NMT Medical closes migraine trial in U.S. - a case to watch

This news-snippet rings a few alarm bells. I have posted about some apparently dodgy dealings in a clinical trial involving Boston-based NMT Medical, the MIST I trial, and UK clinical investigators.

The previous saga involved a medical device, and the conduct and conclusions of the Migraine Intervention with STARflex Technology (MIST) I trial. MIST I had two co-principal investigators:

1. Dr Peter Wilmshurst, a respected cardiologist and
2. So-called headache specialist Dr Andrew Dowson. Although Dowson described himself as a neurologist, he is not. More importantly, Dowson has restrictions on his medical practice following previous research misconduct.

Wilmshurst states that NMT has repeatedly "blocked his attempts (as principal investigator) to view the complete MIST I data set, has lied about whether echocardiograms from the MIST patients have been independently reviewed, and has massaged the data to portray its PFO device in the best possible light". He was sidelined from the study, his concerns were ignored, and Dowson presented the findings which have now been questioned. For details see here.

Several ethical, procedural and scientific issues arose in MIST I which went beyond the issue of migraine to other aspects of the device. One can only hope that NMT are not going be so foolish as to attempt to threaten Dr Wilmshurst for quite properly discussing scientific procedures involving patients. The of MIST I is ongoing, and it seems that NMT may have resorted to legal threats - always a credible scientific tactic. This case is worth keeping on the radar.

Now we read that NMT is shutting down the MIST II trial. This may be appropriate as MIST I showed no efficacy for migraine. However questions have to be asked when trials are shut down. If the continuation of MIST II was in any way dependent on the outcome of MIST I, then the ethics of starting MIST II have to be questioned. If the termination was truly related to difficulty with recruitment then this raises other issues.

NMT Medical closes migraine trial in U.S. Mass High Tech, 23 Jan 2008

NMT Medical Inc. reports plans to shut down its migraine technology trial, MIST II, to instead focus on using its technology to prevent the onset of stroke.

According to officials at Boston-based NMT, the move should save the company approximately $14 million over the next two to three years, as it redistributes funds originally budgeted for MIST II (Migraine Intervention with STARFlex Technology). NMT has stopped enrolling patients in MIST II, which was being conducted at 20 centers in the United States.

NMT president and CEO John E. Ahern said that strict enrollment requirements from the U.S. Food and Drug Administration has made MIST II an expensive endeavor "with little likelihood of being completed in a reasonable time frame."

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The politics of pharmaceutical bloggers: Part 2

In a previous post I challenged pharmaceutical bloggers to undertake a political test. Here are the results so far. They key is below the chart. For details see here. Take the test here. Clicking individual "dots" should open the respective blogs in a new window. For comparison, below the plots are scores for political figures and UK political parties according to the authors of the test.

Blogs so far are
Healthcare Renewal (Roy Poses and others) - the serious master of them all
Pharmagossip (Jack Friday) - the less serious master of them all
Pharmalot - and the man behind it - Ed Silverman of The Star-Ledger of New Jersey. Superlative journalism and a key source.
Brandweek NRX and Dr Peter Rost, previous Vice President of Pfizer
Pharma Giles - Good Fun
Pharma Fraud - Doesn't Like J&J particularly
Furious Seasons - Excellent look at seriously bad science in psychiatry
Scientific Misconduct Blog - This blog
Clinical Psychology and Psychiatry: A great blog discussing the malfunction of medical science with an emphasis on psychiatry
Pharma BlogoSphere and much more from John Mack (Editor & Publisher of Pharma Marketing News/Pharma Marketing Blog)
Dr Scot Silverstein, an author at Healthcare Renewal

1, 2 and 3 are three excellent and hard hitting (and deeply depressing) UK-based patient blogs devoted specifically to exposing misconduct and misrepresentation in clinical trials of Seroxat (Paxil) and various aspects of the integrity of GlaxoSmithKline.

1 = Bob Fiddaman Blog
2 = Seroxat Secrets
3 = It's quite an experience: Matt Holford (a compliance lawyer)

4 is Honest Medicine. Julia Schopick created Honest Medicine in honor of her late husband, Tim Fisher, as a way to "work with others to make significant changes to the way people think about, and interact with, our flawed medical system."

Some historical figures


UK Parties


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BMJ Advertising Watch : 26 January 2008

This is the British Medical Journal Advertising analysis for this week.

I'll also continue to comment on any appearance of any discussion in the BMJ about questionable Ezetimibe research.

Rules: As usual this is for the UK version of the BMJ. The classified advertisement section is excluded, as are pages advertising the BMA or products of the BMJ/BMA/BNF.

Comment: This week the BMJ exceeded all records with 24.5 pages of advertising (giving 1 page of advertising for each 2.4 pages of content). Again 98% of the advertising was for pharmaceuticals. The other 2% was a single half page advertisement for Ramsay Healthcare (for more about Ramsay and their cozy arrangements with the Labour Government see here).

Discussion about the Ezetimibe scandal: Finally, the BMJ published a short news piece by the excellent Jeanne Lenzer on the shonky research underlying the approval of Ezetimibe (Ezetriol, Vytorin, Zetia). There remains no discussion in the BMJ about the precise way in which the scientific community were deceived, the delayed reporting, the attempts to circumvent investigators and to alter endpoints, the interesting sale of Schering shares ($25 million) by an executive, or any discussion of the principles of good science. However a belated and half-hearted congratulations. In contrast to the last issue, there were no advertisements for Ezetimibe.

Merck and Schering-Plough state:

"All of us at Merck and Schering-Plough proudly stand by the established efficacy and safety profiles of Zetia and Vytorin."

Define efficacy. Given the evidence of your behavior, why should we believe you?

Our profession remains mute.

Click here for collated BMJ Advertising analyses.

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Pharmaceutical bloggers - Take the political test

The debate about the functioning of the pharmaceutical industry is enmeshed in a wider political debate. There seems to be reluctance to confront the ideological issues head on. This allows the continued burbling of those who create ideological opponents by declaring themselves on the side of "the free market" and against "intrusive regulation" while failing to define the meaning of the words they use. It is why we read twaddle like this from Billy Tauzin of PhRMA or the illogical rants of Robert Goldberg and Peter Pitts on DrugWonks. These individuals (in my view) represent the very antithesis of the free market they espouse.

There is an interesting "Political Compass" that has been working its way through a few political blogs. Take the test here. My score is below. I challenge my friends on the blogroll to report their scores. I suspect we all lie in a similar range - hardly foes of the free market or of industry in general.

As already pointed out, there are some significant flaws in the questionnaire, but it's a useful start. Some propositions are worded in such a way that people with radically different views on the issue would be forced to answer in a similar way.

Here is one example of a proposition one is asked to score:

Question A: "Governments should penalise businesses that mislead the public"

That is an incomplete proposition, and one which begs several qualifying clauses. One could ask a different question:

Question B: "Governments have the right to protect businesses that mislead the public by enacting legislation and through regulatory procedures which
a) disallow scrutiny
b) allow hiding of evidence
c) prohibit litigation by individual consumers through regulatory pre-emption rules"

I suspect these answers would distinguish Billy Tauzin or Robert Goldberg from the ideological straw-men they set up as adversaries. The distinction is between honesty and dishonesty, and open transparent science versus secrecy.

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Jeanne Lenzer on the "clinical trial register"

Last year the US Congress required drug companies to post announcements of clinical studies in a public database.

The "Clinical Trial Register" as currently constructed is most unlikely to solve the problem. In fact it may provide an appearance of a solution, diverting attention from the real problem. There are several obvious reasons for this, some of which are given by the excellent medical reporter Jeanne Lenzer in her NPR interview of 18 January 2008 (Transcript here).

On the "federal fine for pharma companies who misreport or don't report"

LENZER: Ten thousand dollars, it’s meaningless. Even though some of those fines can accumulate after a certain period of time, they get a 30-day warning period, and at $10,000 a day that’s nothing next to the millions of dollars per day that they pull in. And if the past serves as any kind of information, then what we know is, is that they will ignore these.

Death as a trade secret: On the fact that we already had a Clinical Trial Register - it was called the FDA. Those charged with maintaining that register have colluded to hide inconvenient findings.

LENZER: Yes. There was a research scientist who really had a stricken conscience and called me and said that Congress is looking at whether antidepressants cause suicidality or not. And it’s natural to wonder is it really the drug or is it the underlying depression?

And what this research scientist, who remains anonymous, said to me was because they knew there was a question about suicidality with their pills. What they did in this study was they took healthy test subjects, screened them all to not be depressed and then tested them with this drug that they hoped they would be able to use for urinary incontinence.

And what they found was there was about a doubling of the suicidality among these patients. So that sure seemed like important information to patients who were taking that same drug for depression.

INTERVIEWER: But because the drug was not put on the market as an anti-incontinence product, the rules did not require Lilly to disclose the suicide of an otherwise healthy 19-year-old college student in the midst of a trial in its own laboratory.

LENZER: Exactly. And when I filed a Freedom of Information Act request with the FDA for all of the serious adverse events and deaths of patients taking this drug, and when I got that database back, it did not include her death. And it didn't include the deaths of at least four other patients. They weren't even patients. These were healthy volunteers who were taking the drug as part of a clinical trial.

And I asked the FDA why they hadn't released these deaths, and they said, because they are a trade secret. And they were a trade secret because the drug didn't make it onto the market for that particular use, for incontinence. But it was being used by many patients for depression.

The most important comment of all : On raw data

INTERVIEWER: It seems to me that, you know, there’s a very good solution for this at hand, and that would be a change in the law that would allow the FDA to demand and post on the Internet not only the existence of all clinical trials but the results, and then let it be sorted out by the medical community. But that’s not possible now, is it?

LENZER: You’re right, because right now, under trade secrecy rules, which is what affected the girl that we discussed earlier who committed suicide, her death was considered a trade secret. We need to change things so that anyone’s clinical outcome on a trial should never be a trade secret, and that should be available for scrutiny - and I'd also add not just the results of these trials but the actual underlying raw data. They need to be available to other scientists for scrutiny.

For other comments see Clinical Psychology and Psychiatry : Clinical Trial Registry of WHAT?

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BMJ Advertising Watch : 19 January 2008

This is the British Medical Journal Advertising analysis for this week.

I'll also comment on any appearance of any discussion in the BMJ about questionable Ezetimibe research.

Rules: As usual this is for the BMJ as delivered to subscribers in the UK. The classified advertisement section is excluded, as are pages advertising the BMA or products of the BMJ/BMA/BNF.

Comment: This week only 98% of the advertising was for pharmaceuticals (there was a single half page advertisement for a Private Healthcare company). As before, there was no advertising space devoted to other products doctors might be inclined to purchase (stethoscopes, expensive cars, services, holidays, books, cosmetics), or non-pharmaceutical healthcare products. The ratio of advertising space to content was about the same as last week (1 page of advertising for each 2.6 pages of content).

There were two rather good articles about osteoporosis in this issue. I'll discuss these over the next few weeks.

Discussion about the Ezetimibe scandal: Still none at all. There was however a full page advertisement for Ezetimibe (Ezetriol, Vytorin, Zetia). The advertisement states "Better Together", "For patients not controlled by initial statin alone". The advertisement doesn't mention that the only evidence available so far suggests that the drug has no clinical benefit at all. It also doesn't mention what happened to the data.

Click here for collated BMJ Advertising analyses.

Postscript: Matthew Holford posted an interesting commentary on this BMJ Ad-watch. He revealed correspondence with the BMJ asking about their reported rejection of a scientific paper criticising GlaxoSmithKline. This rejection was apparently on the basis of the legal costs of review rather than on factual content. He asked how much an advertisement costs in comparison with legal "peer review" of a manuscript (perish the thought). He received no reply. I'll say more about this next week.

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Ezetimibe Zetia Vytorin - Headless Chicken Award

The Ezetimibe data are out (all those thousands of un-analyzed images that formed the excuse for non release of the results were obviously analyzed at the speed of light). From the WSJ "The long-delayed and much-speculated-about data from Merck and Schering-Plough’s Enhance study comparing whether a combination of Zetia and Zocor works better than Zocor alone were finally released today."

It's a bummer. Time for the first Headless Chicken award of 2008.



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Isaac Asimov on Scientific Fraud: Self Correction or Self Delusion

The famous biochemist and science fiction writer Isaac Asimov claimed to believe in evidence. In his book The Roving Mind he wrote:

Don't you believe in flying saucers, they ask me? Don't you believe in telepathy? — in ancient astronauts? — in the Bermuda triangle? — in life after death?

No, I reply. No, no, no, no, and again no.

One person recently, goaded into desperation by the litany of unrelieved negation, burst out "Don't you believe in anything?"

"Yes", I said. "I believe in evidence. I believe in observation, measurement, and reasoning, confirmed by independent observers. I'll believe anything, no matter how wild and ridiculous, if there is evidence for it. The wilder and more ridiculous something is, however, the firmer and more solid the evidence will have to be."

I subscribe to Asimov's sense of science. It is why I know homeopathy or bone-throwing don't yet pass the sniff test.

The problem is that I don't think Asimov himself believed in evidence. Some who claim the scientific high-ground have an interesting view of evidence as Asimov's 1982 essay below demonstrates.

Striking examples of scientists ignoring reason and facts arise when science confronts actual evidence of its own malfunction. Note for example the newly instituted UK panel for Research integrity. This esteemed body has (as a fundamental principle of its operation) the idea that academic institutions are capable of honest "self-investigation" of misconduct by their own faculty. Evidence based policy this is not. There is voluminous and compelling evidence (n=1000, P<0.0001) that this is delusional nonsense.

The below 1982 commentary by Asimov is an interesting example of science in delusion. He contends that fraud in science (however defined) is rare. He contends that instances of fraud and their management reflect "credit" on science. He would have us believe that it is difficult to be a fraudster because science is always "self correcting". Fraudulent results will fail to replicate (who is going to repeat that $300million clinical trial of a drug controlled by Pfizer). It "is scientists themselves who catch the frauds" - science is after all self policing. He contends that there is absolutely "never any cover-up" and that the perpetrators of fraud are "exposed pitilessly and publicly .... the punishment is absolute - anyone who proves to have violated the ethics of scientific endeavor is ruined for life. There is no second chance, no vestige of status. He or she must drop out, forever disgraced."

Martin Keller is a nice example here, though I can think of many more persons disgraced in this way.

I believe in science, but I will have none of this nonsense. There is so much wrong in this short essay that it would make an ideal background to a teaching series on scientific fraud.

SELF-CORRECTION

From SciQuest, February, 1982, p. 32, By Isaac Asimov

Every once in a while - not often - scientists discover that one of their number has published false data or has plagiarized someone else's work.

This is always deeply embarrassing, especially since these days such news usually receives wide publicity in the nonscientific world.

In some ways, however, these scandals actually reflect credit upon the world of science. Consider:

1. Scientists are, after all, human. There is enormous pressure and competition in the world of science. Promotion and Status depend on how much you publish and how soon you publish, for the lion's share of credit comes if you are first with an important theory or observation. Under these circumstances, there is great temptation to rush things; to make up some data you are sure you will eventually find anyway that will support your theory, or to help yourself to someone else's work. The surprise, really, is not that it sometimes happens, but that it doesn't happen much more often. Scientists resist the pressure marvelously well.
2. When it does happen, the mere fact that it is so publicized is a tribute to scientists. If it were a common event, or if people expected scientists to be corrupt it would make smaller headlines and drop out of sight sooner. Single cases of scientific corruption, however, will be talked about for years and inspire articles and books by the score. It's really a compliment.
3. Cases of scientific misbehavior point out how difficult it actually is to carry them out successfully, or even for very long. .. . A vital principle in scientific research is that nothing counts until observations can he repeated independently and there, almost inevitably, anything peculiar is uncovered. Science is self-correcting in a way that no other field of intellectual endeavor can match.
4. It is scientists themselves who catch the frauds; no one else is equipped to do so. The point is that scientists do catch them. There is never any cover-up on the grounds that science itself must not be disgraced. However embarrassing the facts may be, the culprit is exposed pitilessly and publicly. Science is self-policing in a way that no other field is.
5. Finally, the punishment is absolute. Anyone who proves to have violated the ethics of scientific endeavor is ruined for life. There is no second chance, no vestige of status. He or she must drop out, forever disgraced.
6. Add to all this the fact that scientific ethics requires all scientists to labor to find flaws in their own observations and theories - and to publicize these flaws when they find them - and you will understand how stern the requirements are and how astonishing it is that scandal is so infrequent.

What do you see in the mirror Professor? Self correction or self delusion?

Even in 1982 it would have been obvious to an evidence-based Asimov that his essay was delusional. In 1982 he could have been forgiven for failing to discuss corporate scientific fraud. He might not have noticed that honest scientists who draw attention to fraud are viciously persecuted while the scientific community stands by in silence. Most recent instances of scientific fraud have come to light, not through failed attempts at replication but through actual evidence of manipulation revealed through litigation. He might not have noticed then that the policemen are often government "regulators" who collude with fraud. So much for self policing.

Perhaps Asimov's perspectives would apply to some areas of physics or chemistry.

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BMJ Advertising Watch : 12 January 2008

This new initiative follows my earlier post on the widening gap between the debate about science that is taking place in medical journals and the scientific/ethical discussion outside of those journals. Each week I will collate the advertising in the current issue of the British Medical Journal. I'll comment as we go along, and at the end of some period I'll collate the data, related scandals involving the advertised drugs and discussion taking place within the content pages of the BMJ. I'll also comment on any appearance of any discussion in the BMJ about questionable Ezetimibe research.

Rules: This is for the BMJ as delivered to subscribers in the UK (not to libraries). If anyone wants to help collate data for JAMA, Lancet and NEJM let me know. The classified advertisement section is excluded, as are pages advertising the BMA or products of the BMJ/BMA. Below is the analysis for this week

Comment: 100% of the advertising was for pharmaceuticals. There was no advertising space devoted to other products doctors might be inclined to purchase (stethoscopes, expensive cars, medical devices, services, holidays, books, cosmetics or alcohol). The ratio of advertising space to content was 1:2.55.

The advertisement for Novartis about CML chemotherapy was particularly interesting. This was in essence a one page content-free scientific "review" raising the concept of targeted chemotherapy for CML based on Bcr-Abl.

Discussion about Ezetimibe research: None

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The case of Dr Z

A report in the British Medical Journal yesterday is fascinating:
Dyer, Clare (2008-01-12). "Whistleblower who was excluded from work for five years wins apology". BMJ 336 (7635): 63.

The bullying of doctors and patients who raise concerns, and the gagging of information about those concerns is the most fundamental element of clinical risk. The various "Clinical Governance" policies put in place to (ostensibly) control clinical risk take no account of what actually happens.

What we are allowed to know about this story is that:

• A junior doctor (known only as Dr Z) was excluded from her job in Cambridgeshire Primary Care Trust for 5 years. Her apparent crime was that she objected to inclusion of medical records in a research database without patient consent. Those medical records included her own.
• The reason we do not know her name is that she is under a gagging order.
• Many years before Dr Z suffered from a rare "serious life threatening condition". She wanted the details kept private.
• However her medical details were distributed as part of this research to Addenbrooke's Hospital, Cambridge and from there to personnel involved in her employment.
• Despite giving no consent she was harassed by the researchers.
• The interesting (but common) response of her employers was to suggest that she was ill and to refer her to an "occupational health consultant". She was then put on "special leave from her employment".
• Her employers tried to suggest that her "fitness to practice was an issue" and seemingly tried to (or actually did) refer her to the General Medical Council to be struck off.
• Her employers generated false accusations that she had given a wrong name and address to her own doctor, and had falsified sick notes.
• Her employers maintained that it "was not possible" that her records were held in the research database.
• In September 2006 her employment was terminated.
• Acting on her own she brought a libel action against her employers. The Trust admitted that all the accusations that they had made in their apparent attempts at bullying were false, and that her records were indeed in the research database.
• In this case the person bullied was not only a doctor raising concerns about patients but also a research participant who was apparently told lies.

What can we say of all of this? The same basic elements are played out in variable form over and over again.

1. Individuals are gagged and neither our profession nor patients nor the general public discover the truth.
2. There is abuse through accusations of mental illness.
3. The very bodies who are charged with integrity in medicine (such as the General Medical Council) are used by medical leadership to obfuscate the truth. At the same time the GMC shows no intent to deal with the powerful liars, falsifiers and bullies. Those individuals are neither named nor sanctioned.
4. False accusations are made to divert attention from the real problems.
5. There is almost no support for abused individuals.

There are implications for the confidentiality of medical data. This is another timely incident given the foolish inclination of the Labour government to take control by force of our medical records in a central "database".

John M. Grohol at Psych Central has written an interesting article "Why Would You Lie to Your Therapist?". Patients tell half-truths for many reasons. Concerns that the state or others will abuse the relationship of confidentiality is a powerful one.

We are entitled to ask several questions of Addenbrooke's Hospital, Cambridge:

Why have the full details not been placed into the public domain? What is this research, and has it been published? What are the names of the researchers involved? Did the work receive ethical approval? Did any publication state that some participants had refused consent? What action has been taken to deal with the individuals who bullied Dr Z?

Did any of the various agencies who are supposed to ensure integrity in this context do anything at all to assist Dr Z? Perhaps the General Medical Council did something, or Public Concern at Work, or the British Medical Association, or the UK Panel for Research Integrity, or the Ethics Committee at Addenbrookes Hospital, or the local Medical Staff Committee?

And why did the BMJ use the word "whistleblower"? Dr Z was simply doing her job. It is the job of a doctor to tell the truth in the interests of our patients (and in this case Z was one of those patients). Instead of dealing with her concerns she was bullied, told lies (and probably made ill). Whistleblowing has nothing whatever to do with this -- particularly since everything that the scientific community has to know and has to discuss has actually been suppressed.

Have we learned anything since Bristol? Or Shipman? Or Chan? .... or any of the incidents which have placed our patients and clinical science at risk?

Dr Z said in a statement:

"I raised concerns relating to unethical research practices which threatened patient confidentiality and were being conducted in breach of the law. I was then excluded from work for a period of five years, on the basis of allegations which the trust now concedes were groundless.

See also comments by Ferretfancier and Longrider

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Ezetimibe - where are our medical journals?

The huge ethical and scientific problems with the drug Ezetimibe have been discussed widely in the lay press (especially in the New York Times and some excellent reporting in Forbes). The problems have been discussed by patients, on the internet and in the blogsphere. However as of today, a search of our key medical journals reveals no hint of any ethical discussion. No discussion of the principles of good science. Not even a worthy news report. Nothing at all.

• The British medical Journal : No discussion
• The Lancet: On 24 November 2007 in the midst of the saga, the Lancet published a review entitled "The safety of statins in clinical practice" Jane Armitage, Vol. 370, Issue 9601 Pages 1781-1790. There was no relevant discussion or associated editorial in that issue or in any subsequent issue.
• NEJM: No discussion
• JAMA: No discussion

And the multitude was silent, not a voice, not a sound was heard upon the hillsides, across the valleys where they stood.'
Richard Bach, Illusions

One wonders how long our key medical journals will retain any credibility as honest impartial portals for discussion of science and the principles of good medicine. For the record, here is some of the discussion on the top 100 medical blogs collated in date order. Some have called for a boycott of Ezetimibe.

• 21 Nov 2007 from Your Pharmacist May Hate You: Print Out The Article and Shove It Down The Throat Of your Merck/Schering Rep
• 22 Nov 2007 from PharmaGossip: Is Vytorin about to be renamed Whytorin?
• 24 Nov 2007 from Hooked: Ethics, Medicine, and Pharma: Here We Go Again: Everything That's Wrong with Industry Sponsored Trials
• 24 Nov 2007 from Scientific Misconduct Blog: Ezetimibe (Zetia, Vytorin): the smell of bad science
• 26 November 2007 from Junkfood Science: Even gold can be tarnished
• 26 Nov 2007 from Pharma Marketing Blog: Vytorin Study Stallin' - Notes from the Field Hands
• 26 Nov 2007 from Health Care Renewal: Is it (Clinical) Research, or is it (Pharmaceutical) Marketing? - the ENHANCE Trial of Ezetimibe
• 29 Nov 2007 from MDLinx: ezetimibe: The role of ezetimibe in cholesterol management (evidence-selective article for nurses)
• 22 Dec 2007 from Medical Evidence Blog: Patients and Physicians should BOYCOTT Zetia and Vytorin
• 22 Dec 2007 from Scientific Misconduct Blog: More problems with Ezetimibe (Zetia, Vytorin): Let there be light
• 23 Dec 2007 from Clinical Psychology and Psychiatry: A Closer Look: Changes?
• 24 Dec 2007 from The Healthy Living : Data About Ezetimibe Adverse Effects Suppressed?
• 24 Dec 2007 from Health Care Renewal: Data About Ezetimibe Adverse Effects Suppressed?
• 25 Dec 2007 from Your Pharmacist May Hate You: Merck/Schering don't want You To Know about studies on the liver
• 26 Dec 2007 from Scientific Misconduct Blog: On swearing versus thuggery: a statistical analysis
• 27 Dec 2007 from Your Pharmacist May Hate You: Once Again, The Drugmonkey Gets Results
• 12 Dec 2007 from Pharmalot: Merck & Schering-Plough Backpedal On Vytorin
• 12 Dec 2007 from PharmaGossip: Whytorin Saga contd. - clinical trials, ain't they a bitch!?
• 13 Dec 2007 from Medical Evidence Blog: ENHANCE trial faces congressional scrutiny
• 17 Dec 2007 from Health Care Renewal: Manipulation of ENHANCE Reversed
• 17 Dec 2007 from Pharmalot: Vytorin Researcher Regrets Not Fighting Back
• 18 Dec 2007 from PharmaGossip: ENHANCE your reputation
• 18 Dec 2007 from Dr. Peter Rost: It's never, ever right to change the primary endpoint of a study
• 18 Dec 2007 from PharmaGossip: More on ENHANCE - the case of the shifting endpoint
• 17 Dec 2007 From Pharma Giles: A Doctor's Christmas Carol...some drug reps gave to me, Twelve Zetia Calculators, Eleven Nexium totebags....
• 19 Dec 2007 from Schwitzer Health News Blog: Something smelly about statin trial: Congress investigates
• 21 Dec 2007 from Scientific Misconduct Blog: A ray of light - well done Dr John P. Kastelein
• 21 Dec 2007 from PharmaGossip: Merck/Schering Plough - Zetia: the liver is evil, it must be punished
• 21 Dec 2007 from Clinical Psychology and Psychiatry: A Closer Look: Zetia: But Why Would We Show You the Scary Data?
• 21 Dec 2007 from Pharmalot: How To Find Documents On The FDA Site
• 21 Dec 2007 from Hooked: Ethics, Medicine, and Pharma: New Cholesterol Controversies: Regaining Perspective
• 21 Dec 2007 from Pharmalot: The Vytorin Clock Tells You When To Hide Data
• 21 Dec 2007 from Drug Injury Watch: Cholesterol Drug Zetia May Cause Serious Liver Injury Including Hepatitis And Liver Failure
• 04 Jan 2008 from PharmaGossip: Schering Plough - Zetia/Vytorin: ENHANCE - Listen with Fred
• 05 Jan 2008 from Bad Science: The data belongs to the patients who gave it to you
• 10 Jan 2008 from Scientific Misconduct Blog: The Ezetimibe fiasco - the excuses continue

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The Ezetimibe fiasco - the excuses continue

Several bloggers have been following the saga of Ezetimibe (Zetia, Vytorin), the hidden data, and the threats to science which have resulted from the way in which Merck and Schering-Plough have thrown the usual safeguards of science into the gutter.

Earlier this week Schering-Plough CEO Fred Hassan spoke for 45 minutes at Morgan Stanley’s "Pharmaceutical CEOs Unplugged" conference. He tried to assert that the ENHANCE trial was unimportant anyway as it wasn't being counted on for anything. Also, it was a study conducted in a very rare population of patients and has no implications for the general population of patients with hypercholesterolemia.

Obviously, ENHANCE was THE study designed to demonstrate that ezetimibe has an impact on atherosclerosis. Any impact at all would be nice, since no clinically relevant benefit of Ezetimibe was demonstrated prior to licensing of the agent.

Scientific malfunction is fine when studies can be deemed (in retrospect) by important CEOs to "not matter anyway".

When individual scientists conduct themselves in such a way as to cause our understanding of science to be disturbed, then (unless they are very important people) they get thrown out of science, imprisoned, and their future "findings" are not believed. The rules of participation and believability are different for corporate "science".

Schering-Plough is of course the company that writes £10,000 checks to doctors in exchange for prescribing their drugs.

Schering-Plough clearly has a record, as does Merck. The examples are many. In 1999 it was reported that deaths in clinical trials involving gene therapy were being hidden on demand from companies who were worried that it would "have an impact on their business". The Washington post reported in that "Scientists and drug companies have failed to notify the National Institutes of Health about six deaths that occurred in gene therapy experiments in the past 19 months". Researcher Ronald Crystal "cited concerns about the impact on his business if the death were made public". "Schering-Plough also had demanded confidentiality for three recently filed reports of serious patient illness during gene therapy trials. The lead scientists in two of those studies determined that the complications "probably" were caused by the gene therapy; Schering-Plough officials had downgraded those assessments." It was then reported that Schering-Plough Corporation and the University of California had done preliminary trials in dying cancer patients, but "lowered the dose when two early participants experienced serious drops in blood pressure" (Nelson, Deborah, and Weiss, Rick. Hasty Decisions in the Race to a Cure? Gene Therapy Study Proceeded Despite Safety, Ethics Concerns. Washington Post November 21, 1999: A1, A26-A27 [Link]). These were not reported, and later trial participants were not informed.

Actual people died.

Wilson (the researcher) said: "If a mistake was made, we've got to own up to it and learn from it. Ultimately, the tragedy of Jesse's death would be if we don't learn anything."

What have we learned over 8 years Dr Hassan?

As Ben Goldacre writes in Bad Science, "the data belongs to the patients who gave it to you". Our patients deserve better Dr Hassan. Science deserves better.

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Bisphosphonate induced pain in osteoporosis - statistical analysis discovered

The FDA issued an alert yesterday warning of "severe and sometimes incapacitating bone, joint, and muscle (musculoskeletal) pain" sometimes induced by bisphosphonates used to treat osteoporosis. Bisphosphonates include Actonel (Procter and Gamble) and Fosamax (Merck).

The formal statistical analysis reportedly produced by one pharmaceutical company for the FDA is shown.



Reading:

• 7 January 2008 Actonel, Fosamax, other Osteoporosis Drugs Draw FDA Pain Warning
• 7 January 2008 UPDATE 1-U.S. warns of severe pain with osteoporosis drugs (Reuters)
• Gill Sanson: Bisphosphonate Fact Sheet

According to today’s FDA warning, the severe musculoskeletal pain associated with bisphosphonates may occur within days, months, or years after starting a bisphosphonate. Some patients have reported complete relief of symptoms after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution. The risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown. The FDA recommended that healthcare professionals should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug.

Bisphosphonates have been linked to a variety of other safety problems. In October, the FDA announced that it was reviewing the drugs after studies showed patients taking bisphosphonates ran a higher risk of irregular heartbeat. Research published in the May 7 issue of the New England Journal of Medicine found that bisphosphonates appeared to increase the risk of irregular heartbeats in some older women. Researchers conducting a review of a 1997 study of postmenopausal women on Fosamax found that there appeared to be 50 percent more risk of the serious heart rhythm irregularities in women who took the daily pill than among those who didn’t take it. About half of the 6,459 women took Fosamax, and 47 developed atrial fibrillation, compared to just 31 cases among the other women.

Fosamax has also been linked to Osteonecrosis of the Jaw (ONJ), also known as Dead Jaw Syndrome, a condition in which the bone tissue in the jaw fails to heal after minor trauma such as a tooth extraction, causing the bone to be exposed. The exposure can eventually lead to infection and fracture and may require long-term antibiotic therapy or surgery to remove the dying bone tissue. In 2005, the Fosamax label was updated to include warnings about ONJ.

These are good drugs when used appropriately. However, I'm not sure that the risks and benefits (and possibility of unknown risk) have been appropriately weighed so as to allow correct, cost effective and safe targeting of therapy. We know nothing about the long term (30 year) benefits or risks of bisphosphonates.

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Bill Maher on Big Pharma

The government isn't your nanny....

"A long list of conditions which used to be rare and are now main-streamed.
Things like asthma, and autism and acid reflux and arthritis, allergies, acne, attention deficit disorder, .... and that's just the A's."

Great. Hat tip

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You owe the General Medical Council £5 - the case of Sushant Varma

Although not about medical scientific misconduct, this is directly related.

The General Medical Council (GMC) is one of several bodies in the UK charged with regulating aspects of integrity in clinical medical research. It also registers and regulates other activities of doctors. The functioning of the GMC is therefore of considerable public interest.

Also of interest is the approach of the GMC to their requirement that doctors should be truthful.

In response to a request, the GMC recently confirmed that it spent £175,000 (approximately $350,000) on external legal fees pursuing one medical student/junior doctor, Dr Sushant Varma of Sheffield (my home city).

Our ref: IAT/F1314/EH

Dear ______

I write further to your request made in accordance with the Freedom of Information Act 2000, as set out in your email below.

I can confirm that this case has cost the GMC £175,000. I should add that this does not include the time spent by GMC staff on case administration. We are unable to quantify this as we do not record the amount of time staff spend on individual cases.

If you have any concerns regarding the handling of this request please address these to:

Julian Graves
Information Access Manager
General Medical Council
Manchester M1 6FQ

Given the convoluted machinations of the GMC in this case, it's internal expenses are likely to have been a further £175,000, and considerable expenses were incurred by the Medical and Dental Defence Union of Scotland (who provided some legal support for Varma). Given the number of registered doctors in the UK (~100,000) this single case will have cost each doctor around £5.00. Meanwhile, doctors have noted the recent hike in GMC fees (from £290/year to £390). The GMC states this is "not related to revalidation reform", but rather to other "accumulated expenses" such as those incurred in this case.

Varma is a colorful character, and has certainly told some trivial lies. For example he lied on his CV about an appearance on a television show (Blind Date). He has freely admitted to those lies. He may have told a more serious lie, but the evidence for that is far from clear. The GMC apparently declined to examine relevant evidence. Varma was erased from the medical register and his career was destroyed.

Of broader importance are the precedents raised by this case, and the consistency of GMC action:

1. When can a doctor lie?
2. Are all lies of equal importance?
3. Are the status and responsibilities of the lying doctor relevant?
4. From the point of view of medical regulation, is there a difference between lies told in clinical research, lies in clinical practice, and private lies (which might reflect on the credibility of a doctor)?

To paraphrase Frank Zappa, the GMC is a body of rules, badly written and randomly enforced. What happened to Dr Varma merits some examination, as do the motives that might have led the GMC to spend such a considerable amount of our money on this one relatively trivial case.

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Scientific misconduct according to Wired

A new year, and I thought I would kick off with an irritating year-end piece from Wired magazine. On 27 December Wired ran an item reporting the supposed "10 most important scientific breakthroughs of 2007" (Wired, 27 Dec). It included this illuminating comment:

"Unlike recent years, there were no high-profile cases of scientific fraud -- none that went uncovered, anyway."

Clearly there have been no real concerns about science in this past year. The comment is revealing. It casts light on how we as a society view scientific integrity. I suppose it all depends on the definition of words. The working definition of research misconduct (scientific fraud) on this blog might be summarized as:

"Violation of the standard safeguards of scholarly scientific conduct or reckless disregard of the research process that places the scientific record at risk. It includes misleading the scientific community with regard to the confidence limits or origins or findings (irrespective of whether results are in any sense "correct"). It includes non disclosure of information that results in a distortion of the scientific record by inflating the importance of information which is disclosed. It includes any form of intentional deceit, trickery, or perversion of the truth, or use of a process known to lead to the likelihood of such perversion. It includes serious misrepresentation of any aspect of scientific method, procedure or authorship such that the relevance of findings is misunderstood. It includes violation of informed consent or improper use of information derived from the assumption of risk by other humans".

For the top 10 juiciest ethics scandals of the year, a few words might be worth mentioning for a start:

• Avandia (GlaxoSmithKline)
• Zyprexa (Eli Lilly)
• Seroxat/Paxil/Paroxetine (GlaxoSmithKline), study 329, and the ongoing "criminal" self non-investigation by the UK "regulators"
• NMT Medical and the Starflex trial
• Merck and Schering-Plough and Ezetimibe (Zetia)

I have no idea whether any of the above ethics scandals represent scientific fraud. They certainly are high profile. There have been a hundred "low profile" examples, each of which has been far more damaging to science and to human welfare than the activities of Eric Poehlman or Hwang Woo-suk. I look forward to a piece in Wired discussing their definition of "scientific fraud", of "high profile" and the way in which these ethics scandals represent (or do not represent) scientific misconduct.

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