Can we bank on trust?

In a feature today "Can We Bank on Objectivity" Patti Tereskerz looks at the rules proposed by the National Institutes of Health for dealing with financial conflicts of interest in biomedical research.

While agreeing with the article in large part, it starts from a somewhat misguided position. Take a read and see what you think.

It begins:
"Trust is the crown jewel of the research enterprise. Financial arrangements related to research that call into question the integrity of investigators or research institutions are damaging, not only because they may potentially harm research participants, but because they are associated with the appearance of impropriety. Either way, trust is compromised."

This misunderstands the nature of science. Science is, at its core, based not trust, but on it's very opposite - scepticism. Obviously, some researchers are trustworthy, whilst others are liars. But trust is about predictability - even criminals trust one another to some extent. Companies trust Key Opinion Leaders. Our perception of "what science is" limits the range of solutions we see. It also determines which problems we choose to ignore.

Mertonian ideals

Robert Merton (1973) described four norms that are prerequisites to scientific activity:

1. Organised skepticism: (Nothing is ever taken on trust)
2. Universalism: (acceptance of the integrity of research relies on its merits, and not the black/white/Jewish/Hindu status of the resercher, or whether that researcher is a funded opinion leader like Martin Keller or Richard Eastell)
3. Communalism: Sharing of information, absence of secrecy (inappropriate refusal to release data or methodological information makes work unscientific by definition)
4. Disinterestedness: (Not committed to any ideology - able to criticize and accept research based on its merits, not on a prior view that "vaccines are bad", or "doctors are corrupt")

Trust is important. Trust doesn't always work out that well.

The Gordon Brown reference

1. Macleod, Catherine (2007-05-18). Take me on trust 'Humbled' Brown pledges open and honest government. The Herald (Scotland).

Hat tip: Professor David Healy

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ORI Research misconduct survey reports the obvious - again

The Office for research integrity has just published a survey in Nature.

Sandra L. Titus, James A. Wells Lawrence J. Rhoades (2008-06-19). Repairing research integrity. Nature. 453, 980-982.

The survey suggests that most research misconduct in the United States is unreported to the ORI. Furthermore, fraud is not rare.

The US National Academy of Sciences has asserted that scientists share an 'obligation to act' when suspected research misconduct is observed. However the reported number of investigations submitted to ORI has remained low: on average 24 institutional investigation reports per year.

"The 2,212 researchers we surveyed observed 201 instances of likely misconduct over a three-year period. That's 3 incidents per 100 researchers per year. A conservative extrapolation from our findings to all DHHS-funded researchers predicts that more than 2,300 observations of potential misconduct are made every year. Not all are being reported to universities and few of these are being reported to the ORI."

"These numbers indicate a sizeable disconnect between what universities are seeing and the 24 investigations evaluated by the ORI annually."

There is a leadership problem, whitewashing, bullying, and sham investigation.

The leaders of institutions may also have concerns about handling research misconduct. Because public image is important to institutions, some may try to minimize reporting and keep unfavourable information from reaching the ORI and the press. An institution may choose to ignore conducting an investigation and instead they may simply dismiss an accused person or even a whistleblower in the hope that the problem will go away without needing further examination. Additionally, institutional leaders may wish to ignore or minimize allegations of possible research misconduct to protect the revenue that the researcher generates; some may avoid investigations because they are costly in terms of time and money.

The paper makes six recommendations

1. Adopt zero tolerance. Social responsibility to the academic community and to the public who fund the research will be strengthened when it is apparent that an institution has a real commitment to integrity.
2. Protect whistleblowers: 43% reported that institutions encouraged them to drop the allegation.
3. Clarify how to report
4. Train the mentors
5. Use alternative mechanisms
6. Model ethical behaviour: People imitate the behaviour of powerful role models. Institutions successfully stop cheating, for example, when they have leaders who communicate what is acceptable behaviour, encourage faculty members and staff to follow the policies, develop fair and appropriate procedures for handling misconduct cases, focus on ways to develop and promote ethical behaviour, and provide clear deterrents that are communicated(McCabe, D. L., Trevino, L. K. & Butterfield, K. D. 2001 Ethics Behav. 11, 219–232).

The conclusion is:

"Our study calls into question the effectiveness of self-regulation. We hope it will lead individuals and institutions to evaluate their commitment to research integrity."

There are some problems here. Much serious fraud takes place at the commercial-academic interface with the acquiescence of government. The ORI has no role here. Furthermore, carefully evolved re-definitions of fraud have made it difficult to deal with the most serious instances of fraud. The ORI fails to comment on most cases of fraud which arise.

So much for leadership, role models and the rest.

Despite the appropriate conclusions, the study adds nothing beyond the long trail of other ignored studies which have reported the same. This is a never-ending loop of many roads leading from nowhere to nothing. It's all a heady mix of righteous indignation, hand sitting and some occasional wrist slapping.

So let's say it again:

1. Research fraud is not rare.
2. Investigation of fraud is a sham
3. Fraudsters are usually shielded from criticism except for the occasional random punishment that maintains the illusion.
4. Those who state the obvious are abused.
5. Official integrity bodies and regulators are entirely useless and are often complicit.
6. It is not necessary to conduct research to demonstrate the obvious. In the pharmaceutical arena the list is endless (Vioxx, Avandia, Zetia, Actonel).
7. In each and every instance there are attempts at cover-up, serious damage to the public and damage to science.
8. Most importantly, there is failure of the very organizations who claim to act as guardians of integrity to open their mouths.

It reminds me of the very old story of the Officer and the Thug

OFFICER AND THUG

A CHIEF OF POLICE who had seen an Officer beating a Thug was very indignant, and said he must not do so any more on pain of dismissal.
"Don't be too hard on me," said the Officer, smiling; "I was beating him with a stuffed club."
"Nevertheless," persisted the Chief of Police, "it was a liberty that must have been very disagreeable, though it may not have hurt. Please do not repeat it."
"But," said the Officer, still smiling, "it was a stuffed Thug."
In attempting to express his gratification the Chief of Police thrust out his right hand with such violence that his skin was ruptured at the armpit and a stream of sawdust poured from the wound.

He was a stuffed Chief of Police.

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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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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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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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Ezetimibe (Zetia, Vytorin): the smell of bad science

Concerns are brewing over strange events, quack science and possible scientific misconduct during reporting of the "Enhance" trial of the cholesterol-lowering drug Ezetimibe[1][2][3][4][8]. Ezetimibe is sold by Merck and Schering-Plough (trade names Zetia and Vytorin with annual sales of $4billion). No trials have shown that Ezetimibe reduces cardiovascular events (the main endpoint). No such trials were required prior to FDA approval. The drug does however lower the bad form of cholesterol (LDL).

I personally have no problems with drug approval in the absense of evidence of efficacy, so long as customers (doctors and patients) are not misled. Its a free world. I guess all patients have been told that a) the relationship between LDL lowering and actual clinical disease is not straightforward, b) that some drugs lower LDL but increase risk, c) that the relevant science prescribers have been permitted to see is a sack of potatoes.

The "Enhance" study of Ezetimibe was supposed to look at a surrogate endpoint that is one step closer to actual cardiovascular events - namely the development of atherosclerotic arterial plaques. So what happened?

• Oddly the reporting of "Enhance" was put off by a year, and it is now planned to remove the shroud of secrecy sometime in 2008 (possibly.....). Cardiologists expected to see results at a medical meeting in November 2006, then at another in March 2007, then at another this month. But none materialized [8].
• It turns out the companies have decided to change the study's primary endpoint in retrospect. To convince everyone that this is the right thing to do, they brought in an "outside" expert advisory "panel" who concluded that the wrong thing is the right thing (presumably for a fee). They then refused to state who these supposed experts were.
• It turns out that the company has had full control over all of the study data and that the lead "author" has not yet seen any of it.
• Lead investigator of the study, Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands)stated that "The suggestion that the results are being suppressed because they are negative is simply wrong. People are assuming that anyone can take a peek at the data, but how can they do that if it hasn't even been unblinded and there are 40 000 images to analyze?"

With respect Dr Kastelein, the assertion that altering endpoints before unblinding cannot cause bias is obvious and utter nonsense.

1. Firstly, we have no confidence (P=0.3) that the study has not in fact been secretly unblinded. This lack of confidence is the logical assumption following numerous odd events and data alterations which have taken place in the past (random examples here[5][6]). Unblinding codes are presumably held by the same entity holding the raw data (I guess). That same entity has a huge financial stake in the outcome. That entity is not yourself Dr Kastelein. Nor is that entity a secure impartial honest third party (a complete guess).
2. Secondly, as an experienced scientist you will be fully aware it is perfectly easy to fiddle the results of a randomized trial given a "blinded" study database even without the un-blinding codes. Ezetimibe has many side "effects" that distinguish it from placebo apart from it's intended clinical benefit (LDL lowering is itself such a "side effect"). It would be easy for an individual "exploring" the data to examine the relationship between LDL lowering and various "primary endpoints" without unblinding to get a pretty good idea of the "primary" endpoints to reject, exclusion criteria to be applied, or even the variables that might require a little "recoding".

There is no certainty here, but strange events have taken place on a sufficiently regular basis for the confidence limits to be wide (P=0.3). The smell is not one of science Dr Kastelein. I'm glad you expressed unease with the process, and queried the mysterious need to alter the endpoints. Word is that you are one of the honest people. I believe you should go the whole way, and stand up for honest science and integrity. You might also make some comment about the need for company statisticians to be involved with the data at all.

Others [4] have pointed out some of the key problems with this research, and I have added a few more:

1. Seek to get your drug on the market before we know whether it actually makes us live any longer or prevents real disease.
2. Keep all the data under your strict control; don't even let the (so-called) lead investigator see it.
3. Change the primary study endpoint in the middle of the trial.
4. Pretend that this is science.
5. Keep all the processes as secret as possible at each step of the way.
6. Conduct studies that focus on patients who are not at all representative of the intended target customer for the drug.
7. Pretend that you are a company based on science, but at the same time pretend out loud that altering data or endpoints in a still-blinded study cannot possibly be a means to induce bias.

If you are a patient taking one of these drugs, go ask your prescriber for a summary of the scientific evidence. Alternatively pay a visit to your nearest homeopath (an Ouija board may also prove useful).

References:

1. Hughes, Sue (2007-11-23). Concerns Raised on Delay of Ezetimibe Data. Medscape/Heartwire.
2. Merck/Schering-Plough Update on ENHANCE Trial. Merck Website.
3. Berenson, A (2007-11-21). After a trial, silence Page C1. New York Times.
4. Brody, Howard (2007-11-24). Here We Go Again: Everything That's Wrong with Industry Sponsored Trials. Hooked: Ethics, Medicine, and Pharma.
5. Blumsohn, Aubrey (2007-10-21). Vioxx and a quacking duck. Scientific Misconduct Blog.
6. Blumsohn, Aubrey (2007-05-19). On the redefinition of research misconduct. Scientific Misconduct Blog.
7. Berenson, Alex (2007-11-24). Cardiologists Question Delay of Data on 2 Drugs. New York Times.
8. Herper, Matthew (2007-11-19). Drug Trials: The Vytorin Question. Forbes. Retrieved on 2007-11-27.

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Memory Hole (11 November): UK Government hides clinically relevant science

Scientific Misconduct Blog Memory Hole: Events of November 11th

7 years ago today: UK government hides clinically relevant science

On 11 November 2000 a BBC report indicated a deliberate attempt by the UK Department of Health to hide science and to mislead the public and doctors - a case of scientific misconduct perpetrated by government.

If there was scientific evidence relating to potential transfer of mad cow disease (vCJD) through improperly cleaned surgical instruments would you want your doctor to know? According to a report by BBC Panorama the UK government tried to hide a scientific report that it didn't like. The report suggested that there is a real risk of spreading vCJD via surgical instruments. The report also revealed serious flaws in hospitals' equipment cleaning procedures.

Kate Priestley, Chief Executive of NHS Estates NHS Estates (an executive agency of the Department of Health) ordered microbiologist David Hurrell to destroy all copies of the report "It asked me to destroy or return all the copies of the reports and draft reports and data that I had got and to delete all electronic files." Here is a letter:



BBC Panorama stated "A senior expert on hospital decontamination methods has told Panorama how he was asked to destroy all evidence of a government-commissioned study into standards of decontamination in English hospitals."

The letter read: "In light of the somewhat negative outcome... there is a need to ensure, at the express request of ministers, that the final version and earlier draft reports remain strictly confidential." The benefits of the study "may be compromised if the findings of the report were to enter the public domain in an inappropriate or unauthorised fashion".

Professor Michael Banner who led the team of experts was not allowed to see part of the decontamination report either. Banner says, "It's really quite absurd and unbelievable that the document has not been made available... It's astonishing that anyone would wish to hold back information from the public about the state of hospitals."

Panorama asked the Department of Health three questions:

1. Why has Michael Banner, Chair of the Incident Panel, been refused sight of the report?
2. Why, if this was only an interim piece of work not considered for publication, was consideration given to which photos might be used for the cover of the final report last summer?
3. Why was it decided, in the light of the somewhat negative outcome of the report and at the express request of Ministers, that the final version and earlier draft reports remain strictly confidential?

The Department of Health replied saying only that this line of questioning was "silly". Panorama then asked why "if they were so silly, were many of the people involved in the report being telephoned on Friday and asked not to talk to Panorama?" This is a disgrace. Alan Milburn was the Secretary of State for Health at the time.

See also: BBC: Ministers sought to bury vCJD report; http://darrendixon.supanet.com/cjdreport.htm

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Memory Hole (10 November): What else happened

Scientific Misconduct Blog Memory Hole: Events of November 10th

1 years ago today: Statins decrease cholesterol by 0.13mmol/L

On 10 November 2006 a paper in the Journal of Internal Medicine (260; 551) reported that average cholesterol levels had fallen considerably in Swedish men between 1986 and 2006 - from 6.32 to 5.51 mmol/L. Almost none of this decrease was due to statins. Fewer than 10% of people were a lipid lowering drug, and these accounted for only 0.13 mmol/L of the population decrease.

2 years ago today: GSK: Our product is.......

On 10 November 2005 Chris Viehbacher, head of U.S. operations at GlaxoSmithKline Plc, was quoted as saying "In the long term Glaxo would like to spend a lot more on researching new medicines and a lot less on selling them".."So far we haven't found a more effective way of educating physicians."

The product is science.

Chris Viehbacher is an accountant. I have seen no comment from Viehbacher on any possible deception in GSK drug trials, or those trials that disappeared. Perhaps Silence is part of the "education".

Source: Hirschler, Ben. "Drug giants wary on cutting sales forces", Reuters, 2005-11-10.

3 years ago today: Pfizer and Bextra - optional truthfulness

On 10 November 2004 Pfizer entered the scientific debate over their hidden Bextra data - by abusing critics.

Cardiologist Garret FitzGerald reported a pooled analysis of clinical trial results showed patients taking Pfizer's arthritis drug Bextra were twice as likely to have a heart attack or stroke as those taking a placebo. When reports appeared in the New York Times, instead of addressing the science Pfizer attacked back. The report they said "draws unsubstantiated conclusions about the cardiovascular safety of" Bextra and "is based on information that has not been published in a medical journal or subject to independent scientific review."

Their product is science but there was no science in the response. Five months later on April 7, 2005, Pfizer withdrew Bextra from the U.S. market.

Pfizer has since disclosed that, at the time of those statements, it did indeed have studies that demonstrated heart problems among patients taking Celebrex or Bextra. When a Pfizer scientist said that there was no clear evidence that Celebrex posed a risk, members of the FDA committee stated: "That just doesn't pass the laugh test" (Dr. Alastair Wood, chairman of the hearing). Wood noted that Pfizer omitted from its presentation the key study that documented problems with Celebrex. One panel member accused Pfizer of hiding data. Dr. Curt Furberg of Wake Forest University stated "I'm troubled by some inconsistencies that I have found in the briefing document from Pfizer." Furberg suggested that all of Pfizer's mistakes seemed to benefit the company. "So I wonder how much trust can we put in these presentations" he said.

Professor Ralph D'Agostino told the committee "We really don't know what to make out of any long-term use" based on Pfizer's studies that lasted only a few weeks". Dr. Verburg of Pfizer responded simply, "We recognize all of the faults in what we are doing"

Dr. Byron Cryer of the University of Texas Southwestern Medical Center, described part of the Pfizer presentation as "misleading." Dr. Verburg of Pfizer responded simply, "Point taken."

But the point Dr. Verburg is that this is quackery and bad science. Perhaps it is not science at all. People die as a result.

Sources:
See FDA report 7 April 2005 http://www.fda.gov/cder/drug/InfoSheets/HCP/valdecoxibHCP.htm
Systematic review of Bextra in JAMA http://www.cox2drugreview.org/
Medical Panel Poses Pointed Questions to Drug Makers Over Risks of Painkillers, New York Times 17 Feb 2005

5 years ago today: UK Labour government brings integrity to the NHS

On 10 November 2002 the UK government Health Secretary Alan Milburn was criticized for hiring the American private insurer United Healthcare to help "cut costs in the NHS by keeping the elderly patients out of hospital".

As the Observer "discovered" without much difficulty "United Healthcare has been forced to pay millions of dollars in fines to settle charges that it had defrauded the US government, patients and doctors", had "falsely charged the US government for patients it claimed were in nursing homes" by inventing institutionalized patients, and had been fined for "cheating patients out of money". The firm had also been "failing to give proper notice of the right to appeal" when denying patients healthcare, and Michael Mooney, a United vice-president, was jailed for three and a half years for insider trading.

About time New Labour started saying the unthinkable and admitting their moral and intellectual bankruptcy in the area of healthcare and medicines regulation.

Milburn apparently holds a place on the board of PepsiCo. On 28 February 2007, he launched 2020 Vision, a website intended to promote policy debate (well debate then). There is a Chinese saying, "a fish begins to smell from the head down..."

Source: UK's elderly care plan run by US "cheats", the Observer, Nov 10

4 years ago today: Another P&G spying case

On 10 November 2003 Procter and Gamble were exposed in the Chicago Sun Times for their involvement with Wallmart in an escapade which involved spying on customers. Briefly, Lipfinity lipstick was tagged with an electronic (RFID) tracking device between March and July 2003. Customers unwittingly left the store carrying the tag.

At the same time a live video camera trained on the shelf allowed Procter & Gamble employees (700 miles away) to observe and videotape the Lipfinity display and consumers interacting with it. "Given the players, the Wal-Mart Lipfinity trial probably isn't an isolated incident," says CASPIAN spokeswoman Liz McIntyre. "documents suggest that other products, including Huggies baby wipes, Pantene shampoo, Caress soap, Purina Dog Chow and Right Guard deodorant were also slated for live RFID field trials".

In P&G's defense it could be said that the video material was apparently not kept, and the videos were mostly of the back of customer's heads. Bizarrely, it was also stated that "the test was not secret. There was a sign near the Lipfinity display that alerted customers that closed-circuit televisions and electronic merchandise security systems are in place in the store."

In 2006 P&G's received first prize in the annual Most Trusted Company for Privacy Award. They consolidated their position that year by releasing the long-denied raw data to researchers who had "authored" schlonky publications about their osteoporosis drug Actonel. Onwards and upwards.

See: more on RFID devices

8 years ago today: Scientific fraud involving three drugs - prison anyone?

On 10 November 1999 an editorial in JAMA discussed ondansetron, a drug that was being studied to prevent vomiting. Researchers analyzing the literature found 84 studies involving 11,980 patients -- or so they thought. Some of the data had been published twice, and when the researchers sorted it out, they realized that there were really only 70 studies, in 8,645 patients.

Since the duplicated data was the good data, the reviewers estimated this double-counting would lead to a 23 percent overestimate of the drug's effectiveness.

Similarly data for the antipsychotic agent risperidone had been published multiple times in different journals, under different authors' names.

Other problems involving fluconazole (made by Pfizer) were reported. Fluconazole had been compared with Amphoteracin B, but on close inspection it appeared that the Amphoteracin had been given by mouth instead of intravenously (it is not at all effective orally and is supposed to be given by drip).

Dr. Michael O'Connell, deputy director of the Mayo Clinic Cancer Center in Rochester, Minn., an expert on clinical trials, said: "To publish the same data again with entirely different authorship, as if it were an entirely different data set, is reprehensible".

The problem is that the authors of the papers probably didn't even know, because they had almost certainly never seen the data, and were just brain-dead drones and fraudsters.

The reviewers tried to ask the authors about the design of the studies and for the data. Some ignored the requests, and others said they no longer had the data. Pfizer declined comment to JAMA.

Dr. Bert Spilker, senior vice president for scientific and regulatory affairs at PhRMA, the lobby group for drug manufacturers, said: "We don't have a perfect situation. It probably can be improved." Scientific fraud is not "a perfect situation" when your industry is supposed to be selling products under the banner of science. When patients die as a result of faulty misleading science it is obviously not "a perfect situation" either. As usual, nobody was held to account.

See: Medical Journal Cites Misleading Drug Research, NY Times, 10 Nov 1999

16 years ago today: A company employs "traditional and standard" methods to avoid exposure

On 10 November 1991 the New York Times reported on the way in which one powerful industry thought it was the government, gestapo secret police and the law rolled into one. It raised questions about the lengths to which powerful individuals will go to silence critics and avoid embarrassing disclosures. Although not about scientific misconduct, it is related to the corporate scientific crimes discussed here.

When Trans Alaska Pipeline felt in 1990 that confidential company documents had been taken and conveyed to regulators it hired Wackenhut Corporation.

"For three years in the late 1980's, the owners and operators of the 791-mile-long pipeline had been a target of the unrelenting criticism of a former oil broker from Virginia named Charles Hamel. Mr. Hamel, who was battling several oil companies in court, became a conduit for leaked documents about lapses in Alyeska's environmental and safety programs. The documents turned up in the hands of regulators and the news media, resulting in large fines and millions of dollars in expenditures by Alyeska to fix the problems. With unlimited funds supplied by Alyeska, Wackenhut hired highly trained investigators, bought sophisticated eavesdropping equipment, and set up a sting operation to induce Hamel to disclose his sources."

1. Wackenhut's investigative net stretched from Alaska to Florida to Washington
2. Miniature cameras were installed in hotel rooms in Alaska.
3. Trash was rifled at Mr. Hamel's home.
4. Motorized vans with electronic devices intercepted conversations for recording.
5. Using phony credentials from a fake environmental law group, Wackenhut's agents befriended Hamel, who invited them into his home, where they stole documents from his desk.
6. When Hamel talked with the House Interior Committee and its chairman George Miller, Wackenhut's agents and Alyeska's lawyers considered targeting him as well.

George R. Wackenhut, the company's founder and chairman said the actions taken to prevent the public from finding out were entirely legal and "traditional and standard".

Source: "A Case of Heavy-Footed Gumshoes" New York Times, 10 Nov 1991

17 years ago today: Plagiarism at Boston University

On 10 November 1990 it was reported that substantial parts of the late late Dr. Martin Luther King, Jr's doctoral dissertation and other academic papers from his student years appeared to have been plagiarized.

"analysis of the papers by researchers working on the project had uncovered concepts, sentences and longer passages taken from other sources without attribution throughout Dr. King's writings as a theology student." "scholars who have seen the papers declined to say how great a percentage of the material had been plagiarized, but they said it was enough to indicate a serious violation of academic principles."

Officials at Boston University stated that it is not likely the Ph.D. would be revoked "because neither Dr. King nor his dissertation adviser is alive to defend the work".

Source: DePalma, Anthony. "Plagiarism Seen by Scholars in King's Ph.D Dissertation". New York Times, 10 November 1990.

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Memory Hole (8 November): Mostly about lawyers

Scientific Misconduct Blog Memory Hole: Events of November 8th

Definitions of the day

LAWFUL, adj. : Compatible with the will of a judge having jurisdiction.
LAWYER, n. : One skilled in circumvention of the law.
LITIGANT, n. : A person about to give up his skin for the hope of retaining his bones.
LITIGATION, n. : A machine which you go into as a pig and come out of as a sausage.
(The Devil's dictionary)

23 years ago today: Arthur Rudolph: US hides Nazi crimes

On 8 November 1984 it was reported that Arthur Rudolph imported from Nazi Germany to head the NASA Saturn Program (which led to the moon landing) was known to be an "Ardent Nazi" and a war criminal. He was operator of a slave camp. More importantly, the US knowingly provided cover for him. This is directly relevant to the more specific concerns on this blog - it concerns the role of government in a democracy.
"Papers Show Saturn Rocket Chief Was Called 'Ardent Nazi by U. S.": New York Times, 8 Nov 1984.

14 years ago today: Inventing scientific findings is not fraud say lawyers

On 8 November 1993 the muddle of Scientific Misconduct "rules" reached the outer limits of farce
(Hilts, Philip J. "Science and Law Clash Over Fraud-Case Appeals," New York Times, 8 November 1993).

Procedures of science are designed to ensure the integrity of the scientific record, just as court procedures are designed to make sure that the legal game is played. This is an article about attempts to alter the procedures for deciding whether a scientist is operating within the rules of science. This was the midst of the Baltimore and Gallo "investigations". New rules were put in place by Bernadine Healy when director of the NIH to make lawyers the judge of appropriate science, radically altering the game in retrospect, and leading to these two cases being "lost" (at least legally).

"In the first case before the hearing board under the new rules, Rameshwar Sharma, a scientist at the Cleveland Clinic Foundation, was charged with making false statements in an application to the National Institutes of Health. He wrote that he had done a series of experiments and described the results, when in fact he had not done the work."

By any definition that would constitute research misconduct and a major offense against science, the public, and patients. This is not a game, and it is exactly how patients die.

In his defense, he said that he no intent to deceive but that his statements were 'anticipator writing' because he expected to do the work later. The hearing said this was not misconduct because the Office of Research Integrity could not prove the deliberately false statements were intended to be false. The need to prove intent is part of the new definition. Falsifying results does not constitute intent.

This is lawyers and the "big boys" of science saying that saying that science and honesty don't matter. The muddle began here.

Source: Hilts, Philip J. "Science and Law Clash Over Fraud-Case Appeals" New York Times, 8 Nov 1993

10 years ago today: UK "initiatives" to tackle scientific misconduct

The Journal Science published a bit of reality-free gobbledegook about a November 8th 1997 meeting concerning UK initiatives to "tackle scientific misconduct and fraudulent publication in a more systematic way". There is a disconnect between what folk say and what they fear to do.

Williams, Nigel. "Editors Seek Ways to Cope With Fraud" Science 278 (14 November 1997), p. 1221 [Full report].

Some quotes from the article:

• A new committee, set up by the editors of nine prominent medical journals called last week for governments to tackle scientific misconduct and fraudulent publication in a more systematic way.
• Cases are still exposed mostly by chance, and we worry about the scale of the problem
• "Normal peer review can sometimes identify problems, but sorting through raw data to investigate them can be a miserable business".
• These incidents were described without revealing names because of worries about libel laws [describing scientific deviations is libel]
• The meeting backed calls by one of the legal experts on the committee, Ian Kennedy of University College London, for the development of a protocol for editors to help protect genuine whistle blowers.
• COPE's efforts are being matched by other initiatives in Europe.
• And at the most recent meeting of the European heads of research councils in Dublin last month, the problem of scientific misconduct was at the top of the agenda.
• The council heads are looking in particular at Danish efforts that have culminated in a new national committee on scientific dishonesty. Unlike the U.S. Office of Research Integrity, which can investigate misconduct claims only when they involve government funds, the Danish committee can work across the scientific spectrum.
• Editors can only go so far," says Kennedy. "Eventually you need an independent body to investigate claims fairly.

So what happened ten years later?:

See:
http://scientific-misconduct.blogspot.com/2007/10/memory-hole-15-october-uk-research.html
UK research misconduct Hit-Squad announced (UK-PRI)

Self quotation: You should treat any offer of support from UK-PRI in the same way you would treat the offer of fellatio from a crocodile.

8 years ago today: German Professor fakes 80 clinical studies - not a crime

On 8 November 1999 German investigators report that dozens of bogus scientific papers were published by a cancer research professor over 15 years.

The Professor was Friedhelm Herrmann, a leading cancer research specialist. The report states that "at least 80 of his published papers were faked", and "they developed an aversion to using genuine data."

The last sentence of the news report states: "Faking scientific research, however, is not a criminal offence under German law".

Source: German scientist 'faked cancer research', The Guardian, Nov 8, 1999

4 years ago today: Medical journal editors colluding with fraud

On 8 November 2003 there were some choice quotes from a BMJ article: Have editors got their priorities right? (BMJ 327:1113; 8 Nov 2003):

"Journal editors are much more frightened of being sued for libel by academics or drug companies than they are of publishing fraudulent research" Peter Wilmshurst claimed last week.

He said that every time that he submitted an article highlighting research fraud, every word was scrutinised by an army of libel lawyers and the article was frequently rejected.

"I have submitted many scientific articles for publication and many had implications for survival of patients, but no journal has ever asked me to prove that I got the results claimed. This might suggest that medical journal editors are more concerned with the reputations of academics and their institutions than the lives of patients.

"The simple truth is that editors are most concerned with money. Journals are never sued for publishing false results no matter how many patients died. In scientific research they can have the best of both worlds. They are absolved from blame if a study is wrong and gain an improved impact rating if the research is an important advance..."

"I would like to see whether the policies at journals changed if some were sued by patients harmed by implementation of treatments based on their publications."

"I believe that there should be random checks of raw data of work in progress and of submitted work. We know that the use of performance enhancing drugs is common in competitive sports because of enforced drug checks without warning at sporting events and between events. If we did not have these checks we might mistakenly conclude that doping was not common in sport."

"Failure to produce the raw data should be considered the equivalent of failing the inspection and should result in a ban on future research for a specified period and a review of previous research published.

"The code of silence that pervades the medical profession and the research establishment: There is still considerable reluctance to shop another doctor, no matter how dishonest".

2 years ago today: SSRI advertisements not exactly science-based

On 8 November 2005 PLoS medicine published as article titled: "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature" (Lacasse JR, Leo J 2005 PLoS Med 2(12): e392).

Apparently direct to consumer advertisements for drugs are not exactly truthful. What a surprise. Next episode - the disconnect between the scientific literature and the underlying raw data. Hat tip HCR.

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Memory Hole (1 November): The case of Philip Felig

Scientific Misconduct Blog Memory Hole: Events of November 1st

29 years ago today: Philip Felig - an important misconduct case begins

Around 1 November 1978 Helena Wachslicht-Rodbard submitted a publication to the The New England Journal of Medicine. The article concerned insulin receptors in patients with Anorexia. What followed became a case study in research misconduct, its definition and the typical reality of its handling.

The following is an abstracted summary of a compelling article on the affair from the New York Times of 1 Nov 1981 ("A fraud that shook the world of science").

NEJM sent the article out for peer review. Two reviewers recommend acceptance subject to revision, and one recommended rejection. Wachslicht-Rodbard began the process of revision. While revising the manuscript, Wachslicht-Rodbard received a rather similar paper from The American Journal of Medicine to review. That paper was written by Vijay Soman and his very famous superior, Philip Felig, of Yale. On reviewing the manuscript she found that it looked like her own. Some paragraphs were identical to those in her article and an equation she had devised to calculate receptor numbers was identical. Moreover it appeared that the authors of that paper had been the very reviewers who had recommend rejection of her own unpublished manuscript.

Felig admitted that he had received the manuscript for review, and had passed the paper onto his junior Soman. He did not regard this as inappropriate, and in terms of his rejection of the competing Wachslicht-Rodbard manuscript felt this was "touch and go who got priority" and that "the issue of conflict of interest needed consideration."

Wachslicht-Rodbard wrote to Relman at the NEJM accusing Soman and Felig of plagiarism.

Wachslicht-Rodbard became increasingly incandescent as it appeared that nothing of substance would be done and that the respective institutions were attempting a quiet cover-up. She noted that her own superior had tried to shut her up, and that she was ordered to stop using N.I.H. stationery and time to pursue her grievance. She stated that she was threatened with dismissal.

Soman admitted that he had kept the Wachslicht-Rodbard paper and had copied some of it, including the equation. Felig stated that "I severely reprimanded him for this".

Time went on. Wachslicht-Rodbard became increasingly angry and wrote to Dean Berliner of the Yale School of Medicine expressing doubts about the whole Soman-Felig paper, asking whether the study had been done at all. Felig himself however looked no further and simply stated that there was no problem. Berliner simply accepted this reassurance, and wrote to Wachslicht-Rodbard: "There is no question that the studies of Soman and Felig were done as described in their manuscript" and that he hoped she would consider the matter closed.

She refused. She stated that she would publicly denounce Soman and Felig at a scheduled scientific meeting. It was then agreed that the Soman+Felig paper would be "audited". In the meantime Wachslicht-Rodbard, totally disillusioned, resigned from the NIH, and left research.

Felig selected an "independent" auditor himself. Weeks passed, and nothing happened. However, Felig was then appointed Samuel Bard Professor and chairman of the Department of Medicine at Columbia, a key position. The Wachslicht-Rodbard charges were still confidential and those awarding the post had not been told anything. Felig felt the storm had passed, took Soman along to his new post, and recommended that Soman be appointed assistant professor.

The challenged Soman-Felig paper then appeared in the American Journal of Medicine that very month despite all questions remaining unanswered. Wachslicht-Rodbard was furious and suggested that a new "auditor" be found. New and strange problems were found with the paper (though the conclusions were identical to who own). For one thing, neither the psychotherapists nor the hospital where the studies had been done were named. A graph appeared to have been invented, with data falling neatly on a curve in an impossible manner.

An investigator (Flier) was appointed. Soman then claimed to have thrown away his raw data from the just-published manuscript. The investigator became suspicious. What raw data was available bore no relation to the paper. Soman then admitted to having invented most of the data. At least one of the six participants did not exist. Soman agreed to resign. The Soman-Felig paper would have to be retracted. All of his previous papers would have to be examined - but not to examine them would be far more scandalous.

Felig wrote apologetic letters. However, he did not inform his new prospective employers apart from vaguely mentioning the issue "in the course of discussing other things".

None of Soman's papers could be reconstructed from underlying data. Of 14 papers by Soman and others most appeared to have been fraudulent. Felig was a co-author, along with others, of most of these papers. Felig could no longer constrain the discussion and stories were circulating. Letters of retraction were sent to journals for 12 papers emanating from Yale Medical School, eight co-signed by Felig were retracted.

Felig met with his new employers but told them only of Soman's falsifications. He told nothing about the plagiarism, his rejection of the competing manuscript, or his failure to "discover in the course of a year what [the investigator] had been able to find out in three hours". He had not bothered to show any integrity. He simply moved to New York and started his new post. The rumors reached his new employers and everything Felig had not revealed was made available. A committee was established to review Felig's actions. It was concluded that Felig had failed to communicate incriminating information about himself.

"The Committee must conclude that the events disclosed by the correspondence, and Felig's attitude when asked about these events, reflect ethical insensitivity and the application of unacceptable standards to scientific research." The committee concluded "with the deepest regret" that Felig should not retain his professorship and posts at Columbia.

Felig was fired. But having not been himself guilty of fraud, he returned to Yale and even got some grants.

Helena Wachslicht-Rodbard decided never to return to research.

This all begs the question - what is scientific fraud? What of pretend naivete over the usual norms of scientific behavior? Felig in retrospect felt it was a "mistake" not to investigate his junior colleague's work. "I can't make sense of it. I consider the actions of the people at Columbia so outrageous that I have never been able to explain them in my own mind".

What of actions that are not fraud (as narrowly defined), but are otherwise grossly inappropriate and incompatible with the business of being a scientist? What of the whistleblower who was silenced and ignored? What of the deliberate failure to examine simple questions when it would seem mandatory to do so? What of the collusion with colleagues to "smooth" things over. If actions are not defined as fraud then they are clearly OK.

Source: Abstracted Summary of "A fraud that shook the world of science" - New York Times Nov 1 1981
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Memory Hole (29 October): Redefining scientific misconduct

Scientific Misconduct Blog Memory Hole: Events of October the 29th

Quote of the day

It is sayd there be a rage of mountaynes in the Easte, on one syde of the which certayn conducts are immorall, yet on the other syde they are holden in good esteeme; wherebye the mountayneer is much conveenyenced, for it is given to him to goe downe eyther way and act as it shall suite his moode, withouten offence.
Gooke's Meditations

15 years ago today: Lead studies and the Needleman case

On 29 October 1992 after a decade of debate two new studies of lead levels and IQ in children were reported. One by Baghurst showed impairment in neurological development as lead rose from 10 to 30ug/dL. Another by Bellinger showed significant IQ deficits over a similar range. Previous studies had been challenged repeatedly by industry.

Other studies had not properly controlled for confounding variables (such as maternal IQ) and had therefore been "rejected". Psychologists Claire Emhart and Sandra Scarr hired by the owners of a lead smelter had accused Herbert Needleman of research misconduct following his landmark - but flawed - 1979 study in NEJM. Needleman had in turn (wrongly in my view) refused skeptics access to his raw data. Industry have every right to query scientific findings (just as industry has an obligation to reveal raw data supporting scientific statements).

Source: "Study Documents Lead-Exposure Damage in Middle-Class Children," New York Times, 29 Oct 1992

14 years ago today: A missed ball in scientific misconduct

On 29 October 1993 the journal Science discussed the attempts to frustrate the efforts of the US Office for Research Integrity (ORI) to bring fraudsters to book. The appeals process were insisting that the ORI must prove a) intent to deceive, b) that the false statements were important to the thrust of research claims.

Herein lies a large problem. There are many real-world examples of serious scientific misconduct that make this appear ludicrous. It also presupposes that scientific misconduct must involve the making of false statements. This attempt at narrow redefinition may have had much to do with attempts to protect Gallo and Baltimore at the time. None of this goes back to the purpose of defining misconduct in the first place.

Murder (intentional killing particularly with premeditation) is a crime. So is carrying a loaded gun on an airplane. There is no proof of intent to kill, but there is intent to breach an agreed contract. That is how society protects itself. Here we have lawyers saying that the contract of science is irrelevant to them.

It is sayd there be a raunge of mountaynes in the Easte, on one syde of the which certayn conducts are immorall, yet on the other syde they are holden in good esteeme; wherebye the mountayneer is much conveenyenced, for it is given to him to goe downe eyther way and act as it shall suite his moode, withouten offence.
Gooke's Meditations

Source: "Another Blow for ORI" Science 262 (29 October 1993), p343

13 years ago today: More on the scientific failures in NIH fialuridine case

On 29 October 1994 it was revealed that knowledge of previous hidden studies would have prevented the deaths of patients that occurred in a hepatitis drug trial carried out by Dr. Jay Hoofnagle at the NIH (see Memory hole 23 Oct).

In brief, a clinical trial ended in catastrophe - with the iatrogenic deaths of five participants. The drug was fialuridine, to treat hepatitis B. 5 of the 15 patients who took the drug died, and two more required liver transplantation.

There are comparisons with the regulatory and scientific disaster involving TGN1412 in the UK in that multiple patients were exposed to an "unknown".

Dr. Jay Hoofnagle, the principal scientist in the NIH study had stated that he thought some patients' symptoms were associated with the underlying illnesses, until the deaths began to occur.

Now it is revealed that dangerous side effects in at least two other studies, and four deaths in earlier experiments were not reported to the F.D.A. The FDA stated that "overview of the data, in which deaths and serious adverse experiences were analyzed cumulatively, was not produced and thus was not available" to scientists carrying out the study or to the Government.

Nothing learned in 13 years.

Patients don't matter much in all of this.

Source: "Speed of F.D.A. Action on Rules for Drug Tests is Questioned" New York Times, 29 Oct 1994

8 years ago today: The decline of Dr Koop

On 29 October 1999 a further scandal was revealed involving Dr. C. Everett Koop, the former US Surgeon General.

In spring 1997 Koop made a telephone call to Dr. Linda Rosenstock, director of the National Institute for Occupational Safety and Health. "The agency was about the warn health workers that latex gloves could cause serious, even life- threatening allergic reactions. Dr. Koop told her that the language was "way overstated" and could cause health workers to abandon gloves that could protect them against infection"

Then Koop testified in the House on March 25 before the oversight and investigations subcommittee of the Committee on Education and the Work Force. Dr. Koop told the panel that the hazards being linked to the gloves by scientists and other health authorities were exaggerated. "Borderline hysteria," he called them.

However now it is revealed that Koop had received substantial sums of money under a four-year, $1 million contract he signed in 1994 with a leading manufacturer of the latex gloves, a relationship he did not disclose to Dr. Rosenstock or the subcommittee.

"What this long admired and respective man has done in taking money from a glove manufacturer and than speaking out on its behalf is wrong," said Susan Wilburn, senior specialist in occupational safety and health for the American Nurses Association. "Niosh studies show that 10 percent of workers regularly exposed to the gloves and 17 percent with heavy exposure have developed allergies".

"Dr. Koop has long been one of the nation's most trusted health experts, a reputation he gained as Surgeon General in the 1980's".

"According to filings with the Securities and Exchange Commission, the glove company contract called for Dr. Koop to deliver four speeches a year on health and nutrition. He gave the company the right to use his "name, picture, speeches, and biographical information" and agreed to serve as a company adviser. He also agreed not to endorse products of competitors, and to submit his speeches for editing"

Dr. Koop's testimony in March was still being cited in state legislatures as reasons to delay action on the gloves, even though "it was based on a study that was never done."

Source: Koop Criticized for Role in Warning on Hospital Gloves NYT Oct29, 1999

6 years ago today: The EU Clinical Trial directive and scientific fraud

On 29 October 2001 the BBC discussed the threat to research caused by the new EU clinical trial directive.

"The future of clinical trials in the UK will be jeopardised by a new EU directive, according to research experts". "it will radically increase how much it costs to carry out academic work, or many drug trials". "it will require a huge dossier of information to be compiled by researchers about virtually every aspect of the trial".

"another aim of the directive - to make research fraud more difficult - will fail because determined cheats would still succeed." "There's no evidence that doing this would help the situation"

Not a word about who those "determined cheats" are. Not a word about the beneficiaries of the confusion. The losers are small innovative biotech companies and innovative academics. The control of clinical "findings" are driven away from clinicians and into the hands of those who have incentives to cheat and who have done so repeatedly. Scientific fraud is neatly hidden beneath a layer of impenetrable and expensive red tape.

There is no integrity in any of this. Nor was this ever the intent.

Source: BBC News, Red-tape 'disaster' for medical research 29 Oct 2001

5 years ago today: Neurontin documents exposed

On 29 October 2002 the contents of internal Warner-Lambert documents unsealed in a neurontin lawsuit were revealed.

Instead of conducting clinical trials to test the safety and efficacy of Neurontin (gabapentin) for the conditions it promoted, Warner-Lambert (now owned by Pfizer) spent money "educating" doctors, encouraging them to prescribe the drug for unproven uses in patients with diabetes and bi-polar disorder.

Marketing executives at Warner-Lambert urged their superiors to promote the epilepsy drug Neurontin outside of the domain of science. In a memo, dated May 5, 1997, the marketing executives propose that Neurontin be promoted to treat pain in diabetic patients by creating education classes for doctors, and sponsoring a symposium with the American Diabetes Association. Another memorandum details how Warner-Lambert tracked prescriptions written by doctors after they attended dinner meetings paid for by the drug company at which Neurontin was discussed. The memo, dated June 26, 1995, said that in the Northeast, doctors attending the dinners wrote 70 percent more prescriptions for Neurontin than doctors who did not attend. In the memo, Warner-Lambert executives recommended against doing studies needed to get Neurontin approved to treat diabetic patients.

For detailed discussion of the neurontin documents and the consequences of these actions see "The Promotion of Gabapentin: An Analysis of Internal Industry Documents", Ann Int Med, 5 August 2006 145 :284-293.

The leadership of medicine remains mute. Patients no doubt suffered as as a consequence of thinking that decisions were being made on the basis of scientific evidence. Was anyone punished in any way?

On the same day the press reported that Pfizer had "agreed to pay $49 million to settle charges that a subsidiary defrauded the Medicaid program" over the cholesterol-lowering drug Lipitor.

Sources:

• Documents Show Effort to Promote Unproven Drug New York Times, Oct 29, 2002
• Pfizer to Pay $49 Million in Fraud Case New York Times, Oct 29, 2002
• The Promotion of Gabapentin: An Analysis of Internal Industry Documents, Ann Int Med, 5 August 2006 145 :284-293.

Odds and ends

• 78 years ago on 29 October 1929 the NY Stock Exchange crashed.
• 38 years ago on 29 October 1969 the first computer link was established on ARPANET, the precursor to the Internet.
• 9 years ago on 29 October 1998 in South Africa, the post apartheid "Truth and Reconciliation Commission" presents its report, which condemns both sides for committing atrocities.
• 3 years ago on 29 October 2004 the consumer group Public Citizen renewed its call a ban of the statin Crestor. It was felt that the rate of acute renal failure or renal insufficiency was far higher for Crestor than for all other statin drugs combined. The FDA disagreed with this assessment.

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Memory Hole (28 October): Making punishment fit the crime

6 years ago today: Oxycontin - 282 deaths - purposeful misbranding

On 28 October 2001 "An extensive federal review of autopsy data has found that the powerful painkiller OxyContin is suspected of playing a role in the overdose deaths of 282 people in the last 19 months, more than twice the number in some previous estimates."

Although it was initially put out that the deaths were related to illicit abuse of the drug, in fact less than 10 of the deaths were due to intravenous abuse and only 1 to snorting. Most were conventional patients who took the tablets orally or after crushing. Purdue Pharma heavily promoted the drug as safer than other narcotics because its active ingredient was in a time-release mechanism.

In 2007 the Purdue Frederick Company pleaded guilty to felony charges that they purposely misbranded the OxyContin with intent to mislead and defraud. Purdue and the three executives paid $634,515,475. Those named are President Michael Friedman, Executive Vice President Howard Udell, and former Executive Vice President Paul D. Goldenheim.

Is this scientific fraud? Did anyone go to prison?

See also Pharmagossip Make the punishment fit the crime

Source: New York Times Overdoses of Painkiller Are Linked to 282 Deaths, Oct 28 2001

2 years ago today: MIT fires Van Parijs - fabricating and falsifying

On 28 October 2004 M.I.T fired a biology professor (Luk Van Parijs) for fabricating research data. A group of colleagues reported faking to MIT administrators. Van Parijs admitted to fabricating and falsifying data in a paper several manuscripts and grant applications. The journal "Current Opinion in Molecular Therapeutics" later published a correction of an 2004 article. Van Parijs earned a doctorate in immunology from Harvard. He worked with Cal Tech President David Baltimore.

Another nice easy case. The same names and institutions keep cropping up, but perhaps a coincidence or a confounding variable.

New York Times, M.I.T. Dismisses a Researcher, Saying He Fabricated Some Data, 28 Oct 2005

Odds and ends

• 515 years ago on 28 October 1492 - Christopher Columbus lands in Cuba (predating Michael Moore by 514 years).
• 139 years ago on 28 October 1868 - Thomas Edison applied for his first patent, an electrical vote recorder. [See also <G Bush]

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Memory Hole (26 October): Why there is no scientific fraud in Britain

5 years ago today: British ethics chief explains why fraud never happens in Britain

On 26 October 2002 Dr Michael Wilks, chairman of the British Medical Association's medical ethics committee explained why research fraud never happens in Britain.

His explanation followed a 26 October 2002 BBC broadcast about the the Duke University study in the USA (see 23 October memory hole). The study showed that clinical trials of many new drugs and treatments are flawed and unethical, and that researchers fail to follow international guidelines in studies funded by the pharmaceutical industry.

The BBC cited Dr Michael Wilks, chairman of the British Medical Association's medical ethics committee saying:

"It is different in the UK. Studies are approved by research ethic committees before they can go ahead and I don't think there would ever be a case where they would allow a study to proceed if there was a chance that the drug company could prevent publication of the findings."

Have you heard of GSK or Seroxat Dr Wilks? We can think of many other examples I am sure. I have wondered why the BMA ethics committee has said nothing at all about the most serious integrity lapses in medicine, and why fraud is so effectively hidden here. I think we may have the explanation.

We British are just fine.

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Memory Hole (22 October): What happened this day?

Scientific Misconduct Blog Memory Hole: Events of October the 22nd

97 years ago today: Dr Crippen found guilty - wrongly

On 22 October 1910 Dr. Crippen was convicted at the Old Bailey of poisoning his wife and was later hanged in London. In England, Crippen worked for a homeopathic pharmaceutical company. This month Science Magazine reported that based on mtDNA comparison with matrilineal relatives, the body found beneath Crippen's home was definitely not that of Cora Crippen.
Reference: Notorious Dr Crippen wrongly hanged, Science 16 Oct 2007

70 years ago today: Dr A.S Calhoun on responsibility

On 22 October 1937 this letter was written by Dr. A.S. Calhoun. It was part of a key incident leading to a change in medicines regulation:

"But to realize that six human beings, all of them my patients, one of them my best friend, are dead because they took medicine that I prescribed for them innocently, and to realize that medicine which I had used for years in such cases suddenly had become a deadly poison in its newest and most modern form, as recommended by a great and reputable pharmaceutical firm in Tennessee: well, that realization has given me such days and nights of mental and spiritual agony as I did not believe a human being could undergo and survive. I have known hours when death for me would be a welcome relief from this agony."
(Letter from Dr. A.S. Calhoun, October 22, 1937)

The medicine that killed Dr. Calhoun's patients was Elixir Sulfanilamide (Read more here).

The question is whether our sense of personal responsibility for failing to examine science and integrity should be any different in 2007 given a semblance of "regulation". I like this quote from Dr. A. Dale Console, former medical director for drug giant ER Squibb:

"We could make no greater mistake than to be lulled into a sense of false security by believing that some disembodied force called the government will act like a beneficent big brother and make certain that the special interests will not predominate. If the general welfare is to be protected, it will be protected by the actions of people, not the government."

13 years ago today: More non-consensual radiation experiments disclosed

On 22 October 1994 it was reported that the US President's Advisory Committee on Human Radiation Experiments admitted that many more radiation had been conducted by the Government and the military from 1944 to 1974 than previously suggested. These included injection of plutonium and deliberate release of large amounts of radioactivity into the environment.

The number of human experiments were said to be in the thousands. Most were conducted without consent, and some on retarded and "incorrigible" children in institutions.

A decade ago I was involved in conducting a limited low-dose isotope experiment in osteoporosis (reference below). I had read many of the original studies of skeletal metabolism that were carried out in the 1950's. Some of these were interesting. I had thought little about their origins and will discuss one particularly problematical bone radiation study in a later posting. It's about trust.

References:

• "Panel Says U.S. May Have Done Thousands of Human Radiation Experiments," New York Times, 22 October 1994
• Blumsohn A, Morris B, Eastell R (1994). Stable strontium absorption as a measure of intestinal calcium absorption: comparison with the double-radiotracer calcium absorption test. Clin Sci. 1994 Sep;87(3):363-8. [Pubmed]
• Panel Releases Report on Human Radiation (the US government view)

7 years ago today: Another easy case - Fujimura the archaeologist

On 22 October 2000 a renowned archaeologist Shinichi Fujimura dug some holes in Japan. He arranged some ancient stone tools in a symbolic pattern, and covered them with soil. He and his team then invited journalists to see this important discovery in progress.

Fujimura’s findings had led to the idea that the earliest human habitation of Japan was 600,000 years ago instead of a mere 30,000.

As it happens, reporters suspicious of his previous work had filmed the burial. Fujimura admitted to his fraud. Most of his earlier discoveries also proved to be forgeries.

Another nice cozy case of fraud for those want easy definitions of integrity.

Sources
BBC: Archaeologist exposed as fraud (with nice photographs)
Harvard Asia Quarterly Volume VI (3) 2002

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