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How the Lancet reviewed the 1998 Wakefield Lancet paper

28 Jan

A recent discussion here on LeftBrainRightBrain involved the peer review process and, in specific, how the 1998 Lancet paper by Wakefield and coworkers was reviewed. As I prepared a response I saw that (a) the response was getting long and (b) this gives a discussion of the peer review process in general, which could be of interest to some readers. So I decided to blog yet again about Mr. Wakefield. So, with apologies to those who have tired of Andrew Wakefied:

Here is Richard Horton being questioned about the general process of peer review of papers for The Lancet (from Day 16 of the GMC hearing). Note that it was typical for 3 referees to be engaged. It has been reported that the Wakefield Lancet paper used 6 reviewers. If so, it is very interesting. Why would the Lancet have gone after extra reviewers?

Lower down, you will find a discussion of the process involved in the Wakefield et al. Lancet paper.

Q Once that process is complete, they have seen the paper and written reports on it, what happens next?
A Those reports back in 1997 would have been sent in my mail, collated by the editor and, when all the reports were available, then he or she would present the paper plus the peer review comments at the Thursday afternoon editorial meeting and the debate would ensue.

Q Is it customary for people who have reviewed the paper to say critical things as well as positive things?
A Extremely, yes, very much so.

Q How do you handle those as far as the authors of the paper are concerned?
A We have two separate components. They say things that they are happy to be transmitted to the authors and they also provide confidential comments that they say they report to the editors, which often presents us with a tricky situation because they are frequently very polite to authors and somewhat less polite when they are discussing a paper in front of us privately.

Q On those parts that they are happy to have relayed to the authors, do you discuss any criticisms that have been made?
A On the Thursday afternoon meetings?

Q Or at all?
A We certainly debate all the pros and cons of the paper at the manuscript meeting and make a decision then whether we are going to reject the paper, seek further opinion or open negotiations with the authors.

Q Will there be, at that state, any general discussion about other matters which might be relevant to publication?
A Certainly we will be discussing whether the paper has aspects of it that might cause controversy and should be considered in judging a paper, whether there are any conflicts of interest that should be taken into account in considering the paper or any other aspects of the work that might have cause for concern.

Q At the end of that meeting, do you then make a final decision as to whether you are going to reject the paper or admit it for publication?
A Three options: either to reject, to open negotiations or to seek further opinion.

Q Can you tell us what open negotiations means?
A That means that if there are questions raised by one or more of the peer reviewers that we think require explanation or further elucidation in a revised manuscript by the authors, then we will go back to the authors and say please can you take a look at your paper, in the light of these reviewers’ comments, and make the necessary adjustments. They hopefully will take account of those questions, submit a revised version of the paper and then we go back into a Thursday afternoon discussion to decide whether that is acceptable or not.

Q The third option you said was to seek a further opinion. Is that over and above the peer reviews you have already had done?
A Yes, that is right. Particularly I would say now that is quite a common option but back in 1997 it was less common.

And here is a discussion of the Wakefield et al. 1998 Lancet paper:

Q Do you have any recollection or are you assuming that it would have been the norm as far as the number of others who were concerned?
A Yes, it would have been the norm to have sent it to three external advisers and a statistical reviewer.

Q Do you have any recollection of the nature of the reviews that were received?
A From what I can recall, there were two aspects that were most important. The first was that all of the reviewers remarked on the original nature of the description of the syndrome and felt that this was something that merited consideration for a general medical journal but there was concern about the reporting of the parents’ testimony relating to a possible temporal link with MMR vaccine.

Q We have the log book for when the paper was first discussed. I think it is right, I should say, so the Panel is clear, the actual reviews are no longer available?
A I am afraid that is so.

Q We do have the log book. If you look in the same volume, page 637, we see, in the middle of the page, the left-hand number is a manuscript number, is that correct?
A Correct. That would have meant it was submitted in November, so the first two digits reflect the month, then the next set of digits the simple sequence with which it was entered up by our office.

Q We are about ten figures down at 11096 “new GI syndrome in children”, is that correct?
A Correct, and JB refers to John Bignall under “Ed”.

Q What is the last column?
A The last column is about the decision about the paper. You can see we received two papers: one describing a new G I syndrome in children, and then a second attempting to define the cause of that syndrome. Both papers were taken through peer review by Dr Bignall. The first one, PP means put points, so a set of manuscript reviewer points were put to the authors, and the second paper was rejected after peer review.

Q As far as the title “A new G I syndrome in children” was that of any legal relevance, the title you have given it there?
A This has been a source of much discussion in the past eight or nine years. Many people have focused on the fact or asked the question was The Lancet in some way supporting the linking of MMR vaccination with this syndrome. From our point of view, when we first received the paper, the parental testimony was actually incidental. The central thrust of the paper was this new syndrome. This is not an uncommon kind of report. If you read any text book of epidemiology, the very first description of any new syndrome often comes with either a case report or a case series. If you go back and look in history at, for example, the first reports of HIV and Aids, the first reports of variant CJD, they all began with a simple case series very much like this one. Then it is quite typical for the investigators to ask, and it is their obligation to ask, the families or the patients “Do you have any thoughts yourself about any behaviours or activities you might have done that might have precipitated this syndrome?” For example, if you go back and look at the first reported series of Aids or variant CJD you see questions like that raised and the answers are very speculative. In this case, again, the answers were very speculative. Eight of the 12 families put potential temporal link with MMR vaccination was made. That was very much supplemental to the major theme of the paper which was this new syndrome.

Q Before I turn you to another page, I just wanted to complete things. As far as the second paper, which you rejected, was concerned, did that come from the same research group?
A It did come from the same research group although I cannot recall, and I do not have a record, of exactly what the authorship of that paper was. I do not recollect.

Q Can you help us as to its nature at all?
A From what I can remember, this was a laboratory study trying to identify what the possible cause of the new syndrome was. From what I can remember, this was an attempt to try to isolate a component of the MMR vaccine with this syndrome.

Q Without that paper, the paper with which we are concerned, the 11096 paper made only the temporal link, is that correct, with the MMR vaccine?
A That is exactly right. Not only did it only make the temporal link but it was made very clear in that paper that such a temporal link was not a proof of association, moreover that there was no published evidence to support any association between the vaccine and the new syndrome.

Q If you turn back to the paper, page 783 and go on to 787, the discussion session, we see, in the left-hand column:

“We did not prove an association between measles, mumps and rubella vaccine and the syndrome described. Virological studies are underway that may help to resolve this issue.

If there is a causal link between measles, mumps and rubella vaccine and this syndrome, a rising incidence might be anticipated after the introduction of this vaccine in the UK in 1988. Published evidence is inadequate to show whether there is a change in incidence or a link with measles, mumps and rubella vaccine.”

Then it goes on to the possibilities of a pre-disposition. Do you recall if that paper was, so far as you can remember, in the original submission, the paper originally submitted?
A Those sentences? I certainly remember that “we did not prove an association”, that sentence, was in the final accepted manuscript, yes.

Q When the paper was submitted to you and considered at the manuscript meeting and logged as we have seen with PP beside it, were various amendments then made to the paper in agreement with the authors?
A Yes, that is absolutely routine practice in peer review. Often quite substantial change to papers are made.

Q Then ultimately a decision has to be taken as to whether to publish with those amendments in place, is that correct?
A Correct.

Q If we go back to page 645 we see, the fourth entry down on that page, 11096, now called “new syndrome in children”, is that correct?
A Correct.

Q We see the editor initials JB and then “accepted as ER”, although it is cut off, is that right?
A Yes. ER stands for early report.

Q Rather than asking you to explain that, I would like to go back to look at a description which is given in a editorial which deals with writing for The Lancet, page 615, on the left-hand side, half-way down the page:

“Early reports may simply be preliminary, the first results from a study, whereas subsequent analysis is planned, for example, of an incidental interesting observation from a study set up with another purpose or they may be early in the sense of being well short of changing clinical practice. These papers will tend to be shorter than articles.”

Does that broadly sum up what is meant by early report?
A Yes. What we were trying to do then – and I should say we have dropped the section Early Reports in more recent years – was to offer the opportunity for researchers to identify something at a very early stage before we were absolutely cast solid certain that what was being reported was totally factual. It gave the opportunity for new ideas, for innovation, to be included in the medical literature which we thought was an extremely important function of a medical journal.

Q This report was categorised as an early report and indeed it appears at the top of the actual paper. Can you help us as to which category it fell into? We see here two categories: the first results from a study where a subsequent analysis is planned, or an incidental interesting observation from a study set up with another purpose. Did you have any need to analyse?
A You are very generous in crediting our categorisation in precise terms. The way we felt about early reports was: is this a preliminary observation; is this raising something that is completely original that requires more in-depth investigation to confirm whether it is absolutely true or not. What we were trying to do in instructions to authors, because you can never cover every eventuality in written guidelines, the closest it would come to would be may be early in the sense of being well short of changing clinical practice.

Q I think it is right that when it was actually published it was published with a commentary.
A Yes. There were several mechanisms that we tried to focus on for making sure that when this paper was published it would not cause an adverse public health impact: one was obviously the statement that was obvious already in the paper about no proof of causation or association; a second was making sure that this paper was identified as an early report; but third, and possibly most importantly, we wanted to have external respected experts in measles eradication and control to offer their view. For us the comments that we published was vital in trying to set the context, which was essentially look at this paper with an open mind but please remember that measles vaccination has saved many hundreds of thousands of children’s lives and in considering this first report do not let it have an adverse effect on measles vaccination.

Q Can I ask you, first of all, how common was it at that the time for you to commission this commentary? You commissioned this commentary, is that correct?
A Yes.

Q How common was it for you to commission a commentary to go with a paper that was being published?
A Not uncommon if we were concerned about the interpretation of a paper but much less common than it is today. I would say today in almost every case a research paper will have a comment running with it.

Q Is the comment sought from somebody wholly independent from The Lancet and the researchers?
A Independent of The Lancet certainly. It is very hard sometimes to have people who are completely independent of the investigators. They are often experts in the field and fields, even globally, are often quite small. They will almost certainly be aware of the research or be aware of the investigators. They may even know the investigators very well professionally but we hope they will give an independent judgment about the quality and meaning of the paper, yes.

Q Your commissioning of it in the context of this paper. You have told us that as far as you were concerned, the reference to the link with MMR was relatively tentatively expressed. Did you nonetheless have concerns about the impact it might have?
A We did have concerns. These concerns were raised by the reviewers of the paper and they were also raised by my colleagues and myself in discussion of the paper on a Thursday afternoon. It was clear that if we were going to move ahead and publish this paper, we had two options: either we erased or asked the authors to erase the parental testimony about the possible temporal association with MMR vaccine or, if we were going to publish, we keep that in, but we give as much context as we possibly can.

Q If we could look at the commentary at page 788, it was commissioned from Robert Chen and Frank DeStefano, who work at the Vaccine Safety and Development Activity National Immunisation Program in Atlanta, Georgia. Is that correct?
A Correct. I think just to clarify, the Centre for Disease Control and Prevention is an internationally recognised centre for public health, based, as it is, in the United States, but with very strong global recognition.

Q If you do not mind bearing with me for a moment, just so the Panel can see what this is about – I am not going to read the whole of this, but if we can just run through it – we can see it says:

“Although immunisations rank among the most important public health measures, no vaccine is perfectly safe. Because vaccines are given to millions of healthy people, usually infants, extremely high standards for vaccine safety are demanded. It is therefore important to examine, critically and with an open mind, the report by Andrew Wakefield and colleagues of several children whose chronic bowel and behavioural abnormalities were linked by their parents and physicians to measles, mumps and rubella (MMR) vaccination.”

Then it sets out the various ways that adverse events of a vaccine can be said to be caused:

“ .. if it is associated with a specific laboratory finding and a specific clinical syndrome or both. Alternatively, a clinical or epidemiological study is needed to find out whether the rate of a given syndrome in vaccinated individuals exceeds that expected among unvaccinated controls. Such studies require acquisition of data in an unbiased way. Because of the inherent methodological limitations of epidemiological studies, biological plausibility, consistency, strength and specificity of association must also be considered in inferring causation. How well then do the features of the association reported by Wakefield and colleagues fit with causality?”

Then they point out:

“First, hundreds of millions of people worldwide … have received measles-containing vaccine without developing either chronic bowel or behavioural problems sine the mid-1960s. This finding provides important negative evidence as well as an appropriate framework for the assessment of [the paper].”

It goes on:

“Is the syndrome reported today clinically unique? Ileal lymphoid hyperplasia is non-specific. Autism was known well before MMR vaccine became available. Are there unique laboratory features, including detection of vaccine viruses in clinical specimens where they would not be expected? Although Wakefield has reported the detection of these viruses in patients with inflammatory bowel disease (IBD), other investigators, using more sensitive and specific assays, have not been able to reproduce these findings.”

Then it refers to a negative report which was actually in the same copy of The Lancet. It goes on:

“There is no report of detection of vaccine viruses in the bowel, brain or other tissue of the patients … ”

Then they look at the epidemiological questions:

“Is there selection bias? The Wakefield report is based on cases referred to a group known to be specially interested in studying the relation of MMR vaccine with IBD, rather than a population-based study. A first dose of MMR is given to about 600,000 children every year in the UK, most during the second year of life, the time when autism first becomes manifest. Not surprisingly, therefore, some cases will follow MMR vaccination. Biased case-ascertainment, as in this study, will exaggerate the association.”

Then it says:

“Was there recall bias. It is usually difficult to date precisely the onset of a syndrome such as autism. Parents and others may attempt to relate its onset to an unusual event such as coincidental postvaccinal reaction. The clearest example of such an association was the link between infantile spasms and pertussis vaccine;”

That is, the whooping cough vaccine –

“ … the vaccine tends to unmask rather than cause the syndrome.

There are other reasons for doubt about the association reported by Wakefield and colleagues. They suggest that MMR immunisation may lead to IBD, which results in malabsorption, consequent neurological damage, and ‘autism’. However, behavioural changes preceded bowel symptoms in almost all their reported cases.”

They go on to say:

“Vaccine-safety concerns gain prominence whenever the incidence of vaccine-preventable diseases falls to negligible levels and when the number of vaccine adverse events, whether true reactions or those coincidental to the vaccination but falsely attributed to it … rises as a consequence of high vaccine coverage. False attribution usually occurs because many developmental abnormalities first manifest in the early years of life, which is also when several vaccines – which can cause crying, fever, and, occasionally, febrile seizures – are given.”

Then it underlines the need for effective and credible systems for the detection of vaccine associated adverse events and it ends, you may think, rather prophetically, by saying:

“Without such a system, vaccine-safety concerns such as that reported by Wakefield and colleagues may snowball into societal tragedies when the media and the public confuse association with causality and shun immunisation. This painful history was shared by the UK (among others) over pertussis in the 1970s after another similar case series was widely publicised, and it is likely to be repeated all too easily over MMR. This would be tragic because passion would then conquer reason and the facts again in the UK.”

You published that commentary in those terms, Dr Horton. Did you feel that that was a responsible way forward, given the concerns which you have expressed?
A At the time, most certainly we did.

Q As far as you were concerned, did it highlight the criticisms which could be made in relation to the paper which you were publishing?
A It highlighted the criticisms that, as I recall, were made at the peer review stage, the concerns about possible bias. It highlighted what we were most anxious about, which was any adverse effect which might follow on MMR vaccination, but it also, fairly, we thought at the time, said, “Treat this study with an open mind.”

Q Did the paper in fact result in a very significant amount of correspondence to The Lancet?
A I think you might say that!

Q You say it in that tone of voice. Tones of voice do not always come over in the transcript. Are you suggesting that it was exceptional?
A Well, remember the context. The context was that when the paper was published, it was not published in a medical journal; it was launched, I think would be an appropriate word, at a press conference where other statements were made which were radically different from the statements made in the paper.

Q As far as the press conference is concerned, I think it is right that you did not attend. Is that correct?
A That is correct.

Q But Dr Bignall, the editor directly involved, did attend.
A That is correct.

Q You obviously cannot tell us anything about the press conference, because you were not present, but what I would like you to deal with is this. Did The Lancet have anything to do with the arranging of that?
A No, it did not, sadly.

Q How usual is it as an occurrence for there to be a press briefing or conference prior to the publication of a scientific paper?
A It is not common, but it is increasingly so, because often institutions, funding bodies and authors themselves want to make a splash of their paper to get more publicity for it, especially if it has something important to say. That can be for wholly good reasons. If there is a concern about the efficacy of a treatment or the adverse effect of a treatment, then it is very important that that gets wide publicity.

Q We have in the bundle an example of some of the correspondence which was generated. If you go to page 818, please – I am not going to take you through all that correspondence, Dr Horton, because I am going to invite the Panel to take some time at the end of your evidence to read the documents which we are producing – but just dealing with it very briefly, from page 818, this is the March edition of The Lancet, the paper having been published in February, we see the first letter, for instance, from the Programme on Immunisation of the World Health Organisation, the second one is from the Department of Public Health at Barnsley Health Authority. Then we have a letter which seems to come from a personal address and then at page 819 one from the Scottish Centre for Infection and Environmental Health. Going over to page 820, one from the Institute of Child Health. Would it be fair for me to summarise it by saying that those letters were mainly concerned with concerns as to the public health implications of the paper?
A Oh, absolutely.

Q We see underneath that on page 821 a reply by Dr Wakefield. Again, would it be the norm for you to give publication room to the author of a paper, if that paper has been the subject of significant criticism?
A Yes, indeed. We would consider it a fair way to conduct the debate that there would be responses, but in the same issue allow the original author to respond or in this case, as you can see, the authors divided in their responses.

Q We see, as you say, one from Dr Wakefield and then one from Professor Murch,
Dr Thomson and Professor Walker-Smith. At the end, we see also your own reply:

“The Lancet has been quick to criticise scientific and journalistic exuberance about the release of data that might unduly aggravate public concern. By contrast with these past episodes and with the implied criticism in the letters we publish this week, the paper by Andrew Wakefield and colleagues is an example of how researchers, editors and those concerned with the public’s health can work together to present new evidence in a scientifically balanced and careful way. Wakefield et al informed the UK Department of Health of their findings in 1997 and supplied them with a final copy of their Lancet paper in advance of publication.”

You then say, “(Wakefield A.J, personal communication)” So this arose as a result of information which Dr Wakefield gave to you. Is that right?
A That is right, yes.

Q You say, “There are at least four parts to this story.”
A I should just say, I do not have the second page of that. It goes on.

Q I think that is the end of your reply in relation to the correspondence.
A I think I probably would have gone on to explain what the four parts of the story were. Otherwise it would have been an extremely negligent reply on my part.

Harris poll: Slightly More Than Half of Americans Say Vaccines Don’t Cause Autism

20 Jan

I expect this to be taken as a great victory. The vaccine hypothesis is a part of the national psyche, according to a Harris Poll, recently released.

The poll states that:

Just a slim majority of Americans — 52 percent — think vaccines don’t cause autism, a new Harris Interactive/HealthDay poll found.

Conversely, 18 percent are convinced that vaccines, like the measles-mumps-rubella (MMR) vaccine, can cause the disorder, and another 30 percent aren’t sure.

Of the 18%, 2% felt that it was “certainly true” and 16% “probably true”.

Why will this be considered a victory? A while back an article in Pediatrics discussed vaccine fears, and had this quote:

“Our study indicates that a disturbingly high proportion of parents [25%] continue to believe that some vaccines cause autism in otherwise healthy children.”

That report was met with the following statement by the founder of Generation Rescue, JB Handley:

With less than a half-dozen full-time activists, annual budgets of six figures or less, and umpteen thousand courageous, undaunted, and selfless volunteer parents, our community, held together with duct tape and bailing wire, is in the early to middle stages of bringing the U.S. vaccine program to its knees.

and he felt those in his “community” were responsible:

Community, prepare to take a bow, America is listening.

The idea that 18% definitely believe in vaccine causation is a big step, demonstrating that the idea has become common.

I will not that this is down from the Pediatrics poll (25%) which caused the “take a bow” blog post. But 18% is a sizable amount of the population, and this may not be a significant difference given different methodologies.

Even people who believe in vaccine causation are still mostly getting vaccinated, which brings up a very interesting question of how strongly they believe in the idea. It is one thing to say, “in some very rare cases, vaccines might cause autism” and “there is an epidemic of autism caused by vaccines”. Those who believe in the vaccine-induced epidemic would be, in my naive view, much less likely to vaccinate.

The poll also found that parents who have lingering doubts about the vaccine were less likely to say that their children were fully vaccinated (86 percent), compared to 98 percent of parents who believe in the safety of vaccines.

About 47% of those polled were aware that the Wakefield Lancet study was retracted and/or that it was declared fraudulent. That is huge. How many people are aware of any research paper that is 12 years old?

But here is a very telling result:

Still, the retraction and allegations of fraud do seem to have influenced public perception. Among those who had been following the news about Wakefield, only 35 percent believed the vaccine-autism theory, compared to 65 percent who had not kept up to date on the latest developments.

Informing the public about the retraction of the Lancet study and about Mr. Wakefield’s ethical lapses is having a big effect on reducing the belief in vaccine-causation.

More detailed information can be found here.

Andrew Wakefield’s “do not re-vaccinate” letter

20 Jan

I keep thinking I’ve left the Wakefield story behind. Believe me, I want to. It isn’t easy being repeatedly reminded of a man who subjected disabled children to invasive tests, many of which were not in the clinical best interests of the children, in order to collect data for a litigation driven study. The letter below keeps sticking in my mind. It was blogged by others years back, but I keep thinking that it is worth putting out in the public’s eye once more.

Why? Two reasons.

First it addresses Mr. Wakefield’s defense that his concerns about the MMR vaccine were based on a 200 plus page report he generated. I’ve never seen this report and would welcome a link if someone could provide it. The letter below is from September 1996. To put this in perspective, the first of the Lancet 12 children was seen at the Royal Free in July of that year. So this goes to the state of mind at the time of the Lancet 12 study.

Second, this letter addresses one of Mr. Wakefield’s current methods of deflecting criticism: by claiming he never told people to not vaccinate. Well, he told a senior health official in the UK to stop a vaccination program. Does that count? He even emphasized it. At the bottom of the letter below, he tells the Chief Medical Officer to abandon the plan to re-vaccinate children before entrance to preschool. “Do not re-vaccinate”

As to his state of mind at the time, it is clear from the letter below that in Mr. Wakefield’s mind, the key issue at hand was his hypothesis that the MMR vaccine caused a persistent measles infection, resulting in bowel disease. Strangely, he wrote this just as his own group had just published a paper showing no evidence for measles virus in blood or tissue samples from patients with IBD. Yet he doesn’t appear to cite his most recent work and, instead, states “Persistent infection following vaccination is, therefore, not only biologically plausible but likely.”

Based on this letter, I’d be willing to bet that a substantial portion of Mr. Wakefield’s 200+ page analysis of measles vaccine safety is an attempt to bolster support for his own ideas of persistent measles infections, comparing single measles vaccines to the combined MMR. It is an idea which failed (e.g. here and here)

The discussion below is from day 26 of the GMC hearing, where the letter was read into evidence (one of a few times). GMC comments are in bold. The letter is in regular text.

Thereafter, I want to take you on to the next correspondence from Dr Wakefield which was in September 1996 and is at page 193. This is a letter from Dr Wakefield directly to Dr Calman, the Chief Medical Officer, and there is a manuscript note at the top indicating that it was handed on to you. I do not propose to read again the whole of it and others may wish to take you to other parts, professor, but may we run through it.

“Dear Dr Calman,

I am writing to you in order to express formally my anxieties over your intention to re-vaccinate all pre-school children prior to school entry. I will not go over the history of our exchanges on this subject; this will emerge at the appropriate time.

I feel sure that your independent expert advisers will have alerted you to the detection of vaccine-strain measles virus in children with autoimmune hepatitis, a disease in which measles has been implicated previously on evidence far, far more tenuous than our own for measles and Crohn’s disease.

Doubtless they have also informed you …”

and he then goes into the characteristics of the measles vaccine that he suggests are relevant.

“Persistent infection following vaccination is, therefore, not only biologically plausible but likely.

You will also have seen our recent paper in the Lancet which provides what many consider to be compelling evidence of a causal association between measles and Crohn’s disease following exposure in utero. No doubt your experts will be able to reassure you on this particular issue.

In the future you may have cause to reflect on the ‘independence’ of your appointed experts. Certainly, Dr Miller from the PHLS and Professor Minor of NIBSC cannot be considered independent. If I and my colleagues are right, then they are wrong. Their scientific and professional standing and credibility is inextricably linked to the success of measles vaccination. You may also wish to consider the value of their advice with respect to the depth of their knowledge about measles virus. I refer specifically to comments made by Dr Miler and yourself in letters to the Lancet following the ’94 revaccination campaign (following which paediatric IBD cases have increased dramatically).

In your letters you quote from a letter to the Lancet provided by Professor Herman-Taylor …”

and we have heard his name of course in relation to his theory about Crohn’s Disease.

“Hermon-Taylor illustrates that the emergence of Crohn’s disease in the 1940-50s in the UK took place before either the disappearance of measles epidemics, or the introduction of measles vaccination. Hermon-Taylor puts this forward as categorical evidence that neither measles nor measles vaccine can possibly be the cause of Crohn’s disease, which you and your experts endorse. This is a superficial and naïve perspective that reflects a profound lack of understanding of either the changing pattern of morbidity and mortality from measles in the UK leading up to the emergence of IBD, or the risk factors for persistent infection and delayed disease that are associated with measles virus infection.”

He then sets out his arguments in relation to the rising incidence of Crohn’s disease in three UK centres plotted against measles notifications in England and Wales with graphs indicating that or purporting to do so and he then says,

“It is my concern that the expert advice that you have received has been deficient, and far from independent. If and when the dam bursts it will be you and your department that is standing in the way. We, for our part, have tried to help, only to have our work denigrated and misrepresented. We went into this with our eyes open and will continue to generate peer-reviewed, published data in the true scientific spirit: there is a vast gulf between this and opinion. You may wish to ask your experts what are the longest prospective safety trials of measles vaccine, MMR, and measles re-vaccination at any time, anywhere in the world. The result may surprise you.

Do not re-vaccinate.”

The emphasis in “Do not re-vaccinate” was his, not mine. He chose to underline (which for some reason doesn’t work for me on this blog).

Again, my guess is that the 200+ page report he created critiquing MMR vaccine safety relied heavily on the now disproven link between IBD and measles infection.

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)

Bernie Marcus Sides with Autism Scientists in British Study

19 Jan

I’ve known for a while that Home Depot included autism coverage in their employees insurance benefits. I must admit I didn’t know that their co-founder was so involved with the autism community. Bernie Marcus, co-founder of Home Depot, founded an autism center in Atlanta: the Marcus Autism Center.

Well, Mr. Marcus has stepped forward during the high media attention surrounding the BMJ articles discussing research fraud by Andrew Wakefield. The story, Marcus Sides with Autism Scientists in British Study, is from Channel 11 in Atlanta:

http://c.brightcove.com/services/viewer/federated_f9?isVid=1

I admit that when I read the title of the news piece, I thought he was siding with the “scientists in the British study” as in siding with Mr. Wakefield. No, he is siding with the scientists

“You have two schools of thought, and then you should have this scientific group in the middle that doesn’t have any political agenda that just cares about the kids,” Marcus said. “I’ve tried to associate myself with that group of people that doesn’t necessarily agree or disagree.”

and

“Everything that comes back is the same,” he said. “They cannot find any connection between immunization and autism.”

Marcus has been directly involved in Autism research and treatment for more than 20 years. He founded and funded the nation’s leading center for autism treatment. Now in its 10th year, the Marcus Autism Center has already treated more than 30,000 youngsters, as well as providing family support and counseling.

It’s great to hear someone taking a stand but in a very down-to-earth, non confrontational manner.

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.

Salon retracts RFK Jr. article

16 Jan

In 2005, Salon published online an exclusive story by Robert F. Kennedy Jr. that offered an explosive premise: that the mercury-based thimerosal compound present in vaccines until 2001 was dangerous, and that he was “convinced that the link between thimerosal and the epidemic of childhood neurological disorders is real.”

The piece was co-published with Rolling Stone magazine — they fact-checked it and published it in print; we posted it online. In the days after running “Deadly Immunity,” we amended the story with five corrections (which can still be found logged) that went far in undermining Kennedy’s exposé. At the time, we felt that correcting the piece — and keeping it on the site, in the spirit of transparency — was the best way to operate. But subsequent critics, including most recently, Seth Mnookin in his book “The Panic Virus,” further eroded any faith we had in the story’s value. We’ve grown to believe the best reader service is to delete the piece entirely.

“I regret we didn’t move on this more quickly, as evidence continued to emerge debunking the vaccines and autism link,” says former Salon editor in chief Joan Walsh, now editor at large. “But continued revelations of the flaws and even fraud tainting the science behind the connection make taking down the story the right thing to do.” The story’s original URL now links to our autism topics page, which we believe now offers a strong record of clear thinking and skeptical coverage we’re proud of — including the critical pursuit of others who continue to propagate the debunked, and dangerous, autism-vaccine link.

Well done Salon.

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.”

Wakefield says he’s innocent of fraud…in other news sky still blue

13 Jan

And so…

I want to make one thing crystal clear for the record – my research and the serious medical problems found in those children were not a hoax and there was no fraud whatsoever. Nor did I seek to profit from our findings.

Yeah there was. Yeah you did.

“I stand by the Lancet paper’s methodology and the results which call for more research into whether environmental triggers cause gastrointestinal disease and developmental regression in children. In fact, despite media reports to the contrary, the results of my research have been duplicated in five other countries.

Your paper was fatally flawed. Your research has never been replicated.

“It is not unexpected to see poor reporting and misinformation coming from Brian Deer, the lead reporter of the recent BMJ coverage.

Oooooh, biatchy!

But to see coverage in other media that cites Deer’s shoddy journalism in the BMJ as a final justification to claim there is no link between vaccines and autism is ludicrous.

Who did that? I think most journalists made the link between the MMR and autism, not ‘vaccines’ and autism.

The MMR is only one vaccine of the eleven vaccinations on the pediatric schedule that has been studied for causing developmental problems such as autism. That is fact, not opinion.

Studied and guess what – nothing found AJ!

Any medical professional, government official or journalist who states that the case is closed on whether vaccines cause autism is jumping to conclusions without the research to back it up.

Blah blah blah.

“I continue to fully support more independent research…

Quackery…

…to determine if environmental triggers, including vaccines, are causing autism and other developmental problems. The current rate of autism is 1 in 110 children in the United States and 1 in 64 children in the U.K. My goal has always been and will remain the health and safety of children.

No it hasn’t.

Since the Lancet paper, I have lost my job, my career and my country.

Oh stop being a primadonna. Lost your country?

To claim that my motivation was profit is patently untrue. I will not be deterred – this issue is far too important.

Yeah, you need to find a way to recoup all that lost dosh right?

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