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The Lancet’s two days to bury bad news

19 Jan

Part three of Brian Deer’s series in the BMJ, The Lancet’s two days to bury bad news, has just been released. As you can imagine from the title, he lays out how the Lancet responded to the news that Brian Deer was publishing a story on the Wakefield team’s article in The Lancet.

Brian Deer’s first article in the Sunday Times was published February 22, 2004. On February 18, Mr. Deer met with the editor of the Lancet and other senior staff for five hours.

I had assumed that when I finished Horton would say that an investigation was needed to untangle these complex matters. There were at least three strands: possible research fraud, unethical treatment of vulnerable children, and Wakefield’s conflict of interest through the lawyer. But within 48 hours, and working with the paper’s three senior authors, the journal was to publish a 5000 word avalanche of denials, in statements, unretracted to this day.

Mr. Deer has investigated what was going on behind the scenes at the Lancet and at the Royal Free. Statements to the press claim by Richard Horton, editor of the Lancet, claim that an investigation was made at the Royal Free which “cleared Wakefield of wrongdoing”. According to Mr. Deer’s investigation, no formal investigation was conducted. Rather, the Royal Free chose Doctors Wakefield, Murch and Walker-Smith, authors of the paper in question, to prepare the response.

The Lancet’s statements came on on Friday, 48 hours after the meeting with Brian Deer and 2 days before his article was set to run in the Sunday Times in an apparent attempt to

“The Lancet editor’s actions have been to regard the allegations . . . as allegations of research misconduct, and following the medical editorial code has carried out an investigation according to agreed guidelines, and intends to publish the result of the investigation pre-emptively,” Hodgson told his UCL superiors in a memo that Friday. “No doubt one—but I believe only one—motive is to safeguard the Lancet’s reputation by getting the riposte in first, and ‘spoiling’ the story.”

The media furor over these revelations led to, amongst other things, the GMC hearing which would eventually strip Mr. Wakefield of his license to practice medicine in the UK:

Wakefield attempted to brazen it out, issuing a further statement to media. “It has been proposed that my role in this matter should be investigated by the General Medical Council,” he said on the Monday. “I not only welcome this, I insist on it, and I will be making contact with the GMC personally in the forthcoming week.”

The same day, a caseworker for the regulator called me from Manchester. Did I have any further information? And two days later, at 12.16 Wednesday, I emailed him the conclusions of my research. I summarised what I had said to the Lancet’s senior staff and pledged my cooperation, in the public interest.

The above sets out the timeline for the onset of the GMC hearing. For those who continue to claim that Mr. Deer was the “claimant”, I doubt even more evidence will dissuade them.

The editorial that the BMJ published along side the Deer article is clear in how serious they take the lack of oversight that went into this research and the initial investigation, placing Mr. Wakefield’s work alongside some of the worst examples of medical research gone wrong in the past century:

Unfortunately, we have been here before. Investigators involved with the 1932 US Public Health Service Tuskegee Syphilis Study deceitfully enrolled subjects with latent syphilis and denied them available treatment for 40 years in order to study the natural course of the disease.(4) As part of a 1963 study to determine the body’s ability to reject foreign cells, patients at the Brooklyn Jewish Chronic Disease Hospital were injected with live cancer cells without their knowledge and without oversight from the institution’s research committee.(5) From 1944 to 1974, the US government conducted several radiation experiments, some of which involved the use of non-therapeutic radioactive tracers in children and increased their risk of developing cancer.(6) And in 1981, it was discovered that John Darsee, a clinical investigator at Harvard Medical School, had fabricated data in several experiments published in high profile medical journals that ultimately culminated in widespread retractions of his work and a ban from funding from the National Institutes of Health for 10 years.(7) These experiments have since become symbolic of unethical research on human subjects and of scientific misconduct, and there is little doubt that Andrew Wakefield’s 1998 study will too.(8)

They go beyond this and ask the pertinent question–how did this happen and how do we avoid it in the future?

How could this happen again? To answer this, perhaps we need to focus less on the people involved and more on the defects within the biomedical research enterprise that permit such egregious misconduct. After all, Wakefield was able to circumvent the existing safeguards established to ensure the responsible conduct of research, the protection of research subjects, and the accurate and honest publication of research findings.

The editorial discusses that “research incidents” like those surrounding Mr. Wakefield should be framed as adverse events and attacked similarly. It is a model which will no doubt be criticized by those who see autism as an adverse event to MMR, but it does lay out a framework of how to respond.

The editorial concludes:

Thirteen years later, we are only now beginning to understand the root causes of the multiple system failures involved in the Wakefield incident. We must strengthen our ability to investigate research adverse events. We need to use the tools and techniques available to protect the safety of patients in the clinical realm to protect research subjects. We also need to rethink and reform our customs and culture. The disastrous impact that Wakefield’s study has had on vaccine coverage, recrudescence of disease, public trust, and, most of all, science, requires that we do so in haste.

As we leave this subject, it is worth looking to the words of Andrew Wakefield himself. Words which resonate in a manner Mr. Wakefield did not intend, but resonate nonetheless:

The medical science, the medical system, the scientific system has failed you, for which I am ashamed.
–Andrew Wakefield, May 26, 2009.

He meant the statement as an accusation, that he was ashamed on behalf of the rest of the system, not his own missteps. I find the statement clearly ironic. He is correct, the medical science, the medical system, the scientific system has failed us. His efforts in the Lancet (and elsewhere) are an example of that failure. They do not stand outside of it.

Science has a very difficult choice. To choose between fidelity or collusion.
–Andrew Wakefield, May 26, 2009.

Too right, Mr. Wakefield. Too right. Of course, science had that choice in 1998 as well. You made the wrong choice.

Andrew Wakefield’s erasure from the UK medical register is complete

19 Jan

This just isn’t Andrew Wakefield’s week. Last year the General Medical Council (GMC) in the UK found Andrew Wakefield guilty of multiple counts of improper conduct. These include subjecting disabled children to invasive tests that were not in their clinical interest, placing children in a research program without first obtaining the safeguards of ethical approval, financial and commercial conflicts of interest as well as other breaches of ethical conduct.

Here is one example paragraph from the sanction of Mr. Wakefield:

With regard to nine of the eleven children (2,1, 3, 4, 6, 9, 5,12 and 8) considered by the Panel, it determined that Dr Wakefield caused research to be undertaken on them without Ethics Committee approval and thus without the ethical constraints that safeguard research. Ethical constraints are there for the protection both of research subjects and for the reassurance of the public and are crucial to public trust in research medicine. It was in the context of this research project that the Panel found that Dr Wakefield caused three of these young and vulnerable children, (nos. 3, 9 and 12) to undergo the invasive procedure of lumbar puncture when such investigation was for research purposes and was not clinically indicated. This action was contrary to his representation to the Ethics Committee that all the procedures were clinically indicated. In nine of the eleven children (2,1, 3, 4, 9, 5,12, 8 and 7) the Panel has found that Dr Wakefield acted contrary to the clinical interests of each child. The Panel is profoundly concerned that Dr Wakefield repeatedly breached fundamental principles of research medicine. It concluded that his actions in this area alone were sufficient to amount to serious professional misconduct.

The sanction includes the determination that Andrew Wakefield should have his name erased from the medical register:

Accordingly the Panel has determined that Dr Wakefield’s name should be erased from the medical register. The Panel concluded that it is the only sanction that is appropriate to protect patients and is in the wider public interest, including the maintenance of public trust and confidence in the profession and is proportionate to the serious and wide-ranging findings made against him.

Mr. Wakefield had a period of time to appeal to the High Court. I have word from Brian Deer, the journalist who first broke the story of the Mr. Wakefield’s misdeeds, that the time has passed and the erasure is now effective.

For those who want visual confirmation, here is the GMC’s registry page on Mr. Wakefield. (click to enlarge)

Dowsing for Data

18 Jan

The BMJ has podcasts (something I was unaware of). This week’s edition is called “Dowsing for Data“. They have input from Tom Jefferson of the Cochrane Collaboration on a subject aside from the Wakefield articles which have been published in the past few weeks. In the second part (starting at about 11:30 into the podcast) the BMJ discusses with Brian Deer about the articles.

They discuss the history of the story, how he got started to do background work for a TV program in 2003. He discusses Mr. Wakefield’s aborted attempt to sue Brian Deer for defamation, which caused 2 years of litigation. It was during this period that Mr. Deer became more convinced that the Lancet article “could not be rationally explained”. Since the information was clinically confidential information at the time, Mr. Deer could not take the information into the public domain. This changed with the GMC hearings and, especially the hearing transcript hearings. This allowed for fact checking of Mr. Deer’s articles. He discusses how the story ended up in the BMJ. Also, the advantage of placing this in the BMJ makes it clear that a greater level of fact checking has been performed. He answers the critics who say that this is more journalism than science, questioning the placement in the BMJ. Of course, Brian Deer is a journalist, not a doctor or researcher. But, that this could be done with the accuracy and rigor of a science paper in a more narrative form.

Mr. Wakefield’s business plan as discussed at the GMC hearing.

13 Jan

As Kev has discussed, Mr. Wakefield has put out a press release denying all allegations about research fraud and an attempt to profit from the research he was engaging in. I had hoped to put this all behind us, but I thought for those interested, a more thorough discussion of Mr. Wakefield’s business venture might be appropriate here. I copy below a section of the GMC hearing testimony from Day 31. Mr Cengiz Altan Tarhan, who worked on the finance side of University College London and was brought in to discuss, amongst other things, Mr. Wakefield’s business venture.

Q I am going to be reverting to that role in more detail much later on in the story, but just so everyone knows that is a company that relates to technologies developed by the Medical School, is that correct?
A Not just the Medical School. It is the whole of the university. So it is University College London. The Medical School is a part of the university.

Immunospecifics is discussed below, but it went through name changes, including Carmel. I’ve wuoted a section of testimony below. Questions and answers in the hearing are italicized. The text of the documents is left normal.

The documents discussed involve the plan to spin-out a company from UCL to develop Mr. Wakefield’s invention (as put forth in his patent) into a therapy and as a vaccine replacement.

Q Sir, I am going to call this gentleman from now on in order to protect the confidentiality of the boy, his son, as “Dr 10”. Could we go, please, in volume 2, to page 756a. This is a letter that was sent to you before a meeting. It is from Dr Wakefield to you dated 26 February 1998.

“Re our meeting on Tuesday, 3 March 1997, please find enclosed two references for Alex Korda, our proposed Chairman. I have applied for references for Dr [10], our proposed CEO [Chief Executive Officer], and will pass these on as soon as these are available .

In addition, Dr Kirkpatrick from Denver, Colorado, will be giving a guest lecture on the use of Transfer Factor in the treatment of viral disease on the same Tuesday lunch time in the Department of Paediatric Gastroenterology. I realise that this may be of limited value to you other than reassuring you that Transfer Factor is a credible and rational alternative treatment for viral infections. Dr Kirkpatrick holds certain IPR [intellectual property rights] that may be relevant to our endeavours, and Alex Korda, [Dr 10] and I will be meeting with him to discuss this. I will feed back as soon as I have more information.”

Is that correct?
A Yes.

Q Would you go on to 797, please. That is a memo from you. I am told that is a document that needs to be put back into the bundle. Actually, sir, this is a tranche of documents which goes all the way from 797 to 816. Perhaps I can give them all to you at once so I do not do it piecemeal.

THE CHAIRMAN: I have 797a here.

MS SMITH: In that case you need 797 to precede it and then, after 797a, you go on with the rest of the documents, which go from 798 to 816. Could we go first of all, Mr Tarhan, to 797.
A Okay.

Q This is a memo from you and sent to Mr Dutton, Professor Zuckerman, Mr Blatch and Miss Bishop, dated 6 March 1998.

“Mr Wakefield and potential company proposal

Andy came to see me with two of his colleagues who expressed an interest in setting up a company and acquiring the patents from the School. I asked for some background papers on the two individuals. One is a XXX (10) and the other appears to be an entrepreneur with previous experience with start up companies and is prepared to raise funds for the company.

I have asked them to put forward what they saw as the business plan and way forward and will report back as soon as I have further information.”

Can we then go on to 798. This is your second memo, 6 March 1998, to the same people.

“Further to my memo of 4 March I have now received the attached document from [Dr 10] the Managing Director designate for Immunospecifics Biotechnologies Ltd.

Any comments would be appreciated.”

Attached to that, was there a business plan document?
A That is correct.

Q That starts at page 799. Can I just look in brief terms at the contents of that.

“Immunospecifics Biotechnologies Ltd is a new biotechnology venture specialising in the isolation, production licensing and marketing of a new range of immunotherapeutics, generically known as transfer factors. These compounds are a naturally occurring part of the human immune system and promote specific cell mediated immunity towards the target antigen.

The first clinical condition targeted will be measles virus induced inflammatory bowel disease. It is estimated that this disease costs the NHS about £15,600,000 per annum. The incidence of measles induced inflammatory bowel disease is increasing dramatically in Europe and the States. Immunospecifics … will undertake the start of a two year, double blind, phase 1 clinical trial into the effectiveness of measles specific transfer factor in the treatment of inflammatory bowel disease and an open label study into the effectiveness of the same product in ameliorating pervasive developmental disorder within 3 months of securing funding.

In parallel with the clinical trial the company will develop a clinical diagnostic for the presence of the measles virus. It is estimated that the market for this diagnostic is about £4,000,000 per annum in the UK alone. The company will also investigate the potential of transfer factors as vaccine alternatives. An animal model trial of the value of measles specific transfer factor in preventing inflammatory bowel disease will begin upon securing funding.

On completion of a successful phase 1 clinical trial the company will move towards phase 2 and phase 3 trials for the measles specific transfer factor whilst introducing new potential transfer factor therapeutics to its development portfolio. Prior to the completion of this first phase trial, the company expects to have finished the laboratory development of the clinical diagnostic, completed the open label study into pervasive developmental disorder and finished the animal study into the potential of transfer factor as a vaccine.

The company is looking to raise about £2,100,000 to undertake this development programme.”

Moving on to page 800,

“THE PRODUCTS

[Immunospecifics] will specialise in the production, formulation and sale of a wide range of immunotherapeutics, generically known as transfer factors (TFs). [Transfer factors] are a naturally occurring component of the immune system which have been shown to confer antigen specific cell mediated immunity. This form of immunity is important in overcoming viral infectious agents. Many viral agents have the capacity to suppress the body’s cell mediated immune system (e.g. Human Immunodeficiency Virus). Overcoming this suppression through the introduction of an antigen specific cell mediated immunity promoter has enormous potential clinical significance.”

Then it sets out the history. Would you go on to page 801, the top of the page and second paragraph down,

“It is [Immunospecifics’] aim to use a high potency, standardised TF preparation in one of the first properly controlled clinical trials of these materials. The target conditions for the trials will be specific forms of inflammatory bowel disease (IBD) and a condition affecting children known as pervasive developmental disorder (PPD). These trials will begin within the first three months of the company’s establishment. Whilst these trials are taking place, the company will be purifying and characterising the active compounds in the TF preparation. Once isolated and characterised, the potential for this molecule as a measles specific vaccine will be evaluated in animal model systems.”

Going on to page 802 and just past the middle of the page,

“STRATEGY AND OBJECTIVES

[Immunospecifics] is at present no more than a concept, but one with a unique opportunity. The strategic goal for the venture will be to achieve full regulatory approval for the use of antigen (infectious agent) specific transfer factors in a variety of clinical conditions where existing treatment regimes are either non-existent or have limited effectiveness. This strategy will permit the company to establish a clear technical and medical lead in this area with a resulting dominant market share. Paralleling the use of [transfer factors] as therapeutics will be a research programme aimed at demonstrating the value of [transfer factor] as a vaccine.

The objectives and associated tasks for the first two years to develop the concept into a full-scale venture are summarised in the following points.”

Turning back to page 801 for a moment, Mr Tarhan, and the bottom of the page, the last paragraph reads,

“It is [Immunospecifics’] aim to undertake a phase I clinical trial of a high potency measles specific transfer factor supplied by Fudenberg’s group at a very early stage in the life of the Company.”

Would you turn now to page 804 and this is still under the heading, “STRATEGY AND OBJECTIVES” and to number 7 of 9,

“Establish the potential of the high specific active preparations as a potential measles vaccine

This study will be done in conjunction with ‘Immuno’ a subsidiary of Baxter Health Care, in Austria using simian model systems. The efficacy of the [transfer factor] will be assessed by its ability to prevent measles specific IBD during challenge experiments. ‘Immuno’ have agreed to undertake the preliminary work with the [Royal Free Hospital] at no cost, although Immuno’s contribution is estimated to be of the order of £100,000. If successful this concept will be developed further in collaboration with a major pharmaceutical company, such as Glaxo Wellcome’s Jenner Institute. The full relationship between ISB and Immuno needs to be resolved.”

Going on to page 805,

“Medium term objectives for the venture will be: 1) to take the purified and characterised measles specific [transfer factor] through formal product registration by undertaking phase II and phase III clinical trials; 2) establish the most appropriate route for the commercial development of the product; 3) develop the potential for use of [transfer factors] as vaccine replacements; 4) introduce new anti-infectious agents TFs to the company’s product development portfolio and take them through to formal product registration.”

Secrets of the MMR scare: How the vaccine crisis was meant to make money

11 Jan

Last week, Brian Deer published an article in the BMJ How the case against the MMR vaccine was fixed. In it he lays out how data were misreported in Andrew Wakefield’s now retracted 1998 article in The Lancet. The BMJ editors published an editorial coincident with the Deer article, Wakefield’s article linking MMR vaccine and autism was fraudulent.

In his latest article in the BMJ, Brian Deer lays out: Secrets of the MMR scare How the vaccine crisis was meant to make money

Andrew Wakefield had plans to make money. A lot of money. He created a business to produce diagnostic testing kits. He applied for a patent for a therapeutic agent and a proposed vaccine to prevent measles infections. This in addition to the money he was collecting as a paid expert to the MMR litigation in the UK.

On the diagnostic testing kit. Mr. Deer obtained the prospectus for the company that was formed to develop and market it:

“It is estimated that the initial market for the diagnostic will be litigation driven testing of patients with AE [autistic enterocolitis] from both the UK and the USA,” said a 35 page “private and confidential” prospectus, which was passed to me [Brian Deer] by a recipient.

He predicted £28,000,000 in revenue from the therapeutic and diagnostic products from his company.

Mr. Wakefield used a laboratory in Ireland, Unigenetics, headed by John O’Leary, to test tissue samples for measles virus. This is well known. Mr. Wakefield was a director of that laboratory.

The work by Unigenetics was key to the company’s success. Mr. Wakefield predicted–apparently in September 1996, before the research was completed–that Unigenetics would provide “unequivocal evidence for the presence of the vaccine derived measles virus in biopsy samples”

“Once the work of Professor O’Leary and Dr Wakefield is published, either late in 1999 or early in 2000, which will provide unequivocal evidence for the presence of the vaccine derived measles virus in biopsy samples,” the prospectus said, “the public and political pressure for a thorough, wide ranging investigation into the aetiology of the bowel conditions will be overwhelming.

“As a consequence of the public, political and legal pressures brought to bear, the demand for a diagnostic able to discriminate between wild type and vaccine derived measles strains will be enormous.”

That paper has since been discredited. First, a major attempt to replicate it failed. More importantly, Stephen Bustin, perhaps the world’s foremost expert on the methodology used (PCR), found that the Unigenetics laboratory’s methods were so seriously flawed as to make any results worthless (good summary here). Also, it was found that PCR data from Mr. Wakefield’s own research group were negative for measles virus, and that Mr. Wakefield buried those negative results.

It was because of these (and more) conflicts of interest that he was let go from the Royal Free Hospital (long before the Brian Deer investigation). Mr. Wakefield’s claim that his departure from the Royal Free was because his “research was unpopular”. Contrary to this position, the Royal Free had offered Mr. Wakefield the opportunity to prove his hypothesis.

But the paperwork does not show this. Despite all that had happened, UCL volunteered to support his work. It offered him continuation on the staff, or a year’s paid absence, to test his MMR theories. He was promised help for a study of 150 children (to try to replicate his Lancet claims from just 12) and, in return for withdrawing from the January London conference, he would be given the intellectual property free.

“Good scientific practice,” the provost’s letter stressed, “now demands that you and others seek to confirm or refute robustly, reliably, and above all reproducibly, the possible causal relationships between MMR vaccination and autism/“autistic enterocolitis”/inflammatory bowel disease that you have postulated.”

Yes, Mr. Wakefield had an offer on the table to take a year to prove his hypothesis. The Royal Free already had their doubts, and even more doubts about Mr. Wakefield’s conflicts of interest. And, yet, it would take a few more years before Brian Deer would make this public.

At first Mr. Wakefield agreed to the Royal Free’s proposal. But he never put the plan into action. When it became clear that he had no intent to follow through, he was let go from the Royal Free.

One defintion I found (the top definition at dictionary.com) defines fraud thus:

deceit, trickery, sharp practice, or breach of confidence, perpetrated for profit or to gain some unfair or dishonest advantage.

As presented last week by Mr. Deer, data were manipulated to “fix” the results of Mr. Wakefield’s research. This week’s installment discloses how Mr. Wakefield sought to profit from this work. Pretty clear to this reader that this meets the definition of fraud.

Here is how the BMJ summarized the article:

Andrew Wakefield, the disgraced doctor who claimed a link between MMR and autism, planned secret businesses intended to make huge sums of money, in Britain and America, from his now-discredited allegations.

The Wakefield scheme is exposed today in the second part of a BMJ series of special reports, “Secrets of the MMR scare”, by investigative journalist Brian Deer. Last week we revealed the scientific fraud behind the appearance of a link between the vaccine and autism. Now Deer follows the money.

Drawing on investigations and documents obtained under the Freedom of Information Act, the report shows how Wakefield’s institution, the Royal Free Medical School in London, supported him as he sought to exploit the MMR scare for financial gain.

It reveals how Wakefield met with medical school managers to discuss a joint business even while the first child to be fully investigated in his research was still in the hospital, and how just days after publication of that research, which triggered the health crisis in 1998, he brought business associates to the Royal Free to continue negotiations.

One business, named after Wakefield’s wife, intended to develop Wakefield’s own “replacement” vaccines, diagnostic testing kits and other products which only stood any real chance of success if public confidence in MMR was damaged.

Documents reveal the planned shareholdings of Wakefield and his collaborators, and how much Wakefield expected to receive personally. Financial forecasts made available for the first time today show Wakefield and his associates predicting they could make up to £28 million ($43,367,082; €33,290,350) a year from the diagnostic kits alone.

“It is estimated that the initial market for the diagnostic will be litigation driven testing of patients with AE [autistic enterocolitis] from both the UK and the USA,” said a 35 page “private and confidential” prospectus obtained by Deer, aimed at raising an initial £700,000 from investors. “It is estimated that by year 3, income from this testing could be about £3,300,000 rising to about £28,000,000 as diagnostic testing in support of therapeutic regimes come on stream.”

Deer’s investigation also reveals today that Wakefield was offered support to try to replicate his results, gained from just 12 children, with a larger validated study of up to 150 patients, but that he refused to carry out the work, claiming that his academic freedom would be jeopardised. His research claims have never been replicated.

There will be at least one more installment in this series by Brian Deer in the BMJ.

Timeline of MMR scare

11 Jan

From Brian Deer’s latest article in the BMJ“:

Timeline of MMR scare

October 1988: The three in one measles, mumps, and rubella vaccine is introduced to the UK after successful use in the US since 1971. Previously, single measles and rubella vaccines were used, and there was no licensed mumps vaccine

September 1992: The UK Departments of Health withdraw two brands of MMR vaccine after research shows them to be associated with a raised incidence of transient mumps meningitis, although much lower than with natural disease

January 1994: A campaign group, JABS, is launched in Wigan, Lancashire, alleging that MMR causes brain damage and other problems in children. Autism and inflammatory bowel disease are not initially claimed

March 1995: Andrew Wakefield, a researcher at the Royal Free medical school, files for a patent claiming that Crohn’s disease and ulcerative colitis may be diagnosed by detecting measles virus in bowel tissue and body fluids

September 1995: Paediatric gastroenterologist John Walker-Smith moves with most of his team from Bart’s hospital, London, to set up a service at the Royal Free

February 1996: JABS solicitor, Richard Barr, retains Wakefield, at £150 an hour, plus expenses, to support a speculative legal attack on MMR manufacturers. This contract is not publicly disclosed

July 1996: The first child is admitted to the Royal Free for research to try to show a link with MMR. The research is commissioned by, and supported with a £55000 grant from, the UK Legal Aid Board, but this is not publicly disclosed

September 1996: Wakefield and his mentor Roy Pounder meet medical school managers to discuss market projections for a new business based on purportedly diagnosing Crohn’s disease from the presence of measles virus

June 1997: Claiming that the measles virus in MMR causes problems, Wakefield files for a patent on a “safer” single measles vaccine and for products to treat both autism and inflammatory bowel disease. This, too, is not publicly disclosed

February 1998: The Lancet publishes a 12 patient case series by Wakefield and 12 others, proposing a link between MMR and a “new syndrome” of autism and bowel disease. At a press conference, he urges the use of single vaccines instead of MMR

February 1998: Just days after the press conference, Wakefield and business partners meet Royal Free medical school managers to discuss a joint company to develop products based on his MMR claims, including “a replacement for attenuated viral vaccines”

February 1999: Unigenetics is incorporated, with Wakefield and a Dublin pathologist, John O’Leary, as directors. The company is awarded £800000 by the Legal Aid Board to perform tests on samples from children seen at Walker-Smith’s Royal Free unit

December 1999: Mark Pepys, new head of medicine at the medical school, challenges Wakefield about his business scheme and puts him on notice that he must replicate his research

January 2001: The Daily Mail and other newspapers launch campaigns backing Wakefield, working with JABS, after he publishes a purported review of his evidence and repeats his calls for single vaccines

October 2001: Wakefield is asked to leave the Royal Free after failing to mount a large scale controlled study to confirm or refute his claims about MMR

December 2001: Prime Minister Tony Blair is ambushed by Wakefield supporters, who claim that his youngest son, Leo, did not have MMR. The Blairs initially decline to comment but much later deny the claim

May 2002: Amid continuing media campaigns over MMR, particularly by the Mail and Telegraph groups, the magazine Private Eye issues a special edition, written in collaboration with families that are suing vaccine manufacturers

January 2003: Vaccination among 2 year olds falls to 78.9%: below the 92% the Department of Health says is needed to maintain herd immunity. Figures in parts of inner London are half the national rates

September 2003: The Legal Services Commission stops funding for Barr’s lawsuit after barristers for the claimants report to the commission that, on the evidence, they cannot make a case that MMR causes autism

February 2004: The Sunday Times reveals that the Legal Aid Board funded the Lancet research and that many of the children were litigants. Richard Horton, the journal’s editor, rejects more serious charges against the authors, later proved by the GMC

March 2004: Ten of the 1998 paper’s 13 authors, excluding Wakefield, retract its “interpretation” section, which claimed an association in time between MMR, enterocolitis, and regressive developmental disorders

November 2004: Channel 4’s Dispatches reveals Wakefield’s single vaccine patent and that, despite Wakefield’s claims that the culprit for the disorders is measles in MMR, molecular tests in his laboratory found no trace of the virus

January 2005: Wakefield initiates libel lawsuits, funded by the Medical Protection Society, against the Sunday Times, Channel 4, and Brian Deer over Deer’s website, claiming that all allegations are false and defamatory

March 2005: Among much research rejecting any link with developmental disorders and bowel disease, research is published showing that, after MMR was discontinued in Japan, the incidence of autism diagnoses continued to rise

October 2005: In the London High Court, Mr Justice Eady refuses an application from Wakefield to freeze his libel actions and orders him to proceed to trial of Deer’s allegations against his “honesty and professional integrity”

April 2006: As measles outbreaks are reported across Britain, the first death in the UK from the disease in 14 years is reported—a 13 year old boy from the traveller community

December 2006: The Sunday Times reveals Wakefield’s personal funding from Barr to support the lawsuit over MMR: £435643 plus expenses, from the legal aid fund. Some other Royal Free doctors were also paid

January 2007: Two days after the payments from Barr are revealed, the Medical Protection Society stops funding for Wakefield’s libel actions and through him agrees to pay the defendants’ costs of about £800000 on top of its own legal bills

July 2007: At a fitness to practise hearing in London, the General Medical Council opens its case alleging serious professional misconduct by the Lancet paper’s three senior authors, Wakefield, Walker-Smith, and endoscopist Simon Murch

February 2009: The Sunday Times alleges that Wakefield “fixed” the appearance of a link between MMR and autism. He denies fraud and files a complaint with the UK Press Complaints Commission, which he later abandons

February 2009: In the United States, three test case judgments for 5000 claims based on Wakefield’s theories are handed down in federal court, rejecting the allegation that MMR can cause autism. They are upheld on appeal in August 2010

January 2010: A panel comprising three doctors and two lay members gives findings of fact on the GMC’s case, upholding dozens of charges against Wakefield, Walker-Smith, and Murch and sending all three forward for sentencing

February 2010: Six years after the matters were raised with the Lancet, the journal fully retracts the 1998 paper. Horton describes aspects of it as “utterly false” and says he “felt deceived”

May 2010: After a 217 day inquiry, the GMC panel orders Wakefield and Walker-Smith to be erased from the medical register, but notes that Murch had shown “insight” and finds him not guilty of serious professional misconduct

Fact checking the Age of Autism’s defense of Andrew Wakefield

11 Jan

The BMJ article, How the case against the MMR vaccine was fixed, has had a lot of media coverage in the United States. With that coverage has come the defense of Andrew Wakefield, by himself and a few others. As a part of the defense (arguably the bulk of the defense) has been an attack on Brian Deer, the investigative reporter who wrote the article. I say attack because the main accusation, as you will read below, is false. Easily verified as false.

Consider this, on CNN’s Anderson Cooper 360, Mr. Wakefield made the accusation:

WAKEFIELD: Well, that’s interesting you should say that, because he was supported in his investigation by the Association of British Pharmaceutical Industries, which is funded directly and exclusively by the pharmaceutical industry. So…

On CNN with Ali Valshi, Generation Rescue founder J.B. Handley made the following statement:

“The British Medical Journal is only publishing allegations from a single investigative journalist named Brian Deer, who was funded by a pharma front group for four years to investigate Andy Wakefield.”

He later states that Brian Deer was “…funded by pharmaceutical groups from the getgo”.

Where did this accusation come from?

In a blog post, Mr. Handley let’s us know how he came to this conclusion:

In fact, Deer was originally funded to investigate Andy by a front group for the Association of the British Pharmaceutical Industries, just as Andy Wakefield said. From a confidential source:

“Deer was provided with free assistance by Medico-Legal Investigations a company owned and controlled by the Association of the British Pharmaceutical Industry – I have documentation on this. MLI specialise in getting medical doctors prosecuted by the General Medical Council. And that was done before he published in The Sunday Times in Feb 2004.”

We also see the story shifting we also see the story shifting. Instead of “funded from the getgo” or “funded by a pharma front group for four years” we find that he was given “free assistance” We don’t even know how much free assistance.

An unsupported assertion is made that the company is “owned and controlled by the Association of the British Pharmaceutical Industry”.

At least we have something we can verify. A claim like this should be verified, one way or the other. So I did. I contacted Medico-Legal Investigations. I posed a simple question:

You may be aware that Brian Deer has recently published the findings of his investigations showing that Andrew Wakefield committed research fraud in his investigations into MMR and autism. In retaliation, Mr. Wakefield and his supporters are claiming that Mr. Deer is conflicted himself. As part of this, they claim:

“When Brian Deer began his investigation of Andy Wakefield, he was supported by a pharmaceutical front group”

To support this, they claim:

“Deer was provided with free assistance by Medico-Legal Investigations a company owned and controlled by the Association of the British Pharmaceutical Industry – I have documentation on this. MLI specialise in getting medical doctors prosecuted by the General Medical Council. And that was done before he published in The Sunday Times in Feb 2004.”

Can you confirm whether this statement is, in fact, true?

The response?

The statement in bold lettering is totally false. We had no idea he was undertaking this investigation until he was about halfway through. At that point, and knowing that we were the only people in Europe experienced in the investigation of research fraud and misconduct, he contacted us to seek advice on a general issue related to Ethics Committees. We had a one off meeting with him and were able to offer guidance without knowing the details of the confidential investigation. I would like to know how anyone can say we are a pharmaceutical front group – we have always retained our independence.

We have never been owned or controlled by the ABPI – that is complete and utter nonsense. We have been supported by the ABPI and, indeed, the medical Royal Colleges. In order to ease our cashflow crises (there is never enough work to cover the costs of running a business) a few pharma companies paid an annual subscription to us in return for reduced rates for training and investigations. That does not mean that we were controlled by them. I pay annual subscriptions to magazines and get cheaper copies but I do not have editorial control!

Finally we specialise in the investigation of possible fraud/misconduct in research. When we are 70% certain that we have enough evidence to prove serious professional misconduct we report the facts to the GMC who conduct an Inquiry into the allegations. We also investigate other health sector matters and if a criminal offence is disclosed we report to the police or embark upon a private prosecution through the lawyers of our clients (other statutory bodies). The protection of patients is primarily our concern.

I hope this helps

Shall we count the errors in Mr. Handley’s attack?

1) Medico-Legal Investigations had no part in the investigation. They only offered a one-off meeting on medical ethics. Medico-Legal Investigations was unaware of the specifics of Mr. Deer’s investigations.

2) Medico-Legal Investigations is not “owned and controlled by the Association of the British Pharmaceutical Industry”. Thus it is not a “front group”.

3) On top of all that, Mr. Deer was not even funded by Medico-Legal Investigations.

4) The association with Medico-Legal Investigations was a simple meeting, as Mr. Deer was over half way through his investigation. The association was not “from the get go” and was not “four years” (funded or not).

In essence, we see what Mr. Wakefield and his supporters are reduced to: a publicity campaign. Get their message out, accurate or not. Attack the source rather than address the allegations.

Fact checking Brian Deer on Andrew Wakefield

11 Jan

As Kev recently wrote here on LeftBrainRightBrain, the main defense of Andrew Wakefield is not a defense at all, but an attack on Brian Deer. Rather than look at the facts laid out in the BMJ article, people are claiming that Andrew Wakefield couldn’t possibly have “fixed” the data (lead authors can and have do this, see our recent post). Also, that Andrew Wakefield didn’t have access to the full records of the children, so that he couldn’t have known that there were contradictory data in those records.

It is an odd argument in that it concedes that yes, indeed, the “facts” in the Lancet article do not match the children’s medical records.

It is also an odd argument because it ignores the citations that Brian Deer makes in his article. Mr. Deer cites where he gets the information that contradicts Andrew Wakefield’s reports. Many of which are not hidden in the child’s records but were available to Mr. Wakefield at the time he wrote his article for the Lancet.

Mr. Wakefield has reported in his Lancet article (now retracted) that “We identified associated gastrointestinal disease and developmental regression in a group of previously normal children, which was generally associated in time with possible environmental triggers. ”

Emphasis added.

As Brian Deer has noted in his article in the BMJ, this is not the case. Many of the children reported upon were not “previously normal”. We here at LeftBrainRightBrain have the luxury of more space than did Mr. Deer, so let’s check a few of Mr. Deer’s statements, shall we? Let’s look at the children that Mr. Deer commented upon in his article.

Early on in his article, Mr. Deer refers to Child 8. Child 8 was noted as having facial dysmorphisms. Further, the doctors treating Child 8 “…had significant concerns about her development some months before she had her MMR Vaccination”.

Here is a letter sent to Andrew Wakefield on 3 October, 1996. The Lancet article wasn’t published until 1998:

“ Dear Dr Wakefield

[Child 8’s] mother has been into see me and said that you need a referral letter from me in order to accept Child 8 into your investigation programme. I gather this is a specific area of expertise relating to the possible effects of vaccine damage and her ongoing GI Tract symptoms. As far as I am concerned, if [Mrs 8] is happy to proceed with this and it gives her any further information and peace of mind, I am sure it would be beneficial for both her and for [Child 8]. I enclose photocopies of some recent correspondence which gives a fair idea of [Child 8’s] current state. I would simply reiterate Dr Houlsby’s recent comment that both the hospital and members of the Primary Care Team involved with [Child 8] had significant concerns about her development some months before she had her MMR Vaccination. I take Mum’s point that she has video evidence of [Child 8] saying a few words prior to this vaccination being given and her vocal abilities are now nil but I do not think we can be entirely convinced as yet that the vaccine is the central cause of her current difficulties. However, I am quite prepared to support [Mrs 8] in her quest for further information and I hope some useful results come from these tests.

Best wishes.”

emphasis added.

This was presented to the GMC on Day 29 of the hearing. Mr. Wakefield knew Child 8’s physicians questioned whether child 8 was “previously normal” when he wrote the article in the Lancet. It is unclear if Mr. Wakefield sought out those physicians, or if the “recent correspondence” also noted those early signs. But we do know that Andrew Wakefield had more than just the parent’s report on the child’s history and that the physicians disagreed with the parent’s impression. Given the contradiction between the two sources, at the very least, Mr. Wakefield should have sought out the child’s records.

As an aside here, Child 8 was already funded by legal aid at the time of referral. Mr. Wakefield has claimed that children were not already a part of litigation when they were seen by him at the Royal Free. This is also noted in an doctor’s note in the transcripts:

“Mum taking her to Dr Wakefield, Royal Free hospital for CT scan and gut biopsies.
? Crohn’s – will need a letter.
Dr Wakefield to phone me.
Funded through legal aid.”

Again, the child was “funded through legal aide” before referral to Mr. Wakefield.

Here is how Child 4 is reported in The Lancet paper:

One child (child four) had received monovalent measles vaccine at 15 months, after which his development slowed (confirmed by professional assessors). No association was made with the vaccine at this time. He received a dose of measles, mumps, and rubella vaccine at age 4·5 years, the day after which his mother described a striking deterioration in his behaviour that she did link with the immunisation.

“Confirmed by professional assessors”. I find this interesting. One of the defenses of Mr. Wakefield is that “he was just reporting what parents told him”. But, there it is, “confirmed by professional assessors”. Andrew Wakfield had “professional assessors” check the validity of the claims. Have Andrew Wakefield’s supporters actually read the paper?

Was there anything in this child’s records that a “professional assessor” might flag as possibly showing signs of delay before vaccination? Here is the letter from Child 4’s doctor to Mr. Wakefield dated 1 July 1996.

“Following our recent telephone conversation I would be grateful if you could arrange an appropriate ECR appointment for [4] to undergo assessment regarding his possible autism and his bowel problems.

[Child 4] has had long standing difficulties and shows severe learning difficulties and also bowel disturbance and his mother has always found it difficult to accept that there was no known cause for [Child 4]’s disorder. A few years ago she was chasing the idea that he might have a metabolic disorder and I enclose a copy of a letter I wrote to Dr Wraith in Manchester at that time although his reply was he did not see any value in further tests along these lines. I’m aware that you are looking at the possible links between measles vaccine and various difficulties and [Child 4] certainly had MMR in 1988. In general [Child 4]’s mother thinks that he developed normally initially and then subsequently his problems worsened and he lost some of the milestones he had achieved but that he has subsequently improved on something of a restrictive exclusion diet. The professionals who have known [Child 4] since birth do not entirely agree with this however and there is a suggestion that some of [Child 4]’s problems may have started before vaccination.

Since 1994 4 has continued to have intermittent problems with his bowels and diarrhoea that [Mrs 4] relates to food intake; he has had a negative test for celiac disease and has on at least 2 occasions had giardia but he has had no further investigations regarding the cause of these symptoms.

As I say, [Mrs 4] is convinced that both [Child 4]’s behaviour and his diarrhoea are triggered by his diet and she has him on something of a restrictive exclusion diet. He has not gained weight and we have been very concerned about this and [Mrs 4] feels that this is despite him being on a more normal diet. We have therefore not made any assessment as to whether his failure to gain weight might be due to an inadequate diet or to possible malabsorption.

I would be grateful if you could arrange an appropriate appointment and would be very interested if you feel [Child 4] fits into the sort of category of patient that you are interested in looking at further”.

From Day 6 of the GMC hearing. Note that the “…had MMR in 1988” is likely incorrect and that it was the monovalent measles vaccine in 1988.

Again, Mr. Wakefield was alerted to a child having possible problems before MMR administration, but reported the child as “previously normal”. We are left with a question, did Mr. Wakefield just fail to follow up on this possibility or did he know the details and misreport them?

Here is a statement in the child’s records. Whether this was available to Mr. Wakefield at the time of writing the article in The Lancet is unclear:

A delayed development was acknowledged by the health visitor at 1 year of age but at this stage [Mrs 4] did not accept that [Child 4] was slow.

Here is a letter written to Child 4’s physician after his time with the Royal Free team:

“I will write to Dr Wakefield to see if I have any better luck at getting a summary of their investigations and conclusions. [Child 4] had a course of (I think) sulphasalazine after his investigation at the Royal Free Hospital. He became acutely distressed, apparently with abdominal pain and his autism and behaviour did not improve. It was therefore discontinued after a fortnight”.

Apparently, the therapies Mr. Wakefield’s team supplied were not always beneficial.

Let’s move on to Child 1. Mr. Deer reports in the BMJ:

The remaining five children served Wakefield’s claims no better. There was still no convincing MMR syndrome. Child 1, aged 3 years when he was referred to London, lived 100 miles from the Royal Free, and had an older brother who was diagnosed as autistic.76 Child 1’s recorded story began when he was aged 9 months, with a “new patient” note by general practitioner Andrea Barrow. One of the mother’s concerns was that he could not hear properly—which might sound like a hallmark presentation of classical autism, the emergence of which is often insidious. Indeed, a Royal Free history, by neurologist and coauthor Peter Harvey, noted “normal milestones” until “18 months or so.”

Child 1 was vaccinated at 12 months of age, however. Thus neither 9 nor 18 months helped Wakefield’s case. But in the Lancet, the “first behavioural symptom” was reported “1 week” after the injection, holding the evidence for the lawsuit on track.

Here’s the “new patient” note:

“New patient – recently posted from XXXX. Mum worried re hearing/wax in ears/? Discharge left ear … Reassured.” Then “(NB – older brother … ? behaviour probs and ? family dynamics ?)”.

Here’s the statement by Dr. Harvey (of the Royal Free): “after normal milestones a deterioration from 18 months or so”. The referral letter for this child, sent to the Royal Free, states that the child was normal until age 15 months.

Here is a statement from the records at the Royal Free (day 24 of the transcripts):

“Child 1 was admitted for further investigation of his autism and specifically to look into a possible association between his neurological condition and any gastrointestinal disorders. The main problems are a “classical” autism diagnosed a year ago and of diarrhoea.”

On page 50:

“His diarrhoea started approximately 18 months ago. He passes five watery stools a day which contain no blood or mucous. They do contain some undigested food. He appears to have no control over his bowel movements and frequency is increasing. His appetite has always been poor and there has been no obvious change in this. He has only very occasional episodes of vomiting.

He is up-to-date with his immunisations, including his MMR at 12 months of age. There is obvious parental concern that this has some bearing on his subsequent condition.”

Perhaps not consistent, but Andrew Wakefield knew that the child’s records did not place concern until much time had passed since the MMR vaccination.

The “onset of behavioral symptoms” reported in The Lancet does derive from parental report. But not a very strong report. A letter to Andrew Wakefield about child 1 put it like this:

“I saw this interesting child with autism which began some weeks following MMR although there was 7-10 days after the MMR at the age of 1 a brief illness during which he was pale, possibly had fever and his mother said he may have been delirious. [Mrs 1] was keen that you would have a look at a document that she got concerning homeopathic remedies and I am passing this on to you.”

So, Mr. Wakefield reported Child 1 as having first symptom 1 week after MMR. If you include “fever/delirium”. Not exactly an autism symptom. But developmentally the child was noted as being normal until 15 or 18 months? Is that “fixing” data or just something less than accurate?

The Wakefield 1998 Lancet article did not give an accurate picture of these children, based on the records available to Mr. Wakefield at the time. And that is the important fact: Mr. Wakefield had access to information that put his reported findings into question.

The Big Lie – what Andrew Wakefield did was possible and fraudulent

10 Jan

Earlier this week, the blog Child Health Safety published a piece claiming it was impossible for Andrew Wakefield to have acted fraudulently. Earlier today, JB Handley of Age of Autism published a similar piece:

“It was not possible for Wakefield or anyone else to falsify the prior clinical records of the children because no one at the Royal Free Hospital London had them nor is it normal practice for them to have had them. So there could be no fraud over ‘altering’ those histories. It just was not possible.”

Plain English: In Britain, when you are referred from a local doctor to a major hospital, like the one where Andy worked, your previous doctor’s records DO NOT travel with you.

Hmmm. Lets look at the definition of the claim of fraud from the editorial in the BMJ.

The Office of Research Integrity in the United States defines fraud as fabrication, falsification, or plagiarism. Deer unearthed clear evidence of falsification. He found that not one of the 12 cases reported in the 1998 Lancet paper was free of misrepresentation or undisclosed alteration, and that in no single case could the medical records be fully reconciled with the descriptions, diagnoses, or histories published in the journal.

This quite clear – but don’t CHS blog and JB Handley have a point? If Andrew Wakefield couldn’t see the NHS records, how could he have falsified data? He might have been wrong, but fraud? No. If Wakefield couldn’t have seen those NHS records he could not have altered data from them to enhance his Lancet piece.

Except he _did_ see these children’s NHS records. From the very paper itself, we can glean the following:

12 children (mean age 6 years [range 3–10], 11 boys) were referred to a paediatric gastroenterology unit
with a history of normal development followed by loss of acquired skills, including language, together with diarrhoea and abdominal pain. Children underwent gastroenterological, neurological, and developmental assessment and review of developmental records.
Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were done under sedation. Barium follow-through radiography was done where possible. Biochemical, haematological, and immunological profiles were examined.

Developmental histories included a review of prospective developmental records from parents, health visitors, and general practitioners.

This is quite clear. Wakefield saw the NHS records of the Lancet 12. The claim that he didn’t is incorrect at best.

Wakefield’s Lancet Paper – Lancet published vs NHS records

8 Jan

One of the key things that Brian Deer’s reporting has done is thrown doubt on the oft-repeated claims that

a) The papers subjects nearly all suffered from some form of colitis
b) The papers subjects nearly all suffered from regressive autism
c) The papers subjects nearly all regressed in the days following their MMR jab.

Nowhere is the more apparent than in the data tables supplied by Brian Deer in his report for the BMJ. They are replicated below:

In this first table above, the data shows that contrary to Wakefield’s Lancet data which shows 9 out of 12 having regressive autism, the kids NHS records are either inconclusive or negative, giving a _maximum possible_ amount of kids with regressive autism as 6 out of 12. Wakefield et al were ‘wrong’ about at least 3 kids.

In this second table above, the data shows that Wakefield et al Lancet data shows 11 out of 12 kids having non specific colitis. By comparison their NHS records show that 3 out of 12 have non specific colitis. Wakefield et al were ‘wrong’ about 9 out of 12 kids.

In this last table above, we can see that Wakefield reported in the Lancet that 8 out of 12 kids showed symptoms days after MMR. However, according to these same kids NHS records, a _maximum_ of 2 out of 12 showed symptoms days after receiving their MMR. Wakefield was ‘wrong’ about 6 children.

There is supplementary data on bmj.com

The BMJ claim fraud. It is very difficult to disagree with them.