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...]

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Study 329: Minions no Longer


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



Study 329

Study 329 has just gone live.  The Restoring Study 329 article with its appendices, data, history, accompanying feature by Peter Doshi and editorial by David Henry can be found on the Restoring Study 329 site

Here are the key findings at present.


efficacy png




Three amigos

At Present

The note above says “Here are the key findings at present”.  You can download most of the key data from  We expect others, even GSK, will be able to improve on some aspects of what we have done – suggest refinements to the coding perhaps – or fill in details of the history of this study.

There will be more to come from the 329 Team here and in other settings, along with responses from Keller and colleagues and others .


Study 329: The Data

Science with a conscience 2


The text below reproduces the latest page from the site.  The links mentioned here will become live on the site once Restoring Study 329 is published late Wednesday – early Thursday next week.

In 2004 as part of the resolution of a fraud action taken by New York State, GlaxoSmithKline agreed to post the data from all their studies on the Company Website. They posted lengthy Clinical Study Reports (CSRs) for all the pediatric antidepressant studies (Paxil). They also posted shorter Summary Reports on Avandia and other drugs.

There are two CSRs for Study 329, one for the Acute Phase (528 pages) and one for the Continuation Phase (264 pages).

Clinical Study Report 329: Acute Phase.

Clinical Study Report 329: Continuation Phase.

In January 2012, Peter Doshi noticed that the CSRs for Study 329 referred to a number of Appendices (A to H), but that these were not present.  He wrote to New York State’s Attorney General’s Office who contacted GSK.   GSK agreed to post Appendices A – G, but Appendix H was posted without content.

Appendix A: Protocol & Related Material (952 pages).
Appendix B: Patient Data Listings (640 pages).
Appendix C: Efficacy (660 pages).
Appendix D: Adverse Events (224 pages).
Appendix E: Vital Signs (89 pages).
Appendix F: Laboratory Values (856 pages).
Appendix G: CRF Tabulations by Patient (2073 pages).
Appendix H: [Empty Shell]

Data Periscope

The original coding used by GSK was from an obscure, inaccessible coding dictionary. The Study 329 RIAT Team believed that a more modern and widely-used coding system was more appropriate, and so they re-coded all the adverse events.

Originally, GSK posted all Appendices as PDF documents. Eventually, with the exception of Appendix H,  GSK did provide the data in electronic form to the team. For the harms of treatment, we had already created our own “live” spreadsheets which contain both GSK’s codes and the RIAT team coding side by side. These can be downloaded  and analyzed.  Having the data available is important for debating the meaning of observations, challenging approaches taken and spotting errors.

The most difficult challenge lay in getting access to the data in Appendix H.  Appendix H contains the individual patient level data in the form of Clinical / Case Report Forms (CRFs). There are roughly 77,000 pages – between 200-300 pages for each of 273 patients.  The correspondence with GSK between December 2013 and March 2014 reveals the negotiations that took place to get access to this data.  Click here to view the correspondence.

The Adverse Harms Data Spreadsheet re-created by the 329 RIAT Team contains material from Appendix H which gave rise to adverse events not listed in the original Appendix D. To make the data usable, the Study 329 RIAT Team  had to create Excel Spreadsheets and re-enter the data.

GSK also granted access “for audit purposes” to Appendix H, the CRFs. Even though all patient names and details were redacted, this access was not in the form of a PDF. It was through a “periscope” – a remote access portal that reached into GSK and allowed Joanna Le Noury to scrutinize the 77,000 pages individually without being able to print or download them. She had to make manual notations for each document.

We used the R environment for statistical computing and graphics for this Study. Under our data access agreement with GSK, we cannot post the data.  Consequently, the RIAT team is unable to provide direct access to this data. However, the full efficacy data is available in a PDF format.  (See Appendix B, C, & D above)

Click here for our Harms Data Spreadsheet.

Click here for our Patient Demographics Withdrawal Reasons Spreadsheet.

Click here to view the basic form use for the files imported into R for the analysis, followed by the code for the calculations.

Click here for the Data Sharing Agreement between GSK and RIAT.

The Troubled Life of Study 329: Consequences of Failure to Retract


If someone were to ask the surviving authors of Study 329 the question: “Knowing what you know now, if you had to do it over, would you agree to participate in that study again?”, many would probably say no. The real title of Study 329 was “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial”. It was published in the Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP) in July, 2001. Although it is probably fairly typical of medical research studies, it has been plagued by more than its share of troubles. Next week, fourteen years and two months after it was published, it is about to take yet another hit, when the Restored version is published.

There were many obstacles to doing the work to write Restoring Study 329: A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression. The biggest was getting access to the data.  It took years to get the data, months to analyze it, and another year to get a version of the restored study that BMJ felt comfortable with. The “Restoration” of Study 329 may not have occurred if Study 329 had been retracted. If JAACAP had heeded the earliest calls for retraction, much of the unfortunate history of Study 329 could have been avoided.

In hindsight, the authors may wish that they had not been so adamant that retraction was unthinkable. Of course, there are probably many flawed studies that remain un-retracted. Many of the pitfalls into which Study 329 fell resulted from bad timing, coincidence, an astute and determined journalist, a Senator who found conflicts of interest in medicine unacceptable, and the unwavering commitment of a small group of medical experts who refused to give up and go away. How could those authors have foreseen?

Study 329’s problems started to surface right after it was published. Several doctors wrote letters to the JAACAP Editor with probing questions, mostly centred on the psychiatric side effects of paroxetine, and the measures used to claim its efficacy in treating adolescents.  The authors responded and the questioners did not pursue their concerns further. Except one. Child Psychiatrist Jon Jureidini, M.D. from the University of Adelaide remained convinced that there were serious methodological problems hiding real harms, and he never stopped pushing to expose the truth.

After Study 329 was accepted but before it was published, a Wyoming jury awarded $6.4 million to the relatives of retired oilman Don Schell (Tobin v.SmithKline Beecham). Forty-eight hours after Mr. Schell had been prescribed paroxetine (Paxil), he put bullets through the heads of his wife, Rita, his daughter, Deborah, and his granddaughter, Alyssa. Then he shot and killed himself. The jury decided that Paxil was responsible for the tragedy.

Scottish journalist Shelley Jofre, having learned about the Schell case, did some research on the drug and arranged to do a program on paroxetine, known as Seroxat in the U.K., for BBC’s Panorama. The segment, Secrets of Seroxat, aired in October 2002. It revealed that the drug can cause suicidal and violent thoughts and behaviours, and that many people experience serious withdrawal problems. The show received such a huge public response that a second episode was developed, Emails from the Edge.

Following Secrets of Seroxat, the U.K. public was highly sensitized to the potential problems associated with paroxetine. In December of the year that Emails from the Edge was broadcast, the Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory warning to physicians against prescribing SSRI antidepressants, including Seroxat, to people under age 18.

In June of 2004, New York State Attorney General Elliot Spitzer filed a lawsuit accusing British drug giant GlaxoSmithKline PLC of “repeated and persistent fraud” for concealing known problems with efficacy and safety of Paxil (paroxetine) for children and adolescents. Evidence was largely based on documents that had come to light in the Tobin case. The suit was settled for $2.5 million plus a promise by GSK that they would make their drug trial data accessible. Later that year, the FDA required that a “black box” warning label be added for all SSRI antidepressants, including Paxil.

In 2008, US Senator Chuck Grassley investigated serious violations of conflict of interest policies among high-profile academic psychiatrists, including Martin Keller, lead author of Study 329, and three of his coauthors. Senator Grassley’s investigation brought attention to the fact the nominal authors in many research studies are not the real authors. This was the case in Study 329. GSK hired a “ghostwriter”, Sally Laden of STI, to write the study article under GSK direction.

Over the next few years, many lawsuits involving suicidality and violence caused by paroxetine were settled. In addition, Paxil and other SSRI drugs became the target of lawsuits for causing birth defects. The FDA recognized suicidality and violence as side effects of SSRI antidepressants in all age groups and expanded the required “black box” warning.

In 2012, the U.S. Department of Justice brought an action in U.S. District Court to recover damages and civil penalties from GSK under the False Claims Act, and damages and other monetary relief under common law and equity for causing the submission of false or fraudulent claims to federal health care programs. Three drugs were implicated, including Paxil. This action was settled for $3 billion, the largest settlement of its kind.

All in all, the past decade was not an unqualified success for Paxil and its manufacturer. Still, the conclusion of Study 329, that “Paroxetine is generally well tolerated and effective for major depression in adolescents”, has stayed officially intact, since the study was never retracted, and has been widely cited.

In 2013, Peter Doshi and a number of other researchers published a paper in the BMJ entitled “Restoring invisible and abandoned trials: a call for people to publish the findings”. This is part of a larger campaign to make all data from drug trials available for public scrutiny.

In August, 2015, BMJ accepted for publication a new analysis of the data from the original Study 329. Restoring Study 329: A randomized, controlled trial of the efficacy and harms of paroxetine and imipramine in the treatment of adolescent major depression will be published online sometime the week of Sept 14, and in the hard copy journal later that week. The new team of authors, including those most active in lobbying for retraction, has taken the same data and reached startlingly different conclusions than the original.  Their conclusions should lead us to reassess our assumptions about drug safety regulation.

Stay tuned to this blog as the details continue to unfold.  See also 1boringoldman for a thorough ongoing analysis of this remarkable saga…

Today on the Study 329 site we have added a new section under “Background” which provides a summary of the attempts to get the original Study 329 retracted, together with links to the underlying documents.

Original Study 329 Team







Brown University
Martin B. Keller Professor Emeritus of Psychiatry and Human Behavior
Martin Keller has made major research contributions to the understanding and treatment of mood disorders. He has performed research on the longitudinal course and neuropsychopharmacology of affective disorders and anxiety disorders and on the causes, pathophysiology, treatment, and prevention of depression. He has received more than 20 research grant awards from the National Institutes of Health (NIH) and numerous grants from research foundations and the pharmaceutical industry.
In 2009, Dr Keller was investigated by the US Senate Finance Committee, led by Senator Chuck Grassley, as one of a number of medical academics with a serious conflict of interest in his  medical research, because of money received from pharmaceutical companies.



University of Pittsburgh
Department of Psychiatry
3811 O’Hara St.
PA 15213
Phone: 412-383-5477412-383-5477
Fax: 412-383-5426
Neal Ryan, MD, is one of the nation’s leading experts on pediatric mood and anxiety disorders. He has led large-scale studies of behavioral changes in children and adolescents diagnosed with mood disorders, and he has investigated the effectiveness of medications and various other treatments, including innovative cognitive-behavioral therapies. Dr. Ryan’s ongoing studies of the pharmacological treatment of unipolar and bipolar depression in adolescents have inspired many graduate students to pursue careers in child and adolescent psychiatry. He is currently principal investigator on a large NIMH-funded project titled “Psychobiology of Childhood Anxiety and Depression.” He has co-authored numerous scholarly articles and remains an important public voice on the causes and treatment of mental health disorders in children and adolescents.
In 2009, Dr Ryan was investigated by the US Senate Finance Committee, led by Senator Chuck Grassley, as one of a number of medical academics with a serious conflict of interest in his  medical research, because of money received from pharmaceutical companies.



UCLA David Geffen School of Medicine
Work Phone Number:  (310) 825-2982
Mailing Address:
760 Westwood Plaza
Mail Code 175919
Los Angeles, CA 90095
Work Email Address:
Eating Disorders Program
Director, Eating Disorder Program
Director, Inpatient Child and Adolescent Service
Professor in Residence, Psychiatry and Biobehavioral Sciences
Member, Semel Institute for Neuroscience and Human Behavior
Detailed Biography:Michael Strober is a clinical psychologist who has served on the UCLA School of Medicine faculty since he joined the Department of Psychiatry in 1975. He became a full professor in 1989 and has been Director of the Eating Disorders Program at the Neuropsychiatric Institute since 1982, and Director of the Adolescent Mood Disorders Program since 1989. Dr. Strober earned his B.A. in Psychology with High Honors at Queens College of the City University of New York in 1971, and his M.S. and Ph.D. with distinction in Clinical Psychology at the University of Pittsburgh. Dr. Strober is past President of the Eating Disorders Research Society, and is a founding Fellow of the Academy for Eating Disorders and the American Society of Clinical Psychopharmacology. He is actively involved in medical education and has served as a consultant to the National Institute of Mental Health and the Institute of Medicine.




Fascitelli Family Professor of Child and Adolescent Psychiatry, Department of Child and Adolescent Psychiatry;Professor, Department of Psychiatry
Child and Adolescent Psychiatry
Contact Info
1 Park Avenue
New York, NY 10016Phone:


Dalhousie University
Professor, Department of PsychiatryContact information
Phone: 902-470-6598
Mailing Address:
IWK Health Centre
5850/5980 University Ave.
PO Box 9700
Halifax, NS B3K 6R8In 2011, Dr Kutcher ran in Halifax as the Liberal candidate in the federal election.Author of Ghostwritten Study Runs for Parliament in CanadaIn April, as reported by Halifax Media Co-op, The Coast ( published an article, Retraction Reaction, which stated that Kutcher and the Study 329 research team “essentially lied” to the public about what the study results really showed.On April 27, 2011 Dr. Kutcher issued a press release entitled: Kutcher Demands Retraction. With reference to the Coast article, it read, in part:“Commenting on the story, Dr. Stan Kutcher, Liberal candidate for Halifax, said: “It comes as a great surprise that The Coast is confusing opinion with science – this is something we are more accustomed to hear from the American right wing than the Canadian left wing.”Kutcher has demanded a retraction. The confusion could be costly for The Coast. Dr. Kutcher intends to launch a defamation suit against the publication as a result of its inflammatory innuendo and the potential to damage his personal, professional and political reputation.Dr Kutcher got his retraction, and an apology. He was defeated in the May 2, 2011 election by NDP candidate Megan Leslie.



University of Pittsburgh
Department of Psychiatry
3811 O’Hara St.
PA 15213Phone: 412-246-5788412-246-5788
Fax: 412-246-5230



Department of Child & Adolescent Psychiatry, Children’s Pennsylvania (American Academy of Child and Adolescent Psychiatry)   to 2000

Dr. Owen Hagino is a psychiatrist in Malvern, Pennsylvania. He received his medical degree from University of Hawaii John A. Burns School of Medicine and has been in practice for 27 years.

9 Great Valley Pkwy
Malvern, PA 19355

Phone: (610) 889-8426
Fax: (610) 889-6864




President, Child Mind Institute
445 Park Avenue (entrance on 56th Street)
New York, NY 10022General Inquiries:
212.308.3118 |
Harold S. Koplewicz, MD, founding president of the Child Mind Institute, is one of the nation’s leading child and adolescent psychiatrists. He is widely recognized as an innovator in the field, a strong advocate for child mental health, and a master clinician. He has been repeatedly recognized in America’s Top Doctors, Best Doctors in America, and New York Magazine’s “Best Doctors in New York,” and was named one of WebMD’s 2014 Health Heroes for his activism on behalf of children with psychiatric or learning disorders.Dr. Koplewicz and Brooke Garber Neidich founded the Child Mind Institute in 2009. Dr. Koplewicz leads the Institute’s mission to offer evidence-based clinical care; visionary research engaging the global scientific community in the discovery of more effective treatments; trustworthy information and resources to educate and empower parents; and passionate advocacy to destigmatize childhood psychiatric disorders.
Dr. Koplewicz was Director of the Nathan S. Kline Institute for Psychiatric Research (NKI) from 2006-2011, the third person and the first child and adolescent psychiatrist to hold that position since the institution’s founding in 1952. At NKI he expanded the research portfolio to include child and adolescent psychiatric research.
Dr. Koplewicz founded the NYU Child Study Center in 1997 and served as its director for 12 years. He was the first Arnold and Debbie Simon Professor of Child and Adolescent Psychiatry. In 2006, the NYU Child Study Center was established as the second independent department of child and adolescent psychiatry in the country, and Dr. Koplewicz was appointed as its first chair. Under his leadership, the NYU Child Study Center made tremendous contributions to the field through expert clinical care, a robust research portfolio, and advocacy for child mental health.
A graduate of Albert Einstein College of Medicine, Dr. Koplewicz completed his psychiatric residency at New York Hospital Westchester Division, a fellowship in child psychiatry at Columbia University’s College of Physicians and Surgeons, an NIMH research fellowship in child psychiatry at the New York State Psychiatric Institute, and the Executive Program in Health Policy and Management at Harvard University’s School of Public Health.
An internationally respected psychiatrist, Dr. Koplewicz is the recipient of many awards, including the 1997 Exemplary Psychiatrist Award from the National Alliance of the Mentally Ill; the 1998 Reiger Service Award from the American Academy of Child and Adolescent Psychiatry in recognition of his work in the development of school-based mental health programs; the 1999 Humanitarian Award from Marymount Manhattan College; the 2000 American Grand Hope Award from the Aprica Childcare Institute; the 2002 Catcher in the Rye Award from the American Academy of Child and Adolescent Psychiatry; and the 2009 American Psychiatric Association McGavin Award for lifetime contributions to child psychiatry.




Gabrielle A. Carlson, M.D. – Biography

Gabrielle A. Carlson, M.D., has been professor of Psychiatry and Pediatrics and Director of the Division of Child and Adolescent Psychiatry at State University of New York at Stony Brook since 1985. She did her undergraduate training at Wellesley and subsequently obtained her MD degree from Cornell University Medical College. She did her adult psychiatry training at Washington University in St. Louis and at the National Institutes of Mental Health. She completed a fellowship and research fellowship in Child and Adolescent Psychiatry at UCLA where she subsequently taught on the faculty.

Dr. Carlson specializes in childhood psychopathology and psychopharmacology in general, and the subjects of childhood and adolescent depression and bipolar disorder, specifically. She has written over 200 papers and chapters on those subjects and has co-authored two books, Affective Disorders in Childhood Adolescence (Spectrum Publications) and Psychiatric Disorders in Children and Adolescents (W.B. Saunders). Her research interests include the phenomenology, long term follow up and treatment of young people with bipolar disorder, and the relationship between behavior disorders, like ADHD, developmental disorders and mood disorders. Her most recent grants have focused on those questions.

Dr. Carlson is active in the psychiatry community. She has served on many national committees. These include the APA committee to evaluate DSM III, the DSM IV Task Force on Child and Adolescent Psychiatric Disorders, Emslie Institute of Medicine committees, and various review committees for the National Institute of Mental Health. She has been named in Best Doctors in America and Good Housekeeping’s Best Mental Health Experts. She was recently awarded the APA’s Blanche F. Ittleson Award for research in child and adolescent psychiatry and the Hulse Award for Child and Adolescent Psychiatry in New York. She was president of the International Society for Research in Child and Adolescent Psychopathology and will become program chair of the American Academy of Child and Adolescent Psychiatry in 2011.
Dr. Carlson has a strong commitment to community child and adolescent psychiatry. She is a consultant to a number of school districts, and works with other mental health administrators in her area to improve services for children.




Kaiser Permenante Centre for Health Research
Senior Investigator
Assistant Program DirectorE-mail:
Dr. Gregory Clarke‘s areas of interest include depression prevention and treatment, child and adolescent mental health and treatments, and treatment of patients who have both substance abuse and mental disorders.
Dr. Clarke has been the principal investigator and co-investigator on several grants funded by the National Institute of Mental Health, conducting controlled-outcome trials of depression treatment and prevention in at-risk populations. Some of his most recent controlled trials have examined the costs and clinical outcomes of preventing and treating depression in adolescent offspring of depressed parents enrolled in an HMO; the medication and psychotherapy treatment of depression in adolescents who have failed to respond to an initial course of selective serotonin reuptake inhibitor anti-depressant medication; treatment of depression in adults who are also receiving outpatient treatment for alcohol addiction; simultaneous psychotherapy and medication for depressed adolescents treated in primary care; and Internet self-care programs for depressed adults and adolescents.
Dr. Clarke has conducted mental health research for 20 years. He received his PhD in clinical psychology from the University of Oregon in 1985.



UT Southwestern Medical Centre
Charles E. and Sarah M. Seay Chair in Child Psychiatry
5323 Harry Hines Blvd., Dallas, Texas 75390
Dr. Emslie obtained his undergraduate degree and M.D. at Aberdeen University in Aberdeen, Scotland in 1974. Dr. Emslie did his internship at Aberdeen Hospitals, Scotland in general medicine and neurosurgery. He did his residency training in general psychiatry at the University of Rochester, NY and child psychiatry at Stanford University, where he also completed a research fellowship. Dr. Emslie joined the U.T. Southwestern Faculty in 1981. He has served as Director for both the inpatient and outpatient units of Children’s Medical Center’s Psychiatry Division. Currently, Dr. Emslie is the Chief of Adolescent Psychiatry program at UT Southwestern and Children’s Medical Center of Dallas. Dr. Emslies clinical expertise is in the area of child and adolescent depression. Dr. Emslies research foci are in the areas of conducting efficacy and effectiveness trials with medications and psychotherapy for children and adolescents with depression, anxiety disorders, and attention-deficit disorder. He is also involved with developing and evaluating medication algorithm protocols for children and adolescents with depression. Dr. Emslie is active in the following professional organizations: American Academy of Child and Adolescent Psychiatry, American Psychiatric Association, Texas Society of Child and Adolescent Psychiatry, Texas Society of Psychiatric Physicians, Society of Biological Psychiatry, and the International Society for Research in Child and Adolescent Psychopathology. He is also on several committees, including the National Institute of Mental Health (NIMH) Interventions Committee, NIMH Child Council Work Group, and the Corporate Contributions and Research Committee for the American Academy of Child and Adolescent Psychiatry. In addition, he serves on the editorial board for the Journal of the American Academy of Child and Adolescent Psychiatry. He also past President for the Texas Society of Child and Adolescent Psychiatry. Dr. Emslie has written over 60 papers and 17 chapters. He is known internationally for his work in the treatment of pediatric depression. In 2003, he was awarded the Klingenstein Third generation Foundation Award for his work in this field.
In 2009, Dr Emslie was investigated by the US Senate Finance Committee, led by Senator Chuck Grassley, as one of a number of medical academics with a serious conflict of interest in his  medical research, because of money received from pharmaceutical companies.  The committee was concerned that this conflict was behind fraudulent research that resulted in harmful medication, some with little efficacy, being widely prescribed without adequate warnings.


UCLA David Geffen School of Medicine
Director, Child and Adolescent Outpatient Evaluation and Treatment Clinic
Associate Professor, Psychiatry and Biobehavioral SciencesWork Phone Number:
(310) 267-3516
(310) 267-9315Mailing Address:
757 Westwood Plaza, Suite 1320
Ronald Reagan UCLA Medical Center
Mail Code 740030
Los Angeles, CA 90095
UNITED STATESWork Email Address:
David Feinberg, MD, MBA is the chief executive officer of the UCLA Hospital System and associate vice chancellor. Prior to assuming the leadership role of CEO for UCLA Hospitals, Dr. Feinberg was the medical director of the Resnick Neuropsychiatric Hospital (NPH) at UCLA. He has been a faculty member in the Department of Psychiatry at the David Geffen School of Medicine since 1994. He is triple board certified in Child and Adolescent Psychiatry, Adult Psychiatry, and Addiction Psychiatry. Dr. Feinberg also has his master of business administration from Pepperdine University. Dr. Feinberg areas of expertise include Attention Deficit/Hyperactivity Disorder, Adolescent Substance Abuse and the business of medicine.




Associate Editor, NEJM Journal Watch Psychiatry

About the NEJM Journal Watch Psychiatry Board
Barbara Geller, MD, is Professor Emerita of Psychiatry at Washington University in St. Louis.  She is internationally recognized for research into pediatric bipolar disorders and was principal investigator on multiple NIMH-funded grants. Among her awards were the Cummings Special Research Award from the American Academy of Child and Adolescent Psychiatry and the Exemplary Psychiatrist Award from the National Alliance for the Mentally Ill. Dr. Geller served on numerous federal advisory committees and published more than 130 articles on childhood manic-depressive disorders. She has been writing for NEJM Journal Watch Psychiatry since 1997, specializing in articles on child psychiatry and neuroscience.

VIVEK KUSUMAKAR, M.D.(1951 – 2009)

Professor of Psychiatry
Dalhousie University

No photo available


Assistant Professor, University of Toronto
Division One: Brain and Therapeutics
Division Two: Child and AdolescentContact Information
CAMH – College Street Site
250 College Street
Toronto, ON M5T 1R8
Room: Ste. 725Telephone:
416-535-8501 x4925


Child and Adolescent Psychiatry
3181 SW Sam Jackson Park Rd
Portland, OR 97239



Metropolitan Center for Cognitive Behaviour Therapy (CBT)

Dr. Michael Sweeney is the Director of the Metropolitan Center for Cognitive Behavior Therapy, a private practice center specializing in the treatment of anxiety. Michael prides himself on practical advice for complicated situations.

Dr Sweeney was an assistant professor of Clinical Psychology in Psychiatry at Columbia University’s College of Physicians and Surgeons, CBT supervisor at St. Vincent’s Medical Center, and the external reviewer for the Masters CBT program at University College, Dublin, Ireland. Dr. Sweeney is currently an adjunct professor at Teachers College, Columbia University. Michael has lectured nationally and internationally on the use of CBT.





Dr Wagner is the Marie B. Gale Centennial Professor and Vice Chair in the department of psychiatry and behavioral sciences and Director of Child and Adolescent Psychiatry at the University of Texas Medical Branch at Galveston. She is the Child and Adolescent Psychiatry columnist for Psychiatric Times.

Medical/Professional School:  S.U.N.Y. at Stony Brook, M.D., Grad: 1984

She was one of two winners of the Colvin Prize for Outstanding Achievement in Mood Disorders Research in 2012.
In 2009, Dr Wagner was investigated by the US Senate Finance Committee, led by Senator Chuck Grassley, as one of a number of medical academics with a serious conflict of interest in her medical research, because of money received from pharmaceutical companies.




Elizabeth B. Weller, MD, long-time member of Annals of Clinical Psychiatry’s editorial board, succumbed to breast cancer on November 29, 2009, shortly after her sixtieth birthday. At the time of her death, Elizabeth was professor of psychiatry and pediatrics at the University of Pennsylvania (the first woman holding an endowed professorship at the university) and the first chairof the department of child and adolescent psychiatry at Children’s Hospital of Philadelphia.





First name: Nancy
Last name: Winters
Degrees: MDAddress: 2311 NW Northrup Street #201
City: Portland
State: OR
Zip: 97210Phone: 503.243-1444
Graduate and faculty member at the Oregon Psychoanalytic Institute and Center; and a Professor of Psychiatry at Oregon Health & Science University (OHSU). She received her medical training at the Albert Einstein College of Medicine in NY, her adult psychiatry residency training at Yale University, and child/adolescent psychiatry residency at OHSU. She practices psychoanalysis and psychoanalytic psychotherapy in NW Portland, integrating contemporary, developmental, and neuroscience perspectives. With a background in music and the visual arts, she has a special interest in psychoanalytic explorations of creativity.



No details available.




President, Chesapeake Regulatory Group Inc
Director-Clinical Research Development and Medical Affairs
GlaxoSmithKline plc
Position, Clinical Research and Drug Development Training Course
James P. McCafferty, BS, currently serves as Director, Clinical Research and Development, for GlaxoSmithKline, and is responsible for US clinical programs for the treatment of Alzheimer¿s disease and clinical development support of marketed central nervous system (CNS) products.James serves as instructor for the DIA Advanced Topics in Clinical Research/Drug Development training course.James earned his BS in Biology from LaSalle University.





Sally Laden worked for Scientific Therapeutics Information (STI), a Springfield, New Jersey company specializing in pharmaceutical PR and communications.    She was the “ghostwriter” of Study 329.
As she acknowledged in her 2007 deposition in Cunningham v. Smithkline Beecham, she did not talk to the authors before providing the first draft of the manuscript.



Dr. Mina Dulcan is a psychiatrist in Chicago, Illinois and is affiliated with multiple hospitals in the area, including Ann and Robert H. Lurie Children’s Hospital of Chicago and Northwestern Memorial Hospital. She received her medical degree from Penn State College of Medicine and has been in practice for 41 years. She is one of 16 doctors at Ann and Robert H. Lurie Children’s Hospital of Chicago and one of 183 at Northwestern Memorial Hospital who specialize in Psychiatry.

She was the editor of the Journal of the American Academy of Child and Adolescent Psychiatry responsible for publishing Keller et al 2001

S:  312-227-3413

Ann & Robert H. Lurie Children’s Hospital of Chicago Box 10 225 E Chicago Avenue
Chicago IL 60611

Professor in Psychiatry and Behavioral Sciences and Pediatrics,

Northwestern University Feinberg School of Medicine.  This is a research and educational institution. Science with a Conscience

Consience E

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.

GSK Seroxat advertisement 2

This brochure appears to be an internal advert for the 100,000 people who work for GSK produced in the middle of the Panorama series of programs.


Conscience B

The text is an object of study in its own right – the basis for a doctoral dissertation.


Conscience c

Note ear ring.

Conscience D

See the Famous Grouse Lecture on for context.  This images and brochure were generated at a time when GSK was under intense internal pressure.  They came from one of the 100,000 just like you and me.

Study 329: The Timelines


In addition to hosting the Panorama programs and The Famous Grouse history of Study 329, has a comprehensive timeline on the origins of concerns about the SSRIs and the risk of suicide – initially with Prozac and subsequently with Paxil – Seroxat.

The chronology is laid out year on year with key documents linked to many of these years. Click on the year, then click on any links – there is days worth of reading for anyone not familiar with the story.

The hope is to provide a comprehensive repository for anyone who wants to study SSRIs, RCTs and Study 329 in particular. If there are points you think we are missing and in particular if you have documents you think we are missing please comment below and if possible send documents. We will be able to add them to the list. The more people involved in telling the story the better.

Later this week, we will have a timelines on efforts to get Study 329 retracted and we will begin to present the data – the Clinical Study Reports and their Appendices.

Once the Restored Study has been published we will make our worksheets available containing the data along with the Reviews of the Article and our Responses.