Wednesday, July 29, 2015

AllTrials in the USA

We’re excited to announce that 50 patient groups, consumer organisations and medical societies have come together to launch AllTrials USA today! These groups have said:
"We are calling on everyone in our sector to join us in supporting the AllTrials campaign. Hundreds of thousands of patients have taken part in clinical trials which have never reported results. For every day that passes, more information is at risk of being lost forever. We have to make every clinical trial count. Join us today."
Patient activist AnnaMarie Ciccarella said: “We provided our bodies, our tissue samples, our data. I’ve heard the same sentiment expressed many times from patients in clinical trials, ‘This may not help me, but it may help another person.’ It’s time to honor that sentiment.”
Read more inspiring words from the patients, researchers and groups launching the US campaign today at AllTrials.net.
We got an incredible response when we asked if any of you were able to volunteer some time in July to help with this, thank you! Because so many of you hit the phones and reached out to hundreds of organisations across the US, the campaign is able to hit the ground running. Look out for media coverage and editorials today and throughout this week, announcements of new organisations adding their support and calls for action in the US at #AllTrials on Twitter and Facebook.
Meet the team behind AllTrials USA hereget in touch and add your support!
Best wishes
James
P.S. If you haven’t already, do read this week’s Economist for great coverage of the campaign ahead of the US launch, and check out the Financial Times and The Wall Street Journal for coverage of our announcement last week that investors worth over €3.5 trillion in assets are supporting AllTrials, or read more about it on our site.


Monday, July 20, 2015

Richmond Pharmacology update

Here is a quick note about yesterday's hearing. Judgment is expected next week. 

The judge grasped the importance of trial registration and when he took into account our and the HRA's evidence on legal and ethical obligations to register trials he found that Richmond was left with an extraordinarily narrow argument. It seems the case will come down to some words in a Q&A on HRA's website that wasn't amended at the same time as the sponsors' declaration was. And then whether the ambiguity was significant.

We are so pleased we decided to intervene in the case. The court could find for Richmond on this very narrow point but it ended up exactly where we thought it should be: a principled discussion in which the judge seemed to grasp the issues well, the removal of Richmond’s broad claims that no registration was legally required and that the HRA was acting unlawfully, and alighting on a narrow matter for decision that will not impact on how trials are run or on the EU rules coming into force next year. Of course we would have liked the case refused altogether instead of it wasting public funds, which will be a lot if HRA has to pay Richmond's costs. 

Based on what was said in court, we are hopeful too that the court will find that the HRA has been going about its proper business promoting clinical trial registration. We are pleased that the judge ignored Richmond's attempts to discredit AllTrials, and in fact that these appeared to backfire.

We will share the transcript of yesterday's hearing as soon as we have it. I think you'll enjoy reading it! 

When the judge at the hearing yesterday heard that the HRA does not impose any sanctions on trial sponsors who don't register their trials properly he said, "well, they should." 

Our legal team was amazing - solicitor Robert Dougans and barrister Jonathan Price - before during and after. If any of you read L Phillips' recent speech asking where are the lawyers who are motivated above all by the pursuit of justice, well we know them. 

(Tracey Brown is especially grateful for their patience with her unceasing flow of notes and questions) 

Also yesterday, the pharmaceutical industry body EMIG said that Richmond's actions do not represent the views of the rest of industry. Mark Edwards, the CEO, said that the case could have a disastrous effect on the industry. Read EMIGs letter here. It contradicts Richmond's claim to the court that its concerns are representative. Some of you have told us that but EMIG said it publicly, which matters. 

Thank you so much to those who came to court yesterday and sent messages of support. As well as the judgment, look out for some other big news stories from AllTrials next week: we can't wait to tell you what your support has helped to achieve.

Síle

 

Síle Lane

Director of Campaigns

Sense About Science

Science and evidence in the hands of the public

www.senseaboutscience.org |@senseaboutsci

Wednesday, July 08, 2015

Further Update

Hi AllTrials friends
Yesterday we sent our submission to the court in the judicial review brought against the HRA by Richmond Pharmacology.
We have spent the last few weeks ploughing through the hundreds of pages of documents. Richmond is currently asking the judge to rule that there is no overriding legal requirement to publicly register any trial. That’s not correct. Since 2011 all trials except for adult phase 1 have been publicly registered through the EU Clinical Trials Register. And by next year this legal requirement will extend to all clinical trials unless exempted according to some very tight criteria. Richmond is effectively asking the judge to set the clock back 10 years and wipe out the careful progress that has been made in relation to trials registration at national and EU level. We have set out in detail the legal frameworks related to this, and put forward legal arguments as to why HRA has a duty to monitor compliance with both legal requirements and sound practice for running a trial. However, Richmond has changed its case three times and may yet change it again.  
The hearing will be in open court in Manchester on Thursday 16th July. We will be there. It would be lovely to see any of you who’d like to come along too; we could do with some help capturing what is discussed in Court. We are unlikely to know the result on the 16th, we hope the Judge will make his decision by the end of July but it could be October.We and our barrister Jonathan Price and solicitor Robert Dougans knew that we faced a demanding timetable and it meant that two of us here at Sense About Science have been almost completely absorbed by reading and writing legal arguments (it’s why I don’t have a suntan, when most of London does!).
We have managed to keep the rest of the AllTrials campaign going only in the face of that because many of you have given us help and topped up our fundraising appeal. Thank you! In a couple of weeks I will be able to show you just how significant that is. We are about to break a story about a new group coming on board for all trials registered and all results reported, in a way that should change part of the international scene, for good. We are also reaching the critical mass to be able to launch a US campaign. I can see from the comments on the Just Giving site how determined you are that the challenge of the Richmond/HRA case is not going to stop this. And if you have been thinking about giving something, however small, could I urge you to do it now?  
Let us know if you can join us in court on 16th.
Best wishes
Síle and James

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Thursday, June 25, 2015

AllTrials vs Richmond Pharmacology

Dear AllTrials friend

We hoped to tell you more about the case Richmond Pharmacology is bringing against the HRA. That's not been straightforward. Richmond has now changed their argument three times and has altogether abandoned some arguments it relied upon earlier, so getting to grips with what is at stake has been difficult and time consuming for us and for our lawyers.

At the beginning of this week it looked as though Richmond had narrowed the case down to a technical argument about the wording of HRA’s guidelines which only applied for a period of 10 days earlier this year.

Just as the issues seemed to be narrowing, Richmond then asked the Court not to allow AllTrials to be heard. We had written to Richmond and the HRA outlining our planned argument to the court and inviting their response. HRA replied to us, Richmond did not. Instead they went straight to the Judge and asked him not to hear us.

And then yesterday we saw that Richmond has asked the Court at the very last minute to rule on something huge. They want the Court to declare that no trial sponsor or person running a trial has any legal requirement to publicly register any clinical trial unless the sponsor has given a legally binding commitment to do so, or an ethics committee has asked them to do so for every trial. So now the Court is being asked to rule not on the specifics of the case but on a much broader point.

Richmond has asked the Court for a hastily arranged hearing in Manchester on Monday where they will ask to seek that declaration as part of the case. This is after they have warned the court that AllTrials' references to international rules and protocols are irrelevant and will only add to their costs!

We need to be there on Monday to make it clear to the Court that it is being asked to rule on something that has real ramifications beyond this case. If Richmond win, this would go in the face of international laws, regulations, professional standards and the ethical rules of research. If such a declaration was made it would shatter the progress towards transparency made by AllTrials and the progress made internationally before AllTrials even started.

Today we are writing our submission to the Court to be allowed to speak on Monday. We’ll tell you more as soon as we know it. We have only been able to do this because hundreds of you have sent support, encouragement and donations. Thank you.

Best wishes
James

James Cockerill
Campaigns Manager

Sense About Science
Science and evidence in the hands of the public

Tuesday, June 23, 2015

Ben Goldacre writes in the BMJ - How medicine is broken, and how we can fix it

The chief medical officer’s review on statins and oseltamivir may look for answers in the wrong places

Last week there was extensive news coverage of a leaked letter written by the chief medical officer to the Academy of Medical Sciences. This letter focused especially on concerns around statins and oseltamivir (Tamiflu) and asked the academy for an “authoritative independent report looking at how society should judge the safety and efficacy of drugs.”1 The academy has since announced that it is convening a working group on the subject.

With any such report there are two major risks. The first is a focus on “trust” or even—as a worst case—false reassurance for well documented problems. We do not believe the academy will choose this path. But there is another, bigger risk: the academy may accept shortcomings in the evidence as somehow inevitable. Here there are good grounds for concern. The academy has already announced that its work “will explore how evidence that originates from different sources (e.g. randomised clinical trials and observational data) are used to make decisions about the safety and efficacy of drugs and medical interventions.”2

Focusing solely on existing trials and observational studies would represent a failure of vision and ambition in an era when medicine has both the need and the opportunity to innovate. Well documented problems exist in the funding and prioritisation of research, the conduct of trials, the withholding of results, the dissemination of evidence, and its implementation with patients. Here we briefly examine six domains where the academy could call for simple practical improvements that would address legitimate concerns.

Publication bias—We conduct trials to detect modest differences, and spend vast amounts of money specifically to exclude bias, yet we allow that bias to flood back in through selective publication.3 4 Eminent bodies writing reports will not fix this, but practical action will. We need new funding for simple systematic work to audit which trials are unreported, to highlight the best and worst performers, and to shine a light on withheld studies.5

Independent trials—A recent cohort study found that 97% of head to head trials sponsored by industry give results that favour the sponsor’s drug.6 Doctors and patients are right to want independent trials. On statins and oseltamivir, there are two clear opportunities, and here we declare our own conflicts. With colleagues, one of us (CH) first proposed a trial of oseltamivir in a pandemic in 2009; the other (BG) first proposed a trial of statins examining side effects over a year ago. In both cases we could have the answer by now.

Cost of trials—Replication will be possible only if the cost of conducting trials is radically reduced. Much of this cost is driven by disproportionate regulation around trials of routinely used treatments.7 The National Institute for Health and Care Excellence’s guidance on cholesterol argues for head to head trials in low risk populations; this would require over 100 000 participants, followed up for a decade. Such trials can practically be delivered only by reducing the expensive and disproportionate regulatory burden,7 embedding them in everyday clinical care and gathering follow-up data from existing electronic health records.8

Better evidence—Treatments are routinely approved after trials with only surrogate outcomes.9 Drugs are then extensively promoted, at the moment of approval, when evidence on real world outcomes is paradoxically at its weakest. We could encourage better evidence by, for example, compelling companies to follow-up all phase III trial participants until real world benefits emerge, considering routine randomisation for newly approved drugs when benefits are unclear, and bartering with either patent extension or choice of the start date for market exclusivity. These suggestions would come at minimal cost and deliver more comprehensive data on treatment effects.

Shared decision making—Concern over statins has recently been reawakened by the introduction of a financial incentive for general practitioners to prescribe the drugs to low risk patients. This is ill judged because patients’ informed choices vary widely.10 11 An incentive to prescribe a treatment that many adequately informed patients do not want undermines informed decision making and inflicts avoidable reputational harm on the profession. If instead we incentivise shared decision making then—for the same financial outlay—best practice will be recognised, rewarded, and laid down in the everyday templates of what doctors do.12

Declare conflicts of interest—Declaration of conflicts of interest is currently chaotic, inconsistent, and incomplete. We clearly need a central system of declarations, ideally maintained by the General Medical Council.13 Conflicts, however, become particularly salient when evidence is unclear: when decisions about which treatment works best are made on the basis of a speculative, superficially plausible narrative about a drug’s mechanism of action, or on the interpretation of weak, confounded, observational data when randomised trials are feasible. If we are able to generate better evidence and ensure that we see the complete evidence, then competing interests—although they must always be declared—will become less salient.

This is just a brief tour of six domains, and there is much more to be done. Most of our suggestions are rapidly deliverable. Some require modest funding; most do not. Some require legislative changes. But we should remember that evidence based medicine, in its true modern incarnation, has a relatively short history and that when randomised trials were first introduced they were often regarded as a transgressive, expensive, unnecessary, and unwelcome challenge to medical authority.14 The public is increasingly aware of the shortcomings we collectively tolerate in the evidence base for clinical practice. We now have the opportunity to use public frustration as fuel to update our implementation of evidence based medicine in the light of new technology and get our house in order. To restrict a review of these problems to the interpretation of inadequate existing data—as the academy apparently proposes—would be recklessly backward looking.

Notes
Cite this as: BMJ 2015;350:h3397

Footnotes
Competing interests: We have read and understood BMJ policy on declaration of interests and declare BG and CH are founders of the AllTrials campaign calling for all trials to report their results. BG receives funding from the Wellcome Trust and the Laura and John Arnold Foundation and income from speaking, writing, and broadcasting on problems in science and medicine. CH has received funding from a UK National Institute for Health Research grant (HTA—10/80/01 Update and amalgamation of two Cochrane reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children www.nets.nihr.ac.uk/projects/hta/108001). CH also receives occasional payments for running educational courses at the University of Oxford (see www.phc.ox.ac.uk/team/researchers/carl-heneghan for full details).

Provenance and peer review: Commissioned; not externally peer reviewed.

References
↵Wise J. England’s chief medical officer asks for review of drug evaluation in wake of statins controversy. BMJ2015;350:h3300.FREE Full Text
↵Academy of Medical Sciences. Academy launches new project on evaluating evidence. Press release, 16 Jun 2015. www.acmedsci.ac.uk/more/news/evaluating-evidence-launch/.
↵Schmucker C, Schell LK, Portalupi S, et al. Extent of non-publication in cohorts of studies approved by research ethics committees or included in trial registries. PLoS One2014;9:e114023.CrossRefMedline
↵Song F, Parekh S, Hooper L, et al. Dissemination and publication of research findings: an updated review of related biases. Health Technol Assess2010;14(8).iii, ix-xi,1-193.
↵Goldacre B. How to get all trials reported: audit, better data, and individual accountability. PLoS Med2015;12:e1001821.CrossRefMedline
↵Flacco ME, Manzoli L, Boccia S, et al. Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. J Clin Epidemiol2015;68:811-20.CrossRefMedline
↵Van Staa T-P, Dyson L, McCann G, et al. The opportunities and challenges of pragmatic point-of-care randomised trials using routinely collected electronic records: evaluations of two exemplar trials. Health Technol Assess2014;18:1-146.CrossRef
↵Van Staa T-P, Goldacre B, Gulliford M, et al. Pragmatic randomised trials using routine electronic health records: putting them to the test. BMJ2012;344:e55.FREE Full Text
↵Yudkin JS, Lipska KJ, Montori VM. The idolatry of the surrogate. BMJ2011;343:d7995.FREE Full Text
↵Fontana M, Asaria P, Moraldo M, et al. Patient-accessible tool for shared decision making in cardiovascular primary prevention: balancing longevity benefits against medication disutility. Circulation2014;129:2539-46.Abstract/FREE Full Text
↵Van Staa T-P, Smeeth L, Ng ES-W, Goldacre B, Gulliford M. The efficiency of cardiovascular risk assessment: do the right patients get statin treatment? Heart Br Card Soc2013;99:1597-602.Abstract/FREE Full Text
↵Goldacre B, Smeeth L. Mass treatment with statins. BMJ2014;349:g4745.FREE Full Text
↵McCartney M, Goldacre B, Chalmers I, et al. Why the GMC should set up a central registry of doctors’ competing interests. BMJ2014;348:g236.FREE Full Text
↵Blythe M, Cochrane A. One man’s medicine: an autobiography of Professor Archie Cochrane. BMJ Publishing, 1989.

Friday, June 12, 2015

A message from AllTrials about Richmond Pharmacology's Judicial Review

Dear AllTrials friend
As most of you know Richmond Pharmacology has brought a judicial review against the Health Research Authority because it insists on the registration (not even reporting, but registration) of clinical trials. Read more.
This is a quick note to let you know that we have obtained the court papers (hundreds of them!), we are looking urgently with lawyers at what can be done and we will be in touch next week to tell you. In the meantime, if you have been meaning to help with our campaign fund, now would be a great time...  And if you can help with time over July, please tell us by replying to this email.
Best wishes
James 
James Cockerill
Campaigns Manager
Sense About Science
Science and evidence in the hands of the public

Thursday, June 11, 2015

Sidney Wolfe writes in the BMJ - AllTrials - Selective clinical trial reporting: betraying trial participants, harming patients


Reporting biases found in trials of cardiovascular devices

Reporting biases in published trials were first identified in 1986.1 Published randomized studies of combination chemotherapy compared with treatment with an alkylating agent as first line treatment for ovarian cancer showed a significant survival advantage for combination chemotherapy. Unpublished cancer trial registry data from the same studies, however, showed no such advantage.2 Similarly, in the treatment of multiple myeloma, registry data suggested a smaller survival advantage for combination chemotherapy (over prednisone and an alkylating agent) than the results of published studies. The author who reported the discrepancy concluded that his findings “demonstrate the value and importance of an international registry of all clinical trials.”1Subsequent evidence for biased and selective reporting included prompt or delayed publication depending on whether trial results were positive or negative3 and more favorable results and conclusions in published studies funded by industry than in those funded independently.4

The linked paper by Chang and colleagues (doi:10.1136/bmj.h2613) shows similar reporting biases in trials of medical devices.5 The authors found worrying differences between trial information submitted to the US regulator (the Food and Drug Administration) and trial information reported in medical journals. Among 177 studies of 106 high risk cardiovascular devices submitted to the FDA, fewer than half were published, and fewer than half the published studies (45%) reported primary results that precisely matched the results in submissions to the regulator. Among the published primary results, 11% (17) were judged to be “substantially different” from those submitted to the FDA. The authors concluded that “even when trials are published, the study population, primary endpoints, and results can differ substantially from data submitted to the FDA.”5

Most studies of reporting biases have examined differences in efficacy between unpublished clinical trial data and journal publication data but evidence now exists of under-reporting of adverse events. A recent BMJ editorial cites “the growing body of research on reporting biases, which documents the gross under-reporting of adverse event data in such [medical journal] sources.”6

Unfortunately, selective reporting of clinical trial data in medical journals also extends to companies’ selective non-reporting of safety data to the FDA. In 2012, the US Department of Justice announced that “GSK [GlaxoSmithKline] has agreed to plead guilty to failing to report data to the FDA and has agreed to pay a criminal fine in the amount of $242,612,800 for its unlawful conduct concerning Avandia . . . The United States alleges that, between 2001 and 2007, GSK failed to include certain safety data about Avandia, a diabetes drug, in reports to the FDA that are meant to allow the FDA to determine if a drug continues to be safe for its approved indications and to spot drug safety trends.”7

Efforts to increase the public availability of clinical trial data to prevent the serious public health consequences of overstating benefits and understating risks have triggered strong industry opposition. In 2012 the former executive director of the European Medicines Agency (EMA), Guido Rasi, committed the regulator to “proactive publication of clinical-trial data, once the marketing-authorisation process has ended.” He added “We are not here to decide if we publish clinical-trial data, but how.”8 Two pharmaceutical companies sued the EMA to prevent disclosure, and the EMA has watered down its original plans.9

Beyond adverse effects on patients of selective reporting in medical journals, the absence of publicly available data from clinical trials violates an important ethical principle of the Declaration of Helsinki: “Researchers have a duty to make publicly available the results of their research . . . Negative and inconclusive as well as positive results must be published or otherwise made publicly available.”10 Many people participate in research because they trust that the published results might improve the health of the general population.

Ignoring the Declaration of Helsinki, in 2013 the Pharmaceutical Research and Manufacturers of America (PhRMA) urged the US government to influence the European Union against the EMA’s data disclosure policy. In a letter to a US trade representative, PhRMA wrote that “Disclosure of companies’ non-public data submitted in clinical and pre-clinical dossiers and patient-level data risks damaging public health and patient welfare.”11

It is clear that the reverse is true. Non-disclosure is far more damaging. The letter of rebuttal from leaders of the high profile campaign for public registration and reporting of all trial results (AllTrials) reads,

 “The world is moving towards a recognition that hiding information about what was done and what was found in clinical trials is an abuse of trial participants’ trust and exposes patients to unnecessary harm.”12 

I, and many others, agree.

Notes

Cite this as: BMJ 2105;350:h2753

References

  1. Simes RJ. Publication bias: the case for an international registry of clinical trials. J Clin Oncol 1986;4:1529-41.

  2. US Department of Health and Human Services: compilation of experimental cancer therapy protocol summaries. NIH publication, Government Printing Office, 1977-1983.

  3. Stern JM, Simes RJ. Publication bias: evidence of delayed publication in a cohort study of clinical research projects. BMJ 1997;315:640.

  4. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev 2012;12:MR000033.

  5. Chang L, Dhruva SS, Chu J, Bero LA, Redberg RF. Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports.BMJ2105:350;h2613.

  6. Doshi P, Zito J, dosReis S.Digging for data on harms in duloxetine trials. It’s time for policy makers to get serious about drug related harms. BMJ2014;348:g3578.

  7. Torjesin I. European Ombudsman ramps up action against European Medicines Agency over data transparency plans. BMJ2014;348:g3733.

    http://www.bmj.com/content/350/bmj.h2753?

Tuesday, May 26, 2015

Introducing GlobalLeaks

https://globaleaks.org/

GlobaLeaks is an open source project aimed at creating a worldwide, anonymous, censorship-resistant, distributed whistleblowing platform.

Friday, May 01, 2015

Ben Goldacre - Progress and Barriers on Clinical Trials Transparency

From Evidence-Based Medicine to Marketing-Based Medicine

Dr Peter Parry is an Australian child & adolescent psychiatrist who has researched the "Pediatric Bipolar Disorder" diagnosis emanating from the USA, a diagnosis completely at odds with his training and clinical experience in Australian child and adolescent mental health. 

As part of his research into the PBD phenomenon, he noticed hundreds of internal pharmaceutical industry documents publicly released from court cases against pharmaceutical firms by State and Federal Attorney Generals in the USA. These documents concurred with findings of the US Senate "Grassley Commission" into conflicts of interest between the pharmaceutical industry and academic medicine.

In collaboration with A/Prof Glen Spielmans, psychologist from Minnesota, they researched over 400 internal pharmaceutical documents regarding psychotropic medications. They published an article in 2010 in the Journal of Bioethical Inquiry titled "From Evidence-Based Medicine to Marketing-Based Medicine: Evidence from Internal Industry Documents"[1]. These documents reveal efforts at "disease-mongering" to expand markets e.g. by increasing the number of people diagnosed with "bipolar disorder"; marketing strategies to influence "customers" i.e. physicians, other health professionals and government regulators; and manipulation of the published medical literature to maximise positive findings and minimise or hide negative findings re manufacturers' medications.

The past few years have witnessed a global awakening in the health professions, lay public and government also - to the fact we do not have evidence-based or science-based medicine, but rather a commercially distorted marketing-based medicine environment. Former chief-editor of the British Medical Journal, Prof Richard Smith, summed this up in his 2005 article in PLoS Medicine titled "Medical Journals Have Become an Extension of the Marketing Arm of Pharmaceutical Companies"[2].

The medical profession and journals have ethical duties towards scientific truth and the welfare of patients before all else. Big Pharma as capitalistic corporations have a commitment to their bottom line. There is now a solution to this situation - the AllTrials campaign - to bring all research data (anonymised of patients' names) into view for independent analysis. AllTrials has the full backing of the British medical establishment - but needs international support if we are to have a future of Science-Based Medicine to supply the most beneficial and least harmful treatments and most accurate medical knowledge for us all.

[1] http://link.springer.com/article/10.1... 

[2] http://www.plosmedicine.org/article/i...

AllTrials has changed the world

Wednesday, April 22, 2015

Psychiatrists With Ties to AstraZeneca Resign From Texas State Hospital

Bloomberg News
Two psychiatrists at a Texas state hospital have resigned after being told they would face disciplinary actions for accepting hundreds of thousands of dollars in speaking and consulting fees from AstraZeneca AZN +1.58% while also promoting one of its drugs to state officials, according to a spokeswoman for the Texas Department of State Health Services.
The psychiatrists allegedly violated various department rules as a result of their relationship to the drug maker, which involved efforts to ensure the Seroquel XR antipsychotic would be placed on the state formulary and prescribed by state physicians, according to letters sent to the physicians by the department. A formulary is a list of preferred drugs for which insurance coverage is made.
The physicians were investigated in conjunction with a lawsuit that was filed last October by the Texas Attorney General, a department spokeswoman writes us. The Attorney General alleged AstraZeneca illegally marketed its Seroquel antipsychotic for unapproved uses, paid kickbacks to physician and state health officials, and subsequently caused the state Medicaid program to overpay for the medicine.
The lawsuit notes that people with schizophrenia or bipolar disorder were more likely to be uninsured and not able to afford Seroquel, therefore relying on state health programs, according to an earlier report on this matter. As a result, AstraZeneca anticipated a “significant portion” of its revenue would come from “public sector” payers, according to the lawsuit.
As noted previously, that lawsuit built on claims in other lawsuits that were filed by two former AstraZeneca sales reps, who alleged the drug maker used various tactics to induce doctors to prescribe different versions of the Seroquel pill. The allegations mirror charges of off-label marketing of Seroquel that led AstraZeneca to pay $520 million six years ago as part of a settlement with the U.S. Department of Justice.
An AstraZeneca spokeswoman declined to comment on the resignations, which were first reported by The Texas Tribune, but did write us that its policies “prohibit compensation for services as an inducement to, or any way in consideration of, a healthcare professional’s current or potential prescribing, purchasing, use, formulary status, or dispensing of AstraZeneca products.”
Texas officials say that one psychiatrist, Lisa Perdue, was paid more than $615,000 by the drug maker between 2005 and 2013, and allegedly approached members of the state’s Executive Formulary Committee, although did not disclose she did work for AstraZeneca, according to department documents. And Anthony Claxton received more than $231,000 between 2005 and 2012, according to department documents.
Neither psychiatrist could be reached for comment about the resignations. In an e-mailsent to state officials last week, Claxton acknowledged presenting Seroquel information to other state physicians, but maintained he believed he had supervisory permission. An attorney for Perdue did not respond to messages seeking comment about the resignation.
However, the attorney wrote a letter to state officials denying various allegations, such as the amount of money she accepted or that she “intentionally participated in a plan on behalf of AstraZeneca to use her influence” over formulary committee members. Perdue, he wrote, approached formulary committee members because she thought Seroquel XR “offered less toxic side effects for some patients.”
A department spokeswoman tells us that Seroquel XR was never added to the state formulary, but that the older version of the drug has been on the state formulary since at least 2004. She adds that there were no issues surrounding patient care. Both psychiatrists worked at Terrell State Hospital, which is one of 10 psychiatric hospitals run by the Department of State Health Services.
http://blogs.wsj.com/pharmalot/2015/04/21/psychiatrists-with-ties-to-astrazeneca-resign-from-texas-hospital/

Tuesday, April 14, 2015

Yes!

WHO calls for increased transparency in medical research

Note for the media
14 April 2015
 WHO today issued a public statement calling for the disclosure of results from clinical trials for medical products, whatever the result. The move aims to ensure that decisions related to the safety and efficacy of vaccines, drugs and medical devices for use by populations are supported by the best available evidence.
“Our intention is to promote the sharing of scientific knowledge in order to advance public health,” said Dr. Marie-Paule Kieny, WHO Assistant Director General for Health Systems and Innovation. “It underpins the principal goal of medical research: to serve the betterment of humanity.”
“Failure to publicly disclose trial results engenders misinformation, leading to skewed priorities for both R&D and public health interventions,” said Kieny. “It creates indirect costs for public and private entities, including patients themselves, who pay for suboptimal or harmful treatments.”

Unreported trials lead to misinformation

For example, in a study that analysed reporting from large clinical trials (more than 500 participants) registered on clinicaltrials.gov and completed by 2009, 23% had no results reported. These unreported trials included nearly 300 000 participants. Among clinical trials of vaccines against five diseases registered in a variety of databases between 2006-2012, only 29% had been published in a peer-reviewed journal by the WHO recommended deadline of 24 months following study completion.
“We need the collaboration of all these actors to enforce transparency in their jurisdictions in order to increase the benefits and decrease the risks for patients, clinical trial volunteers and the general public,” concluded Dr. Kieny.

International Clinical Trials Registry Platform furthers transparency

WHO’s call for disclosure includes older unreported clinical trials, the results of which may still have an important bearing on scientific research today. WHO also reaffirms the need for all clinical trials to be registered on a WHO primary clinical trial registry so that they can be accessible through the International Clinical Trials Registry platform. This will ensure transparency as to which clinical trials have occurred, and allow verification of compliance with public disclosure requirements.
The recent WHO move expands on a 2005 call for all clinical trials to be registered, and the subsequent establishment of the International Clinical Trials Registry Platform. This registry platform regularly imports trial records from Clinicaltrials.gov, ISRCTN, EU Clinical Trials Register, Australia New Zealand Clinical Trial Registry, Pan African Clinical Trial Registry and Clinical Trial Registries from China, India, Brazil, Republic of Korea, Cuba, Germany, Iran, Japan, Sri Lanka, The Netherlands and Thailand.
For more information please contact:
Tarik Jasarevic
Communications Officer
Mobile: +41 79 367 62 14
E-mail: jasarevict@who.int
Daniela Bagozzi
Senior Information Management Officer
Mobile: +41 79 603 72 81
E-mail: bagozzid@who.int


WHO Statement on Public Disclosure of Clinical Trial Results

Background

Following a ministerial summit on Health Research in 2004, a World Health Assembly Resolution passed in 2005 called for unambiguous identification of all interventional clinical trials. This led to the establishment of the WHO International Clinical Trials Registry Platform, which collates information on trials that have been notified in a network of clinical trial registries (who.int/ictrp/network). WHO’s existing position on registration is available at who.int/ictrp: “The registration of all interventional trials is a scientific, ethical and moral responsibility”. Deposition of information on trials in such registries, prior to their initiation, is a condition for publishing the results of trials in many leading medical journals. However, concerns have been raised that there may be selective publication of trials dependent on their results, with particular concern that trial results which may be viewed as “negative”, are less likely to be submitted, or accepted, for publication in the scientific literature or made public in other ways. Notification of trials to clinical trial registries has become more widespread, and it is possible to evaluate what proportions of recorded trials have not reported results at different times after the planned end dates of the trials. Multiple analyses have confirmed that a substantial number of clinical trials remain unreported several years after study completion, even in the case of large randomized clinical trials.
In the latest version of the Declaration of Helsinki it is stated that “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.” and that “Researchers have a duty to make publicly available the results of their research .... Negative and inconclusive as well as positive results must be published or otherwise made publicly available”. There is an ethical imperative to report the results of all clinical trials, including those of unreported trials conducted in the past. Furthermore poor allocation of resources for product development and financing of available interventions, and suboptimal regulatory and public health recommendations may occur where decisions are based on only a subset of all completed clinical trials.

Reiteration of WHO position on clinical trial registry sites

Before any clinical trial is initiated (at any Phase) its details are to be registered in a publicly available, free to access, searchable clinical trial registry complying with WHO’s international agreed standards. The clinical trial registry entry should be made before the first subject receives the first medical intervention in the trial.

Updating clinical trial registry entries

All clinical trial registry sites are to be updated as necessary to include final enrolment numbers achieved, and the date of actual study completion (defined as the last data collection timepoint for the last subject for the primary outcome measure). If clinical trials are terminated, their status is to be updated to note the termination, and to report the numbers enrolled up to the point of termination.

Reporting timeframes for clinical trials

Clinical trial results are to be reported according to the timeframes outlined below. Reporting is to occur in BOTH of the following two modalities.

1. The main findings of clinical trials are to be submitted for publication in a peer reviewed journal within 12 months of study completion and are to be published through an open access mechanism unless there is a specific reason why open access cannot be used, or otherwise made available publicly at most within 24 months of study completion.
2. In addition, the key outcomes are to be made publicly available within 12 months of study completion by posting to the results section of the primary clinical trial registry. Where a registry is used without a results database available, the results should be posted on a free-to-access, publicly available, searchable institutional website of the Regulatory Sponsor, Funder or Principal Investigator.

It is noted that several journals allow open access publication of clinical trial findings. Some journals have an explicit policy of supporting publication of negative trials. These 12 month and 24 month timeframes represent the longest possible acceptable timeframe for reporting and shorter timeframes are strongly encouraged. It should be possible in most instances for reporting to occur in shorter timeframes.

Reporting of past clinical trials results

Unreported clinical trials conducted in the past are to be disclosed in a publicly available, free to access, searchable clinical trial registry. In addition it is desirable that unreported clinical trials are published in a peer reviewed journal.

Inclusion of Trial ID in clinical trial publication

The Trial ID or registry identifier code/number is always to be included in all publications of clinical trials, and should be provided as part of the abstract to PubMed and other bibliographic search databases for easy linking of trial reports with clinical trial registry site records. Bibliographic search databases such as PubMed are encouraged to make Trial IDs easily available by inclusion in the abstract of each clinical trial record.

Note on Data Sharing Initiatives


The benefit of sharing research data and the facilitation of research through greater access to primary datasets is a principle which WHO sees as important. This statement is not directed towards sharing of primary data. However WHO is actively engaged with multiple initiatives related to data sharing, and supports sharing of health research datasets whenever appropriate. WHO will continue to engage with partners in support of an enabling environment to allow data sharing to maximise the value of health research data.

Saturday, April 04, 2015

Read it and weep - then get angry!

The Deadly Corruption of Clinical Trials

Illustration: Sam Weber

Update (4/3/2015):  After nearly 11 years of obfuscation and denial surrounding the tragic death of Dan Markingson, the University of Minnesota has suspended enrollment in psychiatric drug trials. This comes in response to a blistering report issued by the Minnesota State Legislative Auditor that cites "serious ethical issues" and vindicates much of the reporting in the story below. Read more from Carl Elliott about the fallout from the report here.

IT'S NOT EASY TO WORK UP a good feeling about the institution that destroyed your life, which may be why Mary Weiss initially seemed a little reluctant to meet me. "You can understand my hesitation to look other than with suspicion at anyone associated with the University of Minnesota," Mary wrote to me in an email. In 2003, Mary's 26-year-old son, Dan, was enrolled against her wishes in a psychiatric drug study at the University of Minnesotawhere I teach medical ethics. Less than six months later, Dan was dead. I'd learned about his death from a deeply unsettling newspaper series bySt. Paul Pioneer Press reporters Jeremy Olson and Paul Tosto that suggested he was coerced into a pharmaceutical-industry study from which the university stood to profit, but which provided him with inadequate care. Over the next few months, I talked to several university colleagues and administrators, trying to learn what had happened. Many of them dismissed the story as slanted and incomplete. Yet the more I examined the medical and court records, the more I became convinced that the problem was worse than the Pioneer Press had reported. The danger lies not just in the particular circumstances that led to Dan's death, but in a system of clinical research that has been thoroughly co-opted by market forces, so that many studies have become little more than covert instruments for promoting drugs. The study in which Dan died starkly illustrates the hazards of market-driven research and the inadequacy of our current oversight system to detect them.

Mary Weiss is a slight, white-haired woman in her late sixties who smiles ruefully at any question, no matter how painful. She is the sort of Minnesota liberal who volunteers for political campaigns and signs her email with flowers. When we first met at a coffee shop in St. Paul, she was wearing an Obama pin on her sweater. Mary raised Dan alone, working a job at the postal service. Old photographs show Dan growing into his good looks; according to Mary, he was also a gifted student. In high school, Dan got a perfect score on the verbal portion of his SAT. He graduated from the University of Michigan in 2000 with an English degree, and that fall he moved to Los Angeles, hoping to become a screenwriter or an actor. To support himself, he got a job as a celebrity-tour bus driver.

Dan and his mom, Mary WeissDan and his mom, Mary Weiss
Photo: Courtesy Mary Weiss

When Mary went out to Los Angeles for a visit in the summer of 2003, it was clear Dan had changed. He'd adopted a new last name, Markingson. His behavior was bizarre. "He said, 'You haven't told me when the event is going to be,'" Mary said. She had no idea what he was talking about. The next day, he took her to his apartment. He'd encircled his bed with wooden posts, salt, candles, and money, which he said would protect him from evil spirits. He showed her a spot on the carpet that he said the aliens had burned.

I asked Mary how she'd reacted to all of this. "I panicked. I called 911," she replied. But when the police arrived, Dan was able to convince them she had overreacted. "He said, 'Oh, my mother just drove from Minnesota and she's very tired,'" she recalled. Worried that Dan was seriously ill, she tried to convince him to return to St. Paul. He visited her in August, returned briefly to California, and then came back to St. Paul in October.

Dan grew convinced that the Illuminati were orchestrating an event in Minnesota—a "storm" in which he would be called upon to murder his mother.

Dan grew convinced that the Illuminati were orchestrating an event in Duluth, Minnesota—a "storm" in which he would be called upon to murder people, including Mary. Some of his emails from late September 2003 suggest the extent of his delusions:

"I'm aware that people can cast spells that can hurt you at a distance.
I'm aware that some people can read minds.
I'm aware that some people might actually be 'hybrids' and not altogether human."

In another email, Dan wrote:

"I'm especially eager to attend this storm and SLAY those who deserve slaying.
I will choose victims immediately...
I HAVE NO EMOTIONAL ATTACHMENTS. I KILL FOR FUN!!"

On November 12, Dan said he would kill Mary if called upon to do so. She called the police. Dan was taken to Regions Hospital in St. Paul. But the hospital had no psychiatric beds available, so after a few hours Dan was transferred to Fairview University Medical Center, a teaching hospital for the University of Minnesota Academic Health Center. He was treated by Dr. Stephen C. Olson, an associate professor in the university's psychiatry department, who prescribed Dan Risperdal (risperidone), an antipsychotic drug often prescribed for patients with schizophrenia or bipolar disorder. (In Minnesota, doctors are allowed to give antipsychotic drugs to mentally incompetent patients without their consent for up to 14 days, but only to prevent serious, immediate physical harm to the patient or others.) Olson believed Dan was psychotic and dangerous, and lacked the ability to make decisions regarding his treatment; on November 14 he signed a document that recommended Dan be committed involuntarily to a state mental institution, noting that he "lacks the capacity to make decisions regarding such treatment." Three days later, a clinical psychologist also recommended involuntary commitment, reiterating that Dan had threatened to slit his mother's throat.

In Minnesota, patients who have been involuntarily committed are given another option: a "stay of commitment." Patients can avoid being confined to a mental institution as long as they agree to comply with the treatment program laid out by their psychiatrist. On November 20, Olson asked for a stay of commitment. The court granted the stay for six months, stipulating that Dan had to follow the recommendations of his treatment team. Olson, however, did not simply recommend standard medical treatment. Instead, he proposed that Dan take part in an industry-funded study of antipsychotic drugs. The university's study coordinator, Jean Kenney, had Dan sign a consent form when Mary wasn't present, and on November 21, he was enrolled in the study.

On the surface, the study appeared benign. Its purpose was to compare the effectiveness of three "atypical" antipsychotic drugs, each of which had already been approved by the FDA: Seroquel (quetiapine), Zyprexa (olanzapine), and Risperdal (risperidone.) The study was designed and funded by AstraZeneca, the manufacturer of Seroquel, and it called for 400 subjects experiencing their first psychotic episode to take one of the three drugs for a year. AstraZeneca called it the "CAFE" study, which stood for "Comparison of Atypicals in First Episode." The management of the CAFE study had been outsourced to Quintiles, a contract research organization, which was conducting it at 26 different sites, including the University of Minnesota. (For more on CROS, see "Trial by Hire.")

Yet the CAFE study was not without risks. It barred subjects from being taken off their assigned drug; it didn't allow them to be switched to another drug if their assigned drug was not working; and it restricted the number of additional drugs subjects could be given to manage side effects and symptoms such as depression, anxiety, or agitation. Like many clinical trials, the study was also randomized and double-blinded: Subjects were assigned a drug randomly by a computer, and neither the subjects nor the researchers knew which drug it was. These restrictions meant that subjects in the CAFE study had fewer therapeutic options than they would have had outside the study.

In fact, the CAFE study also contained a serious oversight that, if corrected, would have prevented patients like Dan from being enrolled. Like other patients with schizophrenia, patients experiencing their first psychotic episode are at higher risk of killing themselves or other people. For this reason, most studies of antipsychotic drugs specifically bar researchers from recruiting patients at risk of violence or suicide, for fear that they might kill themselves or someone else during the study. Conveniently, however, the CAFE study only prohibited patients at risk of suicide, not homicide. This meant that Dan—who had threatened to slit his mother's throat, but had not threatened to harm himself—was a legitimate target for recruitment.

Dan, age 10Dan, age 10
Photo: Courtesy Mary Weiss

When Mary found out that Dan had been recruited into the CAFE study, she was stunned. "I do not want him in a clinical study," she told Olson. Just a few days earlier, Olson indicated in a petition to the court that Dan was both dangerous and mentally incapable of consenting to antipsychotic medication. How could he now be capable of consenting to a research study with the very same antipsychotics—especially when the alternative was commitment to a state mental institution?

After Dan was enrolled, he stayed at Fairview for about two more weeks. By that point, Olson thought Dan's symptoms were under control, but Mary was still very worried by his erratic behavior. She recalls meeting with the doctor: "Olson came in and sat down and opened his file and said, 'Oh, Dan is doing so well.' And I said, 'No, Dr. Olson, Dan is not doing well.' I think he was taken aback." Even so, on December 8, 2003, Dan was transferred to Theo House, a halfway house in St. Paul. He was required to sign an agreement confirming that he understood he could be involuntarily committed if he didn't continue taking his medication and keeping his CAFE study appointments.

At the halfway house, Dan often stayed in his room for days. On March 26, 2004 nearly four months after his discharge from Fairview, his thoughts were still "delusional and grandiose," according to a social worker's note. An occupational-therapy report from April 30 detailed Dan's condition: "Personal appearance disheveled. Isolated and withdrawn. Poor insight and self-awareness." Entries in a personal journal that Dan kept during this period don't show any obvious changes, suggesting that he was improving little, if at all. Mary felt he was becoming angrier. "He was so tense, with this ready-to-explode quality."

When the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.

Olson saw things differently. "I disagree that he had significant deterioration," he testified in a 2007 deposition. However, it's unclear whether Olson actually saw Dan enough to make an informed judgment about his condition. Records suggest most of Dan's care was managed by social workers. In his deposition, Olson said he saw Dan approximately six times from the date he was admitted in November until he committed suicide in May. Whatever the doctor thought, his actions don't suggest that he felt Dan was improving. In late April 2004, as Dan's stay of commitment was about to expire, Olson recommended extending it for another six months—the duration of the CAFE study. He noted that Dan still had "little insight into his mental disorder" and might "place himself at risk of harm if he were to terminate his treatment."

Mary tried to get Dan out of the study or have his treatment changed. She called Olson and tried to see him. She wrote long, detailed letters expressing concerns about everything from Dan's diet and sleep habits to his medications. In total, she sent five letters to Olson and Dr. Charles Schulz—the chairman of the university's psychiatry department and a co-investigator on the CAFE study—communicating her alarm about Dan's condition, especially his inner rage. She received only one reply, dated April 28, from Schulz, who wrote that "it was not clear to me how you thought the treatment team should deal with this issue." Around that time, Mary left a voice message with Jean Kenney, the study coordinator, asking, "Do we have to wait until he kills himself or someone else before anyone does anything?"

Before dawn on the morning of May 8, a police officer and a Catholic priest knocked on Mary's door. Mike Howard, a family friend who lives at her house, answered. Later, in a deposition, Howard described what happened next: "Mary jumped out of her bed and went into the kitchen and stood there, and the priest extended his hand out and said, 'Mary, I'm here to tell you that Dan passed away.' And Mary just literally fell down to her knees and started to shriek and cry, and just started begging, 'Please, no, no, don't let this happen.'"

Dan had stabbed himself to death in the bathtub with a box cutter, ripping open his abdomen and nearly decapitating himself. His body was discovered in the early hours of the morning by a halfway-house worker, along with a note on the nightstand that said, "I left this experience smiling!" Later, when the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.

For most of the past half-century, physicians have considered antipsychotic drugs to be among the most unpleasant chemicals in the medicine closet. Thorazine (chlorpromazine), the first antipsychotic, was developed in 1950, and while it could relieve some of the worst symptoms of schizophrenia, that relief came at a serious cost. Not only do antipsychotics often make patients feel sedated and sluggish (they used to be called "major tranquilizers"), they can also cause irreversible "extrapyramidal" symptoms, such as the shuffling gait, rigid muscles, and involuntary lip-smacking sometimes seen in patients who have been taking the drugs for years. The antipsychotics can also cause akathisia, a type of driven, agitated restlessness that ranges from unpleasant to excruciating. Until recently, psychiatrists reserved the drugs for patients with very severe mental illnesses.

By 2008, antipsychotics were the most lucrative class of drugs in America. Seroquel alone had nearly $4 billion in sales.

Over the past decade or so, however, antipsychotics have undergone an extraordinary rehabilitation. By 2008, they were the most lucrative class of drugs in America. Seroquel alone had nearly $4 billion in sales, making it the country's fifth most profitable drug. The transformation began in the mid-'90s, when pharmaceutical companies began pitching atypical antipsychotics such as Risperdal, Zyprexa, and Seroquel as more effective than older antipsychotics, but relatively free of their ugly side effects. The drugs were also very expensive—one study pegged the cost at 70 to 100 times that of an older drug—but if they didn't produce extrapyramidal symptoms, their enormous expense seemed justifiable. By the mid-2000s, atypicals were being prescribed not just for schizophrenia but also for anxiety, agitation, insomnia, attention deficit hyperactivity disorder, and depression. The most remarkable upswing came for patients diagnosed with bipolar disorder, which used to be seen as a rare illness. Once bipolar disorder could be treated with atypicals, rates of diagnoses rose dramatically, especially in children. According to a recent Columbia University study, the number of children and adolescents treated for bipolar disorder rose 40-fold between 1994 and 2003. Another study found that nearly one in five children who visited a psychiatrist came away with a prescription for an antipsychotic drug, despite early reports of alarming side effects.

Recent years have seen a backlash. The most damaging blow to the atypicals was an authoritative 2005 study funded by the National Institute of Mental Health—the so-called CATIE study—which found that the atypical antipsychotics worked no better than a much older antipsychotic called Trilafon (perphenazine), which was developed in the 1950s. The CATIE study also found that, contrary to the way the drugs had been marketed, side-effect profiles of the atypicals were generally no better than the older drug. Other research showed that atypicals were associated with significant weight gain, increased risk of diabetes, and greater possibility of death in patients with dementia. After another large analysis in The Lancet found that most atypicals actually performed worse than older drugs, two senior British psychiatrists penned a damning editorial that ran in the same issue. Dr. Peter Tyrer, the editor of theBritish Journal of Psychiatry, and Dr. Tim Kendall of the Royal College of Psychiatrists wrote: "The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed."

The cleverest manipulation has been with the clinical trials themselves. For years, critics have charged that pharmaceutical companies massage trials to make their own drugs look better than they really are. One common tactic is to suppress unfavorable data. A notorious example came in the 1990s, when a Wyeth safety officer overwrote the company's computer files, erasing evidence indicating that its diet drug, fen-phen, caused valvular heart disease. A less risky strategy is simply not to publish potentially damaging trials. In 2004, theCanadian Medical Association Journal described a leaked document indicating that GlaxoSmithKline had deliberately hidden two studies from regulators showing that its antidepressant, Paxil (paroxetine), could increase the risk of suicide in children. The company has paid nearly a billion dollars in legal settlements over Paxil, including $390 million for suicides and attempted suicides related to the drug. Evidence of manipulation has also emerged in many of the high-profile pharmaceutical scandals of the past decade, from Merck's pain drug Vioxx to the recent Senate investigation into GlaxoSmithKline's diabetes drug Avandia.

"Thus far, we have buried trials 15, 31, 56. The larger issue is how do we face the outside world when they begin to criticize us for suppressing data."

Something similar has happened with the atypicals. A 2006 study in The American Journal of Psychiatry, which looked at 32 head-to-head trials of atypicals, found that 90 percent of them came out positively for whichever company had designed and financed the trial. This startling result was not a matter of selective publication. The companies had simply designed the studies in a way that virtually ensured their own drugs would come out ahead—for instance, by dosing the competing drugs too low to be effective, or so high that they would produce damaging side effects. Much of this manipulation came from biased statistical analyses and rigged trial designs of such complexity that outside reviewers were unable to spot them. As Dr. Richard Smith, the former editor of the British Medical Journal, has pointed out, "The companies seem to get the results they want not by fiddling the results, which would be far too crude and possibly detectable by peer review, but rather by asking the 'right' questions."

Initially, the controversy over atypical antipsychotics was focused largely on Eli Lilly (PDF), the manufacturer of Zyprexa. In early 2009, it settled litigation for a record-breaking $1.4 billion for illegal marketing and allegedly hiding the risks of the drug. More recently, however, the scandal has spread to Seroquel. In April 2010, AstraZeneca agreed to pay $520 million to settle two federal investigations and two whistleblower lawsuits alleging that it had marketed Seroquel illegally and concealed its health risks. The company faces more than 25,000 civil suits.

Documents unsealed in related civil suits suggest an alarming pattern of deception. Sales reps were instructed to tell doctors that Seroquel doesn't cause diabetes, even though the company knew about the link to diabetes as early as 1997. Internal correspondence reveals company officials discussing how to hide or spin potentially damaging studies. "Thus far, we have buried trials 15, 31, 56," wrote a publications manager in 1999. "The larger issue is how do we face the outside world when they begin to criticize us for suppressing data."

One of those potentially damaging studies led back to the University of Minnesota. In the late 1990s, a clinical trial known as Study 15 unexpectedly failed to show that Seroquel was any better than Haldol, a generic antipsychotic that's been on the market since the 1960s. In fact, on the main measures, Seroquel performed worse than Haldol. The study also showed that Seroquel increased the risk of weight gain and diabetes. Internal correspondence repeatedly refers to Study 15 as a "failed study," and company officials discuss possible ways to spin or bury it. "I am not 100% comfortable with this data being made publicly available at the present time," wrote Richard Lawrence, a senior AstraZeneca official, in 1997. "However I understand that we have little choice...Lisa [Arvanitis, a company physician] has done a great 'smoke-and-mirrors' job." Lawrence referred approvingly to a strategy that he said would "put a positive spin (in terms of safety) on this cursed study." Later, apparently hoping to find a way to present Seroquel in a better light, the "commercial support team" performed an analysis of a number of other studies, but even that did not show Seroquel to be better than Haldol. Yet when a summary of the AstraZeneca data was presented at the American Psychiatric Association annual conference in 2000, the author claimed Seroquel was "significantly superior" to Haldol. That author was Dr. Charles Schulz, the University of Minnesota psychiatry department chair—and a well-compensatedconsultant for AstraZeneca. In a press release claiming Seroquel's superiority over Haldol, Schulz praised it enthusiastically as a "first-choice antipsychotic."

Although the documents unsealed in the Seroquel litigation do not specifically mention the CAFE study in which Dan was enrolled, they do suggest that AstraZeneca planned to establish Seroquel as the "atypical of choice in first-episode schizophrenia," according to a 2000 "Seroquel Strategy Summary." A later document titled "Seroquel PR Plan 2001" discusses the agenda for an advisory panel meeting in Hawaii. Among the potential topics were the marketing of Seroquel to first-episode patients, adolescents, and the elderly. The document refers to these populations as "vulnerable patient groups."

"R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing." 

Even more alarming are internal documents suggesting that AstraZeneca was designing clinical trials as a covert method of marketing Seroquel. In 1997, whenDr. Andrew Goudie, a psychopharmacologist at the University of Liverpool, asked AstraZeneca to fund a research study he was planning, a company official replied that "R&D is no longer responsible for Seroquel research—it is now the responsibility of Sales and Marketing." The official also noted that funding decisions would depend on whether the study was likely to show a "competitive advantage for Seroquel."

Another set of documents from 2003 describes a glucose metabolism study apparently designed to fend off the charge that Seroquel causes patients to gain weight and become diabetic. One slide describes two purposes for the study: a "regulatory" purpose and a "commercial" purpose. The regulatory purpose was to "produce data that will help us defend the Seroquel label." The commercial purpose was to "produce data that will enable us to generate commercially attractive and competitive messages in relation to diabetes and weight." The document suggests several possible names for the study, including "Flexible Dose Approach Trial for Atypical Responses to Metabolism," which could be usefully shortened to the acronym FATFARM. (When I contacted AstraZeneca, a spokesperson would say only that Seroquel has been found "safe and effective" by the FDA and that it stands behind the CAFE study and the rest of its clinical research.)

Many clinical studies place human subjects at risk—at a minimum, the risk of mild discomfort, and at worst, the risk of serious pain and death. Bioethicists and regulators spend a lot of time and energy debating the degree of risk that ought to be permitted in a study, how those risks should be presented to subjects, and the way those risks should be balanced against the potential benefits a subject might receive. What is simply assumed, without much consideration at all, is that the research is being conducted to produce scientific knowledge. This assumption is codified in a number of foundational ethics documents, such as the Nuremberg Code, which was instituted following Nazi experiments on concentration camp victims. The Nuremberg Code stipulates that an "experiment should be such as to yield fruitful results for the good of society," and "the degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment."

But what if a research study is not really aimed at producing genuine scientific knowledge at all? The documents emerging in litigation suggest that pharmaceutical companies are designing, analyzing, and publishing trials primarily as a way of positioning their drugs in the marketplace. This raises a question unconsidered in any current code of research ethics. How much risk to human subjects is justified in a study whose principal aim is to "generate commercially attractive messages"?

In January 2005, the FDA began investigating the circumstances of Dan's suicide. In a report issued that July, before the larger pattern of Seroquel research had begun to emerge, Sharon L. Matson, the FDA investigator, exonerated the university. She wrote, "I did not find any evidence of misconduct, significant violation of the protocol, or regulations governing clinical investigators or IRBs"— the university institutional review board charged with reviewing studies to ensure that they measure up to recognized ethical standards. Matson specifically dismissed the suggestion that Dan was mentally incompetent to consent to the study, writing that "there was nothing different about this subject than others enrolled to indicate that he couldn't provide voluntary, informed consent." (The FDA refused my request to speak with Matson and would not answer questions about the case, citing privacy concerns.) Mary Weiss eventually sued the University of Minnesota, AstraZeneca, Olson, and Schulz, but her case did not even get to trial. District Court Judge John L. Holahan dismissed the suit in 2008 with a partial summary judgment. He ruled that in approving the CAFE study, the university IRB was performing the type of "discretionary function" that is protected from liability under the state's Tort Claims Act. The malpractice suit against Schulz was also dismissed, and the suit against Olson was eventually settled—for $75,000, which Mary says wasn't enough to cover the fees of the expert witnesses her attorneys hired. (Both Schulz and Olson declined to speak about the specifics of the clinical trial or the resulting suit. University spokesman Nick Hanson would say only, "To date, there has been no finding of wrongdoing from any of the investigations or reviews done by the university on this issue.")

The judge also dismissed the case against AstraZeneca. He blasted Mary's lawyers, saying that they had failed to establish that AstraZeneca had a duty to put the interests of research subjects over the interests of the company and the researchers. But he also lamented the lack of case law about clinical trials, saying on this particular point, "Try as it may, this Court's independent research has unearthed not a single case or statute to evidence or support such an alleged duty."

The judge further ruled that Mary's lawyers hadn't shown a causal link between Seroquel and Dan's suicide: An initial drug screening during autopsy had not found any Seroquel in his bloodstream, which suggested that Dan may not have been taking his medication. After the judgment, however, Mary discovered that Seroquel would not be detected in an ordinary drug screening; a special test is required. In the spring of 2008, she called the coroner's office in hopes of getting a special screening for Seroquel. To her surprise, she found that her lawyers and the defendants had already obtained one. The report was dated several days after the summary judgment was issued. It showed 73 nanograms per milliliter of Seroquel in his blood, suggesting that Dan was almost certainly taking the drug, although he may have missed the last scheduled dose before he died.

Although Mary's lawsuit was unsuccessful, it revealed some disturbing financial arrangements at the university. As a patient on public assistance, Dan's treatment would have normally generated little income for the university. Under its arrangement with AstraZeneca, however, the psychiatry department earned $15,648 for each subject who completed the CAFE study. In total, the study generated $327,000 for the department. In fact, during the months before Dan was enrolled, the department was apparently feeling pressure from Quintiles, the CRO that managed the study, to step up recruitment. According to emails written by Jean Kenney, the university's study coordinator, the site had been placed on probation for its recruitment problems, and they were still "struggling to get patients." In November 2002, Olson had managed to recruit only one subject in six months. That began to change in April 2003, when the psychiatry department established a specialized inpatient unit at Fairview hospital called Station 12, in which every patient could be evaluated for research. By December, Olson had recruited 12 more subjects, including Dan, and Olson had been featured in a CAFE study webcast for "turning an underperforming site into a well-performing site."(Quintiles refused to give comment on the case.)

Olson had another financial reason to maintain good relations with AstraZeneca. According to a disclosure statement for a 2006 conference, he was a member of the AstraZeneca "speaker's bureau," giving paid talks for the company. He had similar arrangements with Eli Lilly and Janssen, the makers of the other atypicals being tested in the CAFE study, as well as Bristol-Myers Squibb and Pfizer. In addition, Olson was working as a paid consultant for Lilly, Janssen, Bristol-Myers Squibb, and Pfizer. Although Olson is not required to disclose how much industry money he received, a public database maintained by the Minnesota pharmacy board indicates that Olson received a total of $240,045 from the pharmaceutical industry between 2002 and 2008, with $149,344 coming from AstraZeneca. Dr. Charles Schulz, his co-investigator and department chair, received an even greater sum: more than $571,000 from the industry, with $112,020 coming from AstraZeneca. The database does not reliably distinguish between payment by drug companies for consulting and speaking, which usually goes directly into a physician's pocket, and research grants, which go to the university and are used to help underwrite the salaries of the grant recipients. (Many academic physicians are required by their universities to generate a substantial portion of their salaries by obtaining research grants.)

In the US, the primary bodies charged with protecting research subjects are known as institutional review boards. (Read how IRBs are becoming privatized, next page.) According to the University of Minnesota, the purpose of its IRB is to "protect the rights and welfare of human research subjects." However, when the university's IRB officials were deposed under oath, they refused to admit that protecting subjects was their responsibility. "So it's not the institutional review board's purpose to protect clinical trial subjects, is that what you're saying?" asked Gale Pearson, one of the attorneys representing Mary Weiss. "That's true," replied Moira Keane, the director of the IRB. Astonished, Pearson kept returning to the question, to make sure that she understood it correctly. Keane refused to budge. Instead, she claimed that the role of the IRB was to make sure that Olson and the trial sponsor had a plan to protect subjects. (If this were true, it would render IRBs worthless: The sponsor and investigator are the ones that the IRB is supposed to protect subjects from.)

The University of Minnesota doesn't exactly have a stellar record of investigating internal misconduct. In 1994, the director of child and adolescent psychiatry, Dr. Barry Garfinkel, was sentenced to federal prison for five felonies related to research fraud involving the Ciba-Geigy drug Anafranil (clomipramine). The research assistant who blew the whistle in 1989 lost her job, and under the terms of a secret agreement struck with Garfinkel, the university kept the fraud secret for four years, until he was finally indicted. In 1995, the university was sanctioned by the National Institutes of Health after revelations that the head of transplant surgery, Dr. John Najarian, had generated millions of dollars for the university by illegally manufacturing and selling an immunosuppressant drug without FDA approval; an investigation by the Minneapolis Star Tribune revealed that the university had known of the illegal activity for years. Still more scandals have recently emerged, including a Senate investigation of the chairman of spinal surgery, Dr. David Polly, for failing to disclose $1.2 million he had been paid to consult for the device manufacturer Medtronic, and a series of investigative reports in the New York Times about the industry ties of Minnesota physicians, including some connected to the university. When the scandals began to escalate several years ago, Dr. Deborah Powell, then the dean of the university's medical school, appointed a task force to devise a new conflict-of-interest policy. The policy was discarded after theStar Tribune revealed that the co-chair of the task force, Dr. Leo Furcht, had funneled $500,000 of university grant money into his own private company, which he later sold for $9.5 million. Furcht remains chairman of the laboratory medicine and pathology department at the university.

In 2007, the American Journal of Psychiatry published the results of the CAFE study. Among the 18 "serious adverse events" recorded for the 400 subjects in the study were an alleged homicide and five suicide attempts, including two successful suicides, both by patients taking Seroquel. (One of these patients, of course, was Dan Markingson.) According to the study authors—three AstraZeneca employees and seven academic physicians, many of whom also consulted for the company—the suicides occurred "despite the close attention provided in clinical research aftercare programs." The authors claimed that the CAFE study showed Seroquel to be of "comparable effectiveness" to Zyprexa and Risperdal for first-episode patients.

According to some experts, the study could hardly have shown otherwise, because it was designed to produce a good result for Seroquel. When I showed the published study to Dr. Peter Tyrer, the editor of the British Journal of Psychiatry, he said, "I would have major problems accepting a manuscript of that nature." According to Tyrer, the main problem is the small sample size. Of the 400 subjects enrolled, all but 119 stopped taking the drug before the yearlong study was finished. With so few subjects, the CAFE study was statistically underpowered and thus unlikely to detect any difference in effectiveness between the three drugs. The failure to detect a difference allowed AstraZeneca to claim that Seroquel was as good as the other drugs (or in the language of the study, "non-inferiority"). Tyrer told me, "In scientific terms this study is of very little value."

That's not the only problem. The CAFE study was supposedly designed to test the effectiveness of the three antipsychotics, but the way it did this was by measuring the rate of "all-cause treatment discontinuation," or the percentage of subjects who stopped taking their drug. That is, the CAFE study counted an antipsychotic as "effective" if a subject kept taking it until the end of the study. On the face of it, this type of measurement seems highly misleading; simply because a patient continues to take an antipsychotic does not mean that it is working. Many psychiatrists defend treatment discontinuation as a "pragmatic" way of measuring a drug's overall acceptability, but even by "pragmatic" standards the CAFE study presents a problem. More than 70 percent of subjects in the CAFE study stopped taking their assigned drug, and the most common reason was simply coded as "patient decision." According to Dr. John Davis, the Gillman Professor of psychiatry at the University of Illinois-Chicago, the authors of the CAFE study obscured their results by failing to say whypatients decided to stop taking the drug—whether patients felt the side effects of the drug were too severe, for example, or if they felt the drug was not working. "It is the hiding of the critical outcomes that gives me pause," he says. "It does not make scientific sense to do a study and not measure one of the most important outcomes."

Yet another problem with the CAFE study is its failure to compare Seroquel to any older antipsychotics. "It's quite a marketing exercise to put all patients in the CAFE study on atypical antipsychotics," says Dr. Glen Spielmans, an associate professor of psychology at Minnesota's Metropolitan State University. "It removes the older drugs from the discussion." One reason AstraZeneca may have done this, he suggests, is that Study 15 had already shown Seroquel to be inferior to the older antipsychotic, Haldol.

The bluntest assessment of the study came from Dr. David Healy, a senior psychiatrist at Cardiff University in Wales. Healy is a former consultant to AstraZeneca, among other pharmaceutical companies, and a prominent critic of the industry. "This is a non-study of the worst kind," he said. "It is designed not to pick up a difference between the three drugs. It looks like an entirely marketing-driven exercise."

If these experts are right, then the study in which Dan Markingson committed suicide was not simply a matter of inadequate informed consent, or financial conflicts of interest, or even failure to monitor a subject's care. The ethical breach was built into the study from the start. It is one thing to ask people to take risks for science, or the common good, or to help other people. It is another thing entirely to ask them to risk their lives for the marketing goals of AstraZeneca.

Mary Weiss is a quiet woman, but her experience has left her angry and bitter. It's not hard to see why. In the years since she lost her son, she has written letters and filed complaints to one oversight body after the other, and so far she's gotten little but form letters, rejections, and dismissals. "Well, I don't think the loss can ever be replaced," her friend Mike Howard said in his deposition. "There is probably not a day in Mary's life that she hasn't thought about her son, and there is probably not a week goes by that she doesn't shed tears." Mary told me that until she and I had coffee last year in St. Paul, no one at the university had ever apologized or expressed regret for her son's death. In fact, after Dan died, Mary received a plant with a card from the CAFE study team. In words that echoed the bizarre, grisly message in Dan's suicide note, the card read, "We will miss his smile."

Of all the ways in which Mary Weiss has been damaged by the University of Minnesota, there is one episode that still brings a sting of shame to my face. When the lawsuit over Dan's death was dismissed, the university filed a legal action against Mary, demanding that she pay the university $57,000 to cover its legal expenses. Gale Pearson, one of Mary's attorneys, says that while such suits are technically permissible, she had never seen one filed in her previous 14 years of legal practice. The university agreed to drop the lawsuit against Mary only when she agreed not to appeal the judge's decision. "Maybe they want to chill anyone who might think of challenging the university, even if her child had died," Pearson said. "It gave me a sick feeling."

http://www.motherjones.com/environment/2010/09/dan-markingson-drug-trial-astrazeneca