GENERAL MEDICAL COUNCIL
FITNESS TO PRACTISE PANEL (MISCONDUCT)
Friday 19 October 2007
Regents Place, 350 Euston Road, London NW1 3JN
Chairman: Dr Surendra Kumar, MB BS FRCGP
Panel Members: Mrs Sylvia Dean
Ms Wendy Golding
Dr Parimala Moodley
Dr Stephen Webster
Legal Assessor: Mr Nigel Seed QC
WAKEFIELD, Dr Andrew Jeremy
WALKER-SMITH, Professor John Angus
MURCH, Professor Simon Harry
(Transcript of the shorthand notes of T. A. Reed & Co.
Tel No: 01992 465900)
A P P E A R A N C E S
MS SALLY SMITH QC and MR CHRIS MELLOR and MR OWAIN THOMAS of counsel, instructed by Messrs Field Fisher Waterhouse, solicitors, appeared on behalf of the General Medical Council.
MR KIERAN COONAN QC and MR NEIL SHELDON of counsel, instructed by Messrs RadcliffesLeBrasseur, Solicitors, appeared on behalf of Dr Wakefield, who was not present.
MR STEPHEN MILLER QC and MS ANDREA LINDSAY-STRUGO of counsel, instructed by Messrs Eastwoods, Solicitors, appeared on behalf of Professor Walker-Smith, who was present.
MR ADRIAN HOPKINS QC and MR RICHARD PARTRIDGE of counsel, instructed by Messrs Berrymans, Solicitors, appeared on behalf of Professor Murch, who was present.
I N D E X
IAN WESTERBY BOOTH, continued
Re-examined by MS SMITH, continued 1
Questioned by THE PANEL 9 Further re-examined by MS SMITH 26
Amendments to charges 28
SIR PETER JULIUS LACHMANN, Affirmed
Examined by MS SMITH 39
THE CHAIRMAN: Good morning, everyone. Ms Smith, I think you were just about to commence the re-examination.
MS SMITH: Yes, that is correct.
IAN WESTERBY BOOTH, continued
Re-examined by MS SMITH
Q Professor Booth, I want to take you back briefly over one or two of the matters that you have covered in your evidence when you were questioned by Mr Miller and Mr Hopkins. On a number of occasions Mr Miller has suggested to you in effect that when you were considering whether a colonoscopy was clinically indicated you were expressing a personal view which differs from that of the doctors at the Royal Free Hospital with whom we are concerned. You described the reasons for the investigations that you have criticised as being “off piste”. Could you explain to us what you meant by using that phrase in that context?
A What I was meaning was that, in my opinion, many of the indications for carrying out colonoscopy in the children that we had been considering would lie outside accepted clinical practice.
Q When you have considered for the purposes of your reports and indeed in the questions you have been answering over the last few days whether these investigations were clinically indicated, were you doing that by reference to that conventional clinical practice or simply by reference to what you yourself would have done in similar circumstances?
A I think probably both sets of criteria. I think I work clinically within accepted guidelines of clinical practice.
Q By reference to that accepted or conventional clinical practice are you critical of the decisions that were made by the two clinicians at the Royal Free in relation to the colonoscopies in those cases where you have said it was inappropriate?
A In those cases where I thought it was inappropriate, yes.
Q Mr Hopkins asked you a number of questions about the indications for colonoscopy in the literature, including those set out in what has been referred to as The Porto Criteria. I want to ask you, first of all, a few specific questions about those particular criteria, if that is the right word for them, and then some more general questions about the indications in the medical literature. Could I ask you to find Professor Murch’s literature bundle, please? The relevant document is behind divider 9. Although the word “guidelines” has crept into the questioning that you have been asked, we see that it is termed a medical position paper, is that correct?
Q The Porto Criteria was the title put on it by the authors. Presumably it arose out of a medical meeting that took place in Portugal?
A Yes, I think it was the second meeting of the group that was held in Portugal.
Q If we look behind divider 8, that is a document that Mr Hopkins took you to briefly and that is the preceding document by this group, is that correct?
Q We see that Professor Murch is indeed the coordinator at that time and at the bottom of the page that all correspondence was to therefore be directed to him. There were documents prior to that but that seems to have been the first one looking at these issues. If you go back to the one behind divider 9, do guidelines normally include recommendations if they are in a formal sense?
Q Looking at the concluding remarks on page 55, Future Plans:
“Current validation of the Porto diagnostic criteria presented here and further collaborative studies by the group are described in the appendix.”
There is a short appendix about the plans to audit a database of paediatric IBD patients which is at pages 56-57. Then we see Concluding Remarks:
“Collection of information on disease expression at presentation, characteristics during the course of disease, potential predisposing factors, extraintestinal manifestations, treatment course, surgery and outcome will generate knowledge about early onset IBD. The essential first step is uniformity in the work-up and criteria used for diagnosis. The Porto diagnostic criteria presented here provide the tool that is needed.”
That was the view of the authors as to the aim, is that correct?
Q You said when you were discussing these with Mr Hopkins that they were not evidence-based.
A Not in the accepted sense of the term that evidence-based guidelines is now used, that is correct. It is not true to say there is no evidence in the guideline. It has not been reviewed in a systematic way.
Q Is there an expectation in formal guidelines? You have told us that they would normally make recommendations. Is the strength of those recommendations classified with some sort of coding system?
A Yes, normally the review team would gather together all the references having done a defined literature search and then go through them one by one and determine whether or not the publications met the predefined inclusion criteria with regard to quality of publication for further consideration or not and a lot would be thrown out at that stage, and then those that remain in are then classified according to the quality of the evidence so that it might be of low quality; it might just be a single case report or something like that. It may be a single author review. It may go through to the best quality of evidence which would be a meta-analysis which is an analysis of multiple clinical trials, for example.
Q As you have said, we do not see recommendations here and certainly no kind of waiting of any recommendations. Guidelines which do not comply with such a system obviously they have a use but how useful are they?
A I would hesitate to say that they are used less but what I would say is that, for example, in the Royal College of Paediatrics and Child Health in this country when I was chairing the academic board we considered the criteria for publishing guidelines and agreed about 10 years ago I think it would have been that we would not publish or put the name of the college to guidelines that were not produced in a systematic way along the lines that I have described and that is practice that has also been in place with the British Society of Gastroenterology with its guidelines for maybe 10 or 12 years and it is also the practice of the collaboration between the Scottish Royal Colleges of Physicians and Surgeons, so those organisations would not consider publishing this kind of document.
Q Going to a related matter, you said both on the first day of Mr Hopkins’ cross-examination of you and yesterday that you cannot in any event you said just apply lists of criteria you have to apply clinical judgment and if it were a question of just ticking off symptoms against a list you pointed out that we would not need medical specialists. Just looking at the criteria for a moment which are at page 52, if this list was indeed meant to be read in the way that Mr Hopkins has suggested to you as separate symptoms which would raise the suspicion of IBD and trigger all the investigations relating to IBD, that would suggest that if a child had two episodes of diarrhoea in six months they should have a full work-up for IBD, including colonoscopy. Would that be a surprising conclusion in your view?
A Yes, it would. It is the conclusion if you interpret the statements here literally which is why I think interpreting them with a lot of mature clinical judgment is important.
Q With regard to the colonoscopies you have referred to a paper which we have already looked at in the context of one of the important considerations being what you described as “diagnostic yield” and that was a paper by Professor Walker-Smith, do you recall?
Q I wonder if we could look at that now. It is in Professor Walker-Smith’s bundle of literature at tab 5. It is a 1993 paper by Professor Walker-Smith. If we straight to the table that I think you were referring to, which is page 41, table 1, the presenting symptoms of 191 new referrals proceeding to colonoscopy, is that correct?
A That is correct, yes.
Q If we just look at that table, Professor Booth, can you explain what you mean by diagnostic yield being a consideration when you all decided whether to do a colonoscopy or not, with reference to that table. Just explain to the Panel, if you would.
A This is a retrospective analysis of 191 children that were being referred to, I think it was, St Bartholomew's Hospital under the care of Professor Walker-Smith. These children went on to have colonoscopies. When you compare whether or not the colonoscopy was abnormal or not, with the main presenting symptoms, which are those listed down the left-hand column, you find that there are marked differences in whether or not the endoscopy was likely to be abnormal. So I was using ‘diagnostic yield’ in the sense of likelihood of an abnormal colonoscopy. You can see that the percentages of children who have an abnormal colonoscopy vary substantially from abdominal pain only, where nought per cent had an abnormal colonoscopy; diarrhoea only, 11 per cent; and so on. So although these figures I think should not be considered as absolute by any means, the point I was making was that the diagnostic yield does vary substantially according to the symptoms that the patient presents with. That is why I had major reservations about accepting the recommendations that were in the Porto Criteria, amongst many other reservations about the Porto Criteria.
Q If you are faced with a child who, if you were to apply a check list, had one symptom or two symptoms which could be attributable to inflammatory bowel disease, and you had to make a decision about whether to undertake invasive investigations on that child, would you take into account at least in broad terms how likely you were, from scientific literature of this kind – whether it was worth doing? In other words, whether it was likely to show you something?
A Yes, I think you would take into account this sort of information. I have to say that the information here presented by Professor Walker-Smith would, I think, very much accord certainly with my experience of the likelihood of getting an abnormal colonoscopy. Even within this kind of examination, though, I think it still comes down to a kind of check-box mentality, and I think that formulating a differential diagnosis is more sophisticated than that, as we have discussed.
Q As far as your point that it is not just a question of ticking a series of symptoms on a list, it is a question of exercising clinical judgement, is that an example of the sort of clinical issue that you are going to be weighing in your own head – not Professor Walker-Smith’s paper, but the contents ---
A Yes, absolutely.
Q --- and whether it is going to be worth it?
Q With respect to the Royal Free Hospital children we have looked at, and whose treatment you have criticised, do you think that that clinical judgement in the broad terms that you have described was exercised within an acceptable range of practice?
A No, not in every case, no.
Q Those where you do accept it was, you have identified.
Q It has been suggested to you that the threshold for colonoscopy was lower at the Royal Free Hospital, and you said that on the basis of the children’s cases that you have looked at, you would not argue with that as a proposition. Do you think that that threshold was within acceptable limits?
Q Turning, if I may now, to another completely separate matter, when Mr Miller was asking you about project 172/96, he suggested to you that these children could not be part of that study because they plainly did not qualify with disintegrative disorder. Of course it is right to say that they did not have disintegrative disorder, on the evidence we have, but I just want to ask you to look at three examples of the records.
Sir, these are all Royal Free records and I will give you all the children at once so you do not have to keep jumping up and down. The Royal Free Hospital records for Child 4, Child 7 and Child 10, please – volume 2 of Child 10.
Can we look at Child 4 first, please, at page 5, the admission clerking note – are you with me?
Q We see at the top:
“Admitted for study of disintegrative disorder/colitis/ MMR.”
Is that correct?
A That is right, yes.
Q I will ask you the questions at the end. Could we then look at Child 7, please. Again, the admission clerking note at page 6:
“Admitted to Malcolm Ward for colonoscopy and investigations as part of the disintegrative disorder/colitis study”.
Is that correct?
Q Then Child 10, please, at page 11 of volume 2:
“Admitted for investigation of disintegrative disorder/measles/IBD.”
There are, as you are aware, other examples, but in respect of those as examples, Professor Booth, if these doctors are now saying that these children were never part of project 172/96, and it is obvious that they could not have been part of project 172/96 because they did not have disintegrative disorder, do you understand those references?
A No. They seem to be inconsistent with what is written in the notes here.
Q I now want to turn to some of the last matters that Mr Hopkins asked you about, and I would like you to put away those records – I promise that this is the last lot I am going to look at – and get out instead the Royal Free records for Child 2 and Child 1. Child 2 first of all, so we can keep them in the right order. Mr Hopkins took you to page 263A. That is the request for the histology, and he suggested to you that it was clear from that that the reason for the colonoscopy was suspicion of Crohn's disease. I do not know if you remember that exchange?
Q You pointed out that that was written post the colonoscopy.
Q I just want to contrast that with what it says on the colonoscopy report itself, which is at page 247. We see there the history of disintegrative disorder, and further down the page:
“This colonoscopy was performed in the further investigation of disintegrative disorder, and was in fact abnormal.”
On that document, if the colonoscopy had been performed because of a suspicion, or whatever word you like to use, a concern, that Crohn's disease might be present, would you have expected it to say so?
A It might have said “Suspected Crohn's” or it might just have enumerated the symptoms that the patient had that was the indication.
Q Staying with this child, Child 2, Mr Hopkins suggested to you on two or three occasions that Professor Walker-Smith having originally, as you will recall, expressly said that he did not think the child had Crohn's disease, he suggested to you that Professor Walker-Smith concluded that there was some other kind of inflammation present. Would you go to page 130, please. This is the letter to the GP:
“I … saw  in the clinic. As you know I first met [Mrs 2] via Dr Wakefield who is concerned with measles immunisation and possible Crohn's disease. I think Crohn's disease is unlikely. Dr Wakefield has the view that there may be some [other] kind of inflammation which may be a relevant factor in [his] illness and we now have a programme for investigating … [that].”
Does that suggest to you that Professor Walker-Smith’s view had changed?
A It indicated that he was still of the view that Crohn's disease was unlikely.
Q Yes. The view as to the other form of inflammation that may be present, does that appear to you from that letter to be Professor Walker-Smith’s view?
A Yes. He is saying that Dr Wakefield has a view, and he is saying “We will therefore investigate” – the implication is they are investigating for that other type of inflammation.
Q Lastly – I am not going to take you to it – with Child 2, you were taken to a number of blood tests which had been performed on this child, which were indeed not part of project 172/92; do you recall?
Q I simply want to ask you this: it does indeed appear that there were other bloods tested. Does that affect your view that the protocol investigations were carried out in accordance with project 172/96?
Q I am sorry, I said blood; I should have said CSF. I do beg your pardon. Putting that one on one side and looking at Child 1, the same point as I made on the first one above – and I should say that there are other examples of this to be found, but I will not trouble the Panel by going over them all again. Page 100C; Mr Hopkins took you to this. Again it is a request for histology, and we see “Query IBD”, and you made the same point, that that was post the colonoscopy. If we look at page 100, please, the only history that is given is that of disintegrative disorder, is that correct?
A That is right.
Q I think you have already made the point, but would you expect the history given to be relevant – obviously relevant in the operator’s mind – to the investigation which is being undertaken?
A Yes, absolutely.
Q That is all I have to ask you about the individual children, but I want to ask you one general question. It has been suggested to you by Mr Hopkins that the findings justified the investigations in the next patient. I want to ask you this. There was a constellation of symptoms in these children in relation to their gastrointestinal histories, as we heard, and we have also been hearing about the various behavioural diagnoses. In circumstances where the patients do not have the same constellation of symptoms, is it in your view a valid justification to go on to the next one, because of what you think you may have discovered in the one before?
A No, I think if each patient is being assessed individually then it is appropriate to decide on the investigations that are going to be carried out on the basis of your assessment in that particular child – which is an issue which has been addressed in the literature with reference to children with autism.
Q Yes. You have referred to two documents, Professor Booth, and that is one of them, a number of times when you have been answering my friend’s questions. I will take you to those in a moment. Lastly I want to ask you, because I think I should: for some reason Mr Hopkins has asked you questions in relation to a matter which does not affect his client at all, which is this issue in relation to the evoked potentials that were ordered when the control value was not available. You have said, and it must be the case, that there is a duty on the person for whom such a test is ordered, to point that out. I want to ask you this. If a researcher orders such an investigation, regardless of the duties of those from whom he ordered it, would you expect him to be aware of whether it was interpretable or going to be potentially useful?
A Yes. What would normally happen would be that if you were wanting to carry out some research-driven investigations on a patient, firstly you would go and speak to your particular colleague and tell them why you were referring patients, show them the protocol, make sure that they were happy with it, and as part of that conversation you would want to clarify and confirm with them that if you referred patients to them, they could actually give you a meaningful, interpretable answer from the investigation.
Q Lastly, the literature. You have referred to two documents which are not in the bundles of literature produced by anybody and I simply want to put those in. The first is a paper you referred to in the context of lymphoid nodular hyperplasia in constipation. Perhaps we could just hand that one out first.
THE CHAIRMAN: (Same handed to the members of the Panel and marked as exhibit C16). So this first paper, “Hyperplasia of Lymphoglandular Complexes in Colon Segments in Hirschsprung's Disease” would be C16.
MS SMITH: Thank you, sir. I do not propose to go through it with you, Professor Booth. I would just simply like you to tell the Panel, now that they have it to look at at their leisure, what the point was that you were referring to in relation to it.
A The point was that it highlights the need to consider other possible interpretations of the finding of lymphoid nodular hyperplasia and some mild degrees of colonic inflammation in a group of children, many of whom, most of whom had constipation other than inflammatory bowel disease. There are other explanations related to constipation and stagnation in the colon.
Q That is the first paper. The second you have referred to, and you just did it a few moments ago with me, was a commentary to a paper that is already in Professor Murch's literature. Perhaps we can hand that out, please, now and then I will take you to where it relates to in the literature. This will be C17, sir.
THE CHAIRMAN: (Same handed to the member of the Panel and marked as exhibit C17). This second paper, The Journal of Paediatrics, November 1999, would be C17.
MS SMITH: If we can now look just to orientate ourselves in Professor Murch's literature at tab 5. This is a paper from Baltimore in the US and published in 1999. I am not going to take you through it. If we can just go straight to the end so we see what it is about, page 28, left hand column at the bottom of the page:
“In summary, our findings suggest that gastrointestinal abnormalities may contribute to some of the behavioural problems frequently described in these children.”
If we go back in it we see on the first page, at page 24, the bottom right hand column, there is indeed a reference to a Lancet article, the Wakefield et al paper. The document that you have referred to is the commentary which was published with that and the Panel will recall that the Lancet paper had a commentary published with it. This is the commentary that was published with the paper that Professor Murch has produced. I think the relevant part, Professor Booth, for the points that you were making yesterday, but tell me if there is anything else that I have not gone to, is on the last page of that commentary. I do not want to take it unfairly out of context, so going to half way down the column where it says, “The study by D'Eufemia et al intriguingly demonstrates consistent physiological abnormalities in autism that are not known to occur in any other specific gastrointestinal disorder. The correlation of these findings with clinical symptoms and it is chronic diarrhea and its response to secreted administration provide further support for a true physiological abnormality.”
Then the part to which you have referred is at the bottom paragraph:
“Should the practitioner refer all his or her patients with autism for an extensive gastrointestinal evaluation. No because the general rule remains the same for all medical concerns in children with autism. There are no bio medical tests or procedures for which autism is, by itself, a sufficient indicator. A child with autism and specific gastrointestinal symptoms should receive a referral for further evaluation on the same basis as a child with symptoms of similar severity but without autism.”
Was that the point you were making?
MR HOPKINS: I wonder, could you read on, please, in fairness.
MS SMITH: I am intending to do so and I have already indicated that I am not going to take it out of context. Is that the point that you were making, Professor Booth, when you were answering?
Q It then goes on:
“Neither should the presence of autism be used to downplay the significance of such symptoms. It is not acceptable for a child with autism to have investigated chronic diarrhoea because the developmental condition makes assessment more difficult.”
I imagine you would entirely agree with that as well?
A Yes, I would.
MS SMITH: Thank you very much, Professor Booth. Thank you, sir. I have no further re examination of this witness.
THE CHAIRMAN: It is about quarter past 10. Professor Booth, as I did indicate earlier, the Panel are entitled to ask you any questions.
A Yes, sir.
THE CHAIRMAN: Before they do, I think they will have to go through some of your notes. We have already done some work on it yesterday afternoon, but I think maybe we will still need to spend a little bit more time before we can ask any questions. What I will suggest is that we actually spend about 20 minutes or so, 20, 25 minutes, depending upon the time it will take, somewhere about that period. So it will take us to about 20 to 11. Then we will have a mid morning break as well. I suspect that it will be about 11 o'clock that we will be able to start our questioning to you.
A Fine, thank you.
THE CHAIRMAN: I hope that is acceptable to you all. If, of course, we are ready any earlier then we will pass on that message to you, but I suspect it will not be before 11 o'clock.
We will now go into camera to start doing our own work and may all the strangers please withdraw.
(STRANGERS THEN BY DIRECTION OF THE CHAIRMAN
WITHDREW AND THE COMMITTEE DELIBERATED IN CAMERA)
(STRANGERS HAVING BEEN RE ADMITTED)
THE CHAIRMAN: Good morning again. Professor Booth, as I said just before we broke that if there are any questions from the Panel members then I will introduce them to you. We have, first of all, Mrs Dean, who is a lay member.
Questioned by THE PANEL
MRS DEAN: Good morning, Professor Booth. In your evidence in chief, you referred to something you called “the barn door symptoms of inflammatory bowel disease”. Could you confirm for me what you consider those symptoms to be?
A I think they would be classically, and we have discussed already how classical this is, opinions vary somewhat, but the absolute classical picture of a patient with Crohn's disease would be diarrhoea, weight loss and abdominal pain. That would be the absolute classic presentation. Equally well, one would think about Crohn's disease with other mixtures of symptoms and signs so that, for example, in a patient who had particular abnormalities around the anus on examination in association with abdominal pain, and if they had mouth ulcers that would also be a very classical presentation of Crohn's disease. I think what I would say is: there is no single classic presentation, but as we have been discussing certain symptoms lead you, when they are in combination, to suspect Crohn's disease very strongly.
Q I wanted to ask you about constipation. How common is it for children to be seen in your clinic with chronic constipation and overflow diarrhoea such as we have talked of here?
A It has always been common. It has become very common indeed because of particular changes in referral practice in the West Midlands, so we are seeing a lot more children with constipation and overflow now, but it has always been a very common out patient problem, both in general paediatrics and in tertiary level, specialty paediatric gastroenterology.
Q Could you clarify for me how you would go about establishing that that is the problem as opposed to something else?
A Sometimes the patient is referred by the general practitioner or the referring paediatrician with a referral letter saying: this patient has been constipated for a number of years. That would be the case, particularly if the referral was coming from another paediatrician in another hospital. They would probably have established that the patient's main problem was constipation and that they would be referring to you for confirmation of the diagnosis, exclusion of a secondary cause for the constipation and then advice about management. Often patients get referred, particularly from general practitioners, with more non specific symptoms like abdominal pain, perhaps sometimes with soiling. If you saw any patient with abdominal pain you would certainly consider constipation within the differential diagnosis, given that, of children in this country who present with recurrent abdominal pain, at least three quarters will turn out to have irritable bowel syndrome in which constipation is a major feature very often.
Q I understood you to say that one of the issues around this is that you cannot always feel by physical examination of the abdomen that the colon is loaded. In that case, given that it is a relatively common problem, why is it not that you would carry out a plain film X ray in every case, for example?
A It depends on the nature of the symptoms, so that, for example, if there is soiling by far and away the most likely explanation of a child who soils would be constipation with overflow. An abdominal examination is not always reliable. You would carry out a plain abdominal film in the presence of suggestive symptoms. That is one of the points that was being made in the publication, I am afraid I cannot remember whose bundle of literature it was in, but it is one of the publications that has been submitted in the series that Professor Murch published in patients with autism, showing that for confirmation of constipation a plain abdominal film is often extremely helpful.
Q In one of the children, I think it was Child 1, I understood you to say that this was the child who was found to be very constipated on the first attempt at colonoscopy. I understood you to say that that was a very strong indication that the child's problem was most unlikely to be inflammatory bowel disease. Can I ask you to clarify why you said that?
A The hallmark, one of the hallmark disorders of inflammatory bowel disease is diarrhoea. That is the consequence of inflammation in the intestine. There are a whole series of changes that get put in train as a result of inflammation that lead the patient to have diarrhoea. Diarrhoea is not invariable in inflammatory bowel disease, particularly in Crohn's disease where, as we have been discussing, the onset can be insidious. There may be very little, if any, gastrointestinal symptoms initially, but in general the hallmark of inflammation in the colon is diarrhoea. If you find a patient who is constipated, in other words who has the exact opposite of diarrhoea, it makes a diagnosis of colonic inflammation very unlikely. There are causes of constipation that involve some inflammatory change in the colon. Those are in children who have cow's milk allergy. If you did see a child who had constipation and you found some inflammation then there would be a precedent for considering that that patient may be intolerant to cow's milk.
Q Also, you told us at one point that these children - this is not constipation now, a different point you told us that these children did not have the clinical characteristics of mitochondrial disease. I wondered if you could tell us what those characteristics are.
A Mitochondrial disorders; one of their characteristics is that they are extremely rare. The view in the mid 1960s was that mitochondrial disorders occurred in between one and two children per million of the population, so they are very rare. Characteristically, they involve many different systems, most commonly: muscle, brain, and liver. It is a so called multi system disorder. It involves lots of different systems. As the disease progresses, the number of different systems that are involved increases. The average age of presentation of children with mitochondrial disorders is in the first year of life. It is true to say that non specific gastrointestinal symptoms are relatively common in those patients, so vomiting, anorexia, diarrhoea, constipation, failure to thrive would be seen fairly commonly but they would be seen within the context of a much broader multi system disorder.
One of the hallmarks of mitochondrial disorders in children is that they have a profound metabolic disturbance. A lot of them are very acidotic. A third of them will have recurrent episodes of severe acidosis. You would start to suspect a mitochondrial disorder within that particular clinical context and go on, in the first instance, to carry out blood tests looking for specific changes in metabolites, the lactate pyrobate ratio looking for raised ketone bodies, abnormal organic acids, and so on. There are some very specific mitochondrial disorders that do predominantly affect the gastrointestinal tract. One of them involves children with chronic diarrhoea and a pseudo obstructive disorder. In other words, these are children who appear to have an intestinal obstruction, but rather than resulting from a mechanical cause they have a pseudo obstruction because the nerves and muscles in the gut are not working appropriately. Then there is another disorder called mitochondrial I have of forgotten the name of it it is MGNIE, I have forgotten what it stands for now. It is a mitochondrial disorder which involves the brain and the gut to a severe degree, but as I say they are very uncommon. I have not knowingly ever seen a patient with a mitochondrial disorder who has been under my care.
Q Thank you, that is very helpful. I wanted to ask about inflammatory cells and lymphoid nodular hyperplasia. My understanding from this hearing is that lymphoid nodular hyperplasia describes the presence of enlarged lymph cells or nodules in the colon. Is that right?
A Yes. There are some terminological difficulties I think because “hyperplasia” means a departure from normal, as the name implies. “Hyper” means “increased”. You might think anything that is called “hyperplastic” would automatically be abnormal, but in this circumstance it is normal to find lymphoid nodular hyperplasia within the colon and the last part of the small intestine under normal circumstances. I think the hearing has already heard debate about what weight could be placed upon that finding. I think that the observations that were made on these patients were perceived as suggesting that there was more lymphoid nodular hyperplasia than you might expect. I have put forward some evidence that suggests that that may, under certain circumstances, be exactly what you would expect in children who are constipated.
Q Something perhaps associated with that. Is it possible that you might get an increase in this particular thing as a result of the restricted and sometimes very unusual diet that some of these children had?
A No. I think you might argue the converse. Lymphoid nodular hyperplasia would tend to suggest that the immunologically active components of the gut lining were responding to some sort of stimulus from within the inside of the lumen of the gut itself, and that, therefore, if children were on a very excluded diet they would be less likely to be exposed to factors to which they would be responding. There is some evidence that in children with constipation, many of whom would subsequently turn out to be cow’s milk allergic, there is a very frequent finding of lymphoid nodular hyperplasia so there may be an issue to do with exposure to foods to which children are allergic. I would not thought you would find it in children who were on exclusion diets.
Q You told us that colonoscopy can be a painful procedure. You talked about stretching the sigmoid loop and so on. I wanted to know is it a momentary thing? Is it something that is painful just while it is taking place or is it something that takes some time for the pain to go away?
A No, it is a short-lived pain because what happens – this was in the days when we did not do this under general anaesthesia. The reason that we moved to general anaesthetic for this procedure was because it is more acceptable for the patient but when it was done under intravenous sedation and the patient was by and large awake then when there was some stretching they would indicate that they were in pain and it would indicate that you needed to pull back a bit and do something different.
Q I would like to talk about anti-inflammatories. You did tell us about the side effects that can be associated with olsalazine.
Q Are those side effects similar in all the anti-inflammatory preparations that were prescribed to these patients. I think we have sulphasalazine, mesalazine and Pentassa. Do all those preparations produce side effects from time to time?
A Some may have in common because they all contain a substance called 5-ASA which stands for five aminosalicyclic acid. The point of these drugs is that you deliver 5-ASA to the lining of the bowel in the lower gut. If you just gave 5-ASA tablets they would be absorbed higher up in the gut and so the patient would not get the drug where they needed it down in the colon. Pharmacologists have used a number of clever tricks to enable the 5-ASA to get down into the lower parts of the bowel.
Sulphasalazine is 5-ASA linked onto a sulphonamide compound and so reactions to sulphasalazine are often reactions to the sulphonamide component of the drug so headaches, skin rashes and grazes, abnormalities in the blood count are more common with that. Mesalazine is a generic title used for 5-ASA compounds in which the release of 5ASA is made in the lower part of the bowel because the 5-ASA is within a matrix which does not release the 5-ASA until it gets down into the lower bowel. Olsalazine is an agent where the 5-ASA is put together in a particular way which again releases it in the lower intestine. So there are some side effects that all have in relation to 5-ASA and those would include, for example, in the long term problems with renal damage – these patients get a disorder called an interstitial nephritis long term which needs to be monitored. That is long term.
One of the problems specific to Olsalazine is that probably five or ten per cent of patients on Olsalazine get diarrhoea fairly early on as a complication and you have to stop it and go on to something different.
Q For one of the children, Child JS, there was some suggestion that the Pentassa might have caused nosebleeds. Is that common?
A I am not aware of that as a complication of Pentassa.
Q In some of these children we know that the view of the histopathology changed after the regular clinical histopathology meeting and in some cases after the children had actually been discharged and after discharge letters and so on had been written. Can you tell us in your view how common is that situation?
A It is common for there to be discussion at the weekly or fortnightly in our case histopathology meeting. It would be unusual to change the diagnosis that had been made by a histopathologist to change the histopathologist’s diagnosis with a frequency that has occurred in the children that we have been looking at is in my experience without any precedent.
Q Child 8 in the Royal Free Hospital notes, at page 15 we have a discharge summary and, as it happened in this case, it was written in November, some eleven months after the child was discharged from the hospital.
Q Would you have any concerns about that sort of delay?
A Because it is important that the general practitioner who is going to be looking after this patient on a day to day basis after the patient has been in hospital is aware of what has been found in hospital. Often when patients are discharged from hospital the GP receives a brief notification that is written by what used to be called the houseman and that says they came in, these were the tests that were done, this is the medication that the patient is on, but that was all, so the full discharge summary is crucially important in bringing the GP up to speed with what was done because often parents after a child has been in hospital will go to the GP and say well I do not really understand what it all meant, can you tell me? Or they go back to the GP to say I have been started on some medication, I do not really know why, or they go back and say I need some more of whatever the drug is. I think the number of reasons why I think most people would want the discharge summary to go out as soon as possible after the child was discharged.
Q In this case on page 16 we can see that the final paragraph it says the results are not indicative marked ongoing information and there is in fact no recommendation for treatment. On page 13 there is a letter written by Professor Walker-Smith in April 1998 recommending treatment of Pentassa. I could not find from looking at this case that there had been any outpatient appointment between the date of the child’s discharge in January 1997 and this letter in April 1998. Is this something that would be of concern? Is it usual for a consultant to write so long after seeing a child with a recommendation for treatment and is it something that would concern you?
A Do you mind if I consult my own notes for a moment? (Pause) I think that there was between the admission of this patient and the letter from Professor Walker-Smith to the GP in April 1998 a letter from Dr Wakefield to Professor Walker-Smith which is at page 14 in the record – I think I have my chronology correct that preceded Professor Walker-Smith’s letter of April 1998 – which would have indicated to Professor Walker-Smith that this patient’s symptoms were particularly severe. I imagine that it was on the basis of the information provided by Dr Wakefield that the medication was started.
Q Is it possible in a child that in 15 months the problem might have changed?
A Yes, it is quite a long interval. The clinical histopathology report in this patient showed minimal inflammatory changes. The conclusion of the discharge summary was these results therefore are not indicative of marked ongoing inflammation. I think after 15 months it would have been appropriate to perhaps have reviewed things oneself.
MRS DEAN: Thank you very much.
THE CHAIRMAN: Dr Moodley is a medical member.
DR MOODLEY: I want to ask about the examination of stool. Ordinarily if you have patients with suspected gastrointestinal problems is it routine to examine the stool?
A I think it would depend on the nature of the symptoms. If a patient presented with a relatively short history of bloody diarrhoea then one of the key things you would want to do would be to make sure that they did not have particularly a bacterial infection of their colon that was causing them to have a colitis, so stool culture would be important under those circumstances. You may also submit stool for children with persistent diarrhoea for microscopy looking for giardiases as well. One of the important causes of persistent diarrhoea in children can be abnormalities in pancreatic function and there are a number of tests on stools that one can do that will give you quite good information about whether the patient’s pancreas is functioning normally as well. There are also tests on stool that one can do after giving the patient a sugar load so that some children have a disorder where they do not digest sugar properly and if you give them a drink of sugar it tends to come straight through and you recover sugar in the stools, so there are a variety of tests that one can do on the stool in children with persistent diarrhoea for a variety of clinical indications.
Q Would you have expected these children to have these tests?
A I think it would depend very much on the clinical symptoms. In a patient who has got recurrent abdominal pain and soiling, for example, I think constipation with overflow would be high on the list so you would not under those circumstances immediately suspect, for example, that they had an infection or that they had pancreatic exocrine insufficiency. On the other hand, if it was a patient who was failing to thrive who had large fatty offensive stools then that would push up towards the top of your list for consideration of abnormalities in pancreatic function. I think it depends on the particular constellation of symptoms and signs that a patient may have.
Q In Child 4, page 49 in the Royal Free records, could you say what is the significance of e-coli cysts in the stool, if any?
A It is entamoeba coli cysts and these are seen from time to time in children and are probably just, as it says here, commensal. They carry them without any particular import. It would depend on the particular clinical context. I think under some circumstances, particularly in travellers, it can produce acute diarrhoea but probably not in this circumstance.
Q You said in your evidence that colonoscopy is not usually indicated if you have an infection. Are there any absolute contraindications in colonoscopy?
A One would certainly avoid it and I think it would probably be an absolute contraindication in a child who had very severe colitis indeed where they were approaching or had established a state that is called toxic mega-colon. That is a very severe form of colitis. It would be very unusual, as we have been discussing, to carry out a colonoscopy in a child who was severely constipated. I suppose you would do a colonoscopy on a child who you knew to be severely constipated if they were repeatedly passing fresh blood and you could not determine a cause by inspecting the anus. As we were discussing previously, under those circumstances you would probably treat the constipation and satisfy yourself that the colon was empty and remained empty and then review the patient’s symptoms. Severe constipation would probably amount to a contraindication, yes.
Q That would be a relative contraindication.
A Yes, not absolute. I think in the case of a child with a toxic mega colon most people would regard that as an absolute contraindication other than perhaps just a very limited inspection of the rectum.
Q When you do colonoscopy what does the normal gut of children look like, because we have heard that there are increased lymphoid cells in children?
A In this exhibit it is normally smooth and shiny. You can see a fine network of blood vessels within the lining. As we have been discussing, it is not uncommon to see lymphoid nodules. One of the first reflections of abnormality that might suggest early inflammation is that you lose the vascular pattern. You cannot see the blood vessels so clearly and that is a reflection that there is some swelling in the lining in the mucosa, but normally it is smooth, shiny and you can see all the blood vessels.
Q I want to change to a slightly different topic. In a research protocol if you are named as a responsible consultant in the application is it unreasonable to assume that you have been involved in the drawing up of that protocol and that you are familiar with it and that you also have some responsibility for the overall delivery of that?
A No, it is not unreasonable that if you are named as a responsible consultant you would be expected to be familiar with all aspects of the document and have agreed them.
DR MOODLEY: That is all, thank you.
THE CHAIRMAN: Ms Golding is a lay member.
MS GOLDING: Professor, staying with the colon, we were told that only a clean colon can be examined. One of the questions I have is how would a doctor know that that is the state of the colon? We saw this morning in Professor Walker-Smith’s bundle how the bowel preparation is considered successful if the patient develops clear watery diarrhoea by the morning of the procedure. How then is it possible for a patient to be then discovered to have severe faecal loading?
A The finding at colonoscopy of unsuspected severe faecal loading is uncommon in my experience. There are varying degrees of cleanliness in the colon at the time of colonoscopy and one suspects that patients do not always take all the laxatives that are prescribed. Under normal circumstances in a non-constipated patient there would be faeces in the colon; that would be normal. If they had for one reason or another not stuck to the diet beforehand that they go on, which is of liquids only to reduce the residue in the colon and/or if they had not taken the laxatives you would find solid stool within the colon under those circumstances to varying degrees, but it is unusual in my experience to find an absolute rock solid colon at the time of colonoscopy.
Q If a child with diarrhoea is given the clearing medicines prior to the colonoscopy what would the feeding chart show? In most of the files we have feeding charts for the children and it indicates whether the bowel was opened or not. If someone comes in with diarrhoea presumably there would be bowel opening several times.
A They would have a worsening of their diarrhoea, yes, which is not a reason for not giving them the bowel prep. You cannot rely on a patient’s history of diarrhoea as indicating that they do not need any bowel prep. They will need some bowel prep.
Q How is weight loss measured in a child?
A Characteristically and most effectively over a period of time, on a chart that is called a centile chart, so you would anticipate that patients within their notes, in every case – because this is of fundamental importance to the management of children in general if they have a long-term problem – would have a centile chart. That is a chart that shows you in effect the range that you can expect within that child at any given age. So you plot weight on the chart, clinic visit after clinic visit, and you can see whether their weight is going up as you would anticipate, or whether it is actually slowing. So in adults, who are not growing, it is easy to know whether they have lost weight or not; but in children who are increasing in weight anyway, what you want to know is are they increasing at the normal rate or have they slowed down. So just looking from clinic visit to clinic visit to see if they have gained may actually mask a substantial failure to thrive.
Q Did any of these children have significant weight loss or any weight loss which would show that there was a problem generally?
A There is a history of weight loss in many of the records, but what is not clear is whether this was a sustained weight loss. Would you just excuse me a moment? (Short pause) I did recently go back through the Royal Free Hospital records to see whether there was a completed growth chart in the charts of these patients, and it was, as far as I could see, variable. I think, as far as I could see, in about half the patients there was a growth chart that had been completed and up to date; in others I could not find the evidence that there was a growth chart which had been completed.
Q Those children, if there was a chart, did they show any kind of sustained weight loss?
A Not as far as I recall.
Q Was there any indication that previous investigations on the patients were taken into account?
A Do you mind if I just refer to my notes?
A (Short pause) I think in virtually every case, as far as I can recall, these children – as indeed was made very clear to the chairman of the research ethics committee in a letter by Professor Walker-Smith – had not been previously investigated, and certainly not been extensively investigated, elsewhere. Some of them had had their constipation recognised, for example, but in general they had not been investigated elsewhere. So these children were being seen for a GI assessment – for a gastrointestinal assessment – for the first time at the time of referral to the Royal Free Hospital.
Q So should there have been other investigations made before the protocol investigations were carried out?
A I think in most cases yes. There is in the case of Child 6, as we have discussed, a history of abdominal pain, diarrhoea, blood, and I think carrying out a colonoscopy in those circumstances was entirely reasonable. In the other children my view has been that a colonoscopy was not appropriate as the first, and I think very often about the only, investigation of gastrointestinal function.
Q I do not know if this is a reasonable question, but is disintegrative disorder an inflammatory bowel disorder or a neuro-psychiatric disorder?
A It is a neuro-psychiatric disorder. I have never seen a case.
Q So what good would a colonoscopy do in terms of investigating a disintegrative disorder?
A I think if you were investigating a child with disintegrative disorder, as we were discussing before the break, it would have to be, in my view, investigations that were based on the patient’s presenting symptoms and signs, so you would evaluate them in the same way that you would any patient, whether or not they had disintegrative disorder. If you were carrying out a colonoscopy for other reasons, then it would be within the context of a research study, and that is clearly one of the issues that has been much discussed here.
Q In any of the children did the lumbar puncture provide any useful information to the study, did you find?
A I am not aware that there was any clinically useful information. I am not aware that there was any useful research information either.
Q Can we look at FTP2, page 770, please. I wonder if you would be able to clarify for me what this sentence means, half-way down this page, where it starts “Lucarelli’s observation”.
Q Then it goes on after the first sentence:
“Similarly, although the present study was not designed as an intervention trial, …”.
Then it goes on. What do you take that to mean?
A This is in a document ---
Q This is the discussion part of the study by Wakefield, Murch, Linnell – and this was part of the study. It starts at 758.
A I am not sure if this was a first draft of The Lancet publication, or whether ---
THE CHAIRMAN: Ms Smith would like to say something.
MS SMITH: Excuse me for interrupting, sir. I was going to say, so Professor Booth knows what the document is, it is a draft, and we do not know which number draft, of the ultimate Lancet paper.
THE WITNESS: Thank you. I am just clarifying what reference 5 is that he is referring to, when it says “indicates a reversible element in this condition”. Presumably it is referring to autism. The statement is:
“Similarly, although the present study was not designed as an intervention trial in each case treated empirically with 5 amino salicylate-based compounds … or elemental diet … marked improvement in behaviour was reported by the parents, case-workers and physicians.”.
That is the relevant section. Could you just repeat your question about that.
MS GOLDING: I wondered what “intervention trial” would mean to you.
A An intervention trial would mean that this was a clinical trial. If it was an intervention trial you would be planning some sort of therapeutic intervention that you would conduct in a way that would enable you to draw some scientifically valid conclusions from your trial. So in other words a clinical trial. Normally when conducting a clinical trial you would randomise patients to the active compound you were considering, or to placebo, or you might actually give each patient either active or placebo compounds in a random order so that you could compare how they were. Basically what you want to know is “How is this patient on the active compared with on the placebo?”
MS GOLDING: Thank you.
THE CHAIRMAN: Dr Webster is a medical member.
DR WEBSTER: Just a few more points. A lot of my questions have been asked beforehand. The first one is going back to bowel preparation. I was thinking of Child 1, the child who had the second colonoscopy because of constipation.
Q He went back to the ward to be prepared, and I asked Dr Casson what form that preparation took, and he said it was oral preparation, but it transpired that it was actually by naso-gastric tube.
Q Is that standard practice?
A No. Normally the medication which is given for bowel preparation for children before colonoscopy is oral, and I cannot recall a circumstance where we have needed to put a naso-gastric tube down.
Q Why do you think it was done in this case?
A I think if you put a naso-gastric tube down you can run in large volumes of colonic irrigation fluid, so it is probably more effective to do it that way than to give the preparation orally. We avoid it because having a naso-gastric tube down is not very pleasant.
Q I have difficulties in my mind with the balance between assent and consent. I can see how consent is a difficult problem with children, particularly perhaps these children, so perhaps more reliance is put on assent rather than consent.
A I think both assent and consent are difficult in these particular patients.
Q We heard I think that Child 5 could not have blood taken in the clinic because the child was not cooperating.
Q So assent seemed to override everything else there.
A Yes. These children are often very difficult in the clinic even before they are confronted with the challenge of having blood taken, though.
Q About research consent, I think you agreed that you have not seen any consent forms relating to 172/96 within the notes that you examined.
A That is correct, yes.
Q But actually for Child 2 there is a research consent form, not the usual biopsy one. It is on page 339. Perhaps start actually on page 15, which is when the child is clerked in. At page 15 it says:
“Referred for investigation of ? association between gastrointestinal disease/autism/ measles” –
which pretty much to me sounds like 172/96.
Q But the actual consent form on pages 338 and 339 is the enteral feeding project, which is dated 9 September, so that is a week after the day of admission.
Q Actually on page 339 towards the bottom, just above who you should contact if you are concerned, it says:
“Subjects are warned not to take part in more than one study at any time.”
This child appeared to be in two.
A Yes. I think, as we discussed the other day, this patient after the colonoscopy was put on an enteral feeding product that had a code name rather than a commercial name, which would indicate that this was part of a clinical trial, and that would be consistent with this consent form. I suspect that the purpose of that warning is in relation to taking part in more than one therapeutic trial at a time, and you could also say that because this patient was started on this compound a week after admission, when the investigations in 172/96 had been completed, their participation in that study had ended and they were now going into a different study.
Q But would the parents have known the predicament they were in, even though it was not a very significant one?
A It is always dangerous to sign above statements that occur beneath your signature in any document. I do not know whether this was highlighted to them or not.
Q Just one final point: anti-inflammatories, are they very palatable medicines to take? Are they nice medicines or nasty medicines when it comes to actually taking it?
A Sulphasalazine comes as a liquid preparation, and I am not aware that children find it particularly difficult to take. The other compounds are more challenging. There is now a chocolate-flavoured granule of 5ASA that children quite like taking. But in general they are not a problem. I think the issue is that in treating patients who fall within the autism spectrum disorder they are difficult to get to take any sort of medication because of their other behavioural problems, so that is an added challenge.
DR WEBSTER: Thank you very much.
THE CHAIRMAN: Professor Booth, it is now my turn to ask you some questions, and I do have to, so I hope you will forgive me for keeping you there for a few more minutes.
Can I first of all ask you – I know it was some two weeks ago when you started giving evidence, and in your evidence-in-chief you said there are now approximately 12 to 15 tertiary centres in the UK for paediatric gastroenterology.
A Yes, something like that, yes.
Q Can you give me some idea of how many centres there were in around 1996?
A Would you give me a moment?
A In London there was the Royal Free Hospital, Great Ormond Street, Barts in London, Chelsea and Westminster. I do not think there was Southampton there. There was Bristol, Cardiff, Birmingham, Manchester, Leeds, not really Newcastle, probably Glasgow. I think that is ten. I apologise to anyone I have missed out, but I think it is about that.
Q There is not that much of a difference from 1996 to now. Are there more centres now, apart from the ones that you have just enumerated?
A Now Southampton has been added, Leicester, Warwick, Stoke. Stoke was a sort of sub regional centre, would go on to my first list, so perhaps three or so centres since then.
Q Can I then ask you about the ethical approval of the studies. I think you said that you obviously need the approval from the ethical committee if you are going to do any research?
Q You said that you also need the ethical committee approval if you do any pilot studies.
A I think if the investigations that you are wanting to perform or if the treatments that you are wanting to give are novel and outside normally accepted clinical practice at the time, yes, you would. For example, you may have a novel compound and you think that it would be appropriate to subject that novel compound to a full clinical trial. In order to set up the trial, you would need some preliminary evaluation of the drug's effectiveness in order to, for example, get an idea of how many patients would need to be randomised in the trial. You would need to carry out a pilot study to get some preliminary information. Notwithstanding that it is a pilot study it would still need to have ethical approval.
Q What about if you want to write about case studies, reports? Do you need the ethical committee's approval then?
A In general, no. Certainly not in 1996. If you are merely reporting your clinical experience in patients that you have seen in whom the identity of the patients cannot be obtained from your description then you would not, in 1996, have needed ethical committee permission for that.
Q Now if you want to open FTP2, page 783, that is the Lancet article. Right at the top, on the right hand and also on the left hand before the title of the paper it says “Early Report”. What does that mean? What do you understand from that term?
A I think that that would mean that this is the initial report of an observation or series of observations where you anticipate more information on the phenomenon that is being reported is going to become available subsequently. This is perhaps regarded as not the final definitive statement on what is being described.
Q Could it mean a kind of case studies report?
A I think that would depend on the nature of the investigations that were being carried out within this. You could say that if you wanted to undertake a series of novel investigations for which you needed research ethical committee permission, that is within the terms a series of case reports. It is the nature of the investigations that are taking place within the clinical case report that is relevant I think rather than anything else. If you are doing investigations as part of your case series that fall outside normal clinical practice, then you would need ethical committee permission.
Q If you look at page 784, the next page, where it says “Ethical Approval and Consent”, is that what you are actually trying to explain, that investigations were approved by the ethical practices committee of the Royal Free Hospital NHS Trust?
A Yes. I have not been able to find any evidence, as we have been discussing, that parents gave informed consent.
Q That is the first bit up to the comma. I am talking about the ethical approval about the investigations.
A Yes. That would be the relevant statement that would lead you to believe that all the investigations that were being described in this paper had been approved by the ethical committee.
Q I will just move on to the next subject and I will just put that away. Can you get FTP1? That is page 40. This is Dr Wakefield's contract. Do you have it?
A Yes, I have. Yes.
Q It is the first paragraph, but the lower one third of the paragraph where it starts, “His research involves...”?
Q The sentence is:
“His research involves the laboratory investigations of resected human tissues, but he will not be involved either in the clinical management of the patients with inflammatory bowel disease ...”
First of all, the first sentence; what did you understand from this part, that his research “involves the laboratory investigation of resected human tissues”?
A Specifically, “resected human tissue” would mean tissue that had actually been cut out at operation or at autopsy, if you took a very literal view of that terminology. If you talk about “resecting tissue”, that normally means you are resecting, cutting out large amounts of tissue. You would not really describe biopsies as resected tissue, but you could say it could involve biopsies as well. It is slightly fuzzy, but resected tissue means cutting out gross amounts of tissue.
Q Obviously if you are involved in a research resected tissue will include biopsies, will it not?
A Yes, that is what I am discussing.
Q I am trying to put two and two together and trying to understand from this.
A If I were reading this I would anticipate that it would include examination of biopsy material because resected tissue does not come along for study as often as biopsy material.
Q If you take that just a little further. Could this include any of the tissues that are taken from the human body for investigation, for example the blood or the CSF or any other body fluids which are taken from the human body?
A Yes, yes. I think tissue could be construed as involving any material of human origin. I am just trying to cast my mind back to the wording of the Human Tissue Act with some difficulty, but I think it is a fairly broad definition.
Q If that is so, could that, in that case, justify for Dr Wakefield to sign the investigation forms?
Q That is because of the second sentence?
A Yes. Signing a request form for a clinical investigation is part of the clinical management of patients.
Q I think that is helpful. Can we actually put FTP1 away as well and just some questions on Child 1. If you open the Royal Free notes, page 54. First of all, the last paragraph, and this is the letter in June 1996 from Professor Walker Smith. That says:
“My plan would be to see him again in three months' time and then if Mrs 1 feels that it is appropriate we could consider performing endoscopy”.
Does that give you the impression that the decision has already been taken to include this particular child in this study?
A No, I do not think it does.
Q The second point from this letter is, and I think that is in the middle of the first paragraph, we have talked about toddlers diarrhoea; that was Professor Walker Smith?
A Sorry, can I go back to your former point? I have read the whole sentence. I was just reading:
“If Mrs 1 feels it is appropriate we could consider performing endoscopy”.
I then read on:
“Further assessments, neurologically and psychologically of his autism to explore the possible link between immunisation, bowel inflammation and autism.”
I do not know that a decision had already been made to include this patient, but it does imply that if this patient was going to have an endoscopy it would be within the context of that research study.
Q I understand that particular point, but it was the first sentence that I was mainly asking you about. Does that mean that the decision has been taken at that stage?
A No, I do not think it does.
Q We have talked about Professor Walker Smith's diagnosis of this particular child as toddlers diarrhoea. That is in the middle of the first paragraph. The sentence actually says, to me it sounds something different, and that says the diarrhoea which one currently has does have the features of toddler's diarrhoea. That means that there are some symptoms which are similar but it is not absolutely diagnostic.
A I did not read it that way, I have to say. I thought that that meant Professor Walker Smith thought the diagnosis was toddlers diarrhoea.
Q How do you feel about it now? What it actually says is: “currently does have the features of toddler's diarrhoea”?
A I think if he had gone on to say, “however, there are other features that would make me consider something else”, then I would think he was being less than specific about toddler's diarrhoea. I think if you say “he does have the features of toddlers diarrhoea”, you think he has toddlers diarrhoea. If he said, “he does have some of the features of toddlers diarrhoea”, I would accept your suggestion.
Q I think you are misunderstanding. If I get a letter from a consultant and it says that the diagnosis is toddlers diarrhoea and that is what this child suffered from and that is what should be the treatment or it says that it has features of that particular disease.
A I think the issue with toddlers diarrhoea is that you can only ever have features because there is no diagnostic test. If he said, “has the features of toddlers diarrhoea and I have measured,” whatever, and that confirms it, if there was that test you would have expected him to say it, but the thing is it is only ever a clinical diagnosis based on the features in the history.
Q The next question. You do not need to open the file of patient this Child 12, but I think because we have discussed it you will know what I am talking about. I think it is Child 12 which says CRP was 6?
Q I think your evidence was that is the lowest part of the increase that could be documented?
Q If you look at the range of up to 5, and please excuse me, I am not a gastroenterologist and the question may be totally irrelevant, but I am just trying to understand this, that if the rise of 1 in the range of up to 5 is a rise of approximately 20 per cent, whereas if it was 100 and was raised by 1 to 101, would actually be totally different to from 5 to 6?
A Yes. My point was that if you were absolutely set on finding a reason for doing a colonoscopy on this child, that would be something that you would light upon.
Q But if it is raised by about 20 per cent would that be significant?
A It is difficult to know what the rise of 20 per cent is without knowing what the precise distribution would be in the reference range. If the reference range was not normally distributed and had a shift to the right in the distribution, then you would not anticipate that a rise from 5 to 6 would be particularly significant. I agree it is outside the reference range for the laboratory, but given the context of soiling as being the principal presenting complaint I still do not think that a minimal rise in CRP would justify carrying out a colonoscopy in the absence of symptoms that did not suggest inflammatory bowel disease.
Q Coming to Dr Wakefield's presentation to mind, and I think you felt that if you want the bloods for controls it is a part of the research, must not be undertaken without the ethics committee approval and under clearly defined the circumstances. Can you tell me what are those clearly defined circumstances?
A Yes. As you have said, the circumstances must include approval from an ethics committee. Because of the difficulty of ethically justifying taking blood from normal children, often what one does is to take blood from children who are having a general anaesthetic for some other reason. For example, elective minor surgery where, essentially, apart from their hernia, or whatever it is, they are completely normal. Under those circumstances, it is not an issue usually in getting consent from the parent and the child and the ethics committee to take the blood. If you are taking blood from children who are not anaesthetised then the circumstances, as I think was alluded to in Professor Hull's commentary, would be that there needs to be consent from the parents and the child if the child is competent to give consent. It needs to be done in an appropriate setting, and that would be something where there is privacy, for example. It would need to be done by somebody who was skilled in taking blood from children and small children. It would need to be done after application of a local anaesthetic cream. That would need to have been applied about an hour before the blood sample was taken and it would need to be done, as I have implied, under circumstances where if the child at the last minute said, “No, I do not want to have it done”, you would say fine, that is perfectly okay.
Q I remember you saying that you probably attended a lecture when Dr Wakefield was invited to Birmingham.
Q Would you remember whether he was invited by the paediatrics department or by the general University of Birmingham?
A He received an invitation I think from the postgraduate education centre at the children’s hospital in Birmingham.
Q It was relevant to the children.
Q I do not expect you remember what the title of the subject was?
A I think it was about MMR vaccine.
Q Can I ask you about the place of screening investigations indicative of the clinical medicine because there are clinical investigations and there are screening investigations.
Q The place of screening investigations in the practise of clinical medicine.
A Typically screening investigations are useful when you are seeking additional evidence before doing usually something that is invasive or unpleasant for the patient. You want as much evidence as possible before you can put it to the patient that they need to have a colonoscopy or need to have a tube put down into their duodenum in order to carry out a pancreatic function test, for example. It is to give you information that might prevent the patient having to have a more invasive investigation. A good example would be at the moment there is a screening test for celiac disease that is carried out at the moment that has actually high sensitivity and specificity and would, in some cases, avoid the patient having to have an endoscopy in order to carry out a duodenal biopsy. It is not an absolute but it is, as screening tests go, probably about as good as one can ever get. That would be the general context in which one would use a screening test.
Q They can raise your suspicion index.
A Yes, they can raise or lower it, yes.
Q My last question to you is about this Porto Criteria that we have been talking about. I know that you have used some very strong language about this. I think you said scientifically naïve and invalid or something to that effect?
A Scientifically invalid and clinically naïve.
Q This is the position paper which, again, please tell me if I have misunderstood it, I understand it is to give the indication to the people who are practising that particular craft to tell them what is the accepted position in that particular field.
A That is the purported aim. The problem is that it has become clear over a number of years that when you get a number of eminent people together to produce this sort of paper it does not accurately reflect the scientific literature.
Q But is it not right that this particular paper is signed by 27 very distinguished people in that particular field, that at least 27 of those would have agreed with that particular paper, or am I wrong?
A I agree it is a paradox but getting the great and the good together does not lead necessarily to a scientifically valid publication and that is why documents of this nature are not published by very many journals now. It lacks a proper transparent evaluation of the evidence. There is no evidence in the document that tells you by what route, for example, the authors who put their name to it came to include these particular publications as the basis for their recommendation in preference to other publications that might have been equally considered. The other issue is that in the references that they cite they do not give any indication about the scientific merit of each publication, so we have gone through a process whereby this GOBSAT process has been used in the past but is now not used because it has been scientifically discredited.
Q This is a European society. Is there any other society of a similar type which has produced or published something different.
A Not that I am aware of. I can give you another example of a European society of paediatric gastroenterology and nutrition working group report that was published I think in 2000 – it may have been 1999 – it was a similar type of publication to this and it was a publication about the treatment of children who had a disorder called gastro-oesophageal reflux whereby gastric contents come the wrong way up into the oesophagus and cause problems and at that time there was a drug called sisapride that was widely used amongst paediatric gastroenterologists in the management of this disorder, myself included. The working group that produced the publication said that sisapride was effective and that it was safe and within 12 months sisapride had been withdrawn from the market in this country and in other countries because of the risk of sudden death in patients and it was considered to be completely contraindicated. So it just indicates that when you get a group of experts together they do not always come to the right conclusion because they introduce various biases into their discussion and into their conclusions.
Q Are you a member of that society?
Q Did you actually write any objection to this particular position?
A I wrote a letter to the editor of the journal that had published that publication that included sisapride and it was published in the journal and I received a letter from the secretary of the society at the time warning me that I would be in serious trouble if I questioned the results of working groups in future and that I would be called to account at the annual general meeting of the society that was taking place in Boston, which did not actually transpire.
THE CHAIRMAN: I have no further questions but the Council can come back to you if they have any questions. I will first of all ask Ms Smith?
Further re-examined by MS SMITH
Q Two very short matters, one arising out of the very first question that you were asked by the Panel which was by Mrs Dean. She asked you for the barn door symptoms for IBD and what the classic picture was. You dealt only with Crohn’s when you answered it.
Q So that we are absolutely clear, did the description that you give cover ulcerative colitis as well?
A No, ulcerative colitis tends to present differently with diarrhoea being a much more predominant feature, often with blood, mucus and abdominal pain.
Q Both those barn door descriptions, each applies to one branch of the conventional categories of inflammatory bowel disease.
A That is correct, yes.
Q The other question arises just for the sake of clarity on the questions the Chairman asked you about screening investigations. Screening investigations in the context in which you are using the term “screening”, are they all part and parcel of normal clinical care of the patient?
A Yes, they are commonly carried out as part of the evaluation of patients, yes.
Q The reason I ask that is because screening can be used in a different sense, can it not? You can have members of the public in for screening.
A Yes, I see what you mean. One can screen populations who do not have symptoms for disorders like, for example, screening for breast cancer would be a good example so we are not using screening in that context, no.
Q You are using it in the sense of initial investigations to see where you are ---
A Yes, helping with clinical decision-making.#
MS SMITH: Thank you very much.
THE CHAIRMAN: If there are no further questions for you, Professor Booth, can I thank you again on behalf of this Panel for giving us the best part of two weeks in giving evidence in this particular case. You are now released.
(The witness withdrew)
THE CHAIRMAN: Ms Smith, we are now in your hands.
MS SMITH: I have another witness to call now. I shall not get very far with him in under 20 minutes. I can start him now or you can rise for an early lunch.
THE CHAIRMAN: If it is convenient to you I would be happy to take an early lunch now.
MR MILLER: My understanding is that the next witness, although not terribly short, is not going to be terribly long either.
THE LEGAL ASSESSOR: Could we have some more specific time estimates as I may have to make alternative arrangements for a legal assessor if you cannot guarantee that we will only need one and a half hours after the normal resumption, otherwise I will have to make provisions for an alternative legal assessor this afternoon.
MS SMITH: I cannot guarantee if I start at a quarter to two, if you are asking whether I will be finished by quarter past three?
THE LEGAL ASSESS0OR: No, I was asking whether all business would we reach a conclusion soon after 3.30 pm today?
MS SMITH: I cannot guarantee that. I think Professor Lachmann is bound to be an hour at least in chief. I do not know whether there is any cross-examination.
THE LEGAL ASSESSOR: I have made it quite clear for some days now that I have a professional public appointment this afternoon and it has been known for a month and I will have to go. I will make alternative arrangements.
(A discussion re timing ensued)
MS SMITH: As I indicated to Mr Seed last night, there is another very short statement to read which will only take minutes. There are some applications in relation to some amendments to make. Mr Coonan has indicated to me that he has objections to one of them. I am aware of Mr Seed’s difficulties and of course I am very sympathetic to them. I think you will appreciate that there is nothing I can do except to present my case properly and not in a hurry. Through absolutely no-one’s fault, and I know that you do not think I mean this critically, but I lost yesterday afternoon. That is the situation I am in and I cannot guarantee that I am going to finish before four o’clock or half past four. I have no idea whether this witness is going to be cross-examined by anybody. I have to take him to documents and he is bound to take an hour or a little longer.
THE CHAIRMAN: How long will the cross-examination take roughly?
MR MILLER: I am not going to be asking any questions.
MR COONAN: I have the same position if the material conforms to the evidence we have been served with.
MR HOPKINS: No cross-examination from me.
THE CHAIRMAN: Does that help you, Ms Smith, to formulate some kind of a working plan?
MS SMITH: Yes, it means that this witness probably will not take longer than an hour and a half but there are other matters, as I have indicated.
MR COONAN: Two points occur to me. It would be unsatisfactory perhaps for another legal assessor to be in effect assisting you on an issue relating to an amendment to the charge or charges, I would have thought. That being said, it may be that Mr Seed and I, and perhaps Ms Smith as well, can have a brief word during the luncheon adjournment and we can deal with it in a way which does not mean that the afternoon is prolonged. It is not necessary for me to say any more at the moment.
THE CHAIRMAN: We will now adjourn and resume at 1.30 pm.
THE CHAIRMAN: Ms Smith?
MS SMITH: Sir, I mentioned to you prior to the lunch adjournment that there were some amendments in relation to the charges, and all but one, which I will deal with in a moment, are the subject of agreement. I am going to deal with those now whilst we have the Legal Assessor here, but I do not anticipate there being any problem. I will tell you about the last one when I have dealt with the, and then I am going to call my next witness, Professor Lachmann.
So far as the amendments are concerned, I think a copy of these has been given now to the Legal Assessor. If I can just deal with those on Professor Walker-Smith’s charge sheet first, Mr Miller has kindly conveyed to me that he has no objections. I suddenly realised that I have not actually checked the situation with Mr Hopkins, and I do apologise.
MR HOPKINS: I know when I looked at them I had none, but I could do with a spare copy in front of me.
MS SMITH: I do apologise for that. I will deal with Professor Walker-Smith first. They relate in his case to paragraph 3(f), and the change is that that paragraph now reads:
“f. Between 16 September 1996 and 15 July 1998 no further applications were made to the Ethics Committee for approval in connection with Project 172-96 nor was the Committee informed of any amendments to your initial application, save as set out in Dr Wakefield’s letter to the Chairman of the Ethics Committee dated 3 February 1997.”
THE CHAIRMAN: Can I make a suggestion. Is it possible that I could have a spare copy of those as well?
MS SMITH: Of course.
THE CHAIRMAN: And if possible, if there are enough copies, I am sure the Panel members would also appreciate having copies of those. If there are only a word or two we could have amended it, but I think there are obviously going to be more than that.
MS SMITH: I was not proposing to hand in copies, because there is the one that is the subject ---
THE LEGAL ASSESSOR: Presumably when this has been admitted there will be a new typed-out version of the charges?
MS SMITH: Yes.
THE LEGAL ASSESSOR: So there is no need for the Panel to amend as we go along, as it were, just to hear the areas that are being amended, and in due course you will be provided with them.
MS SMITH: Yes.
THE CHAIRMAN: Can I just understand the position clearly for the Panel, in that case. Is that correct, then, that we are only going to have the submissions, but we are not going to take the decision whether we agree to those amendments or not? Because even though the defence might agree, we still have to agree to those amendments.
THE LEGAL ASSESSOR: That agreement can come when you make a decision on the contested amendment.
THE CHAIRMAN: Thank you; that is what I wanted to make clear.
THE LEGAL ASSESSOR: It is not necessary to have any amendments decided today. The Panel can be told what they are – because nothing is going to turn on whether or not these amendments are made today.
THE CHAIRMAN: Thank you. In that case, in due course of time then we will be provided with copies of these amendments as well.
MS SMITH: Yes.
THE CHAIRMAN: Thank you, that is helpful. I am sorry I interrupted, Ms Smith.
MS SMITH: The only difficulty with that is in respect of the one which is not the subject of agreement, Mr Coonan has views about when that application is to be dealt with, and I have not agreed that I am deferring all the rest until whatever time Mr Coonan and I subsequently agree in relation to that one. I am sorry to raise a difficulty, but I think it is important that those which are the subject of agreement by everybody, the Panel should consider, and those amendments should be made.
THE CHAIRMAN: In that case obviously we will have to take a decision on those, and then we will need the copies and will have to consider those submissions.
MS SMITH: Would you excuse me for a moment. (Pause while counsel conferred)
Sir, I have a difficulty in relation to this, as you may have gathered, and I do not want to go into all the details of the difficulties between us, but the problem is that in relation to those amendments about which there is no objection from any of the defence – and they have all been perfectly accommodating about it; I am not blaming them in any way – but as you rightly point out those are matters which have to be considered by the Panel. I would be content to leave those over – to close my case and leave those over – until the hearing date in March.
THE CHAIRMAN: Sorry, I thought we were meeting in January.
MS SMITH: I am not sure if we are or not, sir, is the short answer.
THE CHAIRMAN: That is the date that I announced a few weeks ago.
MS SMITH: Yes.
THE CHAIRMAN: There is one week in January that we have all booked.
MS SMITH: Yes, sir, but that is subject to the communications that are made by the defence as to whether they want to make submissions.
THE CHAIRMAN: Yes, indeed.
THE LEGAL ASSESSOR: Perhaps it would help if I dealt with that matter; that was on the record. I have had discussions with the legal representatives of all parties about the submission of no case, because it is anticipated that Ms Smith will close her case this afternoon, and I think everybody accepts that that is going to happen today.
MS SMITH: Yes ---
THE LEGAL ASSESSOR: In which case the defence of course are entitled to make submissions under rule 27, that there is insufficient evidence of professional misconduct, or facts proved – there are two submissions that can be made at that stage. However, in view of the nature and complexity of the case it has been agreed that they should not be required to indicate today whether they wish to make either or both of those submissions, but that notice should be given to the Committee Secretary, Caroline Tomlinson, within seven days, so by 26 October – any party wishing to make such a submission should notify, preferably by email, the Secretary of the Panel, who will then notify the Panel members and myself.
Any party making such a submission, it has been agreed, will submit a skeleton argument in support of that submission, again on all the other parties and to Caroline Tomlinson for the Panel myself, by 23 November. So skeleton arguments in support of the submission of no case by 23 November. The GMC should have until 28 December – that is allowing for the state of the post over Christmas. It is really four weeks with an extra week, because presumably nothing much will happen and the post will be clogged up, but it gives the GMC 28 days to provide a response or responses to any skeletons, again to the other parties and to Caroline Tomlinson.
In the event that nobody indicates within the next seven days that they wish to make a submission of no case, as I understood it, the January dates will not then be needed, because a week had been allowed for arguments and determination on submissions of no case. That is how I understood the timetable, and that is certainly, insofar as the submission of no case, what has been agreed for the submission of papers.
THE CHAIRMAN: I was just going to ask your views on this timetable, so it goes on the transcript.
MS SMITH: That is in accordance with my understanding, what Mr Seed has said, save for the fact that he has told everybody that the case is going to be closed this afternoon. Whilst that is my hope and intention, I do not propose to do so until this matter relating to these proposed amendments has been sorted out, and there are significant difficulties about it. I wonder – the last thing I want to do is waste time now, but I am conscious of the constraints on Mr Seed’s time. What I would like to do is to call Professor Lachmann, finish the evidence – which after all is what is most important this afternoon – and then consider this matter. If the time constraints on me are such that you are telling me that I am unable to do that, then I am afraid that I must ask for a few minutes with Mr Seed in order to explain to him the nature of the difficulty that has arisen, and I will deal with it now.
THE LEGAL ASSESSOR: Insofar as amendments have been agreed by other parties, I have seen those and I can advise the Panel – the decision must be theirs – but they only relate to three paragraphs, so I would not actually have thought it was necessary for the Panel to have copies while it is being read out to them. They can hear what is being said, and I can advise them – although it is a matter for them – but my legal advice would be that it is in the interests of justice, they do appear necessary and are desirable for the way the case and the evidence is, and all parties agree that that is so. Therefore it should really as a matter of law only be a formal decision of the Panel without needing to go into camera, to say “In the light of that advice these amendments could be made”.
THE CHAIRMAN: I accept that particular point of view, but with due respect to the Legal Assessor I think we really do need to have a look at the amendments that are being suggested and make sure that they are in the best interests of justice to everyone, including the GMC, the defence and the public interest.
Is it possible – I am just trying to shorten the whole thing – that we could just have a typed copy of only those three amendments – we do not really need to have a copy of them all, because we have them. Or if there is only a word or two difference, if you want to dictate it we can probably write it down.
MS SMITH: There is no difficulty, sir, in relation to giving you copies of the amendments. As you rightly say, there is the one that is in dispute, and that can either be removed or indeed you can see it and be told it is in dispute; I do not know how Mr Coonan feels about that. But there is no problem in relation to that. The problem arises in relation to when the Panel are actually going to decide if these amendments should be made.
THE CHAIRMAN: Without knowing really what the amendments are, it is quite possible, as the Legal Assessor has suggested, that we may not even need to go into camera, and the members of the Panel might agree with a nod of approval.
MS SMITH: In that case, unless Mr Coonan has any objection, perhaps I can hand in a copy of the amendments that he has seen, and I will tell you which one is not the subject of agreement when I reach it.
THE CHAIRMAN: I will be very content with that course of action.
MS SMITH: Thank you, sir. (Documents handed)
Sir, if yours are in the same order as mine, which I hope they are, you will see that the first are Professor Walker-Smith’s amended charges ---
THE CHAIRMAN: Wakefield is on the first page, but we are not going to look at that at this stage.
MS SMITH: Let us start with Professor Walker-Smith, if we may. The first is paragraph 3(f), and you will see the amendment:
“f. Between 16 September 1996 and 15 July 1998 no further applications were made to the Ethics Committee for approval in connection with Project 172-96 nor was the Committee informed of any amendments to your initial application, save as set out in Dr Wakefield’s letter to the Chairman of the Ethics Committee dated 3 February 1997.”
That is the first one.
THE CHAIRMAN: Yes. Can I raise a question, and maybe the Legal Assessor can advise us on this. This was the head of charge which was already accepted, and therefore I had declared that it has been accepted and therefore found proved. In that case now what is the status of this amendment?
THE LEGAL ASSESSOR: It is accepted by Mr Miller that those further details can also be admitted and found proved.
MR MILLER: Yes. The only alternative would be to add another charge which was in that form, which I would be asked to admit or not admit, so it does not seem to take us anywhere. I am taking no point about that; I am content with it, even though we have admitted it already in its original form.
THE CHAIRMAN: That is why I was asking that particular question.
MR MILLER: I have that point, sir. We take no point on that, and we are content that the amendment should be made to the charge. The same applies, I should say, to the others which we are going to be hearing about in a moment.
THE CHAIRMAN: Then we will deal with all three together, in that case.
MS SMITH: The next relates to paragraphs 12 and 13 of Child 6. In paragraph 12 there is an addition at (f):
“On or about 1 November 1996 child 6 was seen by Dr Berelowitz who concluded that the most likely diagnosis was Asperger's Syndrome”.
And at 13(c)(iii), reading the stem:
“The research study was carried out on child 6 without the approval of the Ethics Committee in that it was not research covered by any Ethics Committee application other than that for Project 172-96 and:
(iii) he did not qualify for the research study as he failed to meet the inclusion criteria set out at paragraph 2(c)(ii) above.”
Just so you are aware, sir, that arises out of the medical report that has been reproduced during the course of the hearing in relation to that child.
THE CHAIRMAN: Thank you. I think 12(f) is an additional charge?
MS SMITH: Yes.
THE CHAIRMAN: So is 13(c)(iii).
MS SMITH: Yes.
THE CHAIRMAN: Mr Miller, I take it that these are acceptable to you, these new additions?
MR MILLER: Yes, and there is 32(a) as well.
MS SMITH: I have not got to that one yet; that is the last paragraph.
THE CHAIRMAN: Shall we just hear the next one as well.
MS SMITH: 32(a) is a replacement of the words “general practitioners” with the words “referring doctors”, so the charge reads:
“… did not constitute routine referrals to the gastroenterology department in relation to intestinal symptoms as the referring doctors referring the children for …”
The reason for that of course is that there was a consultant as well as GPs involved. Those are all the amendments in respect of Professor Walker-Smith.
THE CHAIRMAN: I am sorry, 32(a) ---
MS SMITH: 32(a) at present ---
THE CHAIRMAN: I see.
MR MILLER: So far as those amendments and additions are concerned we do not object to the amendment or admissions, and as far as paragraphs 3(f), 12(f) and 32(a) – I have now become confused.
THE LEGAL ASSESSOR: Mr Miller, can I deal with it. First of all you are saying that you I do not have any objection, and I have already given my legal advice so the next stage is for the Panel to say whether they will accept those amendments.
THE CHAIRMAN: Thank you. One more small question to the Legal Assessor. The one that has already been agreed, 3(f), can we agree, in the exceptional circumstances, because that was found proved?
THE LEGAL ASSESSOR: First of all, you decide whether you will allow the amendment, and you will then ask Mr Miller whether he is going to admit that in addition to the other particulars.
THE CHAIRMAN: Right. Thank you. Can I first of all deal with the other one, so that we can get things out of the way. There are two new heads of charge, and the defence has no objection to it. I am just looking to the Panel members to see if they would wish to go into camera to discuss this, or are they to accept it. (Indicated affirmatively). Right.
First of all, 12(f) and 12(e) are acceptable to the Panel and therefore they are now found proved.
The next one is 32(a), which is an amendment to a non-admitted head of charge. Again I am going to look towards the Panel members to see if that amendment is acceptable to them. (Indicated affirmatively) Right.
This alteration to paragraph 32(a) is acceptable to the Panel and therefore I do declare that that is found proved.
Coming back to 3(f), my question to the Legal Assessor, and I am then going to ask I think Mr Miller has already given his views but, Legal Assessor, can we actually admit it now under exceptional circumstances?
THE LEGAL ASSESSOR: Yes. The first thing is to agree whether or not you can amend it. I have indicated to you that you may make the amendment if you choose to do so.
THE CHAIRMAN: Even though it has been admitted?
THE LEGAL ASSESSOR: Yes, because Mr Miller has indicated he has no objection to that and he will admit the further particulars that have been added to the charge. In fact, he has already done so.
THE CHAIRMAN: Once again, I will look towards the Panel members. This is in view of the evidence that has been adduced in front of us, even though the Head of Charge has admitted. Now there is a small amendment and the Legal Assessor has advised us that it is advisable for us to accept it under the circumstances. I am once again going to look towards the Panel members whether it is acceptable to them. Yes. Can I actually then declare because it is acceptable to the Panel members that Head of Charge 3(f) against Professor Walker Smith is now admitted and, therefore, found proved.
THE LEGAL ASSESSOR: Now we need to ask Mr Miller whether 12(f), which is an additional particular to Head of Charge 12, all the others have been admitted, is the new particular admitted?
MR MILLER: It is admitted.
THE CHAIRMAN: There is also 13(e) which is new as well.
THE LEGAL ASSESSOR: I do not suspect that is going to be admitted. Shall we deal with 12(f) first of all. That has been admitted. The next stage is for the Panel to decide.
THE CHAIRMAN: Again I am going to look towards the Panel members and if they wish to go into camera to discuss I will be happy to do that, but if they are happy to accept it. Yes. That is acceptable. Therefore, I can now declare that 12(f) is admitted and found proved.
THE LEGAL ASSESSOR: Mr Miller, there are two other further amendments. Do you wish to make any admissions in respect of those?
MR MILLER: No. I make no admission on 13(c)(iii) and 32(a).
THE LEGAL ASSESSOR: Thank you.
THE CHAIRMAN: So 13(c)(ii) is not admitted.
MR MILLER: 13(c)(iii).
THE CHAIRMAN: I beg your pardon. 13(c)(iii) is not admitted. Yes. I think that is helpful.
Can we then now move on to the next business, Ms Smith?
MS SMITH: We have to go through the others, I am afraid. There are amendments in relation to Professor Murch.
THE LEGAL ASSESSOR: These are identical amendments, are they?
MS SMITH: These are identical amendments. Yes.
THE LEGAL ASSESSOR: Mr Hopkins has no objection.
MR HOPKINS: They are not identical because we do not have paragraph 32.
MS SMITH: I realise that. I meant those that are on Professor Murch's sheet are identical.
THE LEGAL ASSESSOR: 12(e) and 13(c)(iii).
MR HOPKINS: I can indicate I have no objection to those amendments.
THE LEGAL ASSESSOR: My advice remains the same.
THE CHAIRMAN: It was already admitted exactly under the same circumstances. Is that acceptable to the Panel? Yes. We have again Professor Murch is now admitted as an amended Head of Charge and therefore found proved. The next one is 12(e). 12(e) is a new Head of Charge. Is that acceptable to the Panel? The defence has no objection to it? 12(e) is now admitted.
THE LEGAL ASSESSOR: No, at the moment you are just amending it. You have now amended the charge to add 12(e). We then ask in a moment. You move on to the next one now.
MS SMITH: The next one is 13(c)(iii).
THE CHAIRMAN: Again, that is a new Head of Charge. First of all, do we accept to add? Do the Panel? Yes. The Panel has agreed to accept them. What is the next course of action, Legal Assessor?
THE LEGAL ASSESSOR: Mr Hopkins, you have admitted on behalf of Professor Murch the original 3(f). Do you also admit the further particulars that have been added?
MR HOPKINS: I do.
THE LEGAL ASSESSOR: So that can be found proved as amended.
MR HOPKINS: Whilst on my feet, can I indicate we also admit 12(e), but we do not admit 13(c)(iii).
THE LEGAL ASSESSOR: So the Panel can now find 12(e) admitted and found proved.
THE CHAIRMAN: I am now going to put to the Panel members again about 12(e). Is that acceptable to the Panel? Yes. 12(e) is acceptable to the panel. Therefore, this Head of Charge is now found proved. Of course the next one is not admitted, that is 13(c)(iii).
THE LEGAL ASSESSOR: Ms Smith, it is really a question for Mr Coonan; the identical amendments that are made to Professor Murch's Head of Charge are also, it is proposed by the GMC, wish to make those to Dr Wakefield as well, do you?
MS SMITH: Professor Walker Smith's, in fact. They are identical to Professor Walker Smith's.
THE LEGAL ASSESSOR: They are identical to his, yes. Are those contentious, Mr Coonan, those four amendments?
MR COONAN: No. Can I just run through them just to make sure that we are talking about the same thing. There is an amendment to paragraph 6(f) which in its unamended state is not admitted. There is an amendment to paragraph 16 to add paragraph 16(f) and it is a new amendment so that is fresh.
Then there is an addition to paragraph 17(c)(iii), that is a new allegation and there is an amendment to paragraph 34(a) as you can see set out in your aide memoir.
There is no objection to any of those proposed amendments, but there are no admissions which follow. I hope that is clear.
THE CHAIRMAN: Again, please, Mr Coonan, do hear me when I explain it to the Panel members to make sure that I have understood it correctly.
The Head of Charge, that is the case of Dr Wakefield now, first of all amendment to Head of Charge 6(f). Just to be absolutely sure first of all: is this amendment acceptable?
MR COONAN: It is. There is no objection to it.
THE CHAIRMAN: First of all, the Panel members, do you accept this amendment? Yes. Now that is accepted. The second question on this particular one is: is that admitted?
MR COONAN: No.
THE CHAIRMAN: No. Right. Then the 16(f) is the new addition. First of all, is it acceptable to the Panel members to accept and add this new Head of Charge? Yes, that is acceptable to the Panel. What is the situation about the admission on this one?
MR COONAN: At the moment, no.
THE CHAIRMAN: Okay. That is fine. Head of charge 17(c)(iii), exactly in the same situation as the last one, this is the new addition to the Head of Charges, first of all, the Panel members, is that acceptable to add this one? Yes, that is acceptable. The situation about the admission?
MR COONAN: No admission.
THE CHAIRMAN: Then there is an amendment on 34(a) as it is printed on this new paper. Is that amendment acceptable to you?
MR COONAN: Yes, it is.
THE CHAIRMAN: Panel members? Yes, that is acceptable to the Panel members. Again I take it that there is no admission?
MR COONAN: No admission.
THE CHAIRMAN: Any other thing in your section.
MR COONAN: Not at the moment. There is, but not for today as I understand it.
THE CHAIRMAN: Can I actually just to be absolutely sure, can I give this document the number as C18?
MS SMITH: Yes.
THE CHAIRMAN: Thank you.
MS SMITH: Can I just say one last thing about these, sir, and that relates to the last one which is the one which is not going to be dealt with today. The last one in respect of Dr Wakefield.
You need not trouble yourselves to read it because, as I say, it is the subject of argument. For that reason Mr Coonan and I have agreed that it is not appropriate to try and deal with it this afternoon, but that is subject to the understanding by me that the point will not be taken against me that I did not deal with these amendments prior to the closure of my case. Equally, I understand from Mr Coonan that he may have some wishes as to when this application should be dealt with, which perhaps, I do not know if he would like to deal with it now.
THE CHAIRMAN: Mr Coonan.
MR COONAN: Sir, I agree that Ms Smith that it would be inappropriate for you to have to deal with this today. Quite apart from anything else it is not necessary that it is dealt with today.
Precisely when it is dealt with will be a matter of further discussion, but I do not think the Panel needs to labour with that particular point now. It is a matter which can go off for the future, but clearly will have to be dealt with at some stage.
Could I just simply say this. My learned friend is quite right that of course I would not take a point that the matter has not been dealt with now, but equally, it is in everyone's interests that it be known, as it is now in the transcript, that the matter was raised and that we have agreed, as it were, to park it. Again, I do not mean to be pejorative about this at all, but again, for the sake of the record, we received notice of this by e mail on Monday of this week. I actually saw it myself on Tuesday of this week on Day 44.
THE CHAIRMAN: Thank you very much indeed. I think that is obviously acceptable to Mr Coonan. I just take it, Legal Assessor, there is nothing to add to this?
THE LEGAL ASSESSOR: No, nothing to add.
THE CHAIRMAN: Right. I think, as has been advised, we will park that particular issue for the time being and take it as appropriate as you both would ask us and advise us to take it.
MS SMITH: I am now going to call Professor Sir Peter Lachmann, please, sir.
SIR PETER LACHMANN, affirmed
(Following introductions by the Chairman):
THE CHAIRMAN: Before you start, Dr Webster has something to say.
DR WEBSTER: I have to make the Cambridge declaration again. Both Professor Lachmann and I come from Cambridge. I have never worked with the Professor but he does head a very large and active medical family. I think I have worked with most of the other members of the family.
THE CHAIRMAN: Just to make sure that any of the counsel, first of all, do you have any observations on that, Ms Smith?
MS SMITH: No, thank you.
THE CHAIRMAN: Mr Coonan, Mr Miller, Mr Hopkins? No. Thank you very much indeed. Thank you, Dr Webster.
Examined by MS SMITH
MS SMITH: Professor Lachmann, would you please, first of all, tell us your full name and address, please, and your qualifications?
A My name is Peter Julius Lachmann. My qualifications are: MB from Cambridge and ScD from Cambridge. I am a fellow of the College of Physicians and the College of Pathologists. I am fellow of the Royal Society and the Academy of Medical Sciences.
Q Could you give us an address for the transcript, please? You can give a professional address.
A My professional address is now the Department of Veterinary Clinical Medicine, Madingley Road, Cambridge, CB3 0ES.
Q You should you have a number of bundles to either side of you and you should find amongst them one with your CV in which has FTP7 on the spine. It is on the top, we can see it from here. If you go to page 78 in that bundle, please.
Q We see a CV, short CV from you which I suspect is in somewhat abbreviated form as far as your publications is concerned, is that right?
Q That indicates that you were between 1977 and 1999 a Professor of Immunology in the University of Cambridge?
Q I think it is also right that you were appointed a Fellow of the Royal Society in 1982?
A That is correct.
Q The Panel has already heard from another expert as to what that reflects as your standing as a scientist. You are a qualified doctor. Is that correct?
Q But having said that, I think you practised as research scientist for many years in the subject of immunology, but you have some very specialised consultant practice as a medical practitioner as well?
A That is correct.
Q Does that relate to areas within your specialism of immunology?
Q Just so we are clear, when I say a very specialised practice, you do not have beds in a hospital. You just see patients with a very particular
A I have never had my own beds, but I have admitted people into other people's beds to provide the routine medical care to allow me to do the tests and specialised therapy for those patients. I may say that I am now beyond the age where the GMC would allow me to practise anyway.
Q Absolutely. When I said you were professor I should have said you are now emeritus professor.
Q You have prepared a report in this case and, as you are aware, the Panel do not have that report in front of them but I do and defence counsel do. I am going to follow the format of it in the questions that I have to ask you.
I am going to ask you, first of all, about the background to what transfer factor, which as you know is a substance which is of relevance to the inquiry that this Panel are hearing; first of all, the historical background to it and then I am going to ask you, and I think we all realise it is a fairly tall order, to explain to us what it is. Then I will look at the more relevant features to this case. Can we start off, professor, as you do in your report with the evolution of the concept of transfer factor because I think it is right one has to understand something of the way it has developed to understand in broad terms what it is now. Is that correct?
A Thank you very much. I will go back even a little further in my report. Immunity can be induced in an animal or a person by giving them a vaccine which contains antigen that stimulates the immune response and that produces what is called active immunity. When people started to try to discover what actually went on in this active immunity they used the technique of transferring this from the immunised animal to other animals to see what products from the body would transfer immunity to a naïve recipient who had not seen the antigen. That is called passive immunity.
It turned out that one could transfer very easily a number of immune reactions, neutralisation of bacteria, what makes cells eat bacteria, neutralisation of viruses, etc, with what are known as antibodies, which are large characteristic proteins immunoglobulins that one finds in the plasma. There was, however, a form of immunity of which the tuberculin reaction was the first recognised which gives rise to a skin reaction about 48 hours after you inject the antigen which could not be transmitted with serum and it was discovered originally in 1945 by a scientist at the Rockefeller Institute, Merrill Chase, that one could transfer this immunity to tuberculin to a naïve animal with white blood cells. That is actually I think why this form of immunity is called cell mediated immunity, a term which is still used today. So this was transmitted by cells and many years after this it was found that this was a particular class of lymphocyte called the T Lymphocyte.
Before this was discovered, another scientist in New York, Sherwood Lawrence, did similar experiments to Merrill Chase in humans and took intact white blood cells from one human and injected them into another and was able to transfer a cellular immunity to tuberculin.
A few years later he did a surprising experiment which is that he took these white cells and froze and thawed them a number of times and the cells were all broken and dead and showed that this extract of cells could also transfer cellular immunity at any rate for a period. There was some suggestion that this was specific, though the specificity of these reactions has always been slightly difficult to maintain.
Q Was that what is now known as dialyzable transfer factor?
A No, we have not quite got there yet. You are ahead of me. Even more surprisingly, in 1963 the same group dialyzed these cell extracts and separated the small molecular weight compounds of somewhat less than 10,000 molecular weight from the large molecular weight compounds and to their own and everybody else’s great surprise they found that it was the small molecular weight fraction that had these effects. That is what is known as dialyzable transfer factor and generally what is now known as transfer factor.
Q The term “transfer factor” generally has come to apply really simply to the dialyzable fraction, is that correct?
A Yes, in this particular context that is usual. If you look it up on Pub Med you will find that 90 per cent of transfer factor refers to something totally different which is transferring things across the lungs, but in this immunological sense that is the way it is now used.
Q We are not going to look it up on Pub Med because we have to decide the evidence on the basis of what we hear within this room. If we can go on with the story, you said that that gave rise to surprise. With the progress of understanding in relation to this area, has that surprise increased?
A Yes, indeed. At the time this was done even the structure of immunoglobulins was not known which are now known to be very specialised proteins of about 160,000 molecular weight and the smallest fragment that really does anything that you can make artificially is about 25,000, so they are much larger molecules than transfer factor. It then became recognised that the molecules that T cells use to recognise antigen, although they are distinct from immunoglobulins, they are rather similar in their general protein chemical properties, so they are also much larger.
What also became clear is that cell mediated immunity and antibody mediated immunity are very different in what the response actually looks at. Antibodies look at the structure of whole bacteria or bacterial proteins or viruses and look at their native shapes so that they see them as they are. T cells do not do that at all. T cells recognise small portions of proteins which have been processed through specific cells, the antigen-presenting cells, and are then presented to the T cell on the surface of these cells, not on their own but in the context of what immunologists call the major histocompatibility complex and what the lay public call transplantation antigens. They had already been known for some time and it had always been a puzzle what they were there for because even immunologists found it difficult to believe that we have evolved a whole system of antigens simply to frustrate transplant surgeons by making transplantation difficult. It was pointed out that what these very valuable proteins really do is they react with different bits of a virus or different bits of a bacterium and this allows recognition of multitude of little bits but no one person recognises all of them. In other words, what you can recognise depends on your genetic background. That makes it even more surprising that one can transfer what seems to be cell mediated immunity with very small molecules taking absolutely no account of the genetic background, and indeed in some of the work we are going to discuss even taking them from different species where there is absolutely no reason to believe that any form of T cell recognition of this sort would work.
It is really for these reasons that conventional immunologists lost interest in transfer factor as a specific phenomenon; in other words, the great majority of the immunological community no longer believes that this is a particularly specific form of passively transferring T cell specificity. There is much more evidence that these very mixed preparations of cell extracts contain small molecular weight molecules but have non-specific immuno-stimulatory effects that stimulate what is now called cytokine production in cells and that this may enhance background immunity and that that may give the impression of being specific.
Q You say that, generally speaking, there became less interest in this subject I think you used the word amongst conventional scientific thought, but having said that is there, nonetheless, some indications in the literature of some physicians who did work on it and indeed still do do work on it?
A It is worked on as a therapeutic agent. I was unable to find any literature since about 1985/86 that really looks at this from a basic immunological point of view as giving information on cell mediate immunity. That was the interest originally but it is now used really as an empirical biopharmaceutical.
Q As far as that is concerned, broadly speaking in the literature, have there been any impressive clinical results or indeed any involving really reliable scientific methods with randomised controlled trials to demonstrate its clinical value?
A The trials in general are not terribly satisfactory. This is a field largely for enthusiasts with the problems that gives rise to. Having looked at a quite substantial amount of this now, there seems I would have thought little doubt that there are immuno-stimulatory molecules in these preparations and that some effects are obtained. The evidence for clinical utility is very low. It has not reached a place in clinical medicine in any disease that I know of. There are one or two types of immuno-deficiency, particularly chronic mucocutaneous candidiasis where it has been tried where people claim to have had marginal improvements. In the particular context which we are talking about which is measles there was a very good trial done by Professor Tim Moylan’s (?) group looking at sub-acute sclerosing panencephalitis – do you all know about that?
A Which is the genuine long term complication of measles which destroys the brain and kills children where there were claims it did some good but they demonstrated quite clearly that there were no consistent defects and no clinical benefit many years ago and it has not really been used in that context ever since.
Q You said there was doubt as to whether it contains any active ingredients at all but, generally speaking, at this state of scientific knowledge do you think there is some aspect of an active ingredient in the preparations?
A No, I think there are immuno-stimulatory molecules in this. There are one or two papers, particularly in animals which are controlled, which certainly show some clinical activity; in fact, in one which is probably one of the most recent publications on transfer factor where it was used as an adjunct to treating experimental tuberculosis in mice – if you gave enough of it you killed all the mice so there is something there. If you give lesser quantities they say it has helped the therapy. We know in tuberculosis that cell mediated immunity contributes to the disease as well as to the cure, so this is not absolutely surprising, but it does tend to show that it does have some immuno-stimulatory molecules of some kind in there, not well characterised.
Q Can you explain to us generally speaking rather than the specifics of the way in which the preparations were carried out in this trial, how is transfer factor made if it is going to be used for humans in a therapeutic context? I am in the penultimate paragraph on your page 2.
A If one can talk about conventional transfer factor, the form of transfer factor that has been used in the great majority of cases is made by preparing lymphocytes by on the whole leukophoresis so that you put people on a machine which separates online your plasma and your red cells from your white cells so you can take lots of white cells out without making the patients anaemic and you can to some extent fractionate these so they are mainly lymphocytes and these are then frozen and thawed repeatedly. Frequently, though I notice not always, they are treated with desoxyribonuclease to destroy the DNA nuclear protein which makes them much less viscous and easier to handle and they are then dialyzed in various ways using pressure dialysis or other techniques and dialysed preparations are then usually lyophilized and made up. Usually you get a certain volume from a certain number of leukocytes. Some people, Dr Fudenberg for example, then uses leukocyte migration and admission test as another method of standardising them and gives this a South Carolina unit scale, but essentially they are dialyzed extracts from frozen and thawed human peripheral blood lymphocytes.
Q As far as the method of treatment that is used, is the normal practice to inject the substance?
A It is certainly the majority of people who have injected it and again one would expect these things to work injected but there is a certain amount of literature on their being given by mouth, or in mice by gavage by putting a tube into the stomach to make sure that you know how much the mouse gets and it is claimed that this works. That in itself would make people feel that this is not a specific way of inducing T cell immunity. Some of these small molecules may be absorbed in active form but peptides are the size you would expect to do this; you would not expect to be absorbed from the gastrointestinal tract.
Q I want to turn, with that background, Professor Lachmann, to look at what was said in an ethics committee application in relation to the use of this substance for an open label trial as to how it was proposed to produce it. If you could go into you FTP bundle 2, page 675, I am going to run through this document reminding the Panel that this is an application to the ethics committee which you heard about from Dr Pegg in relation to a proposed trial of transfer factor on children with autistic enteropathy. Its relevance as far as this committee is concerned is not the trial itself, which we have only heard did not ultimately take place because of funding issues, but because Dr Wakefield says, as he says in that letter:
“One child who has received this treatment on a compassionate basis appears to have made substantial improvement without any noticeable adverse effects.”
Turning to the application itself, at page 676 we see the principal clinical investigator and responsible consultants included Professor Walker-Smith and the principal scientific investigator was Dr Wakefield. Going over to page 677 we can see the objective of the study which was to assess the clinical benefit of measles virus specific transfer factor in children with developmental disorder and intestinal inflammation (what is known as autistic enteropathy). The Design, which was an open label study of children with that condition, then under Scientific Background we see:
“We have identified a new syndrome in children that includes developmental disorder and chronic intestinal inflammation. In the majority of children the onset of symptoms had a close temporal relationship to either MMR or measles virus exposure. This association has also been reported in the USA. Early viral exposures have been linked to diseases of the autistic spectrum and measles virus, in particular, is associated with disintegrative disorder (Heller’s disease).”
It sets out the various bases upon which the study is to be done.
Going on to page 679, Substances to be given to the subjects, measles virus specific dialyzable lymphocyte extract – transfer factor apparently envisaged to be given orally for six months. We see the adverse events:
“… virtually free from adverse side effects (reviewed by Fudenberg). When given intramuscularly or subcutaneously it may cause pain at the injection site. Transient low-grade pyrexia may occur. No reports of either hypersensitivity reactions or long term adverse effects.
It is important to note that the method of preparation excludes all infectious agents including viruses and viral enzymes.
How are the substances for this study being provided and how is the study being funded?
The drug is being provided, at cost, by Professor Hugh Fudenberg of the NeuroImmuno Therapeutics Research Foundation, a non-profit-making medical research foundation in South Carolina and is being funded by charitable donations to the Inflammatory Bowel Disease Study Group.”
Going on to page 680,
No anticipated side effects. It has been given in millions of doses without adverse effects, other than mild pyrexia (raised temperature) in rare instances.
Anecdotally we have started one child with autistic Enteropathy on transfer factor on an approved compassionate basis. He has tolerated the therapy for one month so far without any adverse effects and according to his parents has shown definite improvement.”
Then on to page 682, we see the parental information sheet. That was the information that it was envisaged would be given to the parents. I am not going through it all, but we see the fourth paragraph down, “A possible new treatment”, and the sixth paragraph:
“This is the first study of a measles-virus specific transfer factor in patients with this syndrome. There are no guarantees that it will work. To date, transfer factor against other viruses, bacteria and tumours has been given and, as well as being an apparently successful treatment, has been extremely well tolerated without any adverse effects, other than a mildly raised temperature in rare instances … [which] usually lasts … a day or two, and is easily controlled with paracetamol.”
Then setting up, “What does the study involve?”:
“If you agree to your child taking part …a formal, standardises behavioural assessment, …”
Then, “You will receive the transfer factor from a pharmacy, you should be called to discuss any concerns you might have”, and they were going to give a mineral supplement at the same time. Then at the bottom of page 683, “Are there any risks?”:
“Along with the possible desired effects, any medication may cause unwanted effects.
If your child feels unwell or has any unusual discomfort … it is important to tell the doctor … [et cetera].
Are there any benefits?
It is hoped that your child will benefit from the study drug, in terms of both intestinal and behavioural symptoms, but it is not known how long this … [will last].”
Then attached to it is a document that I want to ask you about, which is a clinical research protocol, which starts at page 691. If we go to 692 we see the principal scientific investigator is Dr Wakefield, and Professor Walker-Smith is a principal clinical investigator, and the principal collaborative investigator is Dr Fudenberg.
Then on 693 we see “Clinical study” at the top of the page:
“We have investigated, in a pilot study, a consecutive series of 12 children for a new syndrome comprising ileocolonic lymphoid nodular hyperplasia, chronic non-specific colitis and regressive developmental disorder. A summary … is given below. We have now completed the clinical investigation on … 33 children.”
“The first 12 … were referred with a history of achievement of normal developmental milestones followed by loss of acquired skills …”
et cetera. Going on, please, to page 696, we see the “THE TREATMENT”, and “Transfer Factor: an overview”, and you have already assisted us as to the background. There are the general characteristics, and then “Mechanism of action of transfer factor”. Then on page 698, “Route of administration”, “Adverse events” associated with its use. Then the paragraph I want to ask you about, which is under the heading of “DLE-TF” – transfer factor.
“For the purposes of the present study, measles virus-specific transfer factor has been made from the lymphocytes of … mice immunised by killed measles virus. Isolated cells are freeze-thawed and, following Micropore filtration, the filtrate is added to an immunologically virgin human lymphoblastoid cell line. One cell is serially expanded 10-fold with killed measles virus and interleukin-2 to 1 billion cells. Measles virus-specific transfer factor preparations are made from this expanded cell population.”
Then it gives the exact molecular weights of the preparation. We then see:
“The ability of transfer factor to simulate further transfer factor production, and the cross-species reactivity of transfer factor are subsequently exploited in order to produce large amounts of concentrated transfer factor at low cost. This is achieved by injecting the transfer factor preparation into pregnant goats 3 times prior to delivery. Colostrums are collected during the first 3 days post-delivery and transfer factor preparations made from these by micropore filtration …”.
What I want to ask you: in simple terms are you able to assist us first of all, Professor Lachmann, as to what it is being proposed should be done? Then I am going on to ask you how that, if at all, differs from what you have originally described to us?
A This is a completely novel and otherwise undescribed method of making transfer factor, and it goes from being merely eccentric to being totally bizarre.
Q Is your microphone off? I think it is under the document.
A Sorry. As I say, this has gone from being merely eccentric to being totally bizarre. He is immunising mice and taking cells from them which presumably include measles-stimulated T-cells, and adding these to what he calls an immunologically virgin human lymphoblastoid cell line. It must be pointed out that lymphoblastoid cell lines are nearly always cells of the B lineage and not the C lineage, because that is the way they are made, and he does not characterise it. Nor do I know exactly what means by ‘immunologically virgin’ in this sense.
However, he then says that he is expanding this transfer factor. He does not claim that he is using the measles virus to immunise these cells, and indeed you cannot do that, because that is quite a difficult thing to do and needs other cells in vitro. So he is claiming that he can get these cells to make this transfer factor in what is in fact an hereditable fashion – that he somehow gets it into their genome – because otherwise by the time you have expanded them a billion times there would be nothing left. So that would suggest to me that he thinks this is an integrating virus, which with the size it is it really cannot be.
Having made this material, he then says he can amplify further what is now a protein, or a protein with a few RNA bases on it, by injecting it into a goat. If you inject it into a goat you may make antibodies to it, but you cannot cause it to replicate itself. The only proteins that are known to replicate themselves after injection into somebody are prions, and (a) I am quite sure he would not want to believe these are prions; nor is there the slightest reason to believe that there is any prion material in here. So it is very difficult just from an ordinary understanding of cell biology and molecular biology to understand how he can think he can be replicating this factor in the mouse, and get goat colostrum.
A Nor does he in fact give any characterisation of this material, so it is very difficult to know what is in it. Nor does he make it without the measles virus in it at all, which would be a control preparation which one could test; but there is no control preparation. I have scoured the literature as well as I was able, and I have found no account of the evaluation of this material at all, or even any account of its use.
Q You say you found no details as to its characterisation. Could you find any account of the purity of the preparation ---
Q --- or its composition?
A None at all.
Q As far as you can ascertain from the literature and from your own I have no doubt very extensive knowledge, was it unique to Dr Fudenberg?
A I guess, yes. I mean, it is always difficult to say something is unique, but I am not aware of anybody else having prepared this stuff. Bovine transfer factor has been used in calves; there are some veterinary papers; but I do not think it was made from mouse lymphocytes, it was made in a perfectly conventional way using a cow rather than a human to treat a calf rather than another human.
Q But generally speaking, as you have told us, when you are treating a human you use human lymphocytes; is that correct?
A Yes. Though I can quite understand that if you intend to give the amount that he is proposing, and to give it daily for six months, that would be an extremely expensive thing to do.
Q Are you aware, Professor Lachmann – if I can just call this the Fudenberg-type of transfer factor, just so we know what we are talking about – are you aware of that type of preparation of this substance, if it can be called transfer factor, being used clinically in a published report?
Q I think Dr Fudenberg himself has published a study using transfer factor in autism, but I would like to look at that paper, not to look into the science but simply to see what sort of transfer factor he used in the study. This is FTP6, please, at page 604. As I say, I am only interested in the type of substance; anyone can take you to the rest of that report if they wish to do so, but simply so that we know what it was all about, it was 40 infantile autistic patients studied with transfer factor being administered to them. If we look at page 605 that sets out in the top right-hand corner the way in which the transfer factor was produced. Does that description, apparently for a human, collected by lymphophoresis from a parent who had been a household contact during the previous six months – i.e. from the parent for the child, one assumes – does that conform in general terms with what you have described as the normal way in which this stuff is produced?
A Yes. This is human lymphocytes, both unthawed and dialysed.
THE CHAIRMAN: Professor Lachmann, could you bring your microphone a little bit closer to you.
A I am losing this thing; I do beg your pardon. No, this is made from human lymphocytes which have been frozen and thawed and dialysed, and is ‘conventional’, in inverted commas, transfer factor preparation. It is not in any way like the material that is described here. This presumably is not specific for anything in particular, other than that it is likely that the people it is taken from will have had measles. That is all where the specificity comes from; there is no attempt to make it specific in any other way.
I would also point out to you the dose schedule that he gives is totally different, if you look at that page. He gives it for three consecutive days every six weeks for the first three visits, and then the consecutive three days every three months.
THE CHAIRMAN: Professor Lachmann, hold on ---
THE LEGAL ASSESSOR: Professor Lachmann referred to “this is completely different from something described here”.
MS SMITH: Yes.
THE LEGAL ASSESSOR: Some months on when people are looking at the transcript, by “here” do I take it you are referring to page 699?
A Yes. Sorry.
MS SMITH: So the dosage is different. As I say, I am not too concerned about the logic of this paper, but it seems to be claiming some clinical benefit in that paper from using the method that you have described to us. Do you regard that as being a scientifically significant benefit?
A It is not a great paper. Since it is not controlled, it is a bit difficult to know – I am not an authority on the day-to-day care of patients with autism at all; I do not know how much they change if they are just being looked at every few days. As you know, the placebo effect is always greater in trials than it is in historical controls, because patients get more attention, not just in autism but in everything.
A It is generally regarded as necessary to have controls in trials.
A And to have them randomised.
Q If we could just continue in the story, the researchers who were proposing the transfer factor trial to the ethics committee at the Royal Free were asked to give reassurances with regard to its safety, and in that context we have a letter from Professor Walker-Smith to Professor Dumonde. If you go to FTP3, please, at page 943 that is a letter which, just to remind the Panel, was written in response to enquiries by Professor Zuckerman, dean of the Royal Free medical school, as to the safety of this substance. Professor Walker-Smith undertook to write to Professor Dumonde. He said:
“You doubtless will have heard about the controversial findings Wakefield et al have reported concerning the possible role of measles in children with autism. A study is proposed to give a group of such children who have evidence of measles antigen in tissue, positive measles serology and PCR positivity in circulating lymphocytes, dialysable lymphocyte extract – transfer factor. These will be patients under my care and I will be responsible for safety aspects.
As I have known you so long and always valued your advice, I would much appreciate your confidential opinion of the safety of this extract as will be supplied to us by Dr Charles Kirkpatrick, Professor of Medicine and Immunology, University of Colorado …”
He then goes on to say that he has discussed the matter confidentially. That is the first mention that we can find that this substance was to be produced by Dr Kirkpatrick. If we then go on, please, to page 944, the next page, this is the licence that was obtained from the Medical Control Agency. We see it is specifically relating to a proposed trial using dialysable lymphocyte extract transfer factor supplied by the Division of Clinical Immunology at the University of Colorado. So that again appears to be Dr Kirkpatrick.
We see the remark on the licences:
“It is assumed that the Transfer Factor is produced in accordance with the principle contained in ‘The Rules Governing Medicinal Products in the European Community …’.”
Then if I just take you to the rest of the documents, Professor Lachmann, I will be asking you about them. If we then look at page 960 we see a letter from Professor Walker-Smith to the chairman of the ethics committee:
“… I apologise for not replying before but there has been some time involved in determining details of European Safety Standards … We have no doubt that the transfer factor produced is safe by Dr Wakefield will be flying shortly to Denver, Colorado to see the manufacturers to ensure that all the details of the European Safety Standards are met.”
He says it will not be possible to have the information for the next ethics committee meeting.
Then if we go on to page 961 we see Professor Walker-Smith’s letter to Dr Pegg:
“I now have the safety details concerning the European Standards and Regulations on Drug Safety.”
Accompanying that is a letter at page 962 from Dr Wakefield to Professor Walker-Smith:
“Please find enclosed a summary of safety and efficacy evaluation from Professor Charles Kirkpatrick, Professor of Immunology at the University of Colorado … Both Professor Kirkpatrick and I have now had time to review extensively the EU Regulations on Drug Safety, and concur that transfer factors comply with these safety regulations. Professor Kirkpatrick has gone to the trouble of enumerating the trials that he has … conducted and the adverse events, such as they are, that have been recorded. These are remarkably few and consist of pain on the injection site when given subcutaneously. The plan for our trial, as you are aware, is to deliver the drug orally. In conclusion, therefore, we are confident that the drug and the protocol comply with the European Standards and Regulations on Drug Safety.”
Accompanying that is a long letter, and I am not going into all of it, from Dr Kirkpatrick – and we can see his signature on page 967. Then going back to 963:
“Dear Dr Wakefield
You have asked me to report our experience with treatment with transfer factors in patients with immune deficiency diseases. Specifically, you inquired about clinical efficacy and safety.”
Then he says that they did two clinical trials using two different lots of transfer factor, with the same lot of material used in each trial. He says:
“In preparation for the studies, a formal protocol was prepared that was reviewed and approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases … A investigational New Drug exemption was obtained from the United States Food and Drug Administration.”
Then he says:
“Donors. Donors were healthy volunteers who met all of the medical and serologic criteria for blood donation at the Clinical Center Blood Bank.”
He then sets out the way in which they were screened for cell mediated immunity. In addition, they were screened by measuring antigen and mitogen induced lymphocyte proliferation responses. To be selected, donors were required to have positive or negative results in all three tests that were done on them. He explains how the lymphocyte was collected by leukopheresis. He says expressly at the bottom:
“I should add that I served as one of the donors.”
As I say, I am not going to go through that entire document, Professor Lachmann, but I think you have had a chance to look at it. I want to ask you, and the details of the preparation also set out also on page 964. That transfer factor, it is plain, is using human donors, is that correct?
Q I hesitate to keep using the word conventional to differentiate from Dr Fudenberg because I do not think conventional is the word that you would use about any of these preparations, but is Dr Kirkpatrick's description of that in accord with the more recognised method, namely the method you have described to us?
A Yes. This is very much the method that came from the Lawrence Laboratory in the 1950s and 1960s. These are improved by the fact that they now separate lymphocytes automatically, that is right. These are frozen and thawed lymphocytes which have been dialysed and sterilised and they have had them tested on guinea pigs and mice to show that they are not acutely toxic. Yes. This is the stuff that most of the trials in the literature, this sort of stuff, preparation has been used.
Q We know, and I have taken you to it, that the original ethics committee application refers to one child receiving transfer factor. It is going to be a matter for explanation one assumes by someone and a decision by the Panel as to exactly what that substance was and how it was prepared. What I want to ask you as an expert is this. If that child was given the Fudenberg version of transfer factor involving the mice and the goats as he has described to us, do Dr Kirkpatrick's assurances as to its safety apply to what was given to that child?
A I would have thought clearly not. We have no information that that material was tested, I assume it was tested to be sterile. I am not sure whether it was injected into guinea pigs and mice to show that it was not toxic. No, I think this thing has to be done with every preparation actually. The fact that Dr Kirkpatrick had been through these things does not mean that the materials in South Carolina has. You would need separate assurances from the people who made that on what has been done to it. May I just make an observation about Dr Kirkpatrick's letter?
A In view of the fact that this is supposed to be measles specific material, you may notice that the extensive group of antigens which he described as having his donors tested for, measles is not among them. Whether that is because they assume that everybody in America is positive to measles, or whether it is because they are just not interested I do not know, but they have candida, tetanus toxoid, mumps, tuberculin, trichopyton streptokinase streptodornase, but no measles. One could not really describe this stuff as measles specific, even inferentially because it has not been tested, but I would imagine most people in America would have immunised against measles.
Q I believe, in fact, it is compulsory, so that may explain it, in The States I hasten to add. Yes. Thank you. I emphasise the next question that I am going to ask you relates to Dr Kirkpatrick's method because as you have already told us there is not any literature that you could find with respect to the application of the production of the substances Dr Fudenberg was apparently envisaging as reported by these doctors to the ethics committee. With regard to the transfer factor of the type referred to by Dr Kirkpatrick I think it is right that that is a type which, as you said, has been used in many studies, both in adults and children. Is that correct?
Q You have referred, in particular, to the fact that it has been used in children with SSPE. Have you been able to find any trials involving gastrointestinal disease?
A No, not in particular. It is largely immuno deficiency, chronic infections, but actually the major, there are also some trials on tumours of course, as there would be.
Q As far as autism is concerned, we have seen the study by Dr Fudenberg; you have expressed your views on that. Are you aware of any other study of the use of transfer factor in children with autism, other than the one I have referred to?
A No. Dr Fudenberg claims it is the first study of its kind. I am not sure if there have been others since, not that I have been able to find.
Q We have seen from the information that was given to the parents had that study gone ahead it refers to it being a new use. With regard to side effects, is the literature easy to evaluate on that subject?
A Most of the literature claims that there are very few side effects other than occasional fever and local injection sites. I found two papers that claim other side effects. One I have already mentioned to you is this paper by an Italian group on mice, where they were giving both human and urine transfer factors and adjunct to therapy. They claimed this was helpful at optimal doses, but if you upped the doses the mice actually died earlier, even earlier than the untreated mice if you gave them enough of it. There is one other anecdotal claim which is only a letter. The paper on the mice is published in 2004, it is one of the more recent papers. There is a letter by Fouchet et al in 2000 describing somebody given oral transfer factor therapy, not describing how it was made for the treatment of uveitis which developed white matter lesions of the sort you see in multiple sclerosis. I mention this because it is in the literature. This is entirely anecdotal. There is no evidence of causality. A patient got better from this again and I would not regard this as a major contribution to knowledge on the subject but it is in the literature.
Q Of course, as you say, this relates to the conventional manufacture of this stuff, for want of a better word?
A I am afraid Fouchet and colleagues in this letter give no description whatever of what they are giving. I imagine it was this material, I do not know.
Q As far as the Dr Fudenberg version, I hesitate to ask an eminent scientist to speculate, but are you able to give any assistance at all as to whether that might have side effects and what they might be?
A In general I would imagine it is very much like drinking goat's milk; I would not imagine it was any more dangerous than that. If they have stimulated these goats to make inflammatory cytokines in their colostrum which is possible then it might have the same possibility of improving or creating side effects due to immuno potentiation that you can get from other forms of transfer factor. I would have thought it was fairly unlikely that you would have enough of anything in there to produce cytokine storms or anything of this description. The more probable is that it would have no particular effects at all.
Q I think you have already alluded to this, Professor Lachmann, but do you regard it as satisfactory that assumptions should be made on the basis of one of the Kirkpatrick preparations if such assumptions were made, which is again a matter for the committee, as to say it would be a substance made in a totally different way and involving an animal transfer rather than human?
A No, I am sure they are quite different. You can give them the same name. There is no reason to believe they contain the same materials. In fact, there is every reason to believe they contain completely different materials.
MS SMITH: Thank you very much indeed. Thank you for your assistance. You may be asked questions by either my learned friends or indeed by the Panel.
THE CHAIRMAN: Professor Lachmann, as I mentioned earlier, I think it is now for the counsel representing the three practitioners if they wish to ask you any questions. Mr Coonan?
MR COONAN: No, thank you, sir.
THE CHAIRMAN: Mr Miller?
MR HOPKINS: No, thank you, sir.
THE CHAIRMAN: Mr Hopkins?
MR HOPKINS: No, thank you, sir.
THE CHAIRMAN: And the Panel? We do not have any questions. I suspect, Ms Smith, you do not have anything to re examine. The Legal Assessor has told me you are not allowed to because there has been no cross examination.
MR MILLER: I do not want it thought of as any discourtesy to this witness that we do not ask any questions.
MS SMITH: Thank you, yes. Professor Lachmann, it has been very helpful and very important material. Thank you very much.
THE CHAIRMAN: Can I thank you, Professor Lachmann, on behalf of this Panel for coming this afternoon and giving us very clear evidence on all the issues concerned. Thank you again and you are now released.
A Thank you very much.
(The witness withdrew)
THE CHAIRMAN: Can I now ask you, I think the Legal Assessor did inform you about the provisional timetable. As I made a note of it, up to 26 October the defence counsel have to give any notice to the GMC and to the Panel Secretary if there are going to be half time submissions made. If that is so, then by 23 November they will have to make those submissions. The GMC would have to make their own submissions to those issues by 28 December. First of all, can I just ask your observations first of all on that issue?
MS SMITH: The Legal Assessor anticipated, sir. I am afraid I have not finished yet, but that is correct on the timing, yes.
THE CHAIRMAN: Mr Coonan?
MR COONAN: Yes.
THE CHAIRMAN: Mr Miller and Mr Hopkins.
MR HOPKINS: Yes.
THE CHAIRMAN: Thank you. Can I now ask you for something that you should have done before this and anything else, Ms Smith?
MS SMITH: Would you excuse me for a moment, please? The first thing is that I have a very brief statement to read out, sir. It has been agreed I may read it into the transcript by Mr Coonan because it only relates to the charges in relation to Dr Wakefield. Perhaps I can hand in copies of that statement, sir. It is the second statement of Dr Horton from whom we have heard.
THE CHAIRMAN: (Same handed to the members of the Panel and marked as exhibit C19). This statement from Dr Richard Horton will be C19.
MS SMITH: Sir, that, as I say, is the second statement of Dr Richard Horton. You will see that it is dated October 17 2007 and signed by him. It says this:
“I have already signed a witness statement in relation to this matter dated 6 August 2005. In my previous statement I stated that Dr Wakefield and 12 other authors submitted a paper to the Lancet which was published in February 1998, (“the 1998 paper”) with the title “Ileal lymphoid nodular hyperplasia, non specific colitis, and pervasive development disorder in children”. I have been asked to confirm whether Dr Wakefield disclosed to the Lancet the existence of a patent with short title “Pharmaceutical Composition for Treatment of IBD and RBD” at the time when the 1998 paper was submitted to the Lancet or at any time before publication of the 1998 paper.
“I can confirm that to my knowledge Dr Wakefield did not disclose the existence of this patent or any other patent to the Lancet at the time when the 1998 paper was submitted to the Lancet or at any time before publication of the paper.
“I understand that my statement may be used in evidence for the purposes of a hearing before the GMC Fitness to Practise Panel and for the purposes of any appeal, including any appeal by the Council for the Healthcare Regulatory Excellence. I confirm I am willing to attend the hearing if asked to do so. I believe the facts stated in this witness statement are true.”
That should be part of your consideration when you consider Dr Horton's evidence, sir. Would you excuse me for a moment, please? That is the case for the General Medical Council.
THE CHAIRMAN: Now going back to the timetable can I now just put this quite clearly because as I have said earlier that I think that, not I think, I know that the Panel have that one week already on their diary booked for January for this case. There are obviously some doubts whether we would be needed in that week or not. Can I suggest that if we do not hear anything by the end of October then we will take it for granted that we will not be required in January. Is that acceptable? Mr Miller?
MR MILLER: Sir, I would notify the GMC anyway.
THE CHAIRMAN: Hopefully we will hear something before the end of October. Mr Hopkins?
MR HOPKINS: Likewise, we will let you know one way or the other.
MS SMITH: Sir, you gave the date of 26 October when you gave the dates a few months ago.
THE CHAIRMAN: I did say 26 October. I am just giving the couple of days for this information to come up to us, by the time it comes to the GMC Secretary and then she has to then notify all of us. I was just giving those extra two or three days for no particular reason. Legal Assessor?
THE LEGAL ASSESSOR: I think it might be easier if the advice I gave, if the Panel is happy to make that a direction so that if anybody has got given notice by seven days that they wish to make a submission, then they can be deemed they are not making one. I am going to advise the Panel that if they agree they should make that a direction. Everyone has agreed to it, so I cannot assume anybody objects to it becoming a direction.
THE CHAIRMAN: I am going to look towards the Panel members to check that they are happy. Yes. I do direct that on behalf of this Panel that if there is no notice of submissions to the GMC by 26 October then it will be deemed that there are no submissions coming forward.
In that case, we will not be then required in January, but I am just looking at the date when we are meeting after that. I believe that if we are not required in January then I believe that we are supposed to be meeting on 25 March, but can you please check.
MS SMITH: Because my junior is indicating to me it was not wholly clear, when you talk about the GMC, sir, you appreciate that there is a difference between the GMC as prosecutors. The defence will notify us through my instructing solicitors, Field Fisher Waterhouse, by 26 October.
THE LEGAL ASSESSOR: No. The direction, the advice, and I assume the direction is based on the advice I have given, is that notice is to be given to Caroline Tomlinson, the Secretary of this Panel. As a matter of courtesy one would hope they would tell you as well, but she will then notify Panel members and myself and any other interested party, such as The Press, so that there is one channel of communication. Official notice is to be served on Caroline Tomlinson, the secretary to this Panel.
THE CHAIRMAN: Thank you very much indeed, Legal Assessor, for clarifying that. Is that clear to everyone? If there are no questions can we now adjourn? Mr Hopkins?
MR HOPKINS: Sir, I just want to mention in case it has logistical implications that the day we are due back is Easter Tuesday, the 25th, which means of course it is a Bank Holiday Monday. You know the volume of files we have. We would not be able to get people to bring files on a Bank Holiday Monday I suspect. Just for your own consideration, setting a room up like this again on the Tuesday morning is going to take a little time.
THE CHAIRMAN: I think that is a very practical suggestion. Can I then just suggest in that case the Panel Secretary will communicate with all of us and with all of you how the situation is going to work from that day onwards.
Any more points, clarifications, questions or any other issues that are to be raised at this stage? If not, can I wish you, because I know that we will not be meeting on this side of the end of the year, so all the very best for the New Year and we will be seeing you sometime in the New Year, either in January or the end of March.
(The Panel adjourned sine die)