Making medicines safer for all of us

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

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

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

Archive for AbbVie – Page 2

AbbVie & GSK Can Buy Your Data for Almost Nothing

Computer, padlock and credit card

Editorial Note: This prescient post written by Phil Booth was posted on OpenDemocracy.net under the title Your medical data – on sale for a pound on August 9th 2013. The original intention was to link it into the AbbVie debate about access to clinical trial data – as an ironic contrast.

That opportunity passed – but a stopped clock throws up the right time twice a day. In recent weeks in Britain (apparently the home from home for the NSA) there has been great concern about access to the data compiled on anyone visiting a doctor within the NHS. Our data it would appear is being loaded up on to Google servers and as noted by Ben Goldacre and others is being sold to insurers and others. Government ministers are apparently being economical with the truth when asked about this. (Trans note: Economical with the truth is often interpreted in England to mean lying).

The arbitrary resetting of people’s ‘privacy settings’ is a behaviour one might expect of Facebook, not the NHS.

The government’s announcement today that private companies are to be given access to patient data for the princely sum of £1, is just the latest attack on the principles of patient confidentiality in the interests of commerce.

David Cameron signaled the intent back in 2011 when he announced that we are all to be research patients by default. Behind the window-dressing of scientific progress, lies a determined new policy on ‘open data’ which is about using your data – including your medical records held by the NHS – in order “to drive economic growth”. [http://data.gov.uk/opendataconsultation/annex-1/economic-growth]. Under the new regime, your sensitive health information will be taken directly from your GP’s record system and presumed available for a variety of “secondary uses” that go beyond research or your direct medical care.

To enable this, the NHS Constitution has been rewritten and fundamental assumptions such as medical confidentiality are being overturned. In private, officials admit the end state of all this is unclear, but the public language about what is happening to your confidential medical records is carefully chosen to obfuscate and pacify.

Anonymisation

One of the more misleading half-truths you will hear is that your data will be ‘anonymised’. Quite aside from the fact that NHS England applied for and has now been granted exemptions by the Secretary of State to process and pass around patient data in identifiable form, the ‘anonymising’ of data to avoid the rules which would otherwise apply to personal data does not guarantee privacy.

Truly anonymous data cannot be linked or matched to particular individuals. It requires statistical techniques like removing small number counts, adding ‘noise’ or perturbing aggregate data – to minimise the chance that particular individuals can be identified.

The ‘anonymisation’ proposed for your medical information is nothing like this. What in fact will be done is pseudonymisation ­– substituting identifiers such as your NHS number with less identifiable numbers or removing obvious identifiers such as name or address.

This means – along with the cross-matching of data from different sources – that it will not be hard to apply clever statistical techniques for private companies to obtain data on identifiable individual patients. There has even been a suggestion that the NHS would provide this service for companies itself, for a token fee.

Even if this doesn’t happen, a lifelong aggregation of episodes, diagnoses and prescriptions, even if not in themselves rare or unusual, provides a wealth of reference points. Filtered by age, gender or geographical area it is surprising how few of these are necessary to pinpoint an individual. The task is made even easier when data is made linkable to other information gathered in other contexts in a patient’s life. And that is exactly what will happen: ultimately, each person’s social care records will join with their health records in one single, central repository.

As the marketing industry and researchers know, the value of your data lies in being able to make matches; truly anonymous data that cannot be linked is nowhere near as useful or exploitable.

Consent

Consent means giving your permission. In order to be valid, consent needs to be properly informed and freely given by a competent individual; patients need to know the intended use of their medical information and be able to choose to participate or not.

Most people would agree with the notion of ‘presumed consent’ in the context of their medical treatment. When going to a doctor or hospital, you expect that your information will be shared with other health professionals responsible for your direct care. But this “consent deal” – based in the trust people have in their doctors and the NHS – has been stretched to encompass a whole range of other uses, many of which are obscure or completely unknown to patients.

Dame Fiona Caldicott’s recent Information Governance Review refused to support the proposition that – because patients are presumed to trust their own doctor with their medical data – they should be presumed to trust commissioners, too.

Purposes such as medical research – for which most people are happy for their information to be used, so long as they are asked – are being conflated with uses such as patient-level tracking and monitoring, business planning and contract management. The drive to commodify medical records means the default is to make them accessible to more and more people less and less directly related to your medical care, constrained not by the professional duty of confidentiality that most patients presume but only by data protection compliance or contract terms and conditions.

The word ‘sharing’ has become a euphemism for the systematic extraction, processing and disclosure of vast amounts of deeply personal information. Taking something without consent is not sharing. Passing legislation to override doctors’ duty of confidence may make a practice lawful; however it does not legitimise it.

Explicit consent has been replaced by an assumed consent, with opt-outs about which minimal information is provided to patients. This is not informed consent. Worse still, despite promises that patients who have already opted out will have their wishes respected, new initiatives such as care.data – a monthly upload of identifiable data from millions of patients’ GP-held records – mean that hundreds of thousands of people who have already acted to protect the confidentiality of their medical records will be forced to opt out all over again. Assuming, of course, they are even made aware of what is happening.

The arbitrary resetting of people’s ‘privacy settings’ is a behaviour one might expect of Facebook, not the NHS, and it speaks to a deeper erosion of trust. If patients cannot trust that what they say to their doctor will be kept in confidence, some will withhold information – putting not only their own health but the public health at risk.

Like this piece? Please donate to OurNHS here to help keep us producing the NHS stories that matter. Thank you.

What Do Women Want?

Editorial Note: This is cross-posted from 1boringoldman – Reassure Us. It tackles the most important issue in healthcare and one of the most important in politics. GSK have clearly persuaded Ben Goldacre, Iain Chalmers and David Cameron, and J&J have persuaded Harlan Krumholz and Barack Obama that their model of Data Access – the AbbVie model – is the only game in town. See The House of GSK.

This smells like the advice formerly given by the real powers behind the thrones (now GSK, J&J) to a pair of monarchs (now DC and BO) under siege. “My Lord, the people are revolting”. “You can say that again”. “Here’s what you should do – give the vote to property owning white men”.

Which gives all revolting men and women a slogan “Women Want the Vote”. We just need a President from Illinois to champion the cause.

New York Times

Give the Data to the People

By HARLAN M. KRUMHOLZ,  FEB. 2, 2014

LAST week, Johnson & Johnson announced that it was making all of its clinical trial data available to scientists around the world. It has hired my group, Yale University Open Data Access Project, or YODA, to fully oversee the release of the data. Everything in the company’s clinical research vaults, including unpublished raw data, will be available for independent review. This is an extraordinary donation to society, and a reversal of the industry’s traditional tendency to treat data as an asset that would lose value if exposed to public scrutiny. Today, more than half of the clinical trials in the United States, including many sponsored by academic and governmental institutions, are not published within two years of their completion. Often they are never published at all. The unreported results, not surprisingly, are often those in which a drug failed to perform better than a placebo. As a result, evidence-based medicine is, at best, based on only some of the evidence. One of the most troubling implications is that full information on a drug’s effects may never be discovered or released. Even when studies are published, the actual data are usually not made available. End users of research — patients, doctors and policy makers — are implicitly told by a single group of researchers to “take our word for it.” They are often forced to accept the report without the prospect of other independent scientists’ reproducing the findings — a violation of a central tenet of the scientific method.

To be fair, the decision to share data is not easy. Companies worry that their competitors will benefit, that lawyers will take advantage, that incompetent scientists will misconstrue the data and come to mistaken conclusions. Researchers feel ownership of the data and may be reluctant to have others use it. So Johnson & Johnson, as well as companies like GlaxoSmithKline and Medtronic that have made more cautious moves toward transparency, deserve much credit. The more we share data, however, the more we find that many of these problems fail to materialize…

This program doesn’t mean that just anyone can gain access to the data without disclosing how they intend to use it. We require those who want the data to submit a proposal and identify their research team, funding and any conflicts of interest. They have to complete a short course on responsible conduct and sign an agreement that restricts them to their proposed research question. Most important, they must agree to share whatever they find. And we exclude applicants who seek data for commercial or legal purposes. Our intent is not to be tough gatekeepers, but to ensure that the data are used in a transparent way and contribute to overall scientific knowledge.

There are many benefits to this kind of sharing. It honors the contributions of the subjects and scientists who participated in the research. It is proof that an organization, whether it is part of industry or academia, wants to play a role as a good global citizen. It demonstrates that the organization has nothing to hide. And it enables scientists to use the data to learn new ways to help patients. Such an approach can even teach a company like Johnson & Johnson something it didn’t know about its own products. For the good of society, this is a breakthrough that should be replicated throughout the research world.

1BoringOldMan

It feels like we’re only going to have one shot at Data Transparency, and we need to get it right. And at least in the realm of psychoactive medications, the level of misbehavior by the pharmaceutical industry is the stuff of legend. When and if the history is ever written, Johnson & Johnson will probably have a whole chapter all to themselves. The TMAP Program in Texas alone would qualify them, but there were other things including the nearby Excerpta Medica that ghost wrote Risperdal® articles faster that J&J could recruit KOLs to sign them, the J&J Center at MGH for Dr. Biederman’s Childhood Bipolar fantasies, Omnicare contracts for over-medicating the elderly, etc. Before getting a warm glow about this article, read the Rothman Report from the J&J trial in Austin several years ago. Their track record defines the word ruthless. So pardon me if I approach the plan above with a skeptical eye.

[http://media2.kxan.com/PDF/Daniel_Rothman_Expert_Report_300dpi.pdf]

Dr. Harlan M. Krumholtz is in charge of the Yale Center for Outcomes Research and Evaluations [CORE] and its Yale University Open Data Access [YODA] Project [http://medicine.yale.edu/core/projects/yodap/index.aspx]. I have no reason to doubt his credentials, but there are a couple of things that need to be thoroughly investigated:

Harlan M. Krumholz, MD, SM

Editor-in-Chief  NEJM Journal Watch Cardiology

About the NEJM Journal Watch Cardiology Board

Harlan M. Krumholz, MD, SM, is the Harold H. Hines, Jr., Professor of Medicine in the Section of Cardiovascular Medicine at the Yale University School of Medicine, New Haven, Connecticut. He serves as Director of the Robert Wood Johnson Clinical Scholars Program and Director of the Yale-New Haven Hospital Center for Outcomes Research and Evaluation (CORE). Using methods of outcomes research, he has sought to illuminate the balance of risks, benefits, and costs of specific clinical approaches and to implement strategies to improve the prevention, diagnosis, and treatment of cardiovascular disease. He is an elected member of the American Society of Clinical Investigation, Association of American Physicians, and the Institute of Medicine. He has been an Editor for NEJM Journal Watch Cardiology since the publication’s launch in 1995 and Editor-in-Chief since 2000.

Disclosures

Consultant / Advisory board United Healthcare
Speaker’s bureau Centrix
Equity ImageCor
Grant / Research support FDA; NIH-NHLBI; Commonwealth Fund; The Catherine and Patrick Weldon Donaghue Medical Research Foundation; Robert Wood Johnson Foundation; Medtronic
Editorial boards American J Managed Care; American J Medicine; Archives of Medical Science; BMJ.com/US; Central European J Medicine; Circulation: Cardiovascular Quality and Outcomes; Congestive Heart Failure; Critical Pathways in Cardiology; Current Cardiovascular Risk Reports; JACC: Cardiovascular Imaging; J Cardiovascular Medicine
Leadership positions in professional societies American Board of Internal Medicine; American College of Cardiology; American College of Physicians; American Heart Association; Centers for Medicare & Medicaid Services; Oklahoma Foundation for Medical Quality; VHA, Inc.

The Robert Woods Johnson Foundation is “the United States’ largest philanthropy devoted exclusively to health and health care.” “Robert Wood Johnson II built the family firm of Johnson & Johnson into the world’s largest health products maker. He died in 1968. He established the foundation at his death with 10,204,377 shares of the company’s stock.”

And I say good for him. But the Board is built from J&J former executives as I recall from the testimony in the TMAP Trial where the chairman was deposed because they financed the start-up of that infamous program in Texas. While no connection was established, it wasn’t disproved either. No allegations here. It’s just something that needs thorough checking.

The pharmaceutical companies have insisted on talking about what I call Data Transparency as if it is a synonym for Data Sharing. It’s not. Data Sharing is a magnanimous act on the part of the company to allow other researchers access to the data from their clinical trials for further research for the good of mankind. I’m all in favor of the good of mankind, but that’s not what I’m interested in here. I want us [some us] to be able to check their work independently starting from the same place they do – the instant the blind on a clinical trial is broken – the raw data itself. And the reason I want to do that is the outrageous record they have for cheating in the way they handle that raw data. Here’s just one example where the Risperdal® data was hidden or distorted:

In the South Carolina penalty settlement the Judge noted that they had evidence that the manufacturer knew that Risperdal® was associated with metabolic side-effects of some magnitude:

risperdal-sc-2

… then, when instructed to send a “Dear Doctor” letter about those side effects in 2003, they sent out an advertisement instead:

risperdal-sc-3

So this bothers me –

‘We require those who want the data to submit a proposal and identify their research team, funding and any conflicts of interest. They have to complete a short course on responsible conduct and sign an agreement that restricts them to their proposed research question.’

– in two ways:

  1. Those of us who want to “check their work” aren’t necessarily academics, particularly in psychiatry. We might not have any funding at all, and may be voluntarily operating with a PC, Excel, and a free copy of “R.”
  2. We need some recognition that our goal is considered a research topic – namely, “Are they telling the truth in the published paper or are they presenting the data in a way that misleads the reader [like so many have done before]? Are they withholding data to make their drug look more efficacious or safer than it really is [like so many have done before]?” Putting the “re” in research!

Those are topics aimed at the good of mankind too! I don’t care if the pharmaceutical companies want to save face with the way this is presented to the world, as a generous humanitarian act, so long as the process allows for the kind of Data Transparency we need to prevent the kind of shameful criminal behavior J&J engaged in with Risperdal®.

Dr. Krumholz needs to prove to us that his program knows what I’m talking about here…

EMA v AbbVie

Editorial Note: Three months ago we launched an AbbVie campaign and followed it up with a petition calling on AbbVie and InterMune to drop their action against EMA (European Medicines Agency). The hope was to raise awareness of this critically important issue that had been sailing beneath the radar.

Over 6000 of you from more than 120 countries responded.

This interim judgement is not a victory. It may be more a stay of execution. See links here for how things are playing out in the press for example. But it does mean that for the moment EMA is open for business again – except for Humira trials – so anyone who can should now access any trial data they can in case the window closes again.

 

———- Forwarded message ———-

From: Rasi Guido <Guido.Rasi@ema.europa.eu>
Date: 5 December 2013 11:10
Subject: Update on EMA appeal of EU Court interim measures decision in AbbVie and InterMune court cases
To:

Dear colleagues and friends,

I have written a number of times over the past months to keep you informed of developments in the AbbVie and Intermune cases.

There is an important news I would like to share with you concerning the appeal procedures lodged by the EMA in Cases C-389/13 (P) R and C-390/13 (P) R.

As you recall, early in July this year the EMA lodged appeals against the Orders of the President of the General Court suspending the decisions to disclose under Regulation (EC) No 1049/2001 documents contained in the dossier for marketing authorisation of the medicinal products Humira and Esbriet.

We have been recently notified of the two Orders of the Vice-President of the Court of Justice annulling the previous Orders and referring back the cases to the General Court for a new decision on the interim relief applications. The ordinary procedures will follow their normal course.

In the Orders, the Vice-President of the Court of Justice concludes that the President of the General Court erred in law in finding that the alleged infringement of the companies’ fundamental right to the protection of their business secrets and of their right to an effective remedy was sufficient in itself to establish the risk of serious and irreparable harm in the circumstances of the present cases.

Accordingly, the Vice-President of the Court of Justice asks the President of the General Court to examine one by one, the arguments and evidence put forward by the companies and intended to prove the serious and irreparable harm to those companies. In the event that the companies produce such proof with regard to certain information or certain documents, the Vice-President of the Court of Justice explicitly provides that the interim measure sought be granted to them, in respect of that information or those documents only.

The full text of the Orders will shortly be available on the website of the Court of Justice.

Although we have not won the case yet, this is a first important result since the litigation started. We would like to share with you our positive feelings and would like to thank you again for your continuing support, contribution and inspiration for the achievement of our common transparency objectives.

Kind regards

Guido

Guido Rasi

Executive Director
European Medicines Agency
7 Westferry Circus | Canary Wharf | London E14 4HB | United Kingdom

guido.rasi@ema.europa.eu | www.ema.europa.eu

The Church of GSKology 2

A century ago Freud and Jung made us aware of the biases underpinning what patients say. Not everything should be accepted at face value. In particular claims of abuse may not be based on reality. We needed experts – analysts – they claimed to tease out what is real from what is not.

The Catholic Church was once intensely hostile to Freud, but when it came to child abuse adopting a Freudian approach was very convenient. But while Freud essentially denied that real abuse was taking place and got away with it in his life-time, the Catholic Church has learnt to its cost that many claims of abuse are real.

The Pope

This intensely dramatic picture shows a former Pope convening the US cardinals in Rome. They were ostensibly there to put the problem of child abuse in the Church to right but it now seems that the meeting was about managing the consequences for the Church rather than for any of its victims.

Habemus papam?

There is no pope in medicine. The Presidents of National Associations perhaps once came close. Now someone like Andrew Witty comes closest to fitting the bill.

Whatever about a Pope, there are lots of Cardinals. These usually come with the title professor. Just as with the analysts, these professors have had a training that stresses that you cannot believe everything you are faced with. In this case it’s more a matter of not believing the evidence of our own eyes as it is doubt about what someone says. We see patients balloon in weight in front of us or voice suicidal thoughts that clear when the treatment is stopped but the Cardinals are the people who on behalf of the Pope tell us this is not happening.

How often eagerness to see a positive response can mislead

The primary training these Cardinals now get is in evidence based medicine (EBM). Psychoanalysis was once a significant advance, as was EBM. Both made us keenly aware of the biases that both doctors and patients bring to therapy – how often their eagerness to see a positive response to a treatment can mislead them as to what is going on.

Psychoanalysis made us more aware of the importance of fetishes – especially sexual fetishes. A fetish is a part that substitutes for a whole. Adherence to psychoanalysis ultimately itself became a fetish that impaired many doctors’ abilities to engage with the real complaints of their patients.

EBM has fetished RCTs in a way that endangers our ability to handle many of the real problems our patients have and our ability to tackle the abuse to which they are subject.

If the skepticism that underpins controlled trials were applied primarily to the claimed benefits of treatments – the original purpose of these trials – there would be little problem. But instead these trials have become a means to deny the harms that drugs cause. Your observation that your patient has been injured by treatment is an anecdote, we are told. There is no evidence here.

Our Cardinals feel sympathetic for your problems but advise you in the interests of the Church at large to keep quiet. You will be doing the Devil’s work if you speak out about things you know nothing about.

Remaining quiet for how long?

We have reached a critical juncture. On the one hand we have evidence from company run trials, up to half of which remain unpublished and over 80% of which are ghostwritten, and close to 100% of which the data are unavailable for independent scrutiny. On the other hand we often have evidence of a problem appearing on a drug, that clears when the drug is stopped and reappears when it is restarted.

This kind of evidence until recently was thought to be the strongest causal evidence there was in clinical practice. In over 80% of cases evidence like this turns out retrospectively to have been right. So which is the more dependable when treatments go wrong, the evidence from company trials or the evidence from doctors and patients own eyes?

When they hear Evidence Based Medicine most people think they are hearing Data Based Medicine. It is an irony that trials are used to drown out good observations from individual case studies when such case studies are often the one group of studies in modern medicine where we actually have the data – the person who was injured and their clinical record.

It seems, if only for rhetorical purposes, we need a way to demonstrate how unreasonable it is not to take such reports seriously. If the Church is to survive, we need some Cardinals to take up this cause.

Meanwhile back in the church of GSKology…

In the Church of GSKology, the striking parallels between the way the Catholic Church is handling abuse cases in the Archdiocese of Minneapolis and GSK are handling access to clinical trial data were pointed out.

The legal system in Minneapolis though seems to be sorting the Catholic Church out. Judge van de North has just ordered the Archdiocese of St Paul and Minneapolis and the Diocese of Winona to release the names of 58 priests “credibly linked to episodes of child abuse”. (Although the story seems to have vanished from the Star Tribune site – http://www.startribune.com/lifestyle/234042431.html).

The legal system is not getting to grips with the Church of GSKology or with Astra-Zeneca in Minneapolis in anything like the same way.

In the case of Study 329, GSK got patients to sign consent forms saying they would not receive treatment that differed from standard clinical practice, when in fact the plan was to force titrate these children up to imipramine 300 mg per day.

At the end of the study there was a statistically significant increase in the rates of suicidality on Paxil compared to placebo.

Children have been abused. Whose duty is it to inform these now grown children. Pope Andrew?

Or the doctor involved in the trial or their institutions?

  • Marty Keller, or if not him, Brown University?
  • Barbara Geller from St Louis?
  • Rachel Klein from New York?
  • Neal Ryan from Pittsburgh?
  • George Papatheodorou or CAMH where he was working then?
  • Stan Kutcher from Dalhousie?
  • Gabrielle Carlsson from Stony Brook?
  • Graham Emslie from Dallas?
  • Karen Wagner from Dallas?
  • Michael Strober from UCLA?
  • Greg Clarke from Portland?
  • Elizabeth Weller from Columbus?

There were lots of others pulled in to the exercise, pleased perhaps to get their name on a paper. Boris Birmaher for instance.

Rumor has it there are a bunch of bioethicists and lawyers who have got greatly exercised about things going wrong in a St Paul and Minneapolis Astra-Zeneca clinical trial. Perhaps some of them could weigh in on the issue of what should happen next in the case of 329. GSK and A-Z are both British companies – perhaps this is a British thing.

What are the duties of companies, doctors, universities and clinical institutions in a situation like this?

The Church of GSKology

Editorial Note: This post is about midway through a series of posts that are broadly part of the AbbVie series. The series began with GSK’s Transparency and Access Journey, moved on to The House of GSK and will have at least two more posts after this.

Reading the Minneapolis StarTribune, it was the reference to privacy that clinched it.

Facing a sexual abuse lawsuit, the archdiocese of St Paul and Minneapolis made a big deal of putting an independent panel in place to investigate. They put the Reverend Reginald Whitt in charge of appointing the panel and receiving its reports on behalf of the archdiocese.

An independent panel that sticks to the rules

Rev. Whitt told priests and deacons that the task force may review specific files to determine whether the policies of the archdiocese concerning clergy sexual misconduct were properly followed. But, he wrote, “Access to these files will be within my control, and limited only to what is necessary for the task force.”

He also wrote that he recognized that many priests and deacons “may be anxious about your right to privacy and a good reputation.” He assured them that the archdiocese will proceed according to the principles of due process and uniform application of canon policy.

This sounds terribly like the approach Sir Andrew Witty is attempting to put in place for GSK, AbbVie and the rest of the branded pharmaceutical industry vis-a-vis abuses, including child abuse committed in their name.

Investigating abuse

Is Abuse too strong a word? In Study 329, a controlled trial of Paxil given to children, there was a statistically significant increase in suicidality on Paxil compared to placebo. These children were unquestionably injured but it seems about as likely that GSK have contacted the children involved to tell them what happened as the Catholic Church have voluntarily got in touch with anyone who has been affected by their priests or nuns to inquire about their wellbeing.

In Study 329, the consent form tells parents and children that the child will not be exposed to any danger or risks beyond what would be found in normal clinical practice – but the protocol for the study involved an attempt to force titrate children up to a dose of 300 mg of imipramine. This is double the standard dose used for adults – at least in Europe. One reasonable hypothesis as to why this might have been done was that it was an effort to make Paxil look good. Pretty grim if it was.

Privacy rights

Just as the Church is insisting on the Privacy Rights of its priests, GSK, AbbVie and others have taken a legal action against the European Medicines Agency in an effort to claim Corporate Privacy Rights (See Let’s Do the AbbVie AgainAvoiding Adverse Events).

Just as we respect an individual’s right to believe what they want – to be a Muslim, Hindu, Christian or Jew – and defend a pregnant woman’s right to control what happens to her body, GSK and AbbVie are claiming a comparable right to decide what the clinical trial data they hold means.

They are asserting their right to spin their version of what it is you put in your body even though this clashes fundamentally with your right to know what you are putting in your body.

Canon law

Companies operate their own version of Canon Law. Canon law is the Church’s own internal legal system that the Church insists has primacy over national judicial systems. The Bishops and Cardinals adhere to this rather than the laws of the US or other countries. Whether intended or not, this is a system that favors the clerical abusers over abused children. It is this that has fueled the anger of those who have been abused. There would be little problem if the Church’s legal system were harder on the Clerics than on Children. But using a system that defies natural justice to safeguard Clerics not unsurprisingly causes anger.

GSK and other companies run something similar. They actively attempt to over-ride the legal systems of the United States and other countries with claims that unless findings are demonstrated in controlled trials to a statistically significant extent that they simply aren’t happening.

The US Federal Judicial Manual states that convincing evidence of challenge, dechallenge and rechallenge is the way to demonstrate that a drug has caused an adverse event. No place here for statistical significance.

With a flourish worthy of the best Jesuits, internally GSK and other companies apply exactly the approach advocated by the Federal Judicial Manual when assessing whether Paxil has caused a birth defect or suicide, but even after deciding in private their drug is guilty, in public they insist there is no absolutely no evidence that their drug has caused a problem.

This can even leave GSK personnel stating in public that they are not aware of a single side effect that is caused by Paxil or likely any of their drugs. See Burn in Hell.

The US Supreme Court has weighed in on this question and decided that GSK’s model is wrong. People have a right to make up their own minds as to what an adverse event profile means. The only people who have this right at the moment though are investors. Patients and doctors have no rights – at least not established.

Church of GSKology

GSK have applied to be treated as engaged in Science. They say that what they do has all the features of Science – clinical trials, peer reviewed publications.

Ideally the Courts would decide that rather than being a Science they are a Church – they operate a system that requires belief without evidence. There is less doubt that their publications are ghost-written than the Bible is.

While they have people with great public relations skills like James Shannon who say all the right things in public, like the Catholic Church GSK appear to operate an Opus Dei like arm which enables them to place their people close to heart of Britain’s regulator the MHRA and other bodies. They are close to being the Established Church in England.

In the face of abuse, GSK make a big deal about apparent reform but the Rev Whitt described the mechanism GSK have put in place perfectly: “Access to these files will be within my control, and limited only to what is necessary for a Responsible research proposal.”

Waiting for a Frances?

When it comes to reform it seems Andrew is a Ben not a Frankie.

We need some Martin Sixsmith or Dan Brown to write a book and make a movie on the lines of The Lost Child of Philomena Lee.

Don’t hold your breath. GSK are a lot scarier than the Catholic Church.

The House of GSK

In a just published article in the BMJ, Peter Doshi notes how in recent months the English pharmaceutical company GlaxoSmithKline (GSK) have assiduously portrayed themselves as advocates of transparency and in support of access to clinical trial data.

Well in support of ‘Responsible Access’. Responsible essentially means that a researcher commits to the primacy of RCTs and statistical significance over an analysis of adverse events. It would not for example be responsible to claim that an SSRI causes suicide, a statin muscle damage or cognitive failure, or hypoglycemics cause hypoglycemia unless a trial has shown this to happen to a Statistically Significant extent – and they never do.

This scenario suggests a variation on the old joke that Cricket is the English idea of fair-play – eleven against one. Efforts to get at the raw data are just not Cricket.

Gunfight at the GSK corral

A failure to be converted to a Responsible way of looking at the data underpins the stand-off between GSK and the RIAT team attempting to restore Study 329 to what it should have been. Study 329 is GSK’s most famous clinical trial. RIAT stands for Restoring Invisible and Abandoned Trials (see Reading the RIAT Act).

The Doshi article along with the correspondence between GSK and the RIATers makes for eye-opening reading.

To recap, in 1998, SmithKline Beecham reviewed the final data from Study 329, a study begun in 1994, comparing Paxil, imipramine and placebo. They concluded that it demonstrated that paroxetine (Paxil-Seroxat) did not work for children. They decided they couldn’t show the data to FDA but they could go ahead and publish the “good bits” of the study.

This ultimately led to a publication in 2001 in the leading journal in the field of child psychiatry, the Journal of the American Association of Child and Adolescent Psychiatrists, with an authorship line to die for. The first author was Marty Keller of Brown University. There were over twenty others.

The article states clearly that Paxil is safe and effective in children. Most doctors eyeballing it, and its distinguished authors and the journal in which it was published, would be much more inclined to use Paxil afterwards. That so many doctors in New York State in fact went on to prescribe so much Paxil to children led New York State to take a fraud action against GSK in 2004. This study was later at the center of the US Department of Justice’s case against GSK that resulted in a $3 Billion fine.

None of the apparent authors, it transpired, were authors in the sense people in the street would be likely to understand authorship. The real author – Sally Laden – appeared nowhere on the authorship line. The story behind the publication of 329 is laid out on Healthy Skepticism along with the efforts by Leemon McHenry and Jon Jureidini to get the “authors”, or the cuckolded institutions who lent their prestige to this ghostwritten article, or JAACAP, the journal in which it was published, to retract.

Which all refuse to do. And GSK as of a few weeks ago state that “GSK does not believe the article is false, fraudulent or misleading” (see GSK to RIATers).

Enter stage left

This is astonishing but there is another equally astonishing story to tell.

The temptation is for non-academics reading this to glaze over at the sight of theologians arguing about how many angels can dance on the head of a pin. But in fact those of you who have nothing to do with healthcare – the Irresponsibles – as it turns out were then and always are better placed to know when there is a problem. It was the doctors, ethicists and theologians, the Responsible Adults, who missed it. And if this is true of 329, it is likely to be true of everything else as well.

Study 329 began to unravel because a journalist, Shelley Jofre, working for BBC’s Panorama, accidentally left to her own devices, begin to dig. She went to the American Psychiatric Association Meeting in Philadelphia in May 2002, clutching the Keller-Laden paper. She was interested to interview some of the “authors”. One of her questions was “What is emotional lability?” There was a surprising number of children in 329 who became emotionally labile – what’s this? she asked. No-one seemed to know.

At APA, she approached one of the 329 authors Neal Ryan, who gave a non-answer and quickly got in touch with GSK to let them know a journalist was asking questions.

A few weeks later in July and again in August, GSK send a dossier to FDA seeking approval for Paxil for children.

A few weeks after that, on October 7th, to coincide with World Mental Health day (October 10th), Newsweek hit the streets featuring a depressed teenager on the front cover and a strapline Teen Depression: 3 million kids suffer from it. What you can do. The message inside was that Prozac was already being marketing for children and Paxil and Zoloft were about to be. What you can do – is get children on Prozac, Paxil and Zoloft.

Celebrating world mental health day

Three days later, on October 10th, World Mental Health Day, and the 40th anniversary of the passage of the 1962 amendments to the Food and Drugs Act, FDA sent GSK a letter saying Paxil was approvable for kids.

Among other things, the letter notes that GSK had already told FDA that Study 329 showed that Paxil doesn’t work for depressed children. FDA were happy to go along with GSK’s suggestion that this should not be mentioned in the labeling of the drug. Given that the Study 329 publication majored on how effective Paxil was, it would have been inconvenient if the label said otherwise.

There are many notable things in this approvable letter. Perhaps the most interesting is FDA asking GSK to clarify just what emotional lability meant.

FDA have later spun this into a story that their reviewers detected there was an increase of emotional lability events in Study 329 that needed looking at. In fact this idea came on their radar after conversations between Jofre and third parties led to a visit to FDA on August 28th and a suggestion to FDA that they explore the issue of emotional lability.

FDA at the time had a few weeks to respond to GSK’s request to market Paxil for children. Neither Jofre nor the third parties knew at the time that GSK were seeking pediatric approval for Paxil.

The secrets of Seroxat – The perils of Paxil

On October 13th Jofre’s program, The Secrets of Seroxat aired on BBC. This led to one of the biggest responses the BBC had ever had to a Panorama program – 65,000 calls and over 1000 emails.

Panorama had never repeated a topic before. Jofre and Panorama have revisited paroxetine and GSK a further four times – each time demonstrating that when it comes to the blindingly obvious sometimes what you need is plain Curiosity rather than Responsibility.

In dealing with the RIAT team, GSK still insist there is nothing wrong with the Keller-Laden paper and show no interest to co-operate with setting the record right, even though the “fraudulent” version is still the only one on the public record. As such it is still being built into guidelines on the management of children who are depressed – a trial that showed paroxetine doesn’t work and leads to a statistically significant excess of suicidality (emotional lability).

When facing requests from others such as Peter Gøtzsche to be Responsible (see GSK’s Transparency and Access Journey), GSK have typically invited them to meet GSK experts in GSK House. This is more awkward with a RIAT team that is dispersed from Atlanta to Adelaide.

It’s a lot more awkward with a journalist like Jofre, who asks herself along to GSK House with a list of questions in need of an answer.

Despite a haircut between programs, Jofre and Andy Bell produced a second Panorama program, in May 2003, Emails from the Edge that brought the walls of the Temple down. A few days after the second Panorama program, Britain’s MHRA blew a fuse and Seroxat-Paxil was on its way to being banned for children. To be continued…

The moral of the story perhaps is GSK figure letting Responsible adults in to the Club is no problem, but they recognize that a motivated lay-person, particularly a woman spells trouble.

Trade Wars we have known and loved: Brand EFPIA v Korea

Editorial note: a slight variation of this appeared last week on The Conversation.

In 2010, the European Ombudsman ruled that the European Medicines Agency should open access to clinical trials data when companies applied to get their drugs on the market. The ombudsman decided public health was more important than considerations of commercial confidentiality.

In February this year, the US pharmaceutical company AbbVie, who make Humira – the best-selling drug in the world today – took legal action against the EMA’s open access policy after they were tipped that competitors had requested access to clinical study reports and the EMA was going to grant it. In one of the most important healthcare legal actions ever taken, the court upheld the pharmaceutical companies’ positions.

On August 27th, EFPIA – The European Federation of Pharmaceutical Industries and Associates – convened a meeting in Bruxelles to look at issues of accessing clinical trial data, at which Neal Parker of AbbVie created quite a fuss, starting off with a wonderful Freudian slip saying that AbbVie’s mission is to discover new diseases.

A video of the meeting is linked to the Trade Wars AbbVie v China post. Close to the middle of the meeting, the director general of EFPIA, Richard Bergström, intervened to say

“Most of our members are quite relaxed” about data disclosure. For most products there would be no issues, though for highly competitive fields such as biologics there might be.

“You might get companies from South Korea or China breathing down your neck trying to copy your technology, then you get extra sensitive,”

As noted at the time, this comment raises the question as to whether this is what AbbVie’s action against EMA was really all about? The room and the entire commentariat have been debating access to clinical trial data – but was the action elsewhere?

Enter Inflectra stage – left

A little over two weeks after this meeting, EMA provisionally approved Infliximab Biosimilar (Inflectra) for use in Rheumatoid Arthritis, Crohn’s Disease, Psoriasis and related conditions.

Infliximab is the core compound in Remicade. Remicade was developed by Johnson & Johnson. It was one of the first biologics or MABs (monoclonal antibodies), of which AbbVie’s Humira has become the most famous. The branded pharmaceutical industry have always fought hard against generic drugs which eat into their blockbuster profits but they have fought tooth and nail to stop “generic” versions of any biologics being launched.

The argument has been that no generic can be identical to its parent biologic. There are in fact irreducible differences between all original MABs and any derivative biologics. This has given rise to the concept of a Biosimilar. The pipeline for new drugs is so poor that blocking Biosimilars almost seems like a life or death issue for the branded companies.

We must unite against Korea?

Richard Bergström may have let the cat out of the bag mentioning Korea.

Inflimab Biosimilar was made by Celltrion – a Korean company. Celltrion working in collaboration with Hospira, a new kind of pharmaceutical company that has emerged to help develop Biosimilars, based in both the US and UK, filed the application to market Hospira’s Inflectra in America and Europe and Celltrion’s Remsima in other markets.

This could lead to the price of biologics, which can cost anywhere between $20,000 and $500,000 per year falling dramatically, Inflectra – Remsima will likely cost 33% less than Remicade and this will have knock on effects for Humira.

Dr Margaret Chan, Director General of the World Health Organisation, said earlier this year:

“The costs of many new medical products are becoming unsustainable for even the wealthiest countries in the world. [Of the 12 cancer drugs approved last year], 11 were priced above the $100,000 per patient per year. This price is unaffordable, for most patients, most health budgets and most insurance companies. These are problems for all countries, not just the developing world.”

Eastward look, the land is bright?

Up to the MABs, insurance companies like UHG, Humana and others simply paid out on new drugs. They offered a reimbursement rather than an insurance service. But now that biologics are so much more expensive than older drugs, companies in this area, especially larger companies who self-insure like General Motors or WallMart, have to become insurers rather than just reimbursers. And in this arena, a Biosimilar offers insurance companies huge leverage.

Companies like Hospira and Celltrion have a chance to effect huge changes for the better – will they grasp them? Does Salvation lie in the East?

Was AbbVie and EFPIA’s action against EMA a shot across the bows? Was it all about trying to deter EMA from licensing Inflextra – Remsima?

Health Action International: Access to Trial Data

Editorial Note: Leah Cowan and Ancel-la Santos from Health Action International wrote this post covering the release of a HAI position paper on Access to Clinical Trial Data. HAI have been to the forefront of the move to patient reporting of Adverse Events. It has a position as a partner with the European Consumer Organization (BEUC) in support of EMA in the current legal action triggered by AbbVie.

Health action international – HAI

In light of the current negotiations on the Clinical Trials Regulation and the EMA’s work towards the proactive publication of trial data, HAI Europe has published a policy paper “Protecting citizens’ health: transparency of clinical trial data on medicines in the EU”, with the objective to further shape the debate towards greater data transparency.

Clinical trial data must be made publicly available for three main reasons:

  1. Firstly, to strengthen the protection of public health; many adverse drug reactions (ADRs), including deaths, could have been avoided, had the public known about the undisclosed effects of the medicines that caused them harm. In addition, open access to trial data can facilitate independent re-analyses of medicines’ claimed efficacy and comparison between therapies.
  2. Secondly, disclosure of CT data will enhance the cost-effectiveness of public health expenditure, by ensuring that resources are allocated to medicines which have an assured safety and efficacy profile.
  3. Lastly, CT data should be made available for ethical reasons. If trial data is not publicly available, it would be an affront to the large number of participants that are exposed to safety risks when participating in a trial. According to the Declaration of Helsinki, authors have the duty to publish the results of their studies – whether positive, negative or inconclusive.

For too long, unfounded concerns over commercial confidentiality have prevented public access to full clinical trial data. However, in a previous assessment the European Ombudsman found that the disclosure of clinical study reports and trial protocols does not jeopardise commercial interests. In addition, according to the Treaty on the Functioning of the EU, human health is an overriding public interest. Whilst it is suggested that open access to trial data could endanger patients’ confidentiality, in order to allow for accurate re-analysis by independent researchers, de-identification methods can be applied in ways that patient confidentiality is upheld whilst the robustness of the data maintained.

The consolidation of recent advances on data transparency and the achievement of public access to full sets of trial data depend on the outcomes of on-going policy and legal developments. HAI Europe’s policy paper argues that increased public knowledge on the effects of medicines plays an unquestionable role in the strengthening and protection of public health.

You can access the Policy Paper for free.

GSK’s Transparency and Access Journey

Editorial Note: This post has been put together by Peter Goetzsche and David Healy

Dear Dr Goetzsche

“At GSK we firmly believe that making more information available, including clinical study reports and anonymised patient-level data, will enable researchers to study the science behind today’s medicines more closely, to learn more about them and how they can best be used.

For GSK the transparency and access journey [i] started with online clinical trial studies in 2004 and has so far led us to the endorsement of the AllTrials Campaign last year, as well as access to anonymised patient data launched in May 2013. Ultimately this has the potential to improve patient care and drive open innovation.

When patients volunteer to take part in research they have a legitimate expectation that the data will be used to enhance knowledge and improve patient care. Our actions towards transparency are an essential part of meeting those expectations. By being open and accessible we become an even stronger and more trusted partner for society, patients and health care professionals and at the same time improve patient care.

We have been open in describing the steps we have taken. Our initiatives has been acknowledged and welcomed by governments, NGO’s and research institutions.

The recently published report from the Science & Technology Committee in UK, states regarding patient level data: “We recognise the efforts of some members of the pharmaceutical industry, particularly GSK, to increase clinical trial transparency and hope that other companies will act in the same spirit in implementing industry-wide principles for responsible clinical trial data sharing”.[ii]

Our initiatives have been commended by campaign groups as setting a new standard for greater transparency. In response to our commitment to develop a system for access to patient level data, Ben Goldacre, (author of “Bad Pharma” and co-founder of AllTrials) said: “It is a great initiative; I call for it in the book, I hope it happens at GSK, consistently, and I hope it is copied”.[iii]
 
Similarly, in response to GSK signing up to AllTrials, where the Cochrane Institute is one of the partners, and committing to post CSRs, Tracy Brown from Sense about Science said: “GSK signing up to the campaign is very important, off course, because they are a large global player in clinical research so they have a lot of potentially useful information to share, but also because they are finding a way to put in place the infrastructure needed to do this. Which makes it realistic for others and sets a new standard”.[iv]

In a BMJ article published March 2013, CEO Andrew Witty explained our commitment to transparency[v] and our global position is also reflected in the recent submission of our views as part of the consultation process with respect to EMA’s ‘Policy 0070 on publication and access to clinical-trial data’.

We regret that you find a personal meeting irrelevant and would like to repeat our invitation. In GSK we find dialogue very valuable and ultimately to the benefit of patients, and thus our dialogue should be continued in a face to face meeting either in London or in Copenhagen.

A GSK & AllTrials coalition?

Here’s that Branded tone again – mentioned in SHIT Happens. A plaintiff note about how the world just doesn’t understand we are the good guys. GlaxoSmithKline (GSK) seem to have bought their own propaganda about being champions of transparency.

As they mention, the House of Commons has rolled over and put its paws in the air so pleased are they – despite being told by GSK that the UK is not a fit place for Pharma to run trials in. No reference here to the recent fines in the USA for $3 Billion against GSK or the fraud action by New York State against GSK in 2004 hinted at above as the kickstart to GSK’s journey to transparency and access.

Worryingly, there almost appears to be a hook-up between AllTrials and GSK. AllTrials have been campaigning to have all trials registered. When GSK endorsed this campaign, Ben Goldacre described it as a “cartwheel moment”.

In fact the idea of registering all trials – and in this sense the start of the journey – is one that Glaxo Wellcome endorsed 15 years ago when Richard Sykes was CEO of the company. GSK then drew back from this commitment, after Glaxo Wellcome merged with SmithKlineBeecham.

Getting closer?

The links between GSK and AllTrials have appeared to get even closer recently with Iain Chalmers of AllTrials co-authoring an editorial with Patrick Vaillance of GSK. (The Attitude of Chicks to Trojans and Horses). This editorial pushes trial registration. But it also endorses GSK’s proposal of only releasing some of the material from those trials and then only releasing data in response to a request that contains an analytic plan and even in response to such a request only offering a form of release that actively blocks investigators from having a clear view of what might actually have gone on in the trial.

Transparency GSK-style, like Gangham-style, seems to have gone viral. It went viral went it was a press release with not a shred of policy detail in sight – Won’t get Fooled Again. A case study perhaps for those who think that to get something to go viral needs Jupiter to be in alignment with a cat’s eye in Southern Africa when the wind blows East.

Everyone wanted to hear this message.

The Chalmers-Vaillance editorial justified GSK-style in part by making a case that patient confidentiality was extremely important and that the risks of identification were great. This is a strategy Pharma have deployed from the start of the current Data Access Debate – using the patient group Eurordis to make the case for them (The Data Access Wars).

It flies in the face of what the overwhelming majority of people signing consent forms probably intend – which is to make their data available for scrutiny by independent experts. If those of us who have been participants in trials thought some remote risk of a breach of privacy were being used to prevent a disclosure of details that would save someone else’s life but threaten GSK’s profits, most of us would likely be horrified.

It also flies in the face of the original use of consent forms in drug trials – which was solely to establish that you knew you were taking a novel, not-yet-marketed compound. See When Does Yes Mean No.

The moral high ground?

GSK are claiming the moral high ground of concern for patient welfare. Have they in the process managed to co-opt groups from the House of Commons to AllTrials who might otherwise hold them to account?

Study 329 is GSK’s most famous clinical trial. In this a large number of children became suicidal on paroxetine. Antidepressants like paroxetine – thanks to Study 329 but not thanks to GSK – now come with a Black Box Warning that they may cause suicide.

Study 329 was worth roughly $1 Billion to GSK. It enabled the company to get six months patent extension on Paxil-Seroxat.

The children who became suicidal on Paxil in Study 329 are more likely than others to become suicidal again if exposed to another SSRI.

Against this background

  • What should a company genuinely concerned about the welfare of patients who have done so much for the welfare of the company (participating in this trial without payment) do at this point?
  • Should GSK’s concern about patient welfare extend to informing the subjects in Study 329 of the link between their treatment and their problems and future risks they may run?
  • Andrew – have you contemplated the possibility that if you don’t inform those affected you are in fact still to this day making suicide more likely for some of those affected?
  • Has GSK – or any pharmaceutical company – ever gone back to any of the subjects enrolled in any of its trials to explain to them what might have happened to them and the role their drug might have played in what happened? Please send known examples.
  • Would explaining to people how their injury arose not be a more telling indicator of concern for patients than an effort to keep identifiers out of the public domain?
  • What would the patients who have participated in clinical trials think was the more important indicator of genuine company concern?
  • What do Flaminia Macchia and Eurordis think would be the most appropriate indicator of genuine company concern?

Confidentiality

Following a legal action taken by New York State in 2004, GSK agreed to post Clinical Study Reports (CSRs) for their pediatric Paxil trials and other trials on the company website along with further details of their Avandia and other trials on the company website.

Any good investigative journalist could likely identify each of the children who became suicidal on paroxetine from the CSRs available on GSK’s website. Pretty well the only additional details that the patient level data that the company refuses to release contains are the patients’ initials. These could easily be redacted. This raises the question as to why GSK are so resistant to making the original case report forms (CRFs) available?

The only obvious other details that the CRFs contain not found in the CSRs are adverse effects. Its clear from looking at the CSRs, there are a very large number of mismatches (several hundred) between what the CSRs show and the CRFs are likely to contain.

Testing GSK

There is a team attempting to rewrite Study 329 according to the RIAT process. See Reading the RIAT Act. The difficulties they are having in getting data out of GSK have been covered by Ed Silverman of Pharmalot. [No longer at http://www.pharmalive.com/is-glaxo-keeping-its-commitment-to-releasing-paxil-trial-data].

1boringoldman has also covered this ground and the apparent growing links between GSK and AllTrials, and how GSK are using their model of transparency to block access to the data.

Because there is a mismatch between the CSRs and CRFs, the Study 329 RIATers are at a point where they require the raw data – the CRFs. GSK refuses to hand over the CRFs.

What would the now 35-year-old or so children who participated in Study 329 think should happen at this point?

Coalition politics

If you are a small player in the scheme of things, you may know just how the world should work but will never get a chance to implement any of your ideas. If you go into coalition with a bigger power you may get to implement policies you have always supported but have no chance to see brought into being. Or perhaps you can temper policies your partners might want to put in place that you disagree with.

What do AllTrials think should happen at this point?

SHIT Happens – 2

Top secret box

SHIT stands for Secret Health Ingredient in Treatment – see SHIT Happens. In the early twentieth century SHIT was some supposedly secret magic chemical. In the early twenty-first century SHIT is important information about adverse effects of a drug that has been kept hidden.

In SHIT Happens, we reported that RxISK has adverse event data on a range of GSK, Pfizer, Lilly and Merck drugs, drawn from patients and doctors within the USA and elsewhere.

Generic pharmaceutical companies have been in contact to find out more about these adverse effects in order to meet their regulatory reporting requirements. Branding companies like Pfizer and GSK have not.

A colleague in response sent this piece by John La Mattina from Pfizer in Pharma & Healthcare, Sept 3rd 2013. The tone – we are poor misunderstood good guys – seems part of the through and through branding that goes with branded drugs. This is fed through to the sales representatives in the field and the cleaners in the building so that everyone is singing from the same hymnsheet when in fact what is involved is an operation that comes closer to a final nail in the coffin of someone who has an adverse event than even the faintest concession by a branded company that their drug might be causing problems.

For more on this Branded tone, see the forthcoming GSK’s Journey to Transparency.

Can pharma hide side effects of marketed drugs in the U.S.?

“At the end of my first year of running research at Pfizer PFE +1.72%, I drafted a year-end letter to send to all my colleagues thanking them for their hard work and dedication, and wishing them a happy and restful holiday season. As a matter of protocol, I ran the letter by the head of HR, who told me that I needed to change it. The reason was that, at the end of the letter, I said that everyone should turn off their computers, take a break from email, and relax with their families and loved ones. My HR head reminded me that some employees had to work over the holidays, specifically those whose job it was to monitor the reporting of any adverse events that might be reported for our drugs. While 99% of the R&D folks were on holiday, a small cadre of colleagues would be working over the holiday break. I changed the letter accordingly, both acknowledging and thanking those who played this important role.I share this story because most people don’t have a clue as to the vigorous requirements put on pharma by the FDA for reporting a drug’s side effects. In fact, when I write about the pharmaceutical industry, particularly posts that support the value that the industry adds to healthcare, I will often get attacked that I am defending an evil empire. Many believe that the industry hides negative data on its drugs. The following is typical: “Side effects should be monitored and updated and told to patients and doctors. Not hidden as they are right now.Actually, specific regulations exist as to how the industry must handle and report adverse events. To make sure that I had my facts right, I checked with a former colleague of mine in a pharma legal department who shared the following information. Pharma’s reporting requirements are defined in the U.S. FDA Code of Federal Regulations (21 CFR 314.80). Essentially, a U.S. Drug Manufacturer (Marketing Authorization Holder) is required to report serious, unexpected, drug related individual case safety reports within 15 calendar days of initial receipt as well as to report any follow-up information within 15 calendar days of receipt of new information.

How does a company hear of an adverse event? There are two ways. First, within the U.S., physicians and other healthcare professionals can utilize the FDA’s MedWatch Adverse Event Reporting System to report an adverse event seen with a marketed product. In addition, physicians can contact the manufacturer of the marketed drug directly by using telephone contact numbers (toll free) and/or websites provided by the company as mandated by the FDA. Should a physician only report the adverse event to the FDA’s MedWatch program, that information is then forwarded to the drug manufacturer.

“This system is not perfect as the MedWatch Program is voluntary. Thus, a physician could be derelict in reporting an adverse event. There are currently no repercussions should a physician choose not to inform the drug manufacturer of an adverse event seen with its product. However, there may be State, County or Institutional regulations (e.g., hospital standard operating procedures) that obligate healthcare professionals to report these events.

“Every pharma company has a group in its regulatory division dedicated to tracking adverse events and duly reporting these side effects both internally as well as to the FDA. This work goes on every day of the year and is taken very seriously. Contrary to the views of some of my critics, side effects are, in fact, monitored – very diligently”.

RxISK data – GSK & Pfizer

For those of you concerned about the poor folk working Xmas Day and Thanksgiving in GSK and Pfizer, it is perhaps worth clipping out a section from the Access to RxISK Data post that ran last November to make it clear just how seriously Pharma tell themselves they take their duties. (See also SHIT Happens and Won’t get fooled again).

If Andrew Witty, John La Mattina or Neal Parker were to take a train tomorrow and I was sitting in the seat behind and was overheard mentioning a side effect I was having on one of GSK’s drugs part of company mythology is that they are legally bound to report this to the regulator.

Here is Leigh Thompson then the Chief Scientific Officer of Eli Lilly being deposed by Paul Smith on this issue in 1994 for the Fentress trial in Louisville Kentucky after Joseph Wesbecker on Prozac shot dead 8 of his co-workers and injured 12 more before killing himself.

Q. The other day you said something that I have a question about. You said something about…. employees calling adverse event reports in?

A. The rules under the DEN system that I put in place … was that any Lilly employee anywhere in the world that learns of any adverse event through any source, and I’ve done it from cocktail parties and overhearing conversations, should in fact report to DEN within twenty-four or seventy-two hours, depending on where they are in the world. So, yes, we got a lot of adverse events, including ones I report because I’ve literally called up DEN and said, you know, that I overheard a conversation in the hallway just now that somebody’s wife was taking Ceclor and had an allergic reaction.

Q. Do you usually stop and ask for more information about that adverse event or do you just report what you overheard in a conversation in the hallway?

A. Depending on who the individual is, but, for example, you remember you showed me the document about that meeting of the expert opinion leaders that I had gone to wherever it was, I had another Lilly employee come to that meeting and follow me around so that that person could in fact report all the adverse events that I was hearing, so that I wouldn’t have to do it myself.

I think it fulfills a regulatory requirement.. if you right now told me that you had heard of a patient who had taken one of our drugs and who had their hair turn blue, I will guarantee you that I would call DEN up within two days and that would be in the DEN database. And I may or may not ask you for more information, but I would identify you.

Q. So let me make sure I understand. You feel it is your absolute duty to report a conversation that you have overheard in the hallway, but you don’t necessarily feel it’s your duty to report an issue raised by another regulatory agency and the analyses that were done by the drug company in response to that issue being raised?

A. Under the FDA laws and regulations, I think you’ve stated it correctly.

Writing to GSK about access to data

Against this background it seemed appropriate to alert Andrew Witty last March to the fact that we expected RxISK to start generating data on GSK’s and other drugs – mentioning that despite everything many still considered GSK to be among the more responsible pharmaceutical companies. GSK’s response was to misattribute the remark that they were a responsible company to me and to thank me for this recognition, but to turn down a possible collaboration while in a follow up letter stating their full commitment to their regulatory obligations. [There’s the Branding again].

We still haven’t heard from GSK or Pfizer despite accumulating large amounts of adverse event data in people taking sertraline and paroxtine and other company drugs – See SHIT Happens.

There are endless ways to adhere to the letter of a regulation but not its spirit. This is why you hire lawyers.

The campaign for access to clinical trial data is about getting a proper picture of the effects of a drug. Company efforts to restrict access to trial data is in fact more about restricting access to information about the hazards than about the relative inefficacy of treatment. GSK’s proposals to have an analytic plan and to underpin access and a Safe Haven – Safe for GSK – in which no-one will be able to snoop around and find adverse events they weren’t meant to find – are all about restricting access to adverse event data.

Clinical trials are not the correct way to establish the hazards of a drug – the diseases in which they are conducted commonly mask the hazards of treatment (The Spin that no Data can Overcome, Cri de Coeur, Once is Never, The Unbearable Lightness of Being.)

The best approach to hazards is to do what RxISK is trying to do. That is harness the real world experience of people taking a medication to get best quality descriptions of events as well as applying standard approaches to causality such as checking for dose response, challenge-dechallenge-rechallenge and other related methods. The best way to determine risk-benefit ratios is to ask doctors and patients what they think of the possible trade-offs between the effects of a drug – as RxISK asks but clinical trials don’t. We get both doctors and patients to look at the wider impact of an event in a person’s life in addition to reporting on just the event.

Rarely in the field of human communication…

In contrast the pharmacovigilance put in place by the branded pharmaceutical industry out seems aimed at frustrating reporting or in the event there are reports it seems aimed at ensuring that we get the most degraded possible descriptions of events with no accompanying details (See American Woman, American Woman 2).

This is an industry that has succeeded in building a culture in which even good descriptions of the effects of drugs are dismissed as anecdotes – except of course for patients reporting stunning benefits on treatment.

An industry where Ian Hudson, then of GSK, now head of Britain’s FDA (MHRA), can get hundreds of reports of a problem like violence on Paxil-Seroxat and still say he has seen no evidence that Paxil-Seroxat causes any problems (See Burn in Hell).

This is an industry that somehow regularly fails to send reports of adverse events to FDA as per regulations – as Neal Parker’s AbbVie appears to have done (See Sharing the Yellow Stuff).

Rarely in the field of human communication has the reality of what happens on the ground been so at odds with what the powers that be proclaim.

This is probably not the way Andrew and John and Neal see it. But they must know that branding is all about pimping things up to look good but – to continue the metaphor – above all making sure the glossy image doesn’t fart.