Procter & Gamble - Let's take the high road

See this article (AAAS Ethics reports 2006 XIX 3 2006) and the rest of this blog for background to this letter. The recipient is Dr Larry M Games, Vice President at Procter and Gamble Pharmaceuticals. The letter is about research misconduct in studies investigating the mechanism of action and clinical monitoring of the osteoporosis drug Actonel.

Dr Larry M Games
Vice President
Procter and Gamble Pharmaceuticals
Health Care Research Center
8700 Mason-Montgomery Road
Mason, Ohio, 45040
USA

23 November 2006

Re: Actonel Studies/Sheffield Situation - Issue of Raw data

Dear Dr Games

I am writing following our previous correspondence. We have a number of matters to discuss. To maintain clarity I will write separately about each matter. The purpose of this letter is to revisit your earlier refusal to allow the raw data you provided in April 2006 to be made available for public/scientific scrutiny.

I again thank you for your eventual provision in April 2006 of raw data underlying the three intended P&G Publications (Eastell et al. 2003 J.Bone.Miner.Res. 18:1051-6 + the two abstracts/draft publications in my name). I also thank you for your commitment to openness, and for writing the Bill of Rights for researchers. All of this is good.

Unfortunately the Eastell 2003 publication (J.Bone.Miner.Res. 18:1051-6) has not yet been retracted.

As stated, the main purpose of this letter is to revisit your earlier refusal to allow the data provided in April to be scrutinized in an open manner. Your refusal to allow the data to be transmitted to a journal editor accompanying a properly corrected manuscript is not appropriate. A journal editor can request raw data from an author at any time, and such refusal (particularly under the circumstances of this case) would be inappropriate.

The raw data you sent me by E-mail in April is attached exactly as sent (PGData.zip - web downloadable data is encrypted in the online letter). The CD-Rom and paper versions of the data you sent are retained by my legal representative.

Obviously the refusal to supply the raw data to authors in the first place has caused some international consternation. There is also the entirely separate matter concerning the potential mis-analysis of data by P&G in the ghost-analyzed/ghostwritten material. I believe the data was mis-analyzed - and quite obviously so. Two statisticians agree with me.

Certainly data must be transmissible to journal editors. This whole matter could be settled most easily by making the full data as attached available for open scrutiny. Secrecy has no further place in this, and I am asking you to allow this. Any other approach is I am afraid not going to satisfy anyone.

You also make the unusual comment in your last letter that the Eastell 2003 article is somehow separate from the other two intended publications and abstracts in terms of data. Obviously you must know that this is not true. You yourself provided me with the data underlying the Eastell 2003 paper (PGData.zip - encrypted). One of the two manuscripts in my name includes the entire Eastell 2003 data (for NTX and fractures) as a subset since it was based on a combined analysis of the HIP and VERT studies. The related abstract in my name involving the Eastell data (as a subset) is referenced below (1). I am sure you have the draft publication of 2003 relating to this abstract.

You will also no doubt be aware of (and have seen) the statistical reports which attempt to reconstruct Figure 1 and related statistics in the manuscript by Richard Eastell (2003) from the data. One of these reports is here ( Professor Martin Bland). Obviously there were several other problems with the analysis in all manuscripts but for the moment I will keep things simple.

There is a high road Dr Games, and I hope that we can work together to take it.

Kind wishes

Dr Aubrey Blumsohn
MBBCh, BSc (hons), MSc, PhD, MRCPath


Reference:

1. A. Blumsohn, IP Barton, A Chines, R Eastell Relative Contributions Of The Early Changes In Bone Resorption And Later Changes In Hip Bone Mineral Density To The Reduction In Vertebral Fracture Risk With Risedronate. J Bone Miner Res 2003;18(S2):S157 Abst#SA337

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Editorial woes at the Journal of Bone and Mineral Research

I have a very old fashioned idea - that Medical Journal Editors should go about their business with as much objectivity and integrity as possible. They should act in the interests of the patients we serve. The Journal of Bone and Mineral Research (JBMR) is seeking a new editor to replace Professor John A. Eisman, MBBS, Ph.D. To apply, see here.

Editors wanting hints as to how to react when approached with concerns about research misconduct involving a major pharmaceutical sponsor and fellow friendly scientists, see the John A. Eisman approach. First try protracted delay. Then try meaningless gibberish, followed by excuses (or exasperation) when asked to reply properly. Then edit a letter of concern to remove all content, and offer to publish it giving a pharmaceutical company the right to respond. Express surprise when the offer is refused. Then decline to review any evidence at all, offering lame excuses. Decline to read statistical reports. Decline to read correspondence relating to denial of access to data. Decine to read anything relating to the concerns raised. Then suggest that those implicated will arrange for the concerns to be addressed. Good trick! It is always a good idea to address concerns that are different from those raised. When the matter reaches the press, write statements so at variance with your previous correspondence that it is hard not to laugh out loud. For collated correspondence and press statements see here. For press see here.

Will the JBMR eventually publish the truth about these three publications and how they came to be? Perhaps not. But then - who cares. Third rate conflicted medical journals that snuggle up to vested interests are steadily losing relevance.

Perhaps the new editor will join me in calling for Procter and Gamble to allow authors (including myself as first author of two of the three intended P&G publications) to make the raw data from the three publications publicly available. So far P&G have declined to allow that. I wonder why that might be?

Alternatively perhaps Professor John A. Eisman would care to perform a teensy tiny statistical analysis himself. He might even consider reading the statistical reports he was offered. Perhaps he would even care to review the evidence with me. Of course there is nothing whatever to hide Professor Eisman - or is there...

Cowardice asks: Is it safe?
Expediency asks: Is it politic?
But Conscience asks: Is it right?"
(William Punshon)

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The General Medical Council - in whose interests?

Figure 1. GMC Guidance improved with a Fig Leaf

The General Medical Council (the UK licensing body for doctors) maintains its purpose is to protect the health of the public by ensuring proper standards in the practice of medicine. But the GMC has an accumulating credibility problem (1-5). Now an important article by Peter Wilmshurst (1, PDF version) adds to the voices (2,3,4,5,6) calling for the Council to be stripped of it's regulatory functions. The GMC is accused of failing to act in a plausible, timely and consistent manner when ethical guidance is ignored (1-6). It appears to apply its ethical rules in a selective way - depending somehow on ethnicity and membership of a mysterious old-boy's club (1,2,3). The Shipman enquiry reported that the GMC failed to deal properly with Fitness to Practice (FTP) cases, particularly involving established and respected doctors (2,4). Most worryingly, it is accused of assisting in victimization of doctors raising concerns, instead of dealing with those concerns. Sir Liam Donaldson, the Chief Medical Officer, echoes concerns about FTP procedures. In his view, "complaints are dealt with in a haphazard manner, the council causes distress to doctors over trivial complaints while tolerating poor practice in other cases".(2, 5). Former President of the GMC, Sir Donald Irvine, called for the current Council to be disbanded and re-formed with new members (2, 6)

Some extracts from the Wilmshurst paper (1, PDF version)

On the private club mentality in dealing with concerns about doctors

"The purpose of the GMC is to protect patients, not doctors. "adjudications by the Professional Conduct Committee were frequently inconsistent, arbitrary and unjust."

"Justified criticisms have led to changes in the GMC in recent years. ..I believe that many of these changes are cosmetic."

"the obligation GMC members feel to those who elected or appointed them represents a conflict of interest that prevents the GMC from working for the good of the public." "the evidence suggests that the medical profession cannot be trusted to regulate itself."

"I can provide many examples of inconsistency in the adjudications of the GMC. One case involved a professor who had falsely claimed an MD research qualification. .... The GMC decided that this dishonesty of the professor required no more than a private warning."

"Some may ask why the Professional Conduct Committee publicly suspended or erased from the Medical Register a number of doctors, all of whom had African or Asian names, for claiming qualifications that they had not been awarded, but the GMC decided that in the case of a white British professor at a major academic institution only a private warning not to do it again was required."

"Another case illustrates the problems of conflicts of interests and the strength of the 'old-boy' network within the GMC. I reported a doctor to the GMC for financial misconduct. Evidence presented at his hearing before the Professional Conduct Committee showed that the senior management of the hospital at which he worked had discovered his dishonesty and reached a severance agreement with him so that if he left without legal challenge, the hospital would destroy documents related to the fraud....The chairman of the Professional Conduct Committee hearing .. had been the medical director of the hospital at the time the deal to conceal the misconduct was agreed. ... The GMC refused to take any action against its member. Contrary to its rules, the GMC refused to tell me why they were unwilling to take action against the GMC member. The GMC member subsequently returned to chairing hearings of the Professional Conduct Committee.

Can one imagine a situation when a judge stood down from hearing a case because he had helped to conceal a crime and then was allowed to return to the bench?"

GMC Victimisation of those raising concerns

"doctors have a responsibility to speak out if they have concerns about behaviour that might endanger patients. A doctor who fails to bring his concerns to attention may be guilty of serious professional misconduct and may be erased from the Medical Register." "However, rather than investigate my concerns, the institution reported me to the GMC for disparagement".

"A more junior doctor, who had serious concerns, effectively had her medical career destroyed by the GMC. Members of the GMC made unfounded allegations that the doctor suffered from mental illness and made it difficult for her to gain employment. The doctor sued the GMC and some GMC employees maintaining that the GMC broke its own rules and failed to follow its own procedures when blackening the reputation of a person raising legitimate concerns...His Honour Judge Harris likened the GMC to a "Stalinist regime".

On creative accountancy

"...one could suggest that it was not in the interests of GMC members to lose these lucrative expenses by upsetting those who elect or appoint them. This only ended recently when public knowledge of this widespread and condoned practice eventually forced the GMC members to behave in a way more in line with normal accounting practices."

The court transcript from the case of PAL vs GMC, May 2004 before Judge Charles Harris is of interest

JUDGE HARRIS: For myself I don't really see why somebody complaining about the behaviour of doctors or the GMC, if that is what they are doing, why that should raise a question about their mental stability, unless anybody who wishes to criticise "the party" is automatically showing themselves to be mentally unstable because they don't agree with the point of view put forward on behalf of the GMC or the party.

MISS COLLIER: That in itself certainly would not be enough.

JUDGE HARRIS: It is like a totalitarian regime: anybody who criticises it is said to be prima facie mentally ill - what used to happen in Russia.

MISS COLLIER: My Lord, that is very far from the circumstances of this case.

JUDGE HARRIS: Of course it is ...

References

1. Wilmshurst P. (2006) The General Medical Council - a Personal View. Cardiology News Oct/Nov 2006 14-15 http://www.pinpointmedical.com/article_read.php?id=57&publication=cardiology-news&link_id=2
2. http://en.wikipedia.org/wiki/General_medical_council (14/11/2006)
3. http://www.guardian.co.uk/racism/Story/0,,349543,00.html
4. Shipman inquiry. Safeguarding patients: 5th report, 2004. Online version
5. Donaldson, L. Good doctors, safer patients: a report by the Chief Medical Officer. Department of Health, 2006-07-14. [Link]
6. Current GMC should be disbanded, says former President. Report by The Royal Society of Medicine.[Link]

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Operation Sisyphus

Sisyphus is a hero of Greek mythology (1), condemned to roll a large rock up a hill. Upon reaching the top the rock rolls back, and the task has to be repeated - endlessly. The story appears to be one of eternal and pointless labor.

One reader suggests that raising issues of pharmaceutical research misconduct is a pointless Sisyphean task (2) - that this whole field of science is already kaput. It sometimes feels that way (3,4). But the story of Sisyphus is not one of unending misery. Despite the best efforts of the gods, they cannot beat him (1).

Fellow medical bloggers are writing about the way in which the pharmaceutical industry is preventing proper understanding of the science upon which our patients rely (5,6,7,8,9). They write about the way in which industry has subverted those organizations whose task it is to act for our patients to preserve integrity.

But we are attacking the wrong beast.

The beast is not the industry - it is ourselves.

Pharmaceutical companies sell products under the banner of science. But their raison d'être is to make money. Industry has to balance genuine hypothesis testing and transparency against commercial interests and the financial consequences of dishonesty. This is not in itself a criticism - it is a simple fact.

We, as doctors, have created the atmosphere which has allowed lethal system malfunction. We have allowed industry to subvert the rules of science and the free-market. We have watched quietly as governments and academics have colluded with industry to hide information critical to our patients. We have remained silent as our medical schools churn out graduates who have no knowledge of the dilemmas and scandals of medicine. We have allowed our medical journals to become corrupted and timid. We have remained silent as our General Medical Councils have taken action against brave doctors for raising questions of integrity (10). We have said nothing while these old-boys' clubs have selectively ignored serious concerns brought to their attention (10) - apparently based on the status and race of those criticised (10,11). We have failed to support our colleagues who have raised concerns. We have said nothing.

I have been waiting very patiently. It is now seven months since Procter and Gamble provided previously suppressed data underlying three intended "ghosted" publications to myself, to the University of Sheffield and to other authors in whose names "science" was ghostwritten (12). The discordance between the data and the ghosted interpretations of that data (in our names) will have been obvious even to the most incompetent of statisticians. The unethical nature of the scientific process will also have been obvious to any observer.

Yet the first of these papers that was published in the names of others (J. Bone. Miner. Res. 2003; 18:1051-6) has not yet been retracted. There has been no comment about the attempts by a senior academic to force a colleague to sign journal declarations in the absence of data - even more important given the status of that senior academic as guardian of research governance within a prestigious medical school. There has been no comment about the ethics of denial of access to data, and about the signing of incorrect declarations to journals about access to such data.

The University of Sheffield has admitted that legal threats were made by Procter and Gamble about return of data that the company "owned" and which had been "obtained without their consent", but have otherwise not commented upon the principles involved

The obvious (and comparatively painless) step of declaring a wrong, and of correcting it, has not yet taken place. There has been no comment at all from those who should comment.

I have waited quietly as the various bodies to whom the matter was referred have done nothing of any relevance.

Once in a while Sisyphus shrugs (13).

How
(John Lennon)

How can I go forward when I don't know which way I'm facing?
How can I go forward when I don't know which way to turn?
How can I go forward into something I'm not sure of?
Oh no, oh no

How can I have feeling when I don't know if it's a feeling?
How can I feel something if I just don't know how to feel?
How can I have feelings when my feelings have always been denied?
Oh no, oh no

You know life can be long
And you got to be so strong
And the world is so tough
Sometimes I feel I've had enough

1. The Myth of Sisyphus by Albert Camus
2. Resistance is futile
3. http://www.slate.com/id/2133061/
4. http://www.thejabberwock.org/presshw.htm
5. Health Care Renewal
6. Pharmagossip
7. Clin Psych
8. Pharma Watch
9. Peter Rost
10. The General Medical Council - a Personal View (Wilmshurst)
11. Wikipedia General Medical Council
12. AAAS: http://www.aaas.org/spp/sfrl/per/per46.pdf
13. http://www.amazon.co.uk/Atlas-Shrugged-Ayn-Rand

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Resistance is futile

A blog comment from reader Odette Lussier is perhaps germane. I thought I would repeat it as a full posting. Comments for and against appreciated. Is there any point resisting the forces of obfuscation, or is it a bit like spitting into the mighty sea?

Aubrey

Odette writes: Having had some contact with the world of scientific research, I had just assumed that fraud was standard practice and that no scientist would put good money at risk by publicly admitting that his basic assumptions were wrong when he started planning an experiment. You can't just lose money in blind alleys and you can't be at the mercy of your data. Time and again, I have seen researchers replacing missing data cells with the group average, removing outliers until they get the variance they want, doing linear transformations and even using mind-boggling statistical techniques of their own invention to get a p-value worth publishing.

As one student told me, everybody does it and she has worked hard to get her doctorate. She had no control over the experiment or the technicians doing the analysis and there is no degree for work done, just one for results obtained. That science is a corrupt field populated by frauds, psychopaths, hucksters and hustlers is not news. It just surprises me when someone comes out of the woodwork to complain because I wonder how a person could get their degrees and spend years surrounded by such colleagues without noticing something amiss before now. As another student told me, "Why can't you just play the game?"

And why not? I know someone who bucked the system like you and as a result, the researcher he was complaining about colluded with the university rector to falsify results in order to hide the original delinquent data. He was dismissed from his doctoral studies and threatened with a libel suit. Can't blame everyone else for keeping quiet.

My attitude towards research now is you find what you're being paid to find and if ten years from now someone finds something different, no one will take away your diplomas, awards, funding etc. retroactively. Besides, theories go in and out of fashion and even if you take the pains to do ethical research, it doesn't mean that anyone will even consider it relevant by then.

Furthermore, the moral argument that human lives are at risk is getting shakier every day. This is not a position based on reason, but on an ancient moral code involving notions of sacredness and higher power that have been discredited by liberalism for some time now. Inasmuch as liberalism seeks to subsume all aspects of human life to the power of reason, it is to be expected that those who operate from this framework desire to exercise the power they devoted their mental abilities to obtain. The ultimate power, that formerly reserved for the gods, is the power over life and death. Thus, having stripped the gods of their moral authority via reason, why would one hesitate to appropriate their ultimate power over human life as one's own because a few faceless individuals are standing in the way of boundless good fortune, prestige and even more power. This is the final power that religion refused us and that rationalism can confer, that it is not rational to let a few lives matter more than all that can be obtained by possibly putting them at risk. And that's why we have unsafe products, bad meds, pollution and a host of other ills that actuarial bean counters allow to be foisted on the public because in their estimation, a few faceless lives that could be lost are not worth the cost of doing things "right".

It also helps to remember that "In the long run, we'll all be dead." It's not like there's someone waiting on the other side to hold you to account because you colluded with a pharmaceutical firm in putting out a bad product that harmed someone. These companies have enough money to keep people tied up in court for a long time, especially if they are poor or indigent, which is why product testing in the developing world is such a good idea. Thus, you could probably escape the negative moral consequences of your rational course of self-interest completely, whereas your irrational devotion to a moral position that would keep poor people picking through garbage in Brazzaville while you have an obscure career with little fame and even less money seems to no one's advantage.

If you think the game is fun now, wait 'til all those Chinese researchers who were trained in the west start churning out publications back home with a trillion-dollar economy to back them up. They can drown us in normal curves and powerpoint presentations and we'll never be able to separate the wheat from the chaff.

As it is, why would we believe any white-coated pharmaceutical/government research apparatchik about anything? These people have secured their position over the rest of us for a hundred years by touting their greater capacity for reason. Problem is, I have lost faith in the power of the white coat and the fancy diploma to know better than me. I just expect them to be more arrogant about it, that's all. So, call me superstitious, call me irrational if you like, but my years in data analysis have taught me that I can demonstrate that astrology works, that homeopathic medecine is a panacea, that aliens communicate with us or any else I want, as long as I am financed by deep pockets who find it in their interest to popularize these beliefs. By the way, you might want to keep all this in mind when you see the bible beaters attacking science. The way I see it, scientists brought it on themselves. Now, if they could only figure out how to get research grants from these people, think what amazing new "facts" they could discover.

Odette Lussier

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Pharmaceutical research games

For researchers and the public

Instructions:

1. You be the researcher
2. Follow the path researchers face
3. Make your own choices along the way

START THE GAME

For the pharmaceutical industry

Instructions:

1. Babble about the free market
2. Claim that you are operating within that free market
   
3. Next pressurise government
4. Ensure that the regulatory body you run immunises you against litigation
5. Hide undesirable data from researchers and regulators
6. Employ public relations firms to spy on critical scientists
7. Silence critical scientists and Journals with the threat of litigation
8. Use the resulting cloud of hilarity to publish falsified findings
9. Mention the "free market" again

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Ghosts in the machine

The American Association for the the Advancement of Science:
Professional Ethics Reports Volume XIX (3) Summer 2006
http://www.aaas.org/spp/sfrl/per/per46.pdf


(Part 1 - the Sheffield Procter and Gamble MHRA "investigation")

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State Secrets and the MHRA (Secret 1)

To: Mr Andy Burnham
Minister of State, Department of Health
The House of Commons
UK

Dear Minster Burnham

I wish to let you know about a state secret, and to seek your opinion about it. I should declare a conflict of interest. I was born in a country where a state secret involved brutal policemen and barking dogs. Secrets which could cause doctors or patients to make incorrect decisions because they have been misled (in even the tiniest way) are not legitimate secrets. I was therefore delighted to note your letter to Stewart Hosie MP (5/9/06) about the UK drug regulator (MHRA) in which you write: "it is important for the [drug] regulatory system and indeed the regulator to operate in as transparent a way as possible".

Your comments relate to urgent concerns raised by many including The Health Select Committee 18 months ago. MP Hosie seemed upset by the rest of your response, since you suggested no time-scale to implement any sort of plausible or honest review of the MHRA. Given your emphasis on transparency Minister, might we consider the legal and moral implications of a small state secret.

Let me paint a picture:

• Let us suppose you were a doctor Mr Burnham:
• You are standing there, syringe in hand, about to inject a potentially toxic drug into a patient.
• You do so in the knowledge that the MHRA, your government agency, has given a stamp of approval.
• It would be your fundamental right to know why the MHRA approved that drug before inflicting potential harm on a fellow human being. You might imagine you would have a right to know that the MHRA scrutinised evidence, what named persons were involved, and how precisely those persons were qualified. You might imagine that it should be your moral obligation to know these things.

So let us consider a small secret

Mr Ian Oulsnam is operations manager of the GCP inspectorate of the MHRA. This is a key role in this public body. He makes pronouncements about matters of science and medicine. He makes decisions which impact on life and death. He "investigates" matters upon which patients and doctors depend. He was involved in the MHRA self-"investigation" of the TGN1412 disaster. He makes public statements to the press on behalf of the MHRA. He received parliamentary instruction to conduct the fascinating "investigation" of P&G's conduct in Sheffield. He informed me that he "has a "relevant" university degree and a postgraduate degree in statistics.

I was thus surprised to note on the MHRA website a Freedom of Information request from Mr RC (MHRA FOI 06/185). The MHRA declined to convey a list of Mr Oulsnam's scientific publications [on Pubmed there are none]. The MHRA declined to say what university degrees Oulsnam has (if any). It was stated this is personal information. In the same spirit of transparency, the MHRA refused to sign this FOI response. When asked repeatedly to reply in writing, they posted an unsigned printout of their Emailed response to RC.

Oulsnam then made a scientifically incorrect and bizarre statement to the press about a drug. That statement was reproduced by yourself in correspondence to a MP. I therefore repeated the FOI request. I did not ask whether Oulsnam felt himself qualified to do his job. I simply wished to know what precise university degree(s) Oulsnam has (if any), and at which University. This was again refused on the basis that it is "personal information".

The REQUEST (FOI 06/303): "Mr Oulsnam stated to me that he has a degree, and that he also has postgraduate degree in statistics"..... "it is not clear whether I was misled. I request under the FOI a list of the university degrees and postgraduate university qualifications held by Mr Ian Oulsnam of the MHRA (and the names of awarding institutions)."

The MHRA RESPONSE (FOI 06/303): "The full details of Mr Oulsnam's qualifications are not released as this is considered to be personal information." [the absence of "full details" in MHRA language = "no details"]

This is bad

Given Mr Oulsnam's job and public pronouncements, this is not personal information. My refusal to convey my degree(s) would be a disciplinary offense. The DoH website urges patients to insist that surgeons, doctors, dentists, nurses and beauty therapists disclose their qualifications. Universities themselves consider degree awards to be public information (eg here, here, here, here, here). Even professional hypnotists are required to make their qualifications available upon request!

Question 1:

Would YOU inject the drug Mr Burnham?

Question 2: Is this behaviour restricted to the MHRA?

A similar FOI request to the Water Inspectorate (DEFRA) requesting degrees of an official yielded a remarkably comprehensive response (within 2 days) listing all degrees, Universities, subjects taken and dates [pdf][image]. I feel strangely confident when I drink water.

Yet the MHRA, which (unlike the Water Authority) uses an intermediary - doctors - to administer potential harm to other humans is as transparent as mud. In another instance the MHRA refused to provide any names of officials who had made decisions about Vioxx on the laughable basis that this might expose them to animal rights activists!

There will always be potential concerns about the training, common sense and conflicts of interest of public officials. But the point is that you, as that syringe-holding doctor are not even allowed to know.

Something is wrong Minister Burnham.

Yours Sincerely

Dr Aubrey Blumsohn
and if it matters .... MB BCh, PhD, MSc, BSc hons, MRCPath

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Dealing with irrational systems

A useful guide to logical fallacies >>here

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Watchdogs and Fig Leaves

Many government, professional and private organizations claim to support ethical conduct in research.

Some of these organizations pontificate and write guidelines, but remain completely silent and unsupportive when those guidelines are breached.

Others are used as a smokescreen allowing "virtuous protestations from those whose success is based upon systemic failures" (1).

They can also be used to create a false impression that "all is well", that "there are safeguards" out there, and that "whistleblowers are supported" - when no plausible safeguards exist.

Sometimes these organizations are completely subverted by those with different aims, and used as a Fig-Leaf to hide systemic failures.

A report in The Times describes just such a Fig-Leaf (Drug trials and errors : An expert watchdog is disbanding in protest. The Times. 7 Oct 2006 Link).

"an expert watchdog has announced that it is to disband, claiming it has been used as a fig leaf for the Government’s failure to provide volunteers with independent advice or support. The watchdog CERES (consumers for ethics in research) launched itself as “the voice of the guinea-pig” in 1989. For the past three years this group of academics and health service experts has lobbied for funding to run helplines for drug-test volunteers. But it is to disband on December 31, claiming that the Government’s clinical ethics committee has been advising drug-trial researchers that simply showing volunteers a leaflet from CERES will satisfy the EU requirement. CERES says this has been done “without our permission or recognition"

Here is how CERES was represented in the Consent form for the ill-fated TGN1412 trial. I hadn't read this consent form before, and I am shocked by it's complacent and misleading content.

It remains to be seen whether the new UK Panel for Research Integrity will turn out to be any less of a Fig Leaf for research misconduct.

References
Girard,M. (2005) Reformulating the principles of Hippocrates. Medical Veritas 2:682.

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Announcing the Drug Regulatory Logo competition

We have a competition as diversion from the main and serious remit of this blog.

Drug regulatory bodies have become experts at shielding their corporate masters by baffling and misleading the public and doctors instead of protecting and informing them (see ducking and weaving, thank you Health Minister, why is the government not acting?, and the FDA halo effect). Following the success of the Science Idol Cartoon Contest (the Union of Concerned Scientists) you are invited to help defend medicine and pharmaceutical science from manipulation and to work for a healthier world by :

Designing a new logo or mission statement for the FDA, the MHRA, Health Canada (or your very own drug regulatory body).

All entries will be posted on this blog as they are received.
The closing date is 01 December 2006.
The first prize is 10,000 Sudanese Pounds.
Entries by Email (can be posted without your name if you wish).

To set the ball rolling we have a logo for the MHRA courtesy of the Seroxat Users support group



Although intended to be a lighthearted diversion from a personal battle to prevent obfuscation of ethical and scientific problems in clinical studies involving Actonel, there is a serious purpose. If drug regulation is required, then our patients deserve that it should be honest and transparent. Our patients also deserve that all those who choose to lead our noble profession should do so because they have the interests of patients at heart. A little humour or sarcasm might help to place a tiny spotlight on this particular disease. As with any problem facing our patients, we have to do what we can:

"You've got to do what you can,
and let Mother Nature do the rest."
MeatLoaf - Paradise by the dashboard light

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Drug watchdog fails the public

The highly respected UK publications Which (formerly the Consumer's Association) and its sister publication Drug and Therapeutics Bulletin (DTB) have long pointed out the failure of the MHRA (the UK drugs regulator) to act in a transparent manner or to provide reliable and timely information to doctors. DTB has always been wholly independent of the pharmaceutical industry, Government and regulatory authorities. Earlier this year, the Labour government pulled funding for distribution of DTB to doctors without any consultation (Hansard) attenuating this reliable information source. Why it did so can only be guessed.

Which? (October 2006 issue) continues to highlight the problems, touching also on the Sheffield MHRA "investigation". At least someone is stating the obvious.



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Union of Concerned Scientists Cartoon Competition

A winner has been announced.



Please support the Union of Concerned Scientists

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Thank you for the praise Health Minister Burnham

To: Mr Andy Burnham
Minister of State, Department of Health
The House of Commons

I don't really need praise Health Minister Burnham. I would however be appreciative if you could reassure me you are doing all you can to ensure that the system designed to ensure integrity in medicine is operating as doctors and patients would imagine it should: - honestly, without intimidation and in a transparent manner. You will be aware of serious concerns that have been raised by others about the Medicine and Healthcare Products Regulatory agency - MHRA (1, 2, 3, 4) the General Medical Council, and the influence of the pharmaceutical industry on scientific debate (3, 5).


For your information I reproduce a paragraph of text from a forthcoming Journal article (6) about the functioning of the MHRA in the Sheffield case. It has also appeared in abbreviated form in Healthwatch (7) this week. I will be writing to you about this with further details shortly.

"The Sheffield dispute was discussed in the UK parliament in December 2005 and was transmitted by the Health Minister to the UK drugs regulator (the Medicine and Healthcare Products Regulatory Agency, MHRA) for "investigation". The MHRA is itself accused of failing to examine or to secure raw data in drug licensing applications, simply accepting the word of industry with blind faith (8,3). Since this was precisely the problem in Sheffield, its disinclination to investigate was hardly surprising.

No investigation (or at least anything fitting that definition) took place. The MHRA failed to produce any report, declined to accept any documentary evidence (9, MHRA response to FOI request #06/115), stated that the matter was of "low priority" (9), and that the agency does not have any procedure for investigating research misconduct (MHRA response to FOI #06/188). Further, it claimed that the drug regulator has no remit, nor any necessary obligation to be interested in the integrity of the scientific literature about drugs (9, MHRA FOI #06/188) unless related to licensing (and collected using documentation appropriate for licensing). It even argued that it is "illegal" for a scientist to have data pertaining to information written in his name without the consent of the company "owning" that data (9,MHRA FOI #06/115). It refused to compare data it was sent from Sheffield with the original data it should have received and examined as part of the licensing process for Actonel. Initially, this refusal was on the basis that it would be "too much work" (MHRA FOI #06/059). Later, it admitted that that it had not in fact seen or retained raw data prior to approving the drug (MHRA FOI #05/404). With governments setting the standard for scientific conduct, it is hardly surprising that independent science has encountered such difficulties. "

Yours Sincerely

Dr Aubrey Blumsohn
MBBCh, PhD, MRCPath

References

1. MHRA continues to duck weave and delay
2. MHRA -Why is the government not acting
3. House of Commons Health Select Committee Report, April 2005
4. Did MHRA Collude over SSRI's
5. Evans and Boseley, The Guardian, September 28, 2006
6. To follow
7. Healthwatch Highlights
8. Healy,D. Did regulators fail over selective serotonin reuptake inhibitors? BMJ 2006:(333):92-5
9. Collated media reports, Sheffield case

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This is what we are up against - The fall of pharmaceutical medicine

The integrity of the scientific literature relating to pharmaceutical products is heading, like the Titanic, towards an iceberg of enormous size [ref, ref]. If you are wondering why, here is a primer. In an astonishing article in the Guardian this week, journalists Boseley and Evans reveal what has been happening at the heart of British government.

Drug firms' lobby tactics revealed Evans and Boseley, The Guardian, September 28, 2006 "In May, the health minister Andy Burnham met Peter Dolan, then chief executive of Bristol-Myers Squibb and chairman of the Pharmaceutical Research and Manufacturers of America (PhRMA), the powerful industry body in the US." "Over the eight months from October to May this year, senior executives from 10 drug companies met ministers to press for favourable decisions on their products."

"Documents obtained by the Guardian under Freedom of Information legislation reveal that": The world's biggest drug company, Pfizer, warned ministers that it could take its business elsewhere. "Pfizer ... noted that there is complacency in some quarters of Whitehall regarding their continued investment in the UK," the minutes of the meeting record." That sounds like blackmail to me.

A memo also reports the summing-up of the view of Johnson & Johnson: "NICE should take into account what the companies see as the overwhelming views of patients, carers and clinicians on the efficacy of the drugs." "Pfizer asked for more public support from the government for a robust pharmaceutical industry in the UK."

Bristol-Myers-Squibb director of external affairs stated "companies want to invest in countries with a 'favourable environment.'"

I wonder who pays those those patient groups and those clinicians? I wonder who pays those academics and journals who publish selective or distorted findings? I wonder who funds the whole system of thought in medicine? I wonder who pays those guideline writers and even kids and teachers for that supposedly "overwhelming view"? Pfizer and its friends perhaps?

It stinks. The scientific method, that supposed cornerstone of Western civilization, has been replaced by the political method. This is characterized by a fuzzy relationship with reality, conflicts of interest and outright lies.

The statement, from the preface to C. S. Lewis's "The Screw Tape Letters" could serve as a summary of all that that is wrong:

"The greatest evil is not now done in those sordid 'dens of crime' that Dickens loved to paint. It is not even done in concentration camps and labour camps. In those we see its final result. But it is conceived and ordered (moved, seconded, carried, and minuted) in clean, carpeted, warmed, and well-lighted offices, by quiet men with white collars and cut fingernails and smooth-shaven cheeks who do not need to raise their voices. Hence, naturally enough, my symbol for Hell is something like the bureaucracy of a police state or the offices of a thoroughly nasty business concern."

That is what we are up against. It is not about that overwhelming view of "patients careers and clinicians". It is not about the free market or about innovation. It is not even about honest science, honest Universities, honest government or honest drug regulation. It is about power and the golden rule in a monopolistic and distorted market - he who holds the gold and the ear of government rules.

See also the excellent discussion at Health Care Renewal about the Guardian report.

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What have they got to hide? The Famciclovir case

Pending further description of methodology in Sheffield Actonel studies, my attention was drawn to a similar scandal in another parallel scientific universe. It involves the drug Famciclovir (Famvir) and is discussed at Pharmawatch and Healthcare Renewal.

Famvir is used for treatment of herpes zoster, and genital/labial herpes. The case involves a nine year delay before partial publication of findings which had adverse implications for the sponsor. As in the Actonel case, it also involved protracted denial of raw data to academic authors. The study and editorial were finally published a few weeks ago (1,2).

The authors relate that (1):

"....companies are understandably wary of devoting resources to a report that is not in favor of their product. Although we received data tables and listings for this study, we were not able to obtain data tapes to verify the analyses and to conduct what we consider the most clinically relevant analyses"

Dr Wald, the first author, notes in correspondence that:

"We asked for raw data and we were not given it. Initially, we were told that the company has other priorities and that they have not looked at the data. Then company has changed hands and we were told that they no longer had it. But we were given the summary tables and report from which i wrote the paper. The whole process took several years."

Should we as clinicians really be prescribing Famciclovir given this corporate approach to science, and given that we don't really know what was hidden from the authors?

The response of the medical profession and medical ethicists to such problems has been feeble. EBM specialists who collect Clinical Evidence scrupulously fail to document attempts to control, suppress or delay that evidence. It is also puzzling that the drug regulators have no interest in contamination of the scientific literature upon which doctors and patients rely. The malaise is reflected in the recent puzzling assertion in the UK that the drug regulatory body (MHRA) has no remit to investigate or to be concerned about allegations of scientific misconduct or contamination of the scientific literature after a drug is licensed. What then are they for?

We would do well to remind ourselves of the story of Betty Dong and the "thyroid storm" (3, 1996 Editorial in Science, another Editorial)

In 1990, Dong, a researcher at UCSF was funded by Boots to carry out research on a widely use thyroid treatment (Synthroid). She discovered the Boots drug was no more effective than three much cheaper competitors. When she tried to publish, Boots threatened to sue. The publication was withdrawn. She received no institutional support. Company executives attempted successfully to publish an inaccurate version of the findings while excluding Dong and threatening legal action. Nine years later the sordid details were exposed in the press and Dong’s paper was published. In 1999/2000 the company paid $170 million to settle class action lawsuits. However it is estimated that the company made a profit of $3billion in inflated costs during the nine year delay. No company executives were prosecuted. The regulators turned a blind eye.

1. Wald A, Selke S, Warren T et al. Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex Transmitted Dis 2006; 33: 529-533.
2. Fife KH. Are the antiherpes nucleosides really all the same? Sex Transmitted Dis 2006; 33: 534-535
3. Rennie D, "Thyroid storm" JAMA, Apr 1997; 277: 1238 - 1243

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Procter research shenanigans 8: A lawyer writes to Eastell

For background to allegations of research misconduct involving the drug Actonel see here , here and here. There were three elements to the problem:

1. A pharmaceutical benefactor (Proctor & Gamble) repeatedly refused to provide raw data including randomization codes to academic "collaborators". Codes were required by the academics to interpret data they had generated. The academics were unable to verify statistical analyses, meeting abstracts, one published paper and two draft publications "ghost written" in their names.
2. Study data was provided to authors 3 years later (in early 2006) following press exposure. "Fair" analysis of the data would not have yielded findings desired by the sponsor.
3. There were multifaceted and intriguing attempts to prevent the problem from being raised or discussed.

This entry summarizes another of the many noteworthy excuses for refusal of access to data.

The legal request:

On May 25 2005 McKay LAW wrote to Professor Richard Eastell. Eastell was the supposed author of the first of three intended P&G publications related to the work. He was senior author on meeting abstracts (1,2) and two related draft publications intended for submission. The legal letter requested raw data underlying the abstracts and the two related draft publications which were "on the table". It also requested data underlying Eastell's previous publication based on a subset of the same data.

The reply:

The reply received from Eastell's legal representative is below: It reiterated that he too had requested the data and had been refused. It justified the denial of data on the basis that "It belongs to the pharmaceutical companies".


See original copies of letter and reply in Acrobat format.

• This ignores the difference between supposed ownership and access.
• It ignores that the Inability of an author to supply raw data would constitute prime facie evidence of research misconduct.
• It ignores the explicit conditions of submission to any respectable medical journal.
• It ignores that statements had already been made to a journal confirming full access to data (see appendix to JBMR 2003 18(6) 1051-6 and BBC broadcast ).

References - Abstracts underlying intended publications

1. A. Blumsohn, IP Barton, A Chines, R Eastell Relative Contributions Of The Early Changes In Bone Resorption And Later Changes In Hip Bone Mineral Density To The Reduction In Vertebral Fracture Risk With Risedronate. [J Bone Miner Res 2003;18(S2):S157 Abst#SA337
2. A. Blumsohn, IP Barton, A Chines, R Eastell. Relationship Of Early Changes In Bone Turnover To The Reduction In Vertebral Fracture Risk With Risedronate - The HIP Study. J Bone Miner Res 2003;18(S2):S89 AbstF338

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Procter research shenanigans 7: Share your secret

Procter & Gamble are proud winners of the 2006 "TRUSTe and Ponemon Institute" most trusted company for Privacy Award.

So secret that prior to March 2006 P&G wasn't happy to allow authors of scientific papers about P&G drugs to see the raw data about which they were "writing" (backstory here and here).

Fortunately P&G have a deodorant for that.

Visit Secret.com and Share Your Secret with P&G.




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Procter research shenanigans 6: Who stands behind the word?

As of April 2006 the Journal of Bone and Mineral Research has placed an undated "Statement of Concern" on its home page (Not on Pubmed though).

The statement relates to one of the three intended Procter and Gamble publications about change in bone turnover and fractures in patients taking Actonel (Eastell et al. 2003 JBMR 18:1051-6). The other two publications based on overlapping data have only been published in abstract form. The intended first author declined to sign journal declarations while being refused access to underlying raw data.

Medical journals face a crisis of credibility (1-15). Collated correspondence with the JBMR over 2 years provides some insight into the real concerns underlying their "Statement of Concern".

And from (11) a quotation that provides an excellent summary of the crisis facing medicine.

1. 23 August 2006: Why Today's JAMA Editorial Doesn't Go Far Enough
2. PLoS takes a stand
3. NEJM and Vioxx
4. Manipulating a Journal Article: NYT
5. Audio interview with NEJM Editor Drazen -(the call from Hrachovec begins at 44:30)
6. For Science's Gatekeepers, a Credibility Gap
7. Just how much 'new research' can we trust?
8. Incident raises questions of editors' and publishers' corporate connections
9. Why you can't trust medical journals anymore
10. Commercial influence and the content of medical journals
11. Presentation by Gavin Yamey
12. A Story Involving JAMA, Harvard Medical School, Baxter International, Cytyc
13. More on lessons from Neuropsychopharmacology
14. Won't Get Fooled Again, Again, Again
15. About the paper in Am J Psychiatry 163:34A (2006)

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The MHRA - continues to duck weave and delay

The UK Medicines and Healthcare Products Regulatory agency - continues to duck weave and delay - read on...

See also the House of Commons Select Committee Report on the MHRA - why is the government not acting?

Addendum: Yet more ducking and delaying: "Delay Breeds Corruption" revealed through the persistence of Charles Medawar. The MHRA continues to function with duplicity.

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Procter research shenanigans 5: Research misconduct summarized in one graph

This is the key graph from Richard Eastell et al. (2003) J. Bone. Miner. Res. 18:1051-6.

The solid lines supposedly show the relationship between the change in bone turnover (NTX) and new spine fractures in patients taking Actonel (Risedronate) at 1 year and at 3 years. The dashed lines show patients taking placebo. The purpose of this posting is simply to show that the scale of graphs in ghost-written papers by P&G had been drawn so that a proportion of the data simply "fell off" the left hand end of plots. I was supposed to have signed off on two further publications containing similar graphs and opaque statistical analysis ...... all while being refused access to underlying data codes held by P&G.

The first step of any statistical analysis is to PLOT THE DATA. Following press exposure P&G eventually released the raw data to authors in April 2006. The distribution of the actual data for NTX change (the X axis variable) in the above paper (Eastell et al 2003) for patients taking Actonel is:
A third of the data would not have appeared within the range of the Procter and Gamble graph as plotted by them (P&G's graph ends at -60%). Strange that.

The relevance of the missing end of the plot will be discussed in later postings. Suffice to say that these patients show responses more typical of the drug produced by P&G's competitor (Merck, Fosamax).

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Why pharmaceutical companies need to be prevented from researching clinical aspects of their own drugs

The past month has seen much pontification in medical journals explaining why pharmaceutical companies should no longer be allowed to control and conduct research informing the public and doctors about the efficacy and clinical use of their own drugs. The Sheffield scenario (this blog) is another reason

Here are a few excellent publicly available ones.

Review of Pfizer internal documents relating to manipulation of science and the perception of science
Annals of Internal Medicine, August 2006

Evidence of an industry out of control
Journal of the Canadian Medical Association, August 2006

From optimism to disillusion
Professor Sir Ian Chalmers, Journal of The Royal Society of Medicine, July 2006

Can We Tame the Monster? "Drug companies should not be allowed to evaluate their own products."
Fiona Godley, Editor of the British Medical Journal, July 2006

Medical journals usually bend at the first sign of a legal raised eyebrow from their corporate masters. Are we seeing the start of a new sanity, or yet more fine words?

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Procter research shenanigans 4: Befriending the red herring

Pharmaceutical companies are accused of overturning the safeguards of science. The accountability of authors is the most fundamental of these safeguards. Readers expect that authors are the authors, that they vouch for the work and would be able to defend their findings if challenged. They expect that authors would be able to provide underlying raw data.

One of the many "red herring" excuses provided by Procter & Gamble to justify refusal to supply data codes underlying ghostwritten material (statistical reports, abstracts, two draft publications) to me as first author and to the Sheffield authors of a previous publication based on a subset of the same data (Eastell et al., 2003 JBMR 18:1051-6) is discussed here. The backstory is here and here.

This particular excuse (see correspondence here) was that they :

"use the approach described in PhRMA guidelines and that in these guidelines there is not access to the data (other than those from your center) for investigators".

So, what's wrong with this excuse:

1. PhRMA (the Pharmaceutical Researchers and Manufacturers of America) is the lobbying organization for the industry. It is recipient of recent awards: The Fox Guarding the Hen House Award (for pushing toothless voluntary guidelines) and The Truth is Stranger Than Fiction Award (for a scandal involving the bribing of authors to produce a thriller as a stealth marketing tool to frighten the public (see Karasik Conspiracy). PhRMA has no authority to override ethical guidance.
   
2. Even PhRMA does not suggest research findings should be closed to scrutiny by authors, or that authors should lie to journals. The cited PhRMA suggestion is that some paid recruiters of patients in multiple-center studies might not get to share in complete data access. This has nothing to do with the rights and obligations of a principal investigator or first author.


3. Inability of a scientist to supply raw data constitutes prime facie evidence of research misconduct. Ability to provide data is an explicit condition of submission to any respectable Journal.


4. Innumerable guidelines make the obligations of authors perfectly clear. For example:
   
   • The European charter for researchers: "details of the data should be open to internal and external scrutiny"
   
   
   • The Association of American Medical Colleges affirms right of "investigator to receive, analyze, and interpret all data generated in the research, and to publish results, independent of outcome" and affirms "an investigator’s accountability for the integrity of any publication that bears his or her name", and "Institutions should not enter, nor permit a covered individual to enter, research agreements that permit a sponsor ..to interfere with an investigator’s access to the data or ability to analyze the data independently".
   
   
   • The International Committee of Medical Journal Editors (ICMJE) requirements: "researchers should not enter into agreements that interfere with their access to the data and their ability to analyze it independently" Editors may request that authors of a study funded by an agency with a proprietary interest in the outcome sign a statement, “I had full access to all of the data in this study and I take complete responsibility for the integrity of the data and the accuracy of the data analysis.”
   
   
   • The World Association of Medical Editors (WAME) state : "Authors should be asked to affirm in writing that they have not entered into an agreement with the funding organization that limited their ability to complete the research as planned and to publish the results". "Authors should state in writing that they have had full control of all primary data. Authors' should agree in writing to allow the journal to review their data if requested."
   
   
   • CIOMS state: "investigators should not enter into agreements that interfere unduly with their access to the data or their ability to analyze the data independently, to prepare manuscripts, or to publish them."
   
   
5. Concealment of raw data is contrary to the rules of any respectable University. Guidance at the University of Sheffield states:
   "research evidence should be made available to other researchers on request, prior to or following the publication of results".
   "Publication of research results does not negate the need to retain original records of research evidence"
   "evidence for research based on clinical samples or relating to public health be retained for twenty years."
   "Errors detected following the publication of results could be mistaken for research misconduct if a researcher could not subsequently provide valid corroborative research evidence."

Scientists may disagree about the presentation of data. There can be no legitimate debate when that data is not available for scrutiny even to authors.

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Procter research shenanigans 3: Research misconduct explained in one letter

Background to the dilemma involving Actonel research in Sheffield is here, here and here. The research involved a secondary endpoint in randomized trials used to demonstrate the efficacy of risedronate (Actonel) for regulatory approval. The company violated the norms of science under whose banner they claim to sell their products.

There were three elements to the problem:

1. A pharmaceutical benefactor (Proctor & Gamble) repeatedly refused to provide raw data including randomization codes to academic "collaborators". Data was required by the academics to verify scientific reports, statistical analyses, meeting abstracts (1,2), and draft publications "ghost written" in their names.


2. Data was provided to authors 3 years later, in early 2006, following press exposure. "Fair" analysis of the data would not have yielded findings desired by the sponsor.


3. There were multifaceted and intriguing attempts to prevent the problem from being raised or discussed.

A single letter summarizes problem 1:

The writer is Professor Richard Eastell, collaborator in this research, and then Research Dean of Sheffield Medical School. It was written after numerous attempts to gain access to data from the company, and after some information had emerged to suggest that the analysis performed by P&G was implausible. A publication based on overlapping data had already appeared in press (Eastell et al., 2003 J. Bone. Miner. Res. 18:1051-6) - the raw data underlying this overlapping paper had also not been disclosed to Sheffield authors (BBC broadcast).

This letter from Professor Eastell was written in response to two letters from myself here and here. Eastell's "response":

1. attempts to rationalize why it was appropriate for authors to be refused access to critical raw data


2. suggests that the first author (Blumsohn) would be removed even as a coauthor unless prepared to sign a journal declaration in the absence of data

Click here for PDF version of letter or on images above to enlarge.

Abstracts underlying intended publications

1. A. Blumsohn, IP Barton, A Chines, R Eastell Relative Contributions Of The Early Changes In Bone Resorption And Later Changes In Hip Bone Mineral Density To The Reduction In Vertebral Fracture Risk With Risedronate. [J Bone Miner Res 2003;18(S2):S157 Abst#SA337


2. A. Blumsohn, IP Barton, A Chines, R Eastell. Relationship Of Early Changes In Bone Turnover To The Reduction In Vertebral Fracture Risk With Risedronate - The HIP Study. [J Bone Miner Res 2003;18(S2):S89 Abst#F338

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