1. Presentation at Radstats British Library, London 24 February 2012
How to smell a rat: Examples of scientific and regulatory failure in medicine
Dr Aubrey Blumsohn
Presentation at Radstats British Library, London 24 February 2012

2. Nature of science – and how we define scientific fraud

3. Data – and access to data

4. Regulators (watchdogs)

5. Individual responsibility in science

6. Science
Data
Regulators
Individual responsibility

7. History
Einstein
Insanity: doing the same thing over and over again and expecting different results.

8. What is Science? UK Science Council (2009)
Spent a year working out a new definition of science.
Claim as the first "official definition of science" ever published.
“Science is the pursuit of knowledge and understanding of the natural and social world following a systematic methodology based on evidence”

9. What is Science? – Mertonian Norms
Communalism
Everyone can see what’s going on
Universalism
Doing of it not restricted to special people
Disinterestedness
An arms length attitude.
Skepticism (Organized Skepticism) -
Claims exposed to critical scrutiny. Awkward questions. Merton, Robert K. (1973), "The Normative Structure of Science",

10. Science demands awkward people
It takes all sorts of people

11. Example 1: “Mr Nobody” and Journal of the American Medical Association (JAMA)

13. Letter #1 to JAMA

14. Letter #2 To BMJ

20. Scientific deception - and its mis-definition

21. The Classics
William Summerlin (Sloan Kettering, 1984) - faked transplantation experiments in white mice by blackening patches of their skin with a pen
Vijay Soman (Yale, 1980) a diabetologist - wrote 12 papers based on invented data. His co-author Felig had to resign

22. The Classics
Robert Slutsky (Radiologist, University of California). Published 137 papers between 1978 and one every 20 days. Many faked.
John Darsee (Cardiologist, Harvard, 1981). Observed falsifying data. His boss, Eugene Braunwald ignored the problem. Later investigations discovered more than a 100 fraudulent papers

23. In these odd cases, the stories, as told, usually minimise the involvement of senior colleagues, University administrators, Hospitals and regulatory bodies who hid the misconduct before it was eventually exposed

24. The impression
The choice of cases implicitly defines what we mean by scientific fraud/misconduct
Fraud is rare
It involves a particular type of activity (painting a mouse)
Usually involves an aberrant (male) acting alone (or duping otherwise honourable collaborators) “Problems of scientific misconduct are rare - the product of psychopathic behaviour’ originating in temporarily deranged minds” President of the National Academy of Sciences (at Congressional Hearings)

25. And the solution Is to create yet more procedures and guidance
And for Universities to create robust, secret, legalistic procedures to investigate these rare rogues

26. Only one problem. As Arnold Schwarzenegger once said: “it's bullshit—all of it”

27. The reality
Not rare
Scientific misconduct often not an individual activity – but a group activity (or involves group collusion)

28. Group-think Hannah Arendt (1965)
"rule by nobody".
No single individual feels responsible for what is ultimately done.
Indeed many people have gone to great lengths to make sure that this exact state of affairs achieved
Legislators
Ethics Committees
Trade bodies
Regulators
System designers responsible for fraud?

29. The reality The offender is often not a lone white male psychopath
Corporate fraud

30. The reality
Corporation acting at the University interface

32. The reality
or a journal editor

33. The reality
or a regulator ….
or government itself

34. The mechanisms also differ
The mechanism of misconduct is also usually not direct fabrication of findings but something far more nuanced

35. Defining pornography
"hard-core pornography" was hard to define, but "I know it when I see it“ Potter Stewart (Associate Justice of the US Supreme Court)

36. Misconduct
Misconduct is nothing to do with the correctness of conclusion
To err is human, and scientific!!!
It has to do with behaviours
Behaviours which could disturb the scientific record
Not binary
We need to get away from ludicrous discussion about restrictive definitions and start discussing behaviours
Openly

37. Example 2: The fearful junior
Approached by a Junior Doctor
In order to gain her pathology registration she had to submit her dissertation
She could not write up her dissertation or prepare the main area of work for publication because her supervisor had made this impossible – for years…..
She could only present the secondary aspects
The work involved looking at physiological changes in healthy volunteers randomised to atorvastatin or placebo
The study showed that atorvastatin induced a diabetes like state
Her supervisor was funded by the manufacturer of atorvastatin

38. Example 3: Does Seroquel cause diabetes and weight gain

39. But there was a cloud on the horizon. The F. D. A
But there was a cloud on the horizon. The F.D.A. was beginning to look into the issue of Diabetes in patients on Atypical Antipsychotics and wrote to Astrazeneca

40. Then somebody noticed the obvious that they had more than just 18 months of data in these subjects

43. Example 4 – Famovir and Herpes
Famvir is used for treatment of herpes zoster
There was a nine year delay before partial publication of findings which had adverse implications for the sponsor

46. What are data? Data is not the same as representation of that data

47. Getting a hamburger when what
you need is the original cow

48. Example 5: Vioxx APPROVE Trial
New York Times May 31, 2006

49. Look at the language
Merck & Co. acknowledged that it misidentified a statistical method
Merck has contended that the study shows
The company said in a statement yesterday
Merck has insisted that its 18-month argument holds up
while outside scientists have cast doubt on the company's interpretation.
Merck research chief Peter Kim said the company stood by its analysis

51. Example 6: Vioxx AVANTAGE Trial
On Oct. 21, 1999 a 73-year-old female participant dies in a clinical trial
The trial was Merck’s Advantage trial of Vioxx
She died a few minutes after calling her son to tell him she felt short of breath

52. The Advantage trial was a very short (12-week) clinical trial
eight people taking Vioxx suffered heart attacks or sudden cardiac death in the trial (compared with only one not on the drug)
The difference was statistically significant, but Merck never showed the data that way

53. In the published study, the “author” (Dr
In the published study, the “author” (Dr. Lisse, University of Arizona), the 8 deaths became` 5, a difference that did not reach statistical significance.
The paper never mentioned the other cardiac deaths of patients taking Vioxx, including the 73-year-old woman.

55. Dr. Lisse said that while he was listed as the paper's first author, Merck actually wrote the report. "Merck designed the trial, paid for the trial, ran the trial," Dr. Lisse said. "Merck came to me after the study was completed and said, 'We want your help to work on the paper.' The initial paper was written at Merck, and then it was sent to me for editing."

56. Results from the trials were also supposed to be blinded when coded
During coding, Dr. Eliav Barr, a Merck employee judged that the woman “had probably died of a heart attack."

57. Dr. Reicin a Merck executive immediately shot back : "I think this should be called an unknown cause of death." A few hours later, she wrote, "I would prefer unknown cause of death so we don't raise concerns."
Read

58. In November 2001, an F.D.A. reviewer who had examined all the company's data concluded in a report to other agency officials that Merck had cheated. But the F.D.A. never told anyone either.
Read

59. Dr. Lisse, the study "author" said he had never heard of the case of the woman who died, until told of it by the New York Times.
Read

60. Example 7: Vioxx - Fake Journals
Merck paid Elsevier to create a number of fake scientific journals
This came to light 2009 in the context of a civil suit filed by Graeme Peterson, who suffered a heart attack in 2003 while on Vioxx
These were designed in such a way that the average medical reader would “mistake the publication for a genuine peer reviewed medical journal”
The articles supported Merck Drugs

63. One of the members of Australasian Journal of Bone and Joint Medicine's "Honorary Editorial Board," Peter Brooks, a rheumatologist said: he didn't recall who asked him to serve on the board, …. "You get involved in a whole bunch of things at this level".

64. Elsevier issued at Press release and an apology
We “published a series of sponsored article compilation publications, on behalf of pharmaceutical clients, that were made to look like journals and lacked the proper disclosures. This was an unacceptable practice, and we regret that it took place.”
But what of the academics involved, and their institutions?

65. REGULATORS AND SYSTEMS
Medical Writers (Ghost writers)
Medical Journals
MHRA (UK Drug regulator)
Medical Ethics system
UK Research Integrity Office
General Medical Council

66. The illusion of due diligence
"We're looking for the illusion of due diligence, Mr. Pope. Two criminal acts successfully prosecuted -- it gives us that illusion."

67. Medical Writers (and Ghostwriters)

69. “When the time comes for publication, the medical writer writes the publication in consultation with the named author(s). This usually begins with discussions between the medical writer and authors(s) about the main features of the paper, after which the medical writer writes the first draft. The draft is then revised (sometimes many times) after review by the author(s). Thus although the authors do not actually write the paper, they do have control over its content, which is far more important. Naturally, they have access to the report of the study and its data tables, so they can verify that the paper is accurate. They often don't have access to the raw data, but it is worth repeating that raw data are of very little use when writing a paper. Results of a study need summarising and analysing before they mean anything, and it is those summaries and analyses that are important for proper interpretation of a study, not the raw data themselves. “
Adam Jacobs – European Medical Writers Association BMJ 21 Nov 2004

70. Journals

71. Motto – Which? Magazine
No advertising, no bias, no hidden agenda. Just expert advice from an independent source

72. Motto – BMJ
“We protect our reputation by careful balance of editorial and advertising, which means your messages will always stand out.” (

73. The Medicines and Healthcare Regulatory Agency (MHRA)

74. MHRA Has absolutely nothing to say on the problem of ghostwriting
Has nothing to say on the problem of denial of access to data (to authors or the scientific community in general)
Have no apparent concerns nor any apparent remit to deal with events at Sheffield University
Even suggested that it might be “illegal” for authors to obtain the randomisation codes in a study they are authoring because commercial companies “own” those codes.

75. Risedronate
FOI:
Did the MHRA receive and scrutinise in any way the raw data relating to the three key clinical trials which led to approval of Risedronate
Has the MHRA got the randomisation codes

76. Risedronate FOI response:
We cannot tell you because part of the response is commercially confidential
Reply: The questions required answers of “yes” or “no”. Which parts of the Yes or No are commercially confidential
Eventual FOI response: The MHRA did not scrutinise or retain any actual raw data before licensing Risedronate. They simply accepted what the company told them.

78. The MHRA (HOC SC Report 2005)
"practices have developed which act against the public interest."
The MHRA relies on company data presented as reports, in its decision whether or not to licence a drug. Raw data is very rarely analysed.

79. The MHRA (HOC SC Report 2005)
“The MHRA Chairman suggested that trust underpinned the stance of the MHRA towards the companies they regulate. We inferred that this extended to the routine acceptance of companies’ summaries of the results of tests on their drugs as true reflections of the raw data on which they were based.”
“Evidence that regulatory agencies are acquiescing in biased later publication of the information they hold.”

80. The MHRA (HOC SC Report 2005)
“Lack of transparency has played a major part in allowing failings to continue.”
“100% of the funding for the MHRA comes from the industry it regulates”
"In view of the failings of the MHRA, we recommend a fundamental review of the organisation."

81. The General Medical Council
Body that “regulates” doctors
A science-based profession
Might have thought they would take scientific integrity seriously
Long history of a very lax approach to scientific fraud
Particularly when it involves very senior academics

82. Dr David Hurlstone Sheffield Teaching Hospitals NHS Trust
Bowel cancer research
2006 BUPA Foundation Research Award
2007 Medical Futures Innovation Oncology & Cancer Care Award
GMC - dishonesty in three research studies published in 2007 & 2008 (not retracted)
Suspended from Medical Register for 3 months
On return to work retained Clinical Excellence Award

83. What did he do? In three publications And so on…..
Submitted authors’ consent forms to journal with false signatures of collaborators
Studied patients without ethical approval
Created consent forms for patient records in retrospect
Stated falsely that patients had been randomised
Made false statements about microscopy having been carried out
Stated falsely that two blinded specialists had exampled samples – they did not exist
Stated falsely that an independent nurse participated in the study and that the study endoscopist was blinded
And so on…..

84. GMC and Richard Eastell
3 publications intended by Procter and Gamble ( )
Authors actively denied randomisation codes by sponsor
Eastell prepared to go along regardless
Prepared to induce a colleague to do the same
False conclusions in all manuscripts
Research Dean of a Medical School R&D Director of Sheffield NHS Trust

86. How to get out of this?
Didn’t write the false statement The “medical writer” wrote that as well
I don’t need raw data as a scientist because I would not know how to analyse it (and presumably neither would my coauthors). It is very hard to analyse data.
The statement was in 2002.
In 2002 I had a watershed moment when I realised this kind of activity was inappropriate.
I would never have done it again after 2002, and I will never do this sort of thing again.
Legal manoeuvres to avoid having the GMC panel examine any information subsequent to this 2002 paper and repeated events

87. The GMC response 2002 statement Epiphany in 2002 2003/2004/2005???
Data are raw data
Data are having the data
It was false
It was misleading
It was negligent
Epiphany in 2002
2003/2004/2005???
No punishment - “it would interfere with his ability to get research funding”!
This type of behaviour has no impact on patient care (according to the GMC)

88. Dr Guirong Jiang Radiologist
Working as a postdoctoral fellow at the University of Sheffield
One of the most experienced radiologists in the world in terms of diagnosis and definition of vertebral fracture
Several complaints about Richard Eastell
Including his wish to author in the absence of data
Apparent secret contracts involving Eastell, Sheffield University and Commercial Companies preventing publication
Jiang not permitted to see contracts apparently preventing her right to publish findings she believed to be true based on studies in which she was involved