headache

Did John Loder’s involvement with Ropes and Gray cause our problems?  In my opinion, no.

Did Elizabeth Loder’s prior links to GSK cause our problems?  In my opinion, no.

Did Elizabeth Loder’s headache expertise cause our problems?  In my opinion, no.  She was finicky but could have been a lot more finicky than she was.

The strongest evidence I have as to why there was such an unconscionable delay is that BMJ have been and still are scared close to shitless about publishing anything that might make a pharmaceutical company uncomfortable.

They have no problem publishing a Beasley et al paper that shows an increased risk of suicidal behavior on Prozac but claims there is no risk and that the data exonerates Prozac.  They have no problem publishing Lu et al in 2014 that claims to show warnings on antidepressants cause suicide – a shoddy piece of work if ever there was one.

Ironically providing access to the data seems to have increased BMJ’s difficulties. A key message from Restoring Study 329 is that when data is made available all authorship (interpretation) becomes provisional.  Despite apparent support for access to data, The BMJ want science to be authoritative – Biblical – rather than provisional.  If an article offers the indisputable Word of God, they can’t get sued.  If there is scope to read the matter in another way as David Linden’s Response to Restoring Stud 329 indicates there is and always will be, the BMJ and their lawyers have a problem.

In my experience journals run by ex-pharmaceutical company employees have been much more courageous than BMJ on matters like this.  However, while they appear to have lied at least twice in the process, BMJ are a long way from being the worst in terms of courage and integrity – they do, though, take some beating in terms of prissiness.

What was galling about the exercise was that BMJ (and everyone else who colludes to put BMJ and other journals in this position) see fit to turn their lack of guts around and blame our conflicting interests.

This is to be expected from people who have themselves been abused or are living in an abusive situation. Medication Time.

Study 329: Conflicts of Interest

BMJ September 2015

Email from Fiona Godlee (Editor of The BMJ) to RIAT July 6th 2015
Re: Study 329

Dear Dr Jureidini,

Many thanks for your letter. I quite understand you concerns. You are right to say that there are few or no precedents against which to compare this article. We ourselves are feeling our way, both with the RIAT process since this is the first full RIAT research paper we will publish, and with the specific challenges posed by this particular study and you as the paper’s authors. I want to stress that we are proceeding in good faith with the clear aim of publishing the article as soon as possible provided we can do so safely. …

All best wishes

Fiona Godlee FRCP
Editor-in-Chief The BMJ

The path to publication

BMJ state that it takes on average 8 weeks from submission to publication of an article. The review process for Restoring Study 329 took a year, with a three month review process involving six reviewers to begin with, and then a further four reviews in a four month process, leading to a provisional acceptance in March that was withdrawn.

Ultimately there were seven versions of the article. All versions and all reviews and responses are available on Restoring Study 329 (See – timeline to publication).

At the time of this email from Fiona Godlee it was far from clear that the BMJ were committed to publishing the paper.

Conflicting interests

The Lancet and BMJ were among the earliest medical journals. They began in Britain in the early nineteenth century with a public health brief.

Public Health began in an effort to contain contagious diseases. No one knew what lay behind epidemics of plague, smallpox, cholera and typhus. The problem might lie in abattoirs that sat in the middle of towns in those days or in the unhealthy constitutions of those who became ill. A lot of powerful interests were at stake.

In the absence of effective treatments, the public health movement stimulated a revolution by focusing on the environment and changes to it rather than on the individual. Removing the handle on the Broad Street pump offered a wonderful symbol of its mission to prevent disease rather than intervening to treat when it it was often too late.

While there might be nervous abattoir owners on one side, in the late nineteenth and early twentieth century public health science and politics and business were largely on the same side. The new science created opportunities for new research based businesses. Establishing that bacteria caused infections opened up the prospect of vaccines and antibiotics and helped the growth of the insurance industry. The wealth that came with these new industries lifted many out of poverty and in this way helped health just as much as they hygiene helped by preventing diseases.

The conflicts of interest at that point lay, as they had done since Galileo, between science and religious or political beliefs – between the evidence that vaccination helped and those who for religious or political reasons were opposed to vaccination or to people being forced to take vaccinations.

Twentieth century conflicts

With the development of bacteriology and the demonstration that bugs caused infections and the hunt for a Magic Bullet, the focus drifted back from preventing disorders to treating individuals. This environment is fine if you take your pills – antibiotics, antidepressants, statins whatever.

This development was linked to another. Because the development of modern science was so interlinked with the development of modern industry, industry were among the earliest to embrace “research”. Long before the Cochrane Collaboration began systematic reviews, the lead industry were systematically collecting all articles in the lay or scientific press about the effects of lead, in order to monitor the threat to their business and to be able to assess what lead blood levels might “wash” with the public and politicians. The industry also supported scientists in research projects to minimize problems. But minimization of problems did not mean doing studies to determine the lowest blood lead level at which biological effects became apparent. It meant studies that would minimize problems to industry.

Lead is not on the radar these days for people in the way it once was or in the way that it and other heavy metal poisonings probably still should be. The epidemiology of schizophrenia for instance shows an initial emergence of this disease in the nineteenth century and a more recent decline and this rise and fall parallels lead usage and lead levels. Dementia and a range of other diseases like cancer likely stem from environmental sources that have a basis in industrial pollution.

In part because the tobacco industry’s famous aphorism Doubt is our Product crystallized a modus operandi for all modern corporations, there is some awareness today that an increasing amount of “scientific” research is done to muddy the waters on questions of environmental induced diseases. This is a use of data against Science, a capturing of the Appearances of Science.

Dwight Eisenhower in a famous address in 1961 just before he left presidential office caught some features of this new world: “In holding scientific research & discovery in respect as we should, we must be alert to the equal and opposite danger that public policy could become the captive of a scientific and technological elite.”

Female genital mutilation

The situation we now have is something like as follows. You want to submit an article to our Journal on the benefits of Female Genital Mutilation? You must declare your “conflict” and we might decide not to publish no matter how good your data looks because this looks like data marshaled in support of a belief system rather than science proper.

This example is not all that far-fetched. Many books and articles routinely carry claims about the supposed results of studies demonstrating the health benefits of circumcision (MGM), about which all men have a conflict.

Whatever anyone’s beliefs about FGM and MGM, at the end of the day the power of science lies in an acceptance that we resolve issues with data. The idea that pharmaceutical companies can hang onto data by Force Majeure is the antithesis of science.

The new biology, pharmacology and trials-ology risks undoing Galileo and putting the individual back at the center of the universe. We can’t randomize environments but we can randomize individuals and if some drug produces a difference in a situation the simplest and most profitable conclusion will usually be that we have corrected a defect in the individual.

The new biology, pharmacology and trials-ology risks undoing the Bible even. The script is being rewritten to tell the story of a vulnerable Goliath, who while laboring away at making the medicines critical to all of us, and providing jobs, is at increasing risk from an unscrupulous and unethical David.

While there is the occasional headline such as a former editor of the BMJ resigning an honorary post from Nottingham University because it took money from the tobacco industry, the new rules of the game are as outlined by Fiona Godlee – anyone who has attempted on the basis of data to challenge a pharmaceutical company about the adverse effects their drugs cause must ipso facto be deemed to have a Conflict of Interest on a par with someone presenting data apparently showing health benefits from FGM.

The BMJ and NEJM reserve the right not to publish material like this, on the basis that while we are committed to resolving issues on the basis of data, anyone who has accessed data on this issue or in this fashion clearly has some strange belief system and must be deemed to be suspect – unlike companies like Pfizer whose actions follow the data in a disinterested fashion.

Medication time

What’s really going on is that journals are scared of industry. This is partly because the leading figures in medicine have become minions concerned more for the health of industry than the health of people and there is no-one who is likely to back up a journal willing to take a tough stand.

There is another reason. While data might really be new data – previously unavailable – the BMJ are scared that if they feature it they will be put out of business. Journals are a business that feeds on science rather than part of science.

These journals are caught in a 1960s style double-bind. They are dealing with a Nurse Ratchet, who writes friendly letters on first name terms to the journal’s Editor – Dear Fiona – but who has made it clear she will sue and put them out of business if they don’t play ball at medication time.

Close to the last thing a journal is willing to do today is feature any article about the biggest public health issue of our day – the biggest source of environmental toxicity – the morbidity and mortality caused by treatment.

In the face of a complex situation like this, the temptation as Daniel Kahneman told us 40 years ago is to resort to the Fundamental Attributional Error which is to look for who to blame. But rather than blame the powers that might house-arrest them (as happened to Galileo), the BMJ, along with society’s new religious authorities, locate the problem in Galileo – the person attempting to produce the data.

In the case of Study 329 there also appeared to be a desperate hunt for some box to tick that would make BMJ fireproof, some proof that the scurvy knaves behind the Restoration of Study 329 were adhering to some protocol that would make the results objective and definitive – exactly the opposite message to the message of the final article which is that the results are provisional and that objectivity as regards what these drugs do for good and for bad arises from having the data out there so they can be contested.

Science involves getting data into the public domain where it can challenge beliefs. But decades ago BMJ and other journals gave up on any attempt to access the clinical trial data behind the claims being made.

Now BMJ are signed up to an AllTrials coalition that includes GSK and is against Data Access.

Study 329 in Japan

jp paxil

Editorial Note: By 2002 GlaxoSmithKline had done 3 studies in children who were depressed and described all three to FDA as negative. As an old post on Bob Fiddaman’s blog reproduced here outlines, several years later they undertook another study in children in Japan.

Regular readers of this blog will know how I broke the news back in 2009 regarding GlaxoSmithKline’s attempts to push Paxil on kids in Japan. [See Here]

I was so outraged at this that I wrote to the Japanese Embassy and the Japanese Ministry of Health, more or less to give them a detailed view of how GSK had previously claimed Paxil was safe for kids to take…when in actual fact they knew that it wasn’t.

I never heard back from either one of them.

I also contacted GlaxoSmithKline in 2010, you can see the email I sent to them here.

In 2008, one year before I broke the news, Glaxo were recruiting kids for a clinical study. I say Glaxo, they, in actual fact were sponsoring the study.

The study was designed to compare the efficacy of oral paroxetine 10 to 40 mg/day (initial dose:10 mg/day) versus placebo administered once daily.

Oral paroxetine is a sickly orange syrup, I’ve been on it myself. It was the only safe way to taper from this highly addictive antidepressant.

And just who were being used as the guinea pigs in Japan?

One look at the inclusion study criteria would have showed you.

Ages Eligible for Study:7 Years to 17 Years.

Yup, that’s right folks. Despite being dragged through numerous courts in the US where evidence was shown that Glaxo manipulated previous clinical trials in children, here they were again back in 2008 recruiting more kids.

A marketing campaign went out in the form of a poster… which I just happened to obtain from a source at Medwatcher Japan. Medwatcher were also furious at this particular clinical trial involving kids and Paxil.

Take a good look at the imagery used in the recruitment poster.

The results

Well, folks… **drum roll** – the trial has been terminated.

According to GSK’s clinical trial database the study was terminated in 2011. They give no reasons as to why this study was terminated.

What we do know is that 56 kids were enrolled. 29 were in the Paxil group whilst the remaining 27 were in the placebo group.

The study results claimed that there were 3 reports of suicidal ideation in the placebo group but none in the Paxil group.

The subjects enrolled had to have a diagnosis of a depressive disorder before being allowed into the study.

So, it would appear that 3 of the kids taking placebo had suicidal ideation. Not one report in the Paxil group. Glaxo must have loved this.

Unfortunately for the Glaxo sponsored trial, Paxil didn’t really show much efficacy.

Open the Outcome Measures on the Clinical Trials website and it tells us how Paxil failed.

Paxil didn’t reduce the depression scores of the children sufficiently to be considered effective and the primary purpose of this study was efficacy. In this study all participants had to have a depression score of 45 or greater to be included. A 50% reduction on the CDRS-R is required to consider children have responded to treatment.

So, not only did Paxil not reach the standard for efficacy but in comparison to, let’s say, fluoxetine, it would be seen to be less effective.

In the Fluoxetine studies [1] [2] the average decrease was 28.9%. In this Japanese study, the decrease was only 16.9% therefore the kids would not be considered to have responded to Paxil treatment.

No wonder the study was terminated, right?

It would appear that GlaxoSmithKline didn’t want to expose the fact that Paxil is less effective than that of their competitor.

Another interesting finding from the Japanese study was the participants only had to have been free from any antidepressant for 1 week prior to the trial commencement.

Anyone who’s anyone will know that one week off an antidepressant is hardly a time to get the champagne corks popping and decorate rooms with bunting and balloons. Any number of these participants could have been suffering withdrawal even before they were entered into the Japanese trial. Any of these patients suffering withdrawal, which remember can mimic depression, would have had immediate relief if they were selected for the Paxil arm of the trial. As the phases of the trial progressed they would have, obviously, reaped the benefits of Paxil but not for their apparent depression, their benefits from Paxil would have merely meant they would not be going through withdrawal anymore.

Take the three patients from the placebo arm of the study who, according to the results, suffered suicidal ideation, and we may just find that these three were also taking antidepressants a week or so before they entered the Japanese study.

Could their suicidal ideation have been caused by the withdrawal effects of the medication they were taking prior to the Japanese study?

Glaxo pretty much shot themselves in the foot with this study, a study that should never have taken place given the findings of the Paxil 329 study.

So, once the Japanese trial was over did the sponsors, GlaxoSmithKline, do any follow-up to see if these kids were okay? The doses used in the study were between 10mg and 40mg, the latter being enough to put a horse into a coma.

The withdrawal phase of the Japanese study lasted three weeks. Two weeks later the participants were contacted to see how they were.

Can you imagine a 7 year old child on 40mg of Paxil a day just having three weeks to taper? Even if the 7 year old was on a lower dose it’s still mind-boggling how one adult human could give someone so young a pill known to increase suicidal thoughts, known to increase completion of suicide.

What on earth were GlaxoSmithKline thinking by using kids in a study for Paxil?

The Japanese public, particularly the children and adolescents, just don’t know what a lucky escape they’ve had from this truly awful abomination of an antidepressant.

Bob Fiddaman

[1] Psychometric Properties of the Children’s Depression Rating Scale–Revised in Adolescents – J Child Adolesc Psychopharmacol. 2010 December; 20(6): 513–516.
[2] Early Prediction of Acute Antidepressant Treatment Response and Remission in Pediatric Major Depressive Disorder – J Am Acad Child Adolesc Psychiatry. 2009 January; 48(1): 71.

Study 329: By the Standards of the Time

Uptown Research

Editorial Note: This post by Johanna Ryan looks at an element of the defense offered by Neal Ryan and others, namely that by the standards of the time the authors of 329 weren’t doing much wrong.

Getting real about clinical research

The controversy over “Study 329” on the effects of Paxil in teen depression has raised questions about the state of ALL medical research. What looked like a study conducted by leading psychiatrists from top medical schools turned out to have been controlled by the company. Individual patient data was hidden or distorted, statistical tests were massaged, and a company ghostwriter spun a narrative that turned an ineffective, risky drug into a safe and effective treatment.

Study 329 was performed in the 1990’s, and the resulting journal article was published in 2001. To this day no one has retracted that article. Top medical journals continue to publish drug-company directed research. When you search “the literature” for the best way to treat depressed teens, you will still find that 2001 paper and others like it (about which we know even less).

The ghost of research past

Study 329 was done at 12 research sites: two in Canada and ten in the U.S. For each site, there was a named author from a major university or teaching hospital actually involved in the research. However, while each of them knew more-or-less what went on at their own site, only the drugmaker knew the whole picture. SK had paid for the study. It ran the analysis, and it produced the draft paper that made the drug look much better than it really was.

The record shows the named authors worried that the results were being distorted, and that SK might leave them to take the blame if the facts came out. In the end, they signed on for whatever reason.

The paper mentions “treating clinicians” made the decisions about raising or lowering doses of paroxetine. Today GSK reassures us that the subjects’ treating doctors were responsible for following up on any problems they had during the study. The investigators apparently decided that none of the truly serious problems were due to paroxetine. Which means that they couldn’t explain to the Paxil Kids what had happened to them, or how to stay safe in the future. Neither, of course, could their colleagues – your doctor and mine.

The ghost of research present: Vraylar

The picture painted by Study 329 is scary, but what if there were fifty study sites instead of twelve, or 150 in several different countries? What if the academic “authors” of an article hadn’t laid eyes on any of those sites, much less been a Site Investigator?

What if the real Site Investigators were professional researchers-for-hire? What if they’d taken part in a hundred studies, but seldom if ever been named as authors? They wouldn’t have to worry if the study design was seen as biased, or the results too good to be true. Their reputations would not be on the line; they’d made their money, and the official “authors” could deal with the fallout.

What if the subjects had no doctors of their own, and were signing up for the study simply to get some medical care? What if their doctor was a professional researcher-for-hire? Either way, the subjects would be dependent on care from a doctor with an economic stake in the success of the study. This could affect their personal welfare, and the reliability of the study results as well.

What happens when a doctor under pressure to recruit subjects with “bipolar depression” is the same one diagnosing you with “bipolar depression”? What if you need, for your health’s sake, to drop out of the study, but “your” doctor needs to maximize the number of subjects who finish? What if you’re a patient with, say, a thyroid disorder or a drinking problem, who figures this will likely disqualify you from the study but you really need the free medical care, and the travel money will come in handy too. Will you be tempted to say Yes, when the integrity of the depends on your saying No?

One drug, twenty countries

I decided to look at the research for the most recent psychiatric drug approved by the FDA, a new antipsychotic called cariprazine or Vraylar. I located twenty studies of Vraylar on, the U.S. government-sponsored registry for clinical trials. Three were still in process, and seventeen were completed. Not one had shared its results on the government website, a supposedly mandatory step.

I found at least a half-dozen published papers directly based on these studies, although only two were posted on The average number of authors? Six to eight. The typical paper had a lone academic as “lead” author, the rest being drug company employees. Some had only employee-authors.

The average number of trial sites per study? Fifty-one. The “median” Vraylar study would involve 403 subjects at 65 different study sites in four countries! Together, the twenty studies spanned twenty countries, from Colombia to Bulgaria and from India to Finland. Unlike those U.S. academics on Study 329, I doubted these people would ever get together, in person or via e-mail, to compare notes and debate what the finished paper should say.

Unlike some sponsors, Forest did not share the site names with – only locations and ZIP codes. However, a few of the papers thanked various “investigators” by name. With some patient searching of PubMed, and Google, it was possible to identify many of the U.S. sites.

Overwhelmingly they were contract researchers. Some were freestanding clinical trial businesses. Others were busy medical practices with a thriving research business “on the side.” The first recruited subjects largely by TV, newspaper and online advertising which emphasized free treatment. The second combined some advertising with recruitment among their own patients.

A study like many others

I picked one study to focus on: “Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebo-controlled, Phase III trial.” It was published, available for free online, and it had a manageable number of study sites.

The lead author, Gary Sachs, is from Massachusetts General Hospital. His seven co-authors include four employees of Forest Pharmaceuticals in New Jersey and one medical writer from a Chicago agency hired by Forest. The last two, Istvan Laszlovszky and Gyorgy Nemeth, work for the drug’s original developer, Gedeon Richter in Hungary. They also hold patents on Vraylar, and are co-authors on most of the published studies.

The paper confirmed the study was carried out at ten sites in the US and 18 in India between February 2010 and July 2011. The authors acknowledged just 14 clinical investigators by name: six Americans and eight Indians. I was able to match all six named Americans with their research sites, whose numbers are listed in bold on the table below, and to figure out the identities of three of the four unnamed investigators using

None of the sites were anywhere near Mass General, or Forest’s Jersey City headquarters either; the closest was in Cleveland, Ohio, some 800 miles from Boston. It appears safe to conclude that Dr. Sachs did not give Vraylar to manic patients or observe the results himself.


# Location PI & hospital affiliation Organization Funding in 2014
001 Flowood, MS 39232 Joseph Kwentus, M.D.

Brentwood Behavioral

Precise Research Centers $897,985.70


002 Houston, TX


Carlos Herrera, M.D.

7 nursing homes

Heights Doctors Clinic




003 Creve Coeur, MO 63141 Franco Sicuro, MD

Advanced Geriatric Mgt

Millennium P.A.




004 Long Beach, CA  90813 Stephen J. Volk MD

Del Amo Hospital

Apostle Clinical Trials $393,715.86

005 Riverside, CA 92506 Sadashiv Rajadhyaksha, MD Clinical Innovations, Inc. None; license revoked 2012
006 Lake Charles, LA 70601 Kashinath Yadalam MD

Lake Charles Memorial

Lake Charles Clinical Trials $1,038,407.13


007 San Diego, CA 92123 Michael Plopper, MD

Sharp Behavioral

Sharp Behavioral Health Mesa Vista $304,782.89


008 Cleveland, OH 44109 [Unknown]


[Metro Health Medical Center] Unknown
009 Chicago, IL


John Sonnenberg PhD

[Michael Reinstein MD]

Uptown Research

Lakeshore Hospital

010 Oklahoma City, OK 73116 Willis Holloway Jr., MD

St. Anthony Hospital

Cutting Edge Research $600,995.75


The funding figures are posted online thanks to the Sunshine Act. The first number is the amount of research funding each doctor received in 2014, while the second tallies “personal” payments for consulting, speaking, and traveling or dining at company expense.

Two physicians had no figures for 2014. Dr. Rajadhyaksha surrendered his medical license in 2012, a year after our study ended, having been found guilty of sexually molesting two women patients. Clinical Innovations, Inc. is still in business but has lost its Riverside “campus” for now. Dr. Reinstein lost his license in August 2014, and is headed for federal prison. But more about him later.

Our lead author, Dr. Gary Sachs, reported no drug-company research funding in 2014, and a mere $4,713.20 in personal payments! With over 100 published articles and a seat on the Harvard Med School faculty, he’s clearly a bigger name in his field than Joseph Kwentus or Kashinath Yadalam. I’m sure there are rewards for such eminence. However, they don’t come from clinical trials these days, at least not directly.

Start your journey to mental health treatment

At Precise Research Centers, just outside Jackson, Mississippi, they don’t make picky distinctions between research and treatment. “Precise is one of the top depression clinics in Mississippi. Dr. Joseph Kwentus is one of the nation’s leading bipolar doctors,” their website declares. Their ads on local TV help you figure out if you are depressed, and tell you where to go for free help.

At Lake Charles Clinical Trials, “A Place Where Change Is Possible,” Dr. Yadalam will even put you in touch with the local chapter of NAMI, the National Alliance for the Mentally Ill. He’s been a board member since 2002. At the Heights Doctors’ Clinic in Houston, a banner outside the clinic in Spanish and English promises “Experimental Medications, Free.”

Dr. Holloway takes another approach. His Oklahoma clinic is actually three facilities in one: Cutting Edge Clinical Trials; Holloway & Associates, his own psychiatry practice; and Optimal Health Weight & Wellness, which treats obesity, chronic fatigue and sexual dysfunction. (If you wonder why a psychiatrist is running a weight-loss clinic, consider the number of new drugs recently tested in this area.) Dr. Herrera at the Heights Doctors’ Clinic also combines a busy internal medicine practice with a clinical-trials business.

Sponsors: Click here for our metrics!

These doctors do have reputations to protect. The sponsors, mainly drug companies, want volume, reliability and speed. While experience and efficiency count, often the first one to recruit ten patients with Condition X wins the contract. Apostle Clinical Trials, like many sites, posts its recruitment statistics online to impress sponsors.

These centers are located outside the major cities, or in low-income areas. Black and Latino Americans may be more likely than whites to find one in their neighborhoods. Some patients, especially immigrants, may be uninsured. Many are on disability, with low-paying public medical plans that aren’t accepted by many doctors. Others have insurance that requires large out-of-pocket payments. For ambitious trialists, a “patient base” like this can be an asset. They get access to lots of people with serious conditions like schizophrenia or multiple sclerosis. Rates of hypertension and diabetes are well above average. And as one of my local trial sites explains, “managing retention” can be easier with a “diverse” population and a clinician-trialist who knows how to talk to them.

Clinical research: An offer you can’t refuse?

Most of this was nothing new. What I didn’t expect was that eight of our ten sites would have close links to (mostly for-profit) inpatient psych units or nursing homes. Dr. Volk is on the staff of Del Amo Hospital, part of the huge Universal Health Services (UHC) chain. Dr. Kwentus is medical director at Brentwood Behavioral Health, the UHC hospital down the road, and his trials are promoted on Brentwood’s website. Lake Charles Memorial does the same for Dr. Yadalam, its former chief of psychiatry and still on its medical staff.

Dr. Plopper is both chief of staff and chief of research at Sharp Mesa Vista, and Dr. Holloway directs the special program for “resistant” youth ages 12-17 at St. Anthony’s in Oklahoma City. Uptown Research offers sponsors an “affiliated inpatient hospital” – Chicago Lakeshore. Dr. Herrera is on staff at seven Houston-area nursing home. Dr. Sicuro, our top doc in research funding, heads a geriatric psych practice which is likely nursing-home based. (In many states, long-term care and housing for people with serious mental illnesses is left to the private nursing-home industry.)

When you hear “private psych hospital” you may think wealth and privilege. Think again. Today’s successful player in the U.S. market is usually investor-owned, often part of a national chain, and may qualify for federal aid due to its “disproportionate share” of poor patients. It also has a keen interest in “non-voluntary” patient groups: troubled teens, people with psychotic disorders, elderly folks with dementia. UHS has opened special units for active-duty soldiers as the military hospitals overflow, and a few companies have won state contracts to treat prison inmates.

In most U.S. states, you can be held involuntarily for brief but renewable periods if you are judged an immediate threat to self or others. Online patient reviews for these hospitals are striking, not for their general negativity (expected), but for the number of people claiming they or their loved ones were kept against their will. Many allege that “suicidal statements” were coaxed from them or fabricated outright. In California, they talk of “5150’s”, while in Florida it’s the “Baker Act.” In Illinois, the good old 72-hour hold seems to have magically grown to five days at Chicago Lakeshore. In all cases, padding the bill seems the obvious motive. Could research be another?

From Dan Markingson to Michael Reinstein

All of this has echoes of a recent, infamous human-research scandal: the death of Dan Markingson in a clinical trial of antipsychotic medication at the University of Minnesota. The hospital made Dan an offer he couldn’t refuse: Sign up for the trial, and they’d agree not to have him forcibly committed. How he could be ill enough to warrant commitment, but not too ill to “consent”, was never explained. In any event, Dan was kept in that trial, despite evidence that he was getting worse on the new medication, until his death by suicide in 2004. It took another ten years for Dan’s mother and a few tireless faculty activists to defeat the University’s coverup campaign.

Which brings us back to Uptown Research Institute and its founder Dr. Michael Reinstein. Chicago’s Uptown neighborhood was for years a hub for rescue missions, flophouses and large nursing homes where thousands of people with serious mental illnesses were (and still are) warehoused. Reinstein amassed a small fortune there, providing psychiatric “care” to as many as 4,000 patients in 13 nursing homes, and parlaying his clout as a mass prescriber into a second career as a paid Pharma researcher and lecturer. Astra-Zeneca, makers of Seroquel, were his first clients, followed by various makers of clozapine, one of the riskiest drugs in psychiatry.

The results, as reported in a 2009 expose by ProPublica, were horrific: Patients “trembled, hallucinated, lost control of their bladders … Staffers said Reinstein had induced some patients to take powerful psychotropic drugs with the promise of passes to leave the home.” Reinstein’s role as the “Clozapine King” of Uptown also resulted in at least three wrongful-death lawsuits.

In 2014 Reinstein lost his license and was charged with felony fraud. Following the 2009 expose, however, control of Uptown Research passed to cofounder John Sonnenberg, a psychologist, who disavowed any further connection to Reinstein. However, Sonnenberg was not a physician. An M.D. was needed to give and monitor medications. Reinstein was still practicing out of a storefront next door to the Institute. If he wasn’t the physician, who was?

All indications are that Reinstein was active in the research at Uptown through at least 2012 – including the period of our Vraylar trial. We don’t know how many Dan Markingson-type tragedies Reinstein was responsible for. But a look at this single study is enough to convince me that other Dr. Reinsteins must be out there – and the system has no way to stop them.

What does it all mean?

Why was the “Sachs study” of Vraylar for mania limited to three weeks? Why were the subjects offered so many extra medications to relieve side effects, from benzos and chloral hydrate to Ambien? If a 4-7 day “medication washout” period was needed at the beginning, what meds were people taking, and how did stopping affect them?

I can’t answer those questions, but I have one of my own: Given what we know about the study’s structure and the system it took place in, how will we ever arrive at any reliable answers?

First, in many cases it may do no good to put pressure on medical-school faculty (or their schools) to share the data, when they themselves know so little. Med Schools now have more in common with celebrities lending their names to a new cologne or athletic shoe than with scientists actually testing a new treatment. The drug companies may be the only source of information.

Second, when investigators have an economic stake in both the trial and the patient’s treatment, patients’ rights and safety are up for grabs. In addition, any diagnoses and treatment records coming out of this system may be valid – or may be fictions created for one billing purpose or another. In other words, the integrity of the research is also up for grabs.

Third, the popular idea of a patient research boycott may simply not work, at least in countries where healthcare is not a right. It’s often said that people volunteer for trials for two reasons: Their conditions haven’t responded well to standard treatments, and they also want to help others by contributing to medical knowledge. If patients just refused to participate in trials, the reasoning goes, they could force study sponsors to agree to open data sharing.

The assumption is that the boycotters can simply go back to “standard care.” In the U.S. and other countries, many don’t have that choice. When patients are dependent on the researcher for medical care, how many will just say no? The problems multiply when psych patients are treated against their will – which may be on the rise in national health systems as well as privatized ones.

The ghost of research future

The focus of reform movements so far, including the landmark expose of Study 329, has been on fighting for open data. Conflicts of interest, and even pharma sponsorship of the research, some say, would not be insurmountable problems if we just had access to the raw data.

In the course of this research, however, I bumped into some emerging trends that might lead to a system where raw data no longer exists, at least as we think of it today. But that’s for the next article.

Study 329: Minions No Longer

Good Pharma

A few weeks ago I was asked to review Good Pharma by Don Light and Antonio Maturo. The published review appears in TES – here. It makes a great foil to the Data Wars post earlier this week. The problem was deciding if the title for this post should read Minions no Longer or Underlings no Longer – let me know your thoughts.


Whatever you think of his politics, there was a certain magnificence to Yannis Varoufakis in the recent Greek crisis. Imagine if he had won. It would have been a victory straight from the pages of Asterix the Gaul.

Well Good Pharma is straight from the pages of Asterix, except in this case the little guys facing off against the Imperial Forces are Italian, standing up initially to the Franco-German pharmaceutical industry and latterly an American industry. The irony here is that, Ho Chi Minh-like, the little guys took their inspiration from the American way of doing transparent and egalitarian research in the 1950s only to find themselves now pitted against those they once admired.

Good Pharma is the story of the Mario Negri Institute which is based in a working class suburb of Milan. Mario Negri was a wealthy patron who on his death in 1960 bequeathed a large sum of money to support independent pharmaceutical research to an upcoming researcher Silvio Garattini. At the time new drugs were spilling out of the pharmaceutical industry in abundance – psychopharmacology had just come into being and Garattini had played a part in its birth. New techniques to detect ever smaller amounts of drugs or neurotransmitters or toxins were also emerging and this played straight into Garattini’s strengths. Garattini and Alfredo Leonardi set about building an Institute centred on the new drugs and new techniques.

Trying to make their way in the world they were met with bemusement at their presumption that anyone stood anything to gain from linking to them. Five decades later having faced down the Italian government, the European regulator, GlaxoSmithKline and endless pharmaceutical companies, no-one even thinks about dismissing them.

Major discoveries in cardiology have come from their organization of the some of the first mega-trials in medicine; major discoveries in chemotherapy have come from pioneering research on new compounds; major discoveries in environmental toxicology from their abilities to detect toxins and more recently drug residues in the environment. There are probably very few families anywhere whose health has not benefited from Mario Negri discoveries or Mario Negri resistance to industry or to political efforts to cut corners or fudge data.

They continue to grow without ever having patented any of their many discoveries or concealing any of the data from experiments that didn’t work out or accommodating any of their trials to industry’s wishes. Reading this history, it feels that if there is a sign saying the conventional wisdom points left, Mario Negri have gone right, until you realize that in fact what has happened is what they’ve done was widely supported in the 1960s and it’s the field that has gone the opposite direction not Mario Negri.

Almost everyone has heard of the Cochrane Collaboration, but Mario Negri were pioneering these paths 30 years earlier and doing so across the full range of medical disciplines rather than just clinical trials. Hard-bitten ex-Army type insiders like Tom Jefferson who took on Roche over its claims about Tamiflu and won view the Mario Negri operation with awe but it’s more than it’s worth for industry to let anyone know that there is another way of doing things. If this caught on in medicine, who knows the example might spread to the wider economy.

Press release

Work began on Restoring Study 329 in September 2013. Almost the week it started the BMJ carried an editorial outlining a bitter dispute between Mario Negri and GSK. As now, GSK were then trumpeting their embrace of transparency. But it was transparency on their terms it seems. See below and link to the BMJ.

The Mario Negri Institute does not bow before GSK

Milan, September 2013 – An editorial in the authoritative BMJ ( refers to news that has caused a sensation in the scientific community. The Mario Negri Institute for Pharmacological Research, a non-profit independent foundation, has withdrawn its involvement in an Innovative Medicines Initiative (IMI) project that was funded 50% by the European Union and involved the clinical research and development of a product owned by GlaxoSmith&Kline (GSK).

The Mario Negri Institute withdrew because GSK wanted to control to whom the data could be disclosed and why, as well as what could be published and when. GSK aims to keep control of the study with regard not only to the scientific community but even to the clinical investigators involved.

“Secrecy on clinical data”, comments Silvio Garattini, the Director of the Mario Negri, “implies undue exploitation of the rights of physicians and patients involved in the studies: in the end the data belong to them.”

The Mario Negri Institute did not want ownership of the data. “We never do that”, continues Garattini “since it is against our ethical principles”. It is known that the Mario Negri Institute does not patent its discoveries and publishes all information for the benefit of the scientific community, patients, and the public.

GSK’s demands are even more inappropriate in the context of an IMI project. “The Innovative Medicines Initiative”, points out Vittorio Bertele’ who participated in the negotiation with GSK,

“supports collaborative research projects with EU funds in order to boost pharmaceutical innovation in Europe. The pharmaceutical companies make the raw products available, but it is up to patients and clinical investigators to develop them, in this case with public funds.”

The Mario Negri Institute researchers only asked that the clinical investigators involved in the study were allowed to look at the overall raw data before publication of the final report. It would have been paradoxical for the authors to have had no chance to look at all the data.

Instead”, emphasizes Guido Bertolini, coordinator of the clinical network that should have been involved in the study,

“we had to discuss with GSK lawyers specious details of a draft agreement that was aimed at leaving GSK in full control of the conduction of the study, data analysis and publication of results.”

This was not acceptable to the Mario Negri researchers and GiViTI, the network of intensive care centres that would have taken part in the study.
Because of the failure to come to an agreement with GSK the Mario Negri no longer has access to the IMI funds.

“This is a substantial sacrifice considering the hard times we are facing”, Garattini concludes. “However, we could not renounce our principles and betray the trust of people who support our research.”

The issue raised by the Mario Negri Institute echoes a problem well known to the scientific community: the need to avoid that commercial interests, however legitimate, prevail over patients’ rights which can only be ensured by the independent planning, conduct and evaluation of clinical research studies.

BMJ. 2013 Sep 4;347:f5354. doi: 10.1136/bmj.f5354.
A failed attempt at collaboration.
Garattini S, Bertele’ V, Bertolini G.
IRCCS-Mario Negri Institute for Pharmacological Research, Milan, Italy.

Editorial – Here

Study 329: Data Wars

What does your doctor know about your medicines?

Sensing the end of the Roman Republic and unhappy at the approach of Empire, Cassius approached Brutus to save the Republic.

“The fault, dear Brutus, is not in our stars,
But in ourselves, that we are underlings.”

The Republic was a Democracy, with a Government answerable to its Electors. Caesar’s conquests meant that the Roman Government was now responsible for swathes of people who would never elect it but who needed to be managed through an apparatus involving Roman Law and military jurisdiction.

The Republic was a place where every Elector could believe that his fate lay in his own hands – that his position was not pre-ordained (in the Stars). He did not have to be an underling.

In an Empire, the apparatus ordains your place and one way or another it is that of an underling.

In the late 1950s, perhaps because he was based partly in Rome, sensing a change in his native America, Gore Vidal warned that the Republic was changing into an Empire. He warned his countrymen that while the world had admired them for their values up till that point, while almost everyone aspired to be an American, they would soon face a world where an increasing number of people would cheer were the Empire to Fall.

The advent of Empire turns values inside out. The transformation in American values was stunningly demonstrated a few years later.

Taking his inspiration from the Foundation of the American Republic, Ho Chi Minh established the Democratic Republic of Vietnam, and in his inaugural address quoted from the Declaration of Independence:

“All men are created equal. The Creator has given us certain inviolable Rights: the right to Life, the right to be Free, and the right to achieve Happiness”

He called on America to help him overthrow the French but by 1963, American Legions were pouring in to put down the Republic and secure Vietnam for “Our way of life and our values”.

Crossing the Rubicon

It can be difficult to pinpoint transitions. The Rubicon that led from a Medical Republic to a Pharmaceutical Empire was crossed in 1962 with the passage of the Amendments to the Food and Drugs Act. This act put in place an apparatus of controlled trials, prescription-only status and disease indications that laid the basis for a global pharmaceutical hegemony, although the drift to Empire could still have been stopped at this point.

It took a while for anyone to notice the threat to the Republic. In the 1970s, sensing a growing threat Ivan Illich inveighed about our approaching Medical Nemesis. One of the few to have a clearer sense of the problem was Louis Lasagna, who was in significant part responsible for the 1962 amendments (See Not So Bad Pharma and The Empire of Humbug and the following 6 posts).

Looking back at the 1980s we can now see the coming Empire as a $30 Billion clinical trials industry run by a new breed of satellite companies (CROs) took shape, as a process was put in place that rapidly led to over 90% of academic articles about on-patent drugs being ghostwritten, as the US patent system was extended globally in the form of TRIPs, and how in 100% of cases the data from controlled trials, that had previously been readily available in the Republic of Science, was sequestered.

The new Empire swallowed the Medical Republic. And values turned inside out.

In the Medical Republic an article like that of Marty Keller and colleagues (Study 329) stating that a drug was Safe and Effective would be taken to mean safe and effective for patients. In the Pharmaceutical Empire, the words mean Safe for GlaxoSmithKline and Effective at generating profits.

When a drug scare hits the headlines and regulators talk about the risk-benefit ratio for the drug still being favorable, they are talking about managing the risks to companies rather than to patients.

In the Republic, medicine’s reach was limited to diseases like melancholia, tuberculosis or heart attacks. In the Empire, healthcare manages SSRI, Statin and Bisphophonate deficiency disorders. Left untreated these will kill the company.

In the Republic Controlled Trials were about limiting the use of drugs; in the Empire Controlled Trials fuel the Therapeutic Bandwagon.

In the Republic Guidelines offered guidance about what not to do; in the Empire Guidelines are Diktats – what must be done.

In the Republic patients entering trials signed Informed Consent forms; in the Empire they apparently sign Confidentiality Agreements.

In the Republic, the CEO of a pharmaceutical corporation might try to meet with the head of an academic medical department or professional grouping but would not have been surprised to be left waiting at the door. In the Empire, heads of university departments are lucky if they can get access to centurions fairly far down the Pharma pecking order.

In the Republic, the leaders of a medical group would welcome a call to the field to insist on the absolutely central notion of science – access to data.

In the Empire, you can expect a recent President of the American Psychiatric Association to get ad hominem:

“The group (Le Noury et al) is a self-appointed watchdog,” Jeffrey Lieberman, chair of psychiatry at the Columbia University College of Physicians and Surgeons, told BuzzFeed News. “One wonders what the motivation is, and how objective they’re going to be.”

Lisa Cosgrove and Bob Whitaker in their recent book Psychiatry under the Influence describe this effect as an illustration of economies of influence.

The change has transformed the former Medical Senators into Minions.

And we, the former Electors, have become Consumers. We consume the security the Empire offers. As Margaret Atwood would say:

We have been given Freedom From in exchange for Freedom To.

Sense about science

Simon Wessely and Clare Gerrada are the power couple of British Medicine. He is the current President of the Royal College of Psychiatrists, and she is a recent President of the College of General Practitioners. When faced with questions about over-prescribing of antidepressants by GPs, she is quick to insist that GPs rarely treat distress and that almost all prescribing is for genuine illness and the drugs work well. He gives similar messages in respect of psychiatry.

These messages look one way in a Republic but look quite a different way in an Empire. If the drugs work well and Evidence Based Medicine is all its cracked up to be – who needs doctors. Nurse are cheaper. Defending doctors needs a very different message. It needs an Expertise Based Medicine.

The existence of a group like Sense about Science of which SW is an advisor also looks very different in an Empire setting.

Sense about Science began in Britain 15 years ago with donations from Corporations in the Risk Management Business – from Monsanto through Nuclear Power to Pharma. These donations have vanished from sight now, replaced by endorsements from all major UK universities and journals like The BMJ and support from Charitable Foundations.

SAS’s stated mission would have appealed to someone like SW who had come under attack from a lot of fringe groups in the 1990s for taking a balanced data-driven approach to Chronic Fatigue Syndrome (M.E.).

But SAS has now become a node to handle any messages in the media that might hurt the interests of a company or corporate sector – such as anything to do with vaccination or my recent editorial on So Long and Thanks for all the Serotonin. BMJ sent this article (as they send all articles) to SAS who got in touch with SW to rustle up statements from Jeff Lieberman types which can be disseminated widely to the media either for citing or as a means to close down stories:

You might not want to take Healy’s work seriously in the light of what these senior figures in the field are saying.

Sense about Science has since spread to Canada, Australia and now the United States and everywhere the mission is the same.

AllTrials & AllData

SAS was a founder of AllTrials. This sounds like AllData – the hashtag for Restoring Study 329 – but at the moment it is quite the opposite.

There has been close to radio silence from AllTrials in the face of the call for AllData, aside from one stunning press release that more or less credits GSK with the efforts to Restore Study 329.

17th September 2015
Many supporters of AllTrials will be interested in a study published in The BMJ today, a reanalysis of previously hidden clinical trial data. The new research used data from a 1990s clinical trial of the GlaxoSmithKline (GSK) antidepressant drug paroxetine. Today’s findings contradict a 14-year-old analysis of the data referred to as Study 329, which found paroxetine to be safe and effective for treating adolescents with major depression.

The new research is the first reanalysis of a drug study under the RIAT (Restoring Invisible and Abandoned Trials) initiative, which calls on companies and academic funders to publish detailed trial information for independent scrutiny. The RIAT team was able to access the original clinical trial data using GSK’s patient-level data access portal, where researchers can request access to this information.

Tracey Brown, Director, Sense About Science and co-founder of AllTrials:

“When all trials are registered and results reported, it becomes possible for researchers to work out what data are available. GSK has gone further and made its patient level data available to researchers. It is disappointing that there are still so many companies not reporting trials. Researchers, doctors, patients and, in July, their shareholders have said they want transparency about trial results. This will confirm their views.”

Sir Iain Chalmers, coordinator of the James Lind Initiative and co-founder of AllTrials:

“Among pharmaceutical companies, GSK under its current management has led the way in promoting clinical trial transparency and provides a practical mechanism to make trial re-analyses possible. The reanalysis of Study 329 illustrates the knowledge dividends from the company’s new policies and contrasts strikingly with the scientific misconduct that characterised the company’s behaviour under previous management. Today’s GSK has shown moral and scientific leadership that puts to shame many in the academic community.”

Pontius Andrew?

Faced in 2012 with questions about the $3 Billion fine imposed on GSK, triggered by a sequence of events starting with Study 329 – is it just the cost of doing business? – Andrew Witty snapped back:

“Although corporate malfeasance cases end up looking very big, they often have their origin in just… one or two people who didn’t quite do the right thing. It’s not about the big piece. The 100,000 people who work for GSK are just like you, right? I’m sure everybody who reads the BMJ has friends who work for drug companies. They’re normal people… Many of them are doctors”.

Everything about Study 329 suggests that Andrew is comprehensively wrong. Corporate malfeasance happens when the system is set up so that the efforts of 100,000 well-meaning people get transformed into the worst of outcomes and it then takes the efforts of a few brave people within GSK to alert the outside world to how things are going wrong.

In tackling these issues, I’ve had more help from colleagues in industry and more grief from clinical colleagues so I’m sure the 100,000 people who work for GSK are at least as good as the rest of us – just as Roman legionnaires were no different to the rest of us – and that some of them are very brave indeed.

Good rather than evil is more likely to happen when people buck the system. The Nazi Oskar Schindler may have been a much better person than Eugenio Pacelli (Pope Pius XII).

“The fault, dear Andrew, is in our stars,
Not in ourselves, that we are underlings.”

It’s the pre-ordained system (our Stars) within which we work that dictates how we behave or the outcomes of our behavior. Systems can twist good intentions such as those of Louis Lasagna into a disaster and lead you to execute someone even when your wife tells you the previous night you are making a bad mistake.

Rip van Keller

As I read it, Marty Keller and his colleagues, the authors of the first published interpretation of Study 329 figured they were operating in a Republic. Their study was designed in 1992 to address substantial issues – were the SSRIs going to be significantly different to older antidepressants.

Their correspondence points to bewilderment at the turn of events.

But where Sally Laden under oath described her relationship with GSK honestly, while Marty Keller’s body language made it clear he was painfully aware of how it would look, under oath in 2006 he resorted to a convenient amnesia rather than telling it as it was.

GSK were working with the cream of the bunch. There are some wonderful people in the group such as Rachel Klein, Gabrielle Carlson and Stan Kutcher.

There are many people in this group – and among their contemporaries – who could tell us more about what it’s like to go to sleep in a Republic and wake up in an Empire.

Whether from someone in this or another generation, we need help to find a way out of being Underlings.


One of my consultants (SC) has drawn my attention to the following promotional material for the recent movie Minions:

Evolving from single-celled yellow organisms at the dawn of time, Minions live to serve, but find themselves working for a continual series of unsuccessful masters, from T. Rex to Napoleon. Without a master to grovel for, the Minions fall into a deep depression. But one minion, Kevin, has a plan – the plan does not involve taking an SSRI.

The Minions adopt Vivien Greene’s slogan:

“Don’t wait for the storm to pass, learn to dance in the rain”.

It doesn’t get more ambiguous than this – “Vivien Greene has been consulted by many corporate leaders anxious to marry her visionary message with the corporate bottom line”.

Study 329: MK, HK, SK, GSK & History

The Doctor exhibited 1891 Sir Luke Fildes 1843-1927 Presented by Sir Henry Tate 1894

The Doctor exhibited 1891 Sir Luke Fildes 1843-1927 Presented by Sir Henry Tate 1894

What happened to those suicidal in study 329?

In May 2014, the RIAT team asked GSK what the children who became suicidal in the course of Study 329 have since been told. (Marty Keller’s “take” on this is at the bottom).

The consent form says that anyone entering the study would be treated just the way they would be in normal clinical practice.

In Study 329, the children taking imipramine were by design force titrated upwards to doses of the order of 300 mg, which is close to double the dose of imipramine given in adult trials by GSK or in normal clinical practice.

In normal clinical practice it would be usual to inform somebody who had become suicidal on an SSRI that the treatment had caused their problem.

  • It is important to the person’s image of themselves, that they are aware this problem might have come from the drug rather than from themselves.
  • It is important that they be told that they are likely to react in the same way to any other serotonin reuptake inhibitors – including some antihistamines, isotretinoin and some antibiotics and that they should be cautious about such treatments in the future.
  • It is important the patient’s family be warned about this adverse event as some blood relatives will be more susceptible to commit suicide on an SSRI than the rest of the population might be.

Responding to our letter, GSK’s Dr James Shannon made it clear that 20 years later the company have still not informed any of the participants in Study 329.

One reason he offered was that it had only recently been agreed these drugs posed risks. [One of the features of GSK’s response to the published study appears to be a public acceptance that SSRIs do cause suicidality in at least this age group].

But the key reason for not doing so that he offered was that:

As I have mentioned in my earlier letters, it is standard in clinical trials carried out according to good clinical practice guidelines for our trial investigators and treating physicians to be responsible for patients’ medical care during and after a trial. This would include the management of any adverse experiences that arise during the trial. Being closest to patients’ medical histories, they are best placed to do this and we are confident of their commitment to provide the care patients need.

This may be the first recorded appeal to the use of the Learned Intermediary doctrine in clinical trial settings.

One lesson of the 329 story is that without access to data, the learned intermediary doctrine is supremely dangerous for patients – and for doctors.

Learned what?

The notion of a learned intermediary arose in the 1950s when the first reliably effective drugs emerged, when an ‘ethical’ pharmaceutical industry distinguished itself from a patent medicines industry by advertising to physicians only, when Congress decided to make all new drugs available on prescription only.

Doctors then were seen as a bulwark against pharmaceutical advertising, by inclination and by training more likely to resist the pressures of advertising than the rest of us.

This was a Marcus Welby world, in which the forerunners of today’s mega-corporations were still divisions within chemical corporations and were run by doctors or scientists rather than by marketing people.

Just as prescription-only status is a police function, the idea of a Learned Intermediary is a legal notion. Neither have anything to do with the practice of medicine.

The term ‘learned intermediary’ was first used in 1966 in Sterling Drug Inc v Cornish, 370 F.2d 82 (8 Circuit):

‘we are dealing with a prescription drug rather than a normal consumer item.’ In such a case the purchaser’s doctors is a learned intermediary between the purchaser and the manufacturer. If the doctor is properly warned of the possibility of a side effect in some patients and is advised of the symptoms normally accompanying the side effect there is an excellent chance that injury to patient can be avoided’.

Based on the doctrine, it is held that:

  • Warnings about a medication’s hazards need only go to physicians because they are the only people that know both a particular patients medical history as well as the risk profile of the drug being prescribed.
  • That directing routine prescription drug information through the doctor in this way preserves the physician patient relationship from outside interference.
  • That the complicated medical terminology necessary to explain the risk benefit profile of prescription drugs is difficult for ordinary patients to understand.
  • It is more effective for drug companies to have to communicate with physicians only rather than directly with all potential patients. [This assume drug companies will tell physicians the truth].

329 & learned intermediaries

The doctrine is premised on the notion that the physician is an objective intermediary who will draw an independent judgment about the best course of treatment for his or her patient.

Two factors have been put forward as compromising the objectivity and independence of doctors – gifts and Direct to Consumer Advertising (DTCA).

But 329 opens up a whole new dimension.

When the learned intermediary doctrine was introduced most information about drugs came from doctors writing up their experience in case studies or running trials where they were in possession of the data and they wrote the manuscripts about what the trial had shown. There was some sales pressure but almost no marketing pressure.

  • From the 1980s, companies ran trials, increasingly hiring second rate investigators to tick the protocol boxes, and latterly locating trials in third world settings where there can be no guarantee the patients exist.
  • From the 1980s, an increasing proportion of the clinical literature about on patent drugs has been written within companies or by ghost-writers. That proportion is likely now over 90%.
  • From the 1980s, companies have sequestered clinical trial data so there is no independent oversight of what this data shows. Not even FDA get to see all the data.
  • From the 1980s, the pharmaceutical companies were on their way to being the profitable corporations on earth, managed no longer by doctors or pharmacologists but by business men with a background in marketing.

In this new world:

  • Few doctors can distinguish between sales and marketing.
  • Few doctors appreciate that RCTs, adopted in 1962 to contain companies, are now the major marketing tool of companies.
  • Few doctors appreciate how adept companies have become at marketing diseases as a means of selling their drugs.
  • Few doctors appreciate that companies make most money from marketing risks such as marginal elevations of cholesterol levels or reductions in bone density, where if the patient takes a medicine they take on risks with little likelihood of benefits.
  • Few doctor appreciate that Safe and Effective in Keller et al 2001 means Safe for GSK and Effective for GSK not safe and effective for their patients.

While there is something to be said for a Learned Intermediary in medical extremis, when a person’s judgment may be compromised, there is much less to be said for having a third party make a judgment call that requires you to accept risks they would not personally accept, for benefits that are unlikely.

Cause and effect

When the Learned Intermediary doctrine was introduced, doctors were trained in how to determine cause and effect in terms of the adverse effects of a medicine.

The way doctors assessed such events through to the SSRIs and Suicide was in line with what the Federal Judicial Reference Manual outlines to this day. Broadly speaking if exposure to a drug produces a problem (challenge) and the problem clears up on stopping the drug or reducing the dose (de challenge) and reappears on re exposure to the drug (re challenge) this is definitive evidence that the drug can at least cause the problem in some of those who are exposed to it.

However under company marketing pressure most doctors have been persuaded that such evidence is anecdotal. That the only evidence of cause and effect that counts is the evidence that comes from controlled trials. For 25 years doctors across medicine have been systematically educated to override the evidence of their own eyes.

  • As a result major problems that came to light quickly in the 1960s may now take 10 or 20 years to be accepted by the field as caused by treatment.
  • As a result drug induced death is now a leading cause of death.
  • As a result, even in the face of Black Box Warnings a majority of doctors may still believe there is no evidence that these drugs can cause this problem.

This extraordinary situation has arisen because in their defense of Prozac 25 years earlier, Lilly deployed selected data from sequestered RCTs and a sophisticated understanding of doctors, to counter compelling clinical evidence that Prozac could cause suicide.

This is caught in this quote from Leigh Thompson, who was coordinating Lilly’s efforts in 1991, contrasting the fate of Prozac with that of the 1980s Oraflex (Opren):

Today at PSC was Medical’s finest hour. Dave Thompson and Gene Stap told me that it suddenly gave them a glimpse of how far medical has come and the vision that they knew (about global databases, super handling of ADE, proactive excellent relations with FDA, complex analyses and presentations made simple, DEN, GPT etc) but had never really had burned into their brains the elegance and mastery of the complexity!

So many of us were not here for the Oraflex , Moxam, etc crises, that it is very hard to measure the progress over the last few months on so very very many fronts.

When you battle the media and politicians, the only thing that counts is the first word. The rebuttals are always on the last page and forgotten. You have to get out front and enlist your allies. The rapid flights to Boston to visit Teicher, the trips to FDA, the consultants coming in, the huge complex database, having so many large trials, the ability to quickly perform elegant analyses, DENs mastery of ADEs, have all come together in a significant effort.

I’ll try to give a global overview of our past (Oraflex and Moxam especially) and our present and our future (with Mobius, Scientology etc after us) tomorrow at DEN. Please pass on my congratulations and profound thanks to your spouses/friends for tolerating your extra work/pressure and to those colleagues whom I have left off the list of addressees in my rush to get out this note.

I’d like to have some buttons or mementos of other kinds made with a logo along the lines of: “I saved Prozac.” Suggestions please for design, memento and words. (Exh 10 in Deposition of J Potvin in Fentress Vs Eli Lilly).

From a company risk management point of view, an aggressive management of adverse events that might jeopardize the sales of a Flagship Brand and in so doing sink the company is a No Brainer. The trouble is it plays straight into a medical blind-spot – Marty Keller and Stan Kutcher and the rest of us would prefer not to think that something we have done might have injured our patient.

Control and consent

Since prescription only status was copper-fastened in place, and since the emergence of the Learned Intermediary doctrine, legal cases in the 1950s tackling the use of radical mastectomy and other drastic treatments for breast cancer and the use ECT within mental health gave rise to a Doctrine of Informed Consent.

Informed Consent is incompatible with notions of a Learned Intermediary whose role includes deciding whether to withhold information from a patient based on his judgement about what is in that patient’s interests.

When the Learned Intermediary doctrine arose it was not unreasonable to think that while patent medicine makers found no difficulty in creating an advertising industry in order to communicate with the general population, there were legitimate grounds to think it might be a problem to convey complex information about an entirely new class of compound that contained ingredients that for the first time ever could save lives and restore function but could also kill.

A case could be made for engaging doctors in communicating that information.

But with the development of the internet, the extension of education, and 75 years of familiarity with modern medicines, the pharmaceutical industry appears to have little problem communicating with the population at large.

And so, there no longer appears to be a good reason to exempt drug manufacturers any more than other manufacturers from a duty to warn – and a duty to make public the data behind their claims.

Instead of helping patients, the Learned Intermediary doctrine now helps companies. It allows companies to keep their data under wraps. It shifts liability from a careless manufacturer onto an intermediary who is responsible for distributing a defective product to a vulnerable citizen.

He (your doctor) is coached by companies in the arts of persuasion to play on his patient’s (your) anxieties so that they (you) take medications they (you) would never take if left to themselves. He was once skeptical of the benefits of drugs and a bulwark against unwarranted treatment, but many of his patients (you) are now more skeptical than him even though they (you) don’t quite know (you’d never guess) the extent to which his recommendations to take a treatment are based on sand.

The fact of prescription only arrangements allows companies to sell to doctors only. In a world where medical education does not cover how companies market medicines, we have produced a generation of doctors more susceptible to marketing that the most designer label addicted adolescent.

Marty Keller & summary judgement

Pharmaceutical companies make medicines. Because doctors use medicines and are trained in medicine, they might appear to be equipped to assist their patients in making decisions about those medicines.

This was true in the 1960s when doctors’ clinical experience (not RCTs) meant they knew more about taking risks with chemicals than their patients did.

Medicines are chemicals that come with information. The chemicals are unavoidably risky. The information component of a medicine and the culture about using chemicals in medicine was commensurate with those risks in the 1960s but the information and the culture have both been degraded and now systematically conceal risks.

Worse again this information is portrayed as objective and scientific. It has become the primary determinant of prescribing, over-riding the natural caution of both doctors and patients.

The problem that sales techniques such as gifts pose in compromising the doctor patient relationship is minor compared with this.

If doctors are now truly to function as Learned Intermediaries, it would be by informing their patients and the Courts that the bulk of the academic literature, especially that in the most distinguished journals, cannot be believed.

Sitting in the midst of a Maelstrom in 2004 when New York State were suing GSK for Fraud, faced with demands to “modify” Study 329, on June 13 Marty Keller emailed some of his co-authors to get a united position about what they would say to GSK about the modification:

that [it must be] 100% clear in this paper that there is no way to read it and think that 329 is being criticized and that it was not written with complete integrity and accuracy given the data we had and should have had….. We also want it to be crystal clear that any new data or analyses, case report forms, narratives etc. you have worked with since 329 was published, was not made available to the 329 investigator’s by SK, otherwise we could look foolish, naïve, incompetent or “biased” (the most likely accusation that will be made) to present things in a way that was favorable to SK, disregarding our responsibility to the proper scientific method, to the public, children and their families.

So as MK & GSK see it, while the Learned Intermediary Doctrine rules, he and his colleagues have a responsibility to their patients. Someone needs to do the right thing by the Paxil 12.

Whose Fault

Study 329: MK, HK, SK and GSK

Martin B. Keller, MD

The Letter below from Marty Keller and colleagues was sent to many media outlets, to retraction watch, and to professional organizations on Wednesday. Paul Basken from the Chronicle for Higher Education asked me for a response which I sent about an hour after receiving the letter. This response is from me rather than the 329 group. This and other correspondence features and will feature on

One quick piece of housekeeping. Restoring Study329 is not about giving Paroxetine to Adolescents – its about all drugs for all indications across medicine and for all ages. It deals with standard Industry MO to hype benefits and hide harms. One of the best bits of coverage of this aspect of the story yesterday was in Cosmopolitan.

Letter from Keller et al


Nine of us whose names are attached to this email (we did not have time to create electronic signatures) were authors on the study originally published in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry entitled, “Efficacy of paroxetine in the treatment of adolescent major depression: a randomized controlled trial,” and have read the reanalysis of our article, which is entitled, “Restoring Study 329:  efficacy and harms of paroxetine and imipramine in treatment of major depression in adolescence”, currently embargoed for publication in the British Medical Journal (BMJ) early this week. We are providing you with a brief summary response to several of the points in that article that which with we have strong disagreement. Given the length and detail of the BMJ publication and the multitude of specific concerns we have with its approach and conclusions, we will be writing and submitting to the BMJ’s editor an in-depth letter rebutting the claims and accusations made in the article. It will take a significant amount of work to make this scholarly and thorough and do not have a time table; but that level of analysis by us far exceeds the time frame needed to give you that more comprehensive response by today.

The study was planned and designed between 1991-1992. Subject enrollment began in 1994, and was completed in 1997, at which time analysis of the data commenced.  The study authors comprised virtually all of the academic researchers studying the treatment of child depression in North America at the time. The study was designed by academic psychiatrists and adopted with very little change by GSK, who funded the study in an academic / industry partnership.  The two statisticians who helped design the study are among the most esteemed in psychiatry.  The goal of the study designers was to do the best study possible to advance the treatment of depression in youth, not primarily as a drug registration trial.  Some design issues would be made differently today — best practices methodology have changed over the ensuing 24-year interval since inception of our study.

In the interval from when we sat down to plan the study to when we approached the data analysis phase, but prior to the blind being broken, the academic authors, not the sponsor, added several additional measures of depression as secondary outcomes.  We did so because the field of pediatric-age depression had reached a consensus that the Hamilton Depression Rating Scale (our primary outcome measure) had significant limitations in assessing mood disturbance in younger patients. Accordingly, taking this into consideration, and in advance of breaking the blind, we added secondary outcome measures agreed upon by all authors of the paper.  We found statistically significant indications of efficacy in these measures. This was clearly reported in our article, as were the negative findings.

In the “BMJ-Restoring Study 329 …” reanalysis, the following statement is used to justify non-examination of a range of secondary outcome measures:

Both before and after breaking the blind, however, the sponsors made changes to the secondary outcomes as previously detailed.  We could not find any document that provided any scientific rationale for these post hoc changes and the outcomes are therefore not reported in this paper. 

This is not correct.  The secondary outcomes were decided by the authors prior to the blind being broken.  We believe now, as we did then, that the inclusion of these measures in the study and in our analysis was entirely appropriate and was clearly and fully reported in our paper.  While secondary outcome measures may be irrelevant for purposes of governmental approval of a pharmaceutical indication, they were and to this day are frequently and appropriately included in study reports even in those cases when the primary measures do not reach statistical significance.  The authors of “Restoring Study 329” state “there were no discrepancies between any of our analyses and those contained in the CSR [clinical study report]”.  In other words, the disagreement on treatment outcomes rests entirely on the arbitrary dismissal of our secondary outcome measures.

We also have areas of significant disagreement on the “Restoring Study 329” analysis of side effects (which the author’s label “harms”).   Their reanalysis uses the FDA MedDRA approach to side effect data, which was not available when our study was done.  We agree that this instrument is a meaningful advance over the approach we used at the time, which was based on the FDA’s then current COSTART approach. That one can do better reanalyzing adverse event data using refinements in approach that have accrued in the 15 years since a study’s publication is unsurprising and not a valid critique of our study as performed and presented.

A second area of disagreement (concerning the side effect data) is with their statement, “We have not undertaken statistical tests for harms.” The authors of “Restoring Study 329” with this decision are saying that we need very high and rigorous statistical standards for declaring a treatment to be beneficial but for declaring a treatment to be harmful then statistics can’t help us and whatever an individual reader thinks based on raw tabulation that looks like a harm is a harm.  Statistics of course does offer several approaches to the question of when is there a meaningful difference in the side effect rates between different groups.  There are pros and cons to the use of P values, but alternatives like confidence intervals are available.

“Restoring Study 329” asserts that this paper was ghostwritten, citing an early publication by one of the coauthors of that article. There was absolutely nothing about the process involved in the drafting, revision, or completion of our paper that constitutes “ghostwriting”. This study was initiated by academic investigators, undertaken as an academic / industry partnership, and the resulting report was authored mainly by the academic investigators with industry collaboration.

Finally the “Restoring Study 329” authors discuss an initiative to correct publications called “restoring invisible and abandoned trials (RIAT)” (BMJ, 2013; 346-f4223).  “Restoring Study 329” states “We reanalyzed the data from Study 329 according to the RIAT recommendations” but gives no reference for a specific methodology for RIAT reanalysis.  The RIAT approach may have general “recommendations” but we find no evidence that there is a consensus on precisely how such a RIAT analysis makes the myriad decisions inherent in any reanalysis nor do we think there is any consensus in the field that would allow the authors of this reanalysis or any other potential reanalysis to definitively say they got it right.

In summary, to describe our trial as “misreported” is pejorative and wrong, both from consideration of best research practices at the time, and in terms of a retrospective from the standpoint of current best practices.

Martin B. Keller, M.D.
Boris Birmacher, M.D.
Gregory N. Clarke, Ph.D.
Graham J. Emslie, M.D.
Harold Koplewicz, M.D.
Stan Kutcher, M.D.
Neal Ryan, M.D.
William H. Sack, M.D.
Michael Strober, Ph.D.

Boxed harms


In the case of a study designed to advance the treatment of depression in adolescents, it seems strange to have picked imipramine 200-300mg per day as a comparator, unusual to have left the continuation phase unpublished, odd to have neglected to analyse the taper phase, dangerous to have downplayed the data on suicide risks and the profile of psychiatric adverse events more generally and unfortunate to have failed to update the record in response to attempts to offer a more representative version of the study to those who write guidelines or otherwise shape treatment.

As regards the efficacy elements, the correspondence we had with GSK, which will be available on as of  Sept 16 and on the BMJ website, indicates clearly that we made many efforts to establish the basis for introducing secondary endpoints not present in the protocol.  GSK have been unwilling or unable to provide evidence on this issue, even though the protocol states that no changes will be permitted that are not discussed with SmithKline.  We would be more than willing to post any material that Dr Keller and colleagues can provide.

Whatever about such material, it is of note that when submitting Study 329 to FDA in 2002, GSK described the study as a negative Study and FDA concurred that it was negative.  This is of interest in the light of Dr Keller’s hint that it was GSK’s interests to submit this study to regulators that led to a corruption of the process.

Several issues arise as regards harms.  First, we would love to see the ADECs coding dictionary if any of the original investigators have one.  Does anyone know whether ADECs requires suicidal events to be coded as emotional lability or was there another option?

Second, can the investigators explain why headaches were moved from classification under Body as a Whole in the Clinical Study Report to sit alongside emotional lability under a Nervous System heading in the 2001 paper?

It may be something of purist view but significance testing was originally linked to primary endpoints.  Harms are never the primary endpoint of a trial and no RCT is designed to detect harms adequately.  It is appropriate to hold a company or doctors who may be aiming to make money out of vulnerable people to a high standard when it comes to efficacy but for those interested to advance the treatment of patients with any medical condition it is not appropriate to deny the likely existence of harms on the basis of a failure to reach a significance threshold that the very process of conducting an RCT will mean cannot be met as investigators attention is systematically diverted elsewhere.

As regards RIAT methods, a key method is to stick to the protocol. A second safeguard is to audit every step taken and to this end we have attached a 61 page audit record (Appendix 1) to this paper.  An even more important method is to make the data fully available, which it will be on

As regards ghostwriting, I personally am happy to stick to the designation of this study as ghostwritten.  For those unversed in these issues, journal editors, medical writing companies and academic authors cling to a figleaf that if the medical writers name is mentioned somewhere, s/he is not a ghost.  But for many, the presence on the authorship line of names that have never had access to the data and who cannot stand over the claims made other than by assertion is what’s ghostly.

Having made all these points, there is a point of agreement to note.  Dr Keller and colleagues state that:

“nor do we think there is any consensus in the field that would allow the authors of this reanalysis or any other potential reanalysis to definitively say they got it right”.

We agree.  For us, this is the main point behind the article.  This is why we need access to the data.  It is only with collaborative efforts based on full access to the data that we can manage to get to a best possible interpretation but even this will be provisional rather than definitive.  Is there anything that would hold the authors of the second interpretation of these data (Keller and colleagues) back from joining with us the authors of the third interpretation in asking that the data of all trials for all treatments, across all indications, be made fully available?  Such a call would be consistent with the empirical method that was as applicable in 1991 as it is now.

David Healy
Holding Response on Behalf of RIAT 329