Monday, February 6, 2012

Day 44 GMC Fitness to Practice hearing for Andrew Wakefield



Tuesday 16 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)


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 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.


Page No


Examined by MS SMITH, continued 1
Cross-examined by MR MILLER 2

THE CHAIRMAN: Good morning everyone. Professor Booth, good morning to you.
A Good morning, sir.

THE CHAIRMAN: Ms Smith, am I correct in thinking that your examination-in-chief had just finished?

MS SMITH: It had, you are correct in saying that, sir, and I expect you hoped that you had heard the last of me for a little while, but there is one very small point which I freely admit I forgot to ask Professor Booth before I concluded my examination-in-chief, and Mr Coonan has kindly said I can deal with it this morning. As I say, it is a very short matter, and I am sorry to ask you immediately to get to your feet again, but could you get the Royal Free records for Child 2, please.

Examined by MS SMITH, continued

Q Professor Booth, if I can just refresh your memory as to what you have already told us on Child 2, if you remember he was the first child, and Professor Walker-Smith wrote to his mother, having seen the child the year before, and then saw him in out-patients in June 1996. Blood tests were taken, and you have told us that the results of those were normal. Then the child was admitted in September 1996. Blood was taken on the day of the colonoscopy, that is 2 September, and the results came back after the colonoscopy, and in fact the specimen clotted on 2 September so there was a repeat. The only thing I want to ask you about is that we have the full set of results, which is at page 326 in the Royal Free records. If you look at the top of the page you will see the two columns in the middle, for 2 September and 5 September. Are you with me?
A Yes.

Q I wonder if you could assist us with the result. As I say, it is because there was a clotting on the 2nd that we have the first three results on the 5th, and then the remainder of the results on the 2nd, but they were all post the colonoscopy. I wonder if you could help us as to any abnormalities. The haemoglobin, first of all.
A The haemoglobin on the 5th is a bit low. You would normally have a cut-off – how old was he? He was eight – the cut-off would be probably eleven.

Q So there is an abnormality there?
A Yes.

Q As far as the rest are concerned, are there any abnormalities?
A The white count platelets are OK. In the column for 2 September ---

Q CRP is at the bottom – or not at the bottom ---
A There is “3”, which is within the normal range for the Royal Free Hospital.

Q Right.
A And the albumen is not low, 48.

Q When you say it is not low, do you mean by that that it is normal?
A You would be looking for a low result if you were doing these in the context of looking for inflammatory bowel disease.

MS SMITH: Thank you very much, Professor Booth.

Sir, that really is all I have to ask Professor Booth for now.

THE CHAIRMAN: Thank you, Ms Smith. Professor Booth, as I mentioned earlier, it is obviously time for counsel representing the three practitioners to cross-examine you on the evidence that you have just given. I am first of all going to ask Mr Coonan on behalf of Dr Wakefield.

MR COONAN: Sir, I have no questions, thank you.


MR MILLER: I have some questions.

Sir, can I start by giving the Panel copies of a bundle of literature, which I do not think you have. The bundle has been prepared – Ms Smith mentioned it several weeks ago but I am not sure that you had copies of that literature given to you.

THE CHAIRMAN: We did not.

MR MILLER: Can I ask you to have that bundle in front of you now.

THE CHAIRMAN: This brown bundle, GMC v Wakefield, Professor Walker-Smith and Professor Murch, with Eastwoods at the bottom, will be D6. (Document handed and so marked).

MR MILLER: I am sorry to ask you to get up again, but could you also have Professor Murch’s literature bundle available as well, please, which is D5.

Questioned by MR MILLER

Q Do you have both of those bundles, Professor Booth?
A Yes, I do.

Q Can you tell us what ESPGHAN is.
A It is the European Society for Paediatric Gastroenterology, Hepatology and Nutrition.

Q So it is a pan-European society?
A Yes, it is.

Q What are its aims?
A To promote research and good clinical practice within paediatric gastroenterology, hepatology and nutrition.

Q And its membership?
A In what terms?

Q What sort of people are members of it?
A The majority of members are consultant paediatric gastroenterologists from around Europe. There are some members from North America as well.

Q In July 2005 the IBD Working Group – is it actually [pronounced]) ESPGHAN, or is it E-S-P-G-H-A-N?
A The H is silent.

Q So it is [pronounced] ESPGAN?
A Yes.

Q In July 2005 the IBD working group came up with recommendations for diagnosis of inflammatory bowel disease in children and adolescents, what were called by them the Porto Criteria.
A Yes.

Q Various recommendations were published in the Journal of Paediatric Gastroenterology and Nutrition which we have behind tab 9 in Professor Murch’s literature bundle. The working group which produced and published those criteria included, I think, a number of English-based paediatric gastroenterologists, on page 57, including Professor Murch; Dr Sandhu, I think, who comes from Bristol; Dr Fell from London; Dr Chong; and Dr Stephen Murphy who is from Birmingham.
A That is correct.

Q It is right, is it not, Professor Booth, that inflammatory bowel disease paediatric patients are principally seen in clinic anyway at the Birmingham Children’s Hospital by a team headed by Dr Murphy?
A Do you mean who is the current clinical director?

Q No. He deals with the majority of the inflammatory bowel disease patients.
A No, it is Dr Protheroe?

Q And Dr Murphy?
A Dr Murphy sees patients as well. But if you are saying who sees most inflammatory bowel disease patients, it is Dr Protheroe, in that Dr Murphy is a clinical academic, so he has fewer clinical sessions on his job plan.

Q But he is very much involved in inflammatory bowel disease, is he not?
A Yes, yes.

Q And that is his special area of expertise, is it not?
A It is one, yes.

Q Who is Professor Deirdre Kelly at your institution?
A Deirdre Kelly is one of the paediatric hepatologists, so she specialises in children with liver disease.

Q There is, as we can see, a link-up anyway in this society or this organisation with hepatology, and I believe that Birmingham has a small bowel transplantation unit, does it?
A That is correct, yes.

Q And there is a good deal of cooperation between various aspects to deal with the problems that arise out of surgery of that type?
A Yes, there is a lot of cross-fertilisation between the gastroenterologists and the hepatologists, yes.

Q Are you involved in that aspect of paediatric care of small bowel transplant unit?
A Not in the management of the patients immediately after transplantation, but I am involved in the pre-transplant assessment and also seeing them post-transplant if they get gut problems, yes.

Q In terms of colonoscopy carried out as a routine, do you do more colonoscopies in relation to that aspect of the Birmingham Children’s Hospital’s work than pure inflammatory bowel disease?
A No.

Q Do you do routine colonoscopy for inflammatory bowel disease as part of a clinic?
A Yes; I colonoscope the patients that I see in my clinic, yes.

Q With what sort of regularity?
A Stephen Murphy and I share a colonoscopy list on a Thursday morning.

Q And Dr Protheroe?
A She has a list on Tuesdays.

Q Shall we go back in time a bit? Can we look at the Porto criteria first. This is a paper which, would you agree, represents the view of those involved in the diagnosis and management of inflammatory bowel disease across Europe?
A Yes.

Q And what they were seeking to do was to set up criteria and advice, recommendations, to those involved in that area?
A Yes.

Q If you look at page 52 in the bundle under “Aims”:

“Primary aims of the ESPGHAN IBD working group were to define consensus-based criteria for the diagnosis of IBD (CD [Crohn's disease], UC [ulcerative colitis)] and indeterminate colitis) in children and to reach agreement on the diagnostic work-up of new pediatric IBD patients.”

Then, under “Patient History”:

“A clinical suspicion of IBD is raised in children with persistent (≥4 weeks) or recurrent (≥2 episodes in 6 months) symptoms such as abdominal pain, diarrhea, rectal bleeding and weight loss.”

Then over the page, at page 53, under “Laboratory Examination”…. Just pausing there, when we see references to “laboratory examination” it more often than not refers to the laboratory examination in this context of blood samples in the way which we have looked at in the individual cases in this case?
A Yes, that is correct.

Q It says:

“Screening blood tests to include full blood count, erythrocyte sedimentation…”.

A It says “should include”.

Q That is exactly what I read, is it not?
A No, you said “to include”.

Q I actually said “should” according to my neighbour here. I am reading from the text.

“Screening blood tests should include full blood count, erythrocyte sedimentation rate”

- that is ESR –

“C-reactive protein, serum levels of urea and creatinine, serum albumin, immuno-electrophoresis, liver function tests and (in certain cases) celiac screen. Reduced level of haemoglobin, raised markers of inflammation (erythrocyte sedimentation rate, C-reactive protein), elevated platelet count and reduced serum albumin are suggestive of IBD. However, in some UC [ulcerative colitis] patients erythrocyte sedimentation rate, haemoglobin and platelet count are found to be normal. Elevated platelets may distinguish IBD from infectious diarrhea in a patient presenting with (bloody) diarrhea.”

Then, on the right-hand column, “Endoscopy and Histology”:

“Colonoscopy including intubation of the terminal ileum and multiple biopsies for histology obtained from all segments of the lower intestinal tract (ileum, cecum, ascending colon, transverse colon, descending colon, sigmoid and rectum) is essential; it is the most important investigation to differentiate between CD [Crohn's disease] and ulcerative colitis and identifies localization and extent of inflammatory disease. Intubation of the terminal ileum with terminal ileum biopsies should always be attempted, as isolated ileal inflammation may occur in the presence of a normal colon in up to 9% of children with CD [Crohn's disease]. Examination of the small bowel by small bowel follow through with ileocolonoscopy is insufficient, as the radiologic examination may give a negative result when the inflammatory changes are subtle.”

Just pausing there, is that reflection to a barium meal follow through?
A That refers to a barium follow through, yes.

“In addition, visualization of the ileum and ileal biopsies are crucial in the differential diagnosis of patients with pancolitis. Rectosigmoidoscopy alone is insufficient, as proximal abnormalities can only be assessed by full colonoscopy.”

Then they talk about:

“Upper endoscopy is advocated in all children irrespective of presence or absence of upper gastrointestinal symptoms.”


“In children, it is preferable if endoscopy is performed under general anesthesia or deep sedation”.

Over the page, at page 54, there is a “Summary of Espghan Diagnostic Criteria for Diagnosis of I believe (Porto Criteria)”.

“Figure 2”

which is found below it –

“shows a summary of the Porto criteria for the diagnosis of IBD. Children and adolescents with symptoms suggestive of IBD should be referred to a pediatric gastroenterologist for diagnostic work-up. Infectious causes of (bloody) diarrhea is to be excluded and laboratory screening tests should be performed. All patients have to undergo endoscopic evaluation (ileocolonoscopy and upper gastrointestinal endoscopy). During endoscopy, biopsies (of inflamed and non-inflamed mucosa) should be taken from each segment of the gastrointestinal tract.”

You are keen to make the point, they are recommending saying that laboratory examination and screening blood tests should include the list that they gave there, but equally they are saying that colonoscopy including intubation of the terminal ileum and multiple biopsies is essential?
A Yes. They are not mutually exclusive though.

Q No. I entirely accept that, but what they are not saying, and we will look at some of the other literature just to see whether anybody else is saying it, is that it is not permissible if you get normal blood screening results to proceed to colonoscopy if you suspect that there is inflammatory bowel disease present?
A If you have a very strong clinical suspicion of inflammatory bowel disease, then it would be entirely appropriate to proceed to more invasive investigations in the presence of a normal set of screening investigations but, as has been pointed out on a number of occasions, it is somewhat unusual to find a completely normal panel of inflammatory indices in the presence of inflammatory bowel disease.

Q We will have a look at some of the other literature, as I say, which makes the point that that is not necessarily so.
A I think figure 2, which you have drawn my attention to, is actually at variance with figures published by Professor Walker-Smith, where conduct of a full blood count, ESR and the other panel of inflammatory indices, precedes invasive investigations in his flow diagram.

Q Yes. The point you make is that this does not get to start off by saying the flow diagram starts with C-reactive protein and laboratory investigations, or other investigations.
A If you just took this figure at face value, you would imagine that every patient in whom you remotely suspected inflammatory bowel disease would automatically have a colonoscopy.

Q That is your gloss. You put the extreme gloss on it, but there is not anything in the text to suggest that is the case. It says, in fact, that you should do both, but by the way in which they describe upper endoscopy and colonoscopy, they appear to put it rather higher up the pecking order than you do?
A I agree entirely that you should do both, as you say.

Q Can we just look back in time a bit – this is relatively recent and there is more recent literature about the results of blood tests – but the period in late or mid-1990s to the end of the century was a period in which first St Bartholomew’s and Queen Elizabeth Hospital for Children and then the Royal Free were amongst the leaders, if not the leaders, in investigating and treating inflammatory bowel disease?
A They had a large experience, yes. I am not quite sure what criteria you are saying for leaders. Do you mean they saw the most patients?

Q Yes. During that period.
A That is certainly possible, yes.

Q And you have made the point, whether it is correct or not we will have to find out from Professor Walker-Smith when he gives evidence, that they appear to have concentrated in this particular unit on inflammatory bowel disease rather than other aspects of gastroenterology which you said was better covered in your own institution?
A My understanding is that there were certain areas of fairly standard paediatric gastroenterology practice that were not available at the Royal Free Hospital.

Q Which were what?
A The management of patients following neonatal surgery, for example; involvement in a multidisciplinary nutritional care team. But that is my understanding.

Q So that is, just for the purpose of the Panel, immediately after birth – gastrointestinal problems which babies might have which have to be dealt with by a team which would include neonatologists and gastroenterologists?
A That is correct, yes.

Q That is one area, is it. What is the other area?
A The multidisciplinary management of patients with that sort of gastrointestinal problem, and others, with a multidisciplinary nutritional care team, involving gastroenterologists and surgeons and other colleagues.

Q That is still the neonatal?
A No. That is across the whole paediatric age spectrum.

Q We will hear from Professor Walker-Smith about that when he gives his evidence. Before you moved to the Royal Free Hospital, you know that he was at St Bartholomew’s Hospital and the Queen Elizabeth Children’s Hospital in Hackney?
A Yes.

Q And you trained for some part of your early training, I think, at the Queen Elizabeth Hospital?
A That is correct, yes.

Q And also at Great Ormond Street Hospital?
A Yes.

Q The Panel has your curriculum vitae. I think it is in FTP7. It starts at page 33, and there are chapters and reviews that start at page 47, and contributions to refereed journals and scientific papers at 52. As far as the papers are concerned, we do not find many scientific papers on inflammatory bowel disease, do we?
A You mean ---

Q I am going to ask you to look at some anyway because you did co-author some, but just overall, specifically on inflammatory bowel disease with which we are concerned in this case. Perhaps that is an unfair thing to say. I put it to you just off the top of my head. Let me just ask you to look at some of them, because the papers which I would wish to refer to are contained at the back of Professor Walker-Smith’s literature bundle. Do you have that there? On page 53 of FTP7, there is a reference to an article called “Inflammatory bowel disease in childhood” but which you co-authored with Professor Harries. It is behind tab 19 in Professor Walker-Smith’s bundle. I think this was something which was written when you were a senior registrar at Great Ormond Street Hospital for Children? It is 1984.
A Yes, I think I was a lecturer at that time.

Q Looking at your CV, with the combination of academic and National Health Service appointments which we have had described to us, honorary senior registrar, I think at Great Ormond Street, and a lecturer at the Institute of Child Health. Is that right?
A Yes, that is right. Yes.

Q It is only in your clinical context seeing patients that you presumably would have been a honorary senior registrar at the Children’s Hospital?
A That is right, yes.

Q It is called a “Progress Report”. And Professor Harries was who? He died, I think, just after this was written.
A Professor Harries was Professor of Paediatric Gastroenterology at the Institute of Child Health and an Honorary Consultant Paediatric Gastroenterologist at the Hospital for Sick Children.

Q If we look at the introduction it is called a “Progress Report”. What does that mean?
A It is summarising recent changes in diagnosis and management of patients with inflammatory bowel disease.

Q Would you look at the first couple of paragraphs:

“Infants and children are not only growing but also developing, both physically and intellectually, and these differences embody the reasons why many diseases, of which inflammatory bowel disease is a good example, produce differing symptoms and management problems compared with adults. It is the aim of this review to highlight these differences rather than to provide a totally comprehensive account of inflammatory bowel disease in childhood.

The more important causes of inflammatory bowel disease in children are similar to those in adults with the exception of food allergy, which is an important and underestimated cause of colitis in infancy, and is discussed more fully later. As there is considerable controversy surrounding inflammatory bowel disease, many of the views in this study reflect or own experience and practice, which are essentially empirical and pragmatic where there are no scientifically well founded guidelines available .”

So do I understand you to mean – or you and Professor Harries to mean – that you are writing about the experiences of the unit to which you were attached and to explain how that unit managed its patients?
A I think we were drawing on our own experience, but also drawing on the experience of other people looking after paediatric patients with inflammatory bowel disease.

Q I think what the message appears to be, “We can tell you our own experiences, also informed by literature which comes from other units, to which we refer in the body of the text”?
A Yes. There are 74 references.

Q And we see in some cases where those references come from and what is being described, so it is not effectively, “This is just the way we do it”. It is, “This is our practice and it is informed from other sources”?
A Yes.

Q On page 190 in the original – this bundle does not have internal numbering so it is just the original numbers – under “Colonoscopy”:

“With the advent of floppy, small diameter paediatric colonoscopes, colonoscopy now provides a safe, quick and accurate method of macroscopically and microscopically examining the entire colon in children, and does not require a general anaesthetic.”

Just for reference, macroscopic means what you can see.
A That is correct.

Q And microscopic what your histology produces?
A That is correct.

“As a result, the barium enema has been largely superseded. In a recent series of 123 consecutive colonoscopies in children ranging from 3 months to 16 years of age, examination of the whole colon was possible in all patients in which the colon was patent”.

There is a footnote, there it is a reference to a paper by Williams et al in 1982 which is headed, “Total colonoscopy in childhood” of which you and Professor Walker Smith were co authors amongst others?
A That is correct.

Q That study was a collaborative study between different hospitals in London, the clinician concerned coming from St Mark’s Hospital, St Bartholomew’s and Great Ormond Street Hospital where you were a lecturer at the time.
A That is correct.

Q Williams, the lead author, can you tell us who Christopher Williams is?
A Christopher Williams is an adult gastroenterologist who was one of the first people in the United Kingdom to provide an endoscopy service for adults based at St Marks Hospital. He was an extremely skilled, and still is as far as I know, and enthusiastic endoscopist and he was very influential in making particularly colonoscopy available for paediatric patients.

Q He was one the pioneer of colonoscopy/endoscopy in England and extended it from adult practice to paediatric practice.
A Yes.

Q Until others trained in paediatric colonoscopy and took over?
A That is correct, yes.

Q He trained quite a few of those who are now the leaders in paediatric colonoscopy. Is that right?
A Yes, I think he did.

Q If we can go back to the paper at page 190, you go on to describe bowel preparation and sedation. In the middle of the second paragraph about halfway down the page, do you see the sentence that starts “although” on the right hand side?
A Yes.

“Although colonoscopic biopsies tend to be small and superficial, it is possible to make a firm diagnosis based on macroscopic, histological, and radiological findings in over 90% of children with inflammatory bowel disease”.

That is based on the same paper is it?

A Yes.

Q Reading on,

“Colonoscopy is therefore mandatory in the diagnosis and management of inflammatory bowel disease in childhood, and the procedure should be performed in centres at which a skilled paediatric endoscopist is available”.

A Yes.

Q Over the page under “Crohn’s disease” under the subheading “Drugs” it reads,

“To date, all controlled therapeutic trials have been performed in adults and the interpretation of many of the findings are somewhat controversial. As a result, the use of drugs in Crohn’s disease in children is based on evidence obtained in adults, clinical acumen, and speculation” –

appreciating that you are writing in 1984 at this time.

A Yes.

Q Then you deal with a suggested treatment regimen from your own practice involving steroid treatment, the first of those in the list under the table. Is that a steroid?
A Yes. We receive any recommendations about treatment by saying that it is particularly important when treating childhood Crohn’s disease to bear in mind that in a relatively quiescent disease the adverse effects of treatment may easily outweigh any benefit, but then we go on to describe the treatment approach to patients with Crohn’s disease, yes.

Q The first is cortico steroid is it?
A That is correct, yes.

Q It looks from the text as though you were advocating that as the starting point for s relatively short period of time.
A Azathioprine is an immunosuppressive agent.

Q We have seen in the course of this case sulphasalazine, which is an anti inflammatory, if colonic disease is present. In the text, about five lines up from the figure,

“In children with colonic involvement, it is our practice to use sulphasalazine in a dosage of 50 100 mg/kg/day beginning at the lower dosage, for one or two years, depending on the course of treatment”.

Can you just explain what your thinking is in relation to that paragraph that it involves the giving of anti inflammatory for a period depending on how the disease progresses or regresses?
A Yes. In 1983 when this was written there were no other agents like sulphasalazine which contained five ASAs, so sulphasalazine was the sole five ASA containing agent, so there was no choice of another agent. These days and by the mid 90’s we had a choice of agents like olsalazine. Many of us tended to stop using sulphasalazine because of the side effects which included reactions like headache and skin rash. It subsequently became clear that sulphasalazine in male patients produced reversible infertility. That led to a move away from sulphasalazine subsequently.

Q I am going to pass over that because I am going to take you to another paper which you wrote which makes the point about how treatment appears to have moved on by the time you get to the 1990’s. We will look at it in the context of what you wrote then. Could we at the footnoted paper to which you referred in that article. This is “Total colonoscopy in children” which is behind tab 18 in Professor Walker Smith’s literature. Williams is the lead author. He was writing from the endoscopies unit at St Marks Hospital, but he was also attached to St Bartholomew’s Hospital as well was he not?
A He had sessions at St Bartholomew’s and at Great Ormond Street, yes.

Q He is the lead author. There is Professor Walker Smith and there is you and Professor Harries. The patients appear to have come from St Bartholomew's and from Great Ormond Street. Can we just look at the summary on page 49 of the original article:

“One hundred and twenty three total colonoscopies were performed on 115 children with ages ranging from 3 months to 16 years. The major indications were suspected inflammatory bowel disease and unexplained rectal bleeding. Ninety seven per cent of all procedures were carried out with sedation only. Adult colonoscopies were used in most of the patients but in babies and small children paediatric instruments were preferable. Total colonoscopy was possible in all patients with a patent colon. The terminal ileum was examined in 63 patients”.

Then you deal with polypectomy which is not relevant in this case. That is removing a polyp from the bowel.

“Total colonoscopy in this paediatric series proved to be at least as easy, rapid, well tolerated, and safe as in adults. In selected patients a single colonoscopy can give an accurate diagnosis with biopsy proof and sometimes the opportunity for definitive treatment”.

Then in the right hand column under, “Patients and methods:

“The series comprises 123 fibreoptic colonoscopies on 115 children performed by a single experienced endoscopist between 1973 and 1980 as part of a total series of at least 5000 adult examinations”.

Was the single experienced endoscopist Dr Williams?
A That is correct, yes.

“The paediatric examinations were performed mainly at St Bartholomew’s Hospital (58 examinations) and at the Hospital for Sick Children, Great Ormond Street (55 examinations) For administrative reasons, most were performed on an inpatient basis. ... Patients were chosen for colonoscopic examination by two of us [J Walker Smith and JT Harries] for the reasons given below or because of possible abnormality on barium enema, previously performed in the majority of cases”.

Pausing there, to avoid confusion, barium enema is introduced in the opposite direction from the barium meal.

A Yes, the barium is inserted into the rectum and then followed round the length of the colon.

Q When you were going through the French literature, there was reference to that still being a practice at the time that was written anyway that was recommended, but it is not something that is now done or was even done in the mid 1990’s as a matter of routine.
A By the mid 90’s, no, barium enema was very rarely used in tertiary centres in the diagnosis of inflammatory bowel disease. The events of colonoscopy made it almost immediately redundant.

Q Over to page 51 in the original text, in the left hand column under “Clinical indications and yield”:

“The indications for examination and the colonoscopic diagnosis are set out in the table. The patients were highly selected and often referred from other hospitals not having colonoscopic facilities. Inflammatory bowel disease known or suspected was the major indication, with a diagnosis being made and confirmed by histology in 76 (96%) of the 79 children 90 assist per cent of the 79 children (Ulcerative colitis 32%, Crohn’s disease 26% indeterminate inflammatory bowel disease 5%, normal 33%”. The other 3 patients had acute colitis with the aetiology not established. One child having normal colonoscopy and histology was shown to have Crohn’s disease on re examination 3 months later. Rectal bleeding (macroscopic 21 and occult 5) was the next important indication with the cause of blood loss established in 38 % of the 26 children examined. Abdominal pain alone, without clinical or other features on special investigation to raise a suspicion of inflammatory bowel disease, was an unrewarding indication since no abnormality was found in any patient”.

Looking at the table, the indications given, the clinical problem on the left hand side is said to be inflammatory bowel disease in 79 cases, if I read it correctly, rectal bleeding in 26 and then polyposis in 3 and poly barium enema in 3 and pain in 3. Am I reading that correctly?

A That is correct, yes.

Q I am not going deal with therapeutic colonoscopies, because that is polypectomy; I am dealing with polyps in the colon.

Under “Complications”, at the bottom of the right-hand column,

“No complication occurred in the entire series of diagnostic colonoscopies after more than 500 diagnostic forceps biopsies in the colon and ileum ...”

Then on page 52 you give the justification for performing a total rather than a limited colonoscopy, the beginning of the paragraph starts “Analysis:

“Analysis of our series shows that, although a diagnosis could have been made in 7% of patients with limited colonoscopy (reaching to the splenic flexure) only 12 of 21 Crohn’s patients would have been diagnosed (6 of our cases had only Crohn’s ileitis) and 5 of 11 children with polyps would have remained undiagnosed. The true extent of inflammatory bowel disease would have been under estimated in most cases and the diagnosis of ‘normality’ would have been less certain in the 46 children in whom no abnormality was found on total colonoscopy”.

The point being made there is if you are going to do it, you ought to do the whole thing, a total colonoscopy rather than limiting it to a study of part of the colon.
A Yes.

Q Then at the top of the right hand column:

“Although we do not foresee total colonoscopy as a routine investigation in children, our results suggest that in certain categories of patients such as those with rectal bleeding and suspected inflammatory bowel disease it can be particularly rewarding. Perhaps colonoscopy should be considered a first line procedure in such patients, since it is easy to establish or exclude bleeding pathology with the colour endoscopic view”.

Then the last paragraph,

“We conclude from our experience that colonoscopy is a practicable and rewarding procedure, likely to make a major contribution to paediatric gastroenterology” -

something which you clearly do not quarrel with?

A No I would not quarrel with that. I have some other comments about the publication, but I would not quarrel with the final paragraph at all.

Q Can I ask you to have a look at one of your works on your own, written in 1991 again in the archives of disease in childhood which is behind tab 20. What is the status of archives of disease in childhood?
A It is a journal based in the United Kingdom which publishes research in children and clinical reviews amongst other things.

Q Is it something that is read by paediatric gastroenterologists and paediatricians?
A Yes.

Q This is behind tab 20. It is chronic inflammatory bowel disease and by this time you are at Birmingham in 1991. It is called a regular review. What is that?
A It is a review that appears regularly in the journal on differing topics.

Q It is a similar, although perhaps shorter, publication than the progress report which you wrote before.
A Yes. The editor of the journal invites specific people to submit a review on whatever topic the journal happens to be interested in at the time.

Q They are interested in chronic inflammatory bowel disease in this instance. Is that what the heading is?
A Yes.

Q If you go over the page, you deal with Crohn’s disease and colitis separately. Over the page, you talk about colonoscopies, I want to ask you about that, page 743 in the original. Do you have that?
A Yes.

“Since early descriptions of colonoscopy in infancy and childhood it has become increasingly clear that this investigations invaluable in the diagnosis and management of inflammatory disease of the colon”.

The reference there to 21 is to the Williams paper that we looked at a moment ago. This is 1991.
A Yes.

“The barium enema in this context is now virtually redundant. The procedure is safe and well tolerated, allows multiple mucosal biopsies to be taken, and often adds important information to the diagnosis. For example, over half the patients in a recent study who had endoscopically confirmed colitis had no radiological evidence of inflammatory disease, although only a single contrast barium examination had been used”.

In that context, Professor Booth, would that be a reference to a barium meal rather than a barium enema?

A That would be a barium enema.

Q It was virtually redundant, and it was not actually producing information that compared with colonoscopy.
A That is correct, yes.

Q In fact, if anything, it was providing misleading information because it did not identify the pathology that was there.
A The sensitivity of the investigation was less than colonoscopy, yes.

Q Then “Drug treatment” and this comes back to the point you made in relation to sulphasalazine earlier, although this is now several years later

“Sulphasalazine is valuable in the management of ulcerative colitis, particularly as a prophylactic”.

In that context what do you mean?

A I mean that when patients with ulcerative colitis have gone into remission, usually following administration of steroids, if treatment with sulphasalazine is then instituted, it reduces the likelihood of a relapse of their clinical symptoms.

Q It would be given to them even though they were in remission and were not, on the face of it, suffering the symptoms that had led to them being treated with steroids?
A Yes. This would have been after a clearly documented episode of ulcerative colitis, yes.

Q By prophylatically, you mean even though there are not any symptoms to treat at that point?
A It makes the chance of a relapse less likely, yes. Whether or not they have continuing symptoms would not necessarily be clear. Some patients continue to have symptoms from time to time with ulcerative colitis whilst on agents like sulphasalazine, so they would not necessarily be completely symptom free.

“Side effects which include reversible male infertility, are common, although probably less troublesome in children. Alternatives to sulphasalazine now exist, and most patients will tolerate mesalazine (delayed release 5 aminosalicylic acid) or olsalazine (altered carrier molecule of salicylate), both of which appear to be as effective as sulphasalazine”.

A Yes.

Q Whatever their brand names are, there are described three different anti inflammatories.
A Yes. The alternatives to sulphasalazine had only just been evaluated back in 1991 when this was published.

Q You said in a much earlier paper that most of the experience with sulphasalazine had come from adult experience rather than from children.
A That is correct, yes.

Q And even at the beginning of the 1990s there was not a huge amount of material to show how children tolerated the other anti-inflammatories.
A No; that is why, I think, most paediatric gastroenterologists were fairly cautious.

Q Then if you look back at the text at page 744, the left-hand column under “COLLAGENOUS AND MICROSCOPIC COLITIS”:

“Patients have recently been described who present with severe diarrhoea, but without blood loss or tenesmus. The colon is macroscopically normal on endoscopy, but histological examination shows appreciable mucosal inflammatory change ...”

The reference is to a paper by Sanderson, Boyle, Williams and Walker-Smith, Histological Abnormalities in biopsies from macroscopically normal colonoscopies. That is what you are referring to, is it not?

Q Then you go on I think to deal with another point arising out of another reference:

“… sometimes with collagenous thickening of the basement membrane. However the existence of collagenous colitis as a separate pathological entity remains somewhat controversial. Patients seem to respond to conventional medical treatment.”

By “conventional medical treatment” what do you mean? By anti-inflammatories and steroids?
A Yes.

Q That paper, the Sanderson et al paper, was a report of a series of children – quite a small series, I think – investigated for inflammatory bowel disease, in six of whom no pathology was identified endoscopically, but histology taken at the time demonstrated mucosal inflammatory change?
A The hallmark of the disorder is the very severe watery diarrhoea that these patients present with, as well as the endoscopic and histological abnormalities.

Q So the watery diarrhoea is there as a clinical sign, but ---
A Yes, that would alert you to the possibility.

Q --- but what happened then in the cases which were referred, a very small number of cases, was that colonoscopy did not indicate that there was any overt pathology there, but it was revealed on histology that there was microscopic colitis – in other words, revealed by the microscope?
A The clinical entity of severe watery diarrhoea, normal endoscopy and histological colitis, yes, is well recognised.

Q I think the central theme of the paper was that biopsies should be taken if the colon looks macroscopically normal.
A Yes, absolutely.

Q Those are some of the scientific papers to which you have either contributed or written and you have, it is true, reported case series of findings of IBD, either single patients or three or four patients, but do we find anything in your literature which goes against what you have written in the papers which we have been through?
A No, I think I have not published anything that contradicts that, but I think practice with regard to colonoscopy in children has moved on substantially over the last 25 years since the paper by Williams et al was published.

Q Yes, that may not be ground-breaking – or perhaps it is ground-breaking, because it continues to be referred to many years later – but that was the beginning, and as we have seen ---
A I think the paper includes the seeds of why we subsequently moved away from performing colonoscopy, for example, under a lot of intravenous sedation. Although the technique was considered to be acceptable to patients, one has to remember that it included the administration, as is pointed out in the Williams paper, of an agent that produced amnesia. So it is a moot point about whether, if you cause pain and discomfort during a procedure that the patient probably does not remember – whether that is acceptable or not is a moot point. I think the other issue that was pointed out in the paper was that the intravenous sedation gave a duration of action of only 10 to 20 minutes, which I think was fine in Christopher Williams’ hands; I think subsequently that was considered to be too short, and that led to increasing doses of pethidine, for example, being used. And as is pointed out in that publication, two of the patients had worrying respiratory depression which had to be reversed. So that was why we moved away from colonoscopy under sedation, and now routinely it is done under general anaesthesia, because it was not subsequently considered to be entirely acceptable.

Q No. It goes back to the same point, that that is experience gained at the time with an extremely skilled endoscopist, over a period. As more and more people began to do it, practices changed for the benefit of all concerned, but principally for the benefit of the children.
A Yes. I think the other point, just to clarify, in the final page of that publication that you took us to, you mentioned a sentence saying “perhaps colonoscopy should be considered a first-line procedure in such patients since it is easy to establish or exclude bleeding pathology with a colour endoscopic view”. I think it is important to be clear that that sentiment is being expressed in relation to patients with rectal bleeding and not to patients with suspected inflammatory bowel disease.

Q Can I take you up on one point. I was just looking at the Porto Criteria. I do not ask anybody to pick it up again, because it is only one small reference. This is 2005, is it not? This is the Porto Criteria of the ESPGHAN Working Party, July 2005. At the bottom right-hand column at page 53 of the bundle, those concerned with putting forward those guidelines say:

“In children, it is preferable if endoscopy is performed under general anaesthesia or deep sedation …”.

So in 2005 certainly those who might be regarded as the leaders in the field in Europe anyway were saying “under general anaesthesia or deep sedation”. Do you have that reference?
A Yes. The practice in the UK at the moment is to preferentially use general anaesthesia as far as I am aware.

Q Those from the UK are Professor Murch, Dr Fell, Dr Chong, Dr Murphy, Dr Sandhu – they certainly signed up to that as part of their advice to the profession generally.
A It is not what they practise.

Q I want to ask you a difficult question, to which I am not expecting a particular answer, but allowing for rivalry between centres, St Bartholomew's and Queen Elizabeth's paediatric gastroenterology unit was a world-renowned unit, was it not?
A Undoubtedly, yes.

Q And various people concerned there wrote extensively on the subject of inflammatory bowel disease and its management?
A Yes.

Q A number of the major players transferred to the Royal Free when the University Department of Gastroenterology was set up there?
A I think Professor Walker-Smith and subsequently Professor Murch transferred. I am not aware ---

Q Professor Philipson?
A Yes, he went. Professor Sanderson – I cannot remember whether he was attached at St Bartholomew's at the time – did not go.

Q I do not think he was a professor.
A Sorry?

Q I do not think he was a professor then, was he?
A Not then, no. Professor Tom MacDonald, who was the mucosal immunologist, did not transfer. I am just aware that Professor Walker-Smith, Dr Philips, Professor Murch, transferred.

Q Units tend to function – I call them a unit – this was the academic department of paediatric gastroenterology – they tend to function with a degree of, not independence, but there is a way in which the unit practises which carries on over a period of time. It may be led by particular people, but they tend to do things in a particularly way, which depend upon the thoughts of those involved.
A Yes. One would hope that their practice changes in the light of new information coming in, but if you are saying do people have a particular style of clinical practice, I suppose that is reasonable.

Q That is exactly what I do mean, because they are units dealing with these problems day in, day out, and it would be surprising if they did not have approaches which went across the unit to different problems that they encountered, because that would be only normal in the way in which they deal with their patients?
A Yes, yes.

Q You have heard, or read anyway, about the weekly histology meetings at which everybody concerned in the care of the patients would be present to discuss that and other patients on a weekly basis. You have heard about that?
A Yes, I have, yes.

Q Is it fortnightly in Dr Protheroe/Dr Murphy’s unit?
A We alternate between radiology and histopathology but then have an additional clinical meeting once a month where we talk mainly about small bowel transplant patients, where we look at the histology as well.

Q If the evidence is at the beginning of the week there is a discussion amongst all concerned about patients who are there to be managed that week, where the clinicians anyway discuss what is going to happen, that would again be only what you would expect, would it not?
A Yes. You mean that the patients who are being admitted are discussed and agreements made about what investigations they will have?

Q Yes. I think in most cases the patients would have already been admitted on the Sunday, but first thing on the Monday those concerned in the care of the patients would meet to discuss what investigations and what was going to happen to them?
A I am not quite following your questions. Do you mean in my own unit or do you mean generically?

Q If that is the practice in this unit that would not surprise you?
A No, not at all. I think it would be good practice.

Q The St Bartholomew's and Queen Elizabeth's unit always had – not a reputation, but known to have – a low threshold for colonoscopy, perhaps influenced by the success that they had with Christopher Williams’ endoscopy in children over man years?
A I cannot say that I m aware of that.

Q But would you see yourself as being somebody who is conservative or a high threshold for colonoscopy or a low threshold, or between the two?
A I think I follow appropriate indications for carrying out a colonoscopy. I could not say if they are high or low.

Q But the unit headed by Professor Walker-Smith had almost unrivalled experience of diagnosing and managing inflammatory bowel disease between the mid-1970s and the 1990s in the United Kingdom?
A I do not know. I could not comment. The publication that you drew my attention to, by Williams et al, which was published in 1982, had virtually equal numbers of patients from St Bartholomew's and Great Ormond Street submitted to that study, so it does not suggest that there was a massive difference.

Q I am not suggesting there was; I said they had almost unrivalled experience. I am not saying that anybody else was doing ---
A If you say they had unrivalled experience ---

Q Almost unrivalled experience.
A If you say they had almost unrivalled experience, that implies to me that you are saying they saw a lot more patients than almost anybody else; and I am not sure that they did.

Q They certainly saw many, many patients, as I say, largely influenced perhaps by the success of having somebody like Christopher Williams doing the endoscopies at the beginning of the practice, which gave them considerable insight into the management of inflammatory bowel disease.
A I would not dispute that they saw lots of patients with inflammatory bowel disease. If you are saying did they see more than anybody else, I could not answer that question. I do not know the answer.

Q Presumably there will be statistics to indicate what the number of inflammatory bowel disease patients seen annually was.
A There would be, I imagine. I do not know whether those data are available retrospectively.

Q I imagine they would have been generated at the time, would they not?
A I could not say. I do not know what data were kept. NHS systems are still notoriously inaccurate and were even worse 15 or 20 years ago.

Q I think you were involved at the beginning of the setting up of a registry to record the number of inflammatory bowel disease cases, new cases, being seen across the country?
A No, I was involved in setting up a registry of patients who were on long-term parenteral nutrition across the country.

Q When was that?
A That must have been in the late 1990s, I think.

Q I will come back to it, because I want to ask you about a group of people who got together in 1996 and 1997 from various units around the country, and what the aspirations of that group were. What I am trying to get at, I am not sure of the basis upon which you can assert that your experience or approach is better than somebody else’s and therefore should be preferred, because, after all, that is what is being put forward to this Panel, that your view about these patients should be preferred to that of those who were seeing the patients at the time.
A I have only been asked to give my expert view, yes.

Q But you are saying “This is what I think about these cases”, and where you say “I wouldn’t have done it” you are saying what your own approach would have been.
A That is correct. But I think that one, in coming to that view, recognises that one does not work in isolation, that one works as part of a team, that one discusses indications for investigating patients. One of the purposes of having regular review meetings is to not only look at the histology and the other findings but also to sometimes challenge colleagues about why they have done a particular investigation, or why have they not done an investigation. It is not given in isolation of having read the paediatric gastroenterology literature for a large number of years; it is not given in the absence of attending meetings where these issues are discussed, and one gets asked for opinions from other colleagues in other centres, and you can also by that mechanism calibrate your own particular feelings about when it is appropriate to do investigations or not against what is being done elsewhere. So opinions are not generated in isolation.

Q No, but the same must apply to Professor Walker-Smith and Professor Murch, that they are in the same position and they are involved in a specialist unit; they are contributing regularly to the literature on the subject; they are having their meetings weekly, the Mondays and the Fridays, so exactly the same applies to the, does it not?
A Yes, it is just that we have been looking at specific children where there were issues, where specifically it was recorded that a colonoscopy was not indicated, and for reasons that did not appear to be related to any new clinical information becoming available, a colonoscopy was carried out. I am pointing out that I cannot understand, amongst other things, the reason for those changes.

Q We are going to go through the individual cases, not in the detail we went into them last week, but certainly in relation to that aspect. But in terms of what is being done, the practice seems to be – although it is slightly different, broadly similar – that it is a team effort involving both the senior and the training grade doctors, the histopathologists, radiologists, and whoever else were involved in other investigations, and regular review and discussion about cases, as you would expect.
A Yes, that is normal practice.

Q They are not doing it in isolation either. It is not only you who are in that position; they seem to have the same overall approach to the practice anyway.
A I think we perhaps differ in our practice, in that we colonoscope, we endoscope, our own patients, and we adhere to that fairly rigorously. An exception in my practice would be this week, when I have had to ask my colleagues to colonoscope my patients, but generally speaking we look at our own patients endoscopically, and we stick to that.

Q But if you are looking at the history, the symptoms and any other material that you have got, to decide whether or not there should be a colonoscopy, you are just as informed as the person who is actually going to do the job about what sort of symptoms, what sort of history, what sort of blood results should give rise to a colonoscopy, if you have been doing it for 30 years.
A Yes, I am just making the point that when it comes to evaluating the patient overall, at the sort of meetings to which you are referring, the decisions that are made about the management do not rest entirely on the histopathology. Obviously they are important, but they also involve, as you say, the patient’s history and examination, but also the findings at endoscopy. So it is important to put all those particular components into the mix when thinking about the diagnosis and the treatment.

Q You can only really get to that position, if you happen to do it between a Monday and a Friday, you can only get to that final position if you have had your investigations and they have provided you with information upon which you can all collectively make a decision as to how to treat the patient.
A It is not a collective decision in the sense that the responsible consultant does not take responsibility for the decisions that are made. It is collective in the sense that other people may express an opinion about what they think so there is a discussion, for the subsequent responsibility rests with consultant whose name is on the notes.

Q Who has brought the patient in has the ultimate responsibility if they are in charge of the patient at the end of the week, to decide what to do, although in many cases – or some cases anyway – the decision as to what to do comes at a later outpatient clinic when all the available information is there?
A Yes. That is absolutely right.

Q Just before we break off, can I just ask you about your own position. It is confusing because it is not quite the same in the two documents that I have seen. Between 1992 and 1996 you were Professor of Paediatric Gastroenterology and Nutrition. Is that right?
A Yes.

Q According to your curriculum vitae that was a personal chair?
A That is correct, yes.

Q What is a “personal chair”?
A A personal chair … Sorry, I will go back a stage. If we just talk about medical schools now, but it is the same across all parts of universities, they have a number of established chairs. So there is a budget line for the cost of that particular chair and often when the chair is vacated, because someone retires, then the post is advertised and someone is appointed to it, or someone may be appointed to it internally. There are, though, funded chairs. In addition, there are professors who have personal chairs, who are appointed to a chair as a mark of their academic achievement, which is held in addition to the substantive chairs.

Q So that is a supernumerary chair. The established chair is one that remains as part of the medical school – “the chair in …” – whatever it is; if it is an academic department, the head of the department has an established chair which, when vacated, moves on to somebody else appointed by the university?
A Yes. Whereas in the case of a personal chair, if that person left, then the university would not normally re-advertise that post at chair level. So it is a title that just goes with that particular person. It is an ad hominem title.

Q Then you were appointed Leonard Parsons Professor of Paediatrics and Child Health. When was that? I could find the date for that.
A I think that was 1996.

Q And was is the Leonard Parsons Professor?
A That is a substantive chair within the medical school and the university.

Q That is your first category which you described – an established chair?
A It is an established chair, yes.

Q And I am not going to ask you who Leonard Parsons is, but is this a newly established chair, or was it there some time before?
A It has been in the medical school since, I think, 1948 when Leonard Parsons died.

Q And it is Professor of Paediatrics and Child Health?
A Yes.

Q I think it is right that you have recently been appointed the Dean of the Medical School?
A Yes.

Q Am I right? That is an appointment which is for this academic year?
A Yes.

Q So it is from 1 October this year, I think, until some date ---?
A Until August next year in the first instance as the university is undergoing major reconfiguration.

MR MILLER: Sir, that would be a convenient point at which to have a break, subject to the Panel’s convenience.

THE CHAIRMAN: Thank you. Yes. It is 11 o’clock and we will now adjourn. Professor Booth, I have to remind you yet again that you are under oath and in the middle of giving evidence.

THE WITNESS: Of course.

THE CHAIRMAN: We will resume at twenty past eleven.

(The Panel adjourned for a short time)

THE CHAIRMAN: You can continue, Mr Miller. Professor Booth, you are ready?
A Yes.

MR MILLER: Professor Booth, I want to ask you a little bit about markers of inflammation and laboratory tests, recognising we are talking about the same thing in terms of tests that may be carried out to see whether or not there is any evidence from the laboratory of the inflammatory process in the bowel. At the beginning of your evidence, you explained by reference to the literature that the role of laboratory testing from blood sampling for the presence, or possible presence, if inflammatory bowel disease, and it looks as though tests were taken at the outset. In some cases they were taken at the time of the colonoscopy or at the time that the child had been admitted, and you pointed to particular tests – ESR, white cell count, platelets, C reactive protein and albumin as being tests which might give you an indication as to whether or not inflammatory bowel disease might be present. Is that right?
A Yes, that is right.

Q I am sure you would be the first to agree that these are only screening tests, and are not diagnosis of the presence, or perhaps more importantly in this case, the absence information inflammatory bowel disease?
A Yes. By definition a screening test cannot be one hundred per cent sensitive or specific, otherwise it would be the definitive test and not a screening test.

Q You can get normal results but still find pathology present at endoscopy and subsequent histology?
A You can, yes.

Q And there is literature from various sources, detailing people’s experience, which is not necessary the same centre, on the reliability of these markers?
A That is correct, yes.

Q And in practice it would be wrong to rely upon normal markers of inflammation simply if they were normal. That would be a wrong approach. You would have to look at other aspects to decide whether or not you were prepared to accept them?
A Yes. You would have to look at the whole picture.

Q First of all, you have to use your judgment as to whether or not to do them in any particular case, given the signs and symptoms, and secondly, whether to rely upon them if the values produced are normal?
A Yes. I think in this respect Professor Walker-Smith and Professor Murch’s publications have been very influential in highlighting the role of screening tests.

Q What is the market to which that literature is directed, do you think?
A I would imagine to publication in The Archives of Disease in Childhood, for example, would be to a combination of general paediatricians and tertiary level paediatric gastroenterologists.

Q We went through that literature when you began your evidence and certainly one of the messages from that paper which you were taken to was that you can delay diagnosis of inflammatory bowel disease if you do not do these blood tests?
A That is possible, yes. Yes.

Q Because if you do not do them, you may not identify pathology which would then need to be investigated in a specialist referral centre?
A Yes. You occasionally find abnormal blood tests in patients who you might not otherwise have had a high index of suspicion. That is why they are done.

Q Were you familiar with, or aware of, the article by Mack and others before it was sent to you yesterday? I should say, it is behind tab 21 in Professor Walker-Smith’s literature.
A No, I was not.

Q This is an article, a report, I think, from 18 US and Canadian centres on children with newly diagnosed inflammatory bowel disease. The title of the paper is “Laboratory Values for Children with Newly Diagnosed Inflammatory Bowel Disease”. Looking just at the list of participants, it is a large number of institutions and a number of prestigious authors, is it not?
A There is a large number of participating centres, yes.

Q What do you say about any of the authors? Do you know any of them?
A I recognise some of the names, yes.

Q And under “Objective”:

“The goal was to determine how often common laboratory tests yield normal results at the time of diagnosis for children with inflammatory bowel disease.”

Then under “Methods”:

“Data were obtained from a registry of children with newly diagnosed inflammatory bowel disease who were enrolled prospectively in 18 US/Canadian centers. Laboratory values investigated included haemoglobin level, platelet count, albumin level, and erythrocyte sedimentation rate. Disease severity was categorised by physician global assessment.”

Then “Results”:

“A total of 526 children (mean age: 11.6 years; 58% male; 292 with Crohn's disease and 135 with ulcerative colitis) were studied.”

All four values, just to remind ourselves, are haemoglobin, platelets, albumin and ESR.

“All 4 values were normal for 21% of patients with mild Crohn disease and 54% with mild ulcerative colitis. In contrast, only 3.8% of children with moderate/severe Crohn disease and 4.3% with moderate/severe ulcerative colitis had normal results for all 4 tests. The erythrocyte sedimentation rate was least likely to be normal; overall, 26% of patients with inflammatory bowel disease had a normal erythrocyte sedimentation rate, including 18% with moderate/severe disease. Hemoglobin levels were normal for 32%, platelet counts for 50 %, and albumin levels for 60%. There was no clear association between Crohn disease and either severity or number of normal laboratory values. In contrast, there were direct correlations between ulcerative colitis severity and both the extent of bowel inflammation and the number of abnormal laboratory tests.

CONCLUSION: The present of normal screening laboratory studies should not dissuade clinicians from considering a diagnosis of instructed inflammatory bowel disease.”

That is the introduction. Can we just go to the “Discussion” on page 1116:

“The finding that a significant number of children with IBD have a normal battery of screening laboratory tests at the time of diagnosis has clear implications for primary health care providers. “

Just help us about who primary health care providers are?
A Sorry. Could you take me to ---

Q “Discussion”. It is the left hand column under the bold heating “Discussion”. Do you see that on page 1116?
A Yes.

Q I will read it again:

“The finding that a significant number of children with IBD have a normal battery of screening laboratory tests at the time of diagnosis has clear implications for primary health care providers.”

I asked you what is meant by primary health care providers?
A In this country, I guess it would be GPs or general paediatricians. I am not quite sure. I am not quite sure what is meant by that.

Q But certainly if it were the same as it is here, it would be GPs and general paediatricians, not referral units?
A That is correct.

Q “Primary” must be those who deal with the child first?
A Yes.

Q “For a child with a history of mild …”
A Sorry. So the implication of that would be that the threshold for referral to a specialist would be, on the basis of this study, somewhat lower.

Q Exactly. But they are not to be misled by the normality, or apparent normality, of the screening test, because if they suspect IBD they should refer, if the symptoms and signs suggest that it is present.
A Which is a different sort of message or impact to the paper by BT Walker-Smith and Murch that we looked at earlier, that was related to colonoscopy and the role of screening tests in that context.

Q The point that they are making, and it is made with some force later on, is that as a primary health care provider you certainly cannot rely simply on the normality of those because a large number of children who are diagnosed subsequently with IBD have normal markers of inflammation.
A There are a number of comments to make about this publication. Firstly, it was published in June 2007, so I am not quite sure how it could have been of relevance to decisions that were being made in 1996.

Q Do not try to argue the case, Professor. This is being put forward as an example from the literature of what has been understood. I prefaced my comments by saying, “It is well understood in the literature that markers of inflammation may be normal in the presence of inflammatory bowel disease”.
A Yes, but one explanation for these differences, compared with the previous publication, is that the authors in the 2007 publication are using substantially different cut-offs for normality and abnormality in their patients, compared with the 1995 publications in The Archives of Disease in Childhood. So if, for example, you look at laboratory values on page 1114 at the bottom left, and compare the cut-offs with the cut-offs that we used in the 1995 paper, the BT Walker-Smith and Murch publication, you find that the haemoglobin cut-off in the 1995 paper was 10; it is given in the publication as 100g/litre, but there are differences in the units being used; whereas in the 2007 paper, the cut-off starts at 11, and then increases with the increasing age of the patients. Similarly, the platelet cut-off in the 1995 paper is 400,000 whereas in the 2007 paper, it is a cut-off of 450,000. The cut-off for ESR is different as well, and in the 2007 paper it is 20 compared with 25. The authors of the 2007 paper have not included in their battery of investigations CRP whereas if you look at the 1995 paper, under the results for CRP you will find, for example, 100 per cent of patients who had Crohn's disease had an abnormal CRP. So there are reasons for believing that the message from the 1995 paper could well be different and could well be more relevant to clinical practice. That is the point I am making.

Q But they do not appear to have included CPR in 2007 in their investigations?
A That is correct. Unfortunately.

Q If they are, it would be surprising that they do not refer to it because otherwise they would say that of course CRP was always positive?
A I do not know why they did not include CRP. It is a very common index of inflammation. I could not say why they have not included CRP.

Q Just to carry on with the discussion for a moment, back at page 1116:

“For a child with a history of mild abdominal pain or diarrhea, the presence of normal screening laboratory studies often implicates functional disorders (eg. irritable bowel syndrome) as a cause of symptoms and precludes additional diagnostic testing.”

What do you understand by the term “functional disorders”.
A Sorry. I cannot find the section you are referring to.

Q It is the second sentence in the bottom left hand side of page 1116. “For a child…”. Do you see that?
A Yes.

“For a child with a history of mild abdominal pain or diarrhea, the presence of normal screening laboratory studies often implicates functional disorders (eg. Irritable bowel syndrome)…”.

What do you understand by the term “functional disorders”?
A I think “functional disorders” are quite difficult to define now. It used to be a term that referred to disorders that were thought to have possibly a psychogenic cause, where there was no evidence of abnormality, in this case the gastrointestinal tract. I think increasingly we are recognising, for example in inflammatory bowel disease, that there are quite well recognised disorders in the gut in patients with inflammatory bowel syndrome. So I think it is a difficult term to define at the moment, and I am not quite sure in what terms they are using it here. I think it is a very vague term.

Q Are they implying that it is non organic?
A They are using it in the sense of non inflammatory bowel disease.

Q Because they go on,

“Although functional disorders are much more common than IBD, our data show that the presence of normal laboratory tests cannot be relied on as an adequate screening tool to exclude mild IBD”.

A I have given you my views on the flaws in this publication.

Q Can we just look on the right hand column on that same page, about two thirds of the way down, do you see that, starting “Beattie et al”.
A Yes.

Q This is paper you are referring to is it not? Do you have that?
A Yes.

Q That is the paper is it not?
A Yes.

“Beattie et al reviewed their experience with blood tests in the extensive evaluation of 91 patients who had been suffering for 3 months with 2 gastrointestinal symptoms of abdominal pain, diarrhoea, rectal bleeding, weight loss or mouth ulceration. Within this group of patients, 39 had either CD or UC and it was concluded that the diagnosis of CD was unlikely if the results of the screening blood tests (haemoglobin level, ESR, albumin level, platelet count, and C reactive protein [CRP] level) were normal. In their review, CRP was included in addition to the blood tests reviewed in the current study”.

The implication there is that they are not reviewing CRP in this study.

A That is right, yes.

“A recent review of CRP findings in adult CD concluded that use of a threshold 2.5 times the upper limit of the normal CRP range detected 70% of those with moderate or severe disease, although the study did not allow for the separation of mild and non active CD. Although disease severity was not indicated in the study by Beattie et al, it seems that the patients were in the moderate/severe category, not only on the basis of the elevated CRP levels but also because the likelihood of an elevated ESR of 85% for their patients was similar to what we found for the patients in the moderate/severe CD category in the current study. Therefore, we conclude that, even if all the simple blood tests yield normal results, children should be considered for referral for additional evaluation when there are chronic gastrointestinal complaints, such as hematochezia” –

which is blood in the stools.

A I have pointed out that there are substantial differences in the tests or the cut offs that were being used in the tests, but the point that the authors make here about the subjects in the 1995 paper being more severely effected as they point out are purely speculative. If you look at the 1995 paper the medium duration of symptoms in the patients in that group was only seven months, so these were not patients who were being studied in the 1995 paper who had long standing and therefore, presumably, severe disease.

Q Do not many labs have slightly different margins or cut off margins for these tests?
A When you are using a screening test, you can elect to choose whatever cut offs you think are going to give the best sensitivity and specificity. That is the whole point of doing a screening test so that as you change the cut off in one direction, the sensitivity may change in a particular direction and the specificity in another. The converse is also true. If you are using a screening test, you can set whatever cut offs you think give you the best separation between normal and abnormal subjects.

Q The message from this paper, whether you think it is valid or not, is that for mild inflammatory bowel disease you may miss an essential number of cases with cut offs where it is clear afterwards that there is inflammatory bowel disease present.
A If you are flawed in your choice of cut offs, you would inevitably have a less sensitive test, I agree.

Q Your answer is that they were flawed in their choice of cut off and therefore they had too many shown as normal who subsequently were shown to have inflammatory bowel disease.
A The sensitivity of a screening test is determined by the cut offs that you use. The differences between the conclusions between the 1995 publication and the June 2007 publication could be explained entirely on different cut offs being used.

Q Help us about the American Academy Paediatric journal; what sort of publication is that?
A It is one of the two first rank north American publications.

Q This study comes from, as we have identified, a large number of centres in north America does it not?
A Yes.

Q As far as those who contributed to that study, Dr Robert Wyllie, do you know him?
A No.

Q Dr Hyams?
A Yes.

Q Some of the other others do you recognise?
A Yes, Anne Griffiths.

Q She is very distinguished paediatrician is she not?
A Yes.

Q Wyllie and Hyams produce a text book for paediatrics did they not?
A Yes.

Q Put aside the literature if you would now. I want to ask you about Dr Wakefield. Were you familiar with publications that arose from Dr Wakefield’s research in the early 1980’s/early 1990’s?
A Perhaps not by names specifically. I was aware that there was research in Crohn’s disease taking place at the Royal Free Hospital round about that time.

Q Specifically research into Crohn’s disease?
A Yes.

Q Did you read the publications?
A Yes. I must have seen them to have been aware that the research was taking place, but may not have studied them in the same detail as I might study publications related more closely to my own research interests or clinical practice.

Q What was that the research interest?
A At the time?

Q Yes?
A I think at that time I was particularly interested in disorders of intestinal electrolyte transport.

Q I may regret the question, Professor Booth, but in a couple of sentences, can you identify what that is, keeping you to a couple of sentences if that is possible?
A It is disorders often inherited leading to early onset diarrhoea, resulting from mutation in a particular protein in the lining of the gut that is responsible for the absorption of whatever the electrolyte or nutrient that one is concerned with.

Q At the beginning of 1997, a Committee met for the setting up of a paediatric inflammatory bowel disease register. Do you recollect that?
A Yes.

Q You were present, were you not, at the meeting on 15 January 1997?
A It was probably held as part of the winter meeting of the British Society of Paediatrics Gastroenterology and Nutrition.

Q There was a meeting in fact to launch the national register for paediatric inflammatory bowel disease which was in October 1996, so slightly earlier, a meeting which you were present.
A I honestly cannot remember.

Q Professor Walker Smith and Professor Murch were there, amongst a number of other paediatric gastroenterologists. Dr Wakefield was there as well. Can you help me by telling me the location? It may help to remind me where it was.

Q I am pretty sure that it was in London. There were various others present: Dr Sandhu, Dr Jenkins from Wales, you, Dr Miller from Manchester.
A Yes, I seem to remember attending a meeting at the Royal Free Hospital.

Q What happened subsequently was that there was a Committee set up under the chairmanship of Dr Jenkins – that is Dr Jenkins from Cardiff, is it?
A That is correct, yes.

Q The co ordinator was Dr Sandhu and Dr Casson. Then the members of the Committee were you, Dr Sullivan, Dr Taylor, Dr Wakefield, Dr Montgomery, Dr Miller. Do you remember that?
A Yes, I think I do.

Q The purpose, as I understand it, was to set up a national register for, as I put to you earlier, paediatric inflammatory bowel disease, so that all cases of paediatric inflammatory bowel disease could be registered centrally in the country.
A Yes.

Q I do not know what became of that register, but I understand that it did take off from that time and the aspiration was that units would report the cases that came to the clinics and subsequently their hospitals, so that some overall national figures could be identified.
A Yes. My memory is that there was some conflict between two registers. I am not entirely sure at this distance which was which, but there was another register that was being undertaken jointly with the British Society of Gastroenterology because it was felt that we needed to include adolescence patients as well and they may not have all been seen by paediatric gastroenterologists. One period of enrolment ran for a relatively short period of time. It was maybe one or two years, but then the other register continued subsequently and was being run by Dr Casson.

Q There were just two methods. One of the problems may have been how children were going to get on to the register and the hardware involved in that. Certainly this its beginning, 1996/1997. Does a register still function?
A Yes.

Q Again, the aspiration if it still functions it must have had some degree of success was that new cases of inflammatory bowel disease would be reported to the central register.
A Yes. I am not sure just how assiduous colleagues are in reporting new cases of IBD at the moment.

Q You made quite a lot in your evidence of the terms of Dr Wakefield’s contract which included no clinical sessions which we have seen from having a look at the document. Were you aware of those terms when you sat with Dr Wakefield on that Committee?
A No.

Q Were you aware of the terms of his contract at any stage before they were disclosed to you by the solicitors acting for the GMC for the purposes of these proceedings – that is the terms of his contract?
A No.

Q So the position in 1996/97 was that he was somebody involved in, and on the committee which was involved in, the setting up of this national register.
A Yes.

Q He was not somebody who you had come across as a paediatric gastroenterologist, but at the time you saw no objection to him playing the part that he did?
A In being involved in the registration of new patients?

Q Yes.
A No,

Q These were not just IBD patients, they were paediatric IBD patients specifically, were they not?
A Yes.

Q You presumably would have known him as someone with considerable background knowledge from his publication, or the work, anyway, on inflammatory bowel disease and the mechanics of inflammatory bowel disease?
A Yes. I cannot remember the precise timing, but I remember that he came round about that time and gave a lecture at the Children’s Hospital in Birmingham, and I think came and gave a lecture at meeting of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition round about that time. So I was aware of his interest, but I did not know about his contract.

Q No, but aware of his interest to the extent that he was coming to your institution and the British Society and lecturing on the topic?
A Yes. I think he was lecturing on the presence or absence of evidence of measles in the gut of patients with Crohn’s disease, but I cannot be absolutely certain.

Q I presume that would involve an invitation to give a lecture rather than a road show?
A Yes, he would have had a specific invitation, yes.

Q Can I ask you this, Professor Booth: have you ever had to carry out an exercise like this before – and I will identify the exercise – to look at the documents, the clinical notes, the correspondence, witness statements, involving a dozen patients, and to decide whether or not the children are being seen as part of a research study or as part of clinical care? Is that an exercise that you have carried out before?
A No.

Q So it is not something in itself in which you have any particular expertise, but that said, you are a paediatrician who has had a lot of children referred to him over the years – that is the first point.
A Yes.

Q Secondly, you have made a number of applications to local research ethics committees, although you have never sat on one?
A That is correct.

Q And thirdly, as others can do, you have noted the references to a study, a trial or a protocol in the papers which you say are more in keeping with a research project than clinical care?
A That is correct.

Q But you would accept, I imagine, that research can and frequently does arise out of clinical care?
A Yes, if you see patients for example with disorders that you do not understand, and who need perhaps novel forms of investigation or investigations, that you would not normally carry out as part of their clinical management, then yes, you would write a protocol and put it before the research ethics committee.

Q It is not that, it is not an area where there is always a rigid demarcation between clinical care and research. Can I just put it ---
A I think it depends. If you define research as an activity that requires the permission of a research ethics committee, then I think it is a fairly clear definition.

Q There would be nothing illogical in planning to do a series of investigations as part of providing a diagnostic service to children with suspected inflammatory bowel disease, with the long-term aim of providing treatment – that must happen every day.
A Patients get investigated according to established clinical practice, yes, every day.

Q But if the short-term aim is diagnosis and the long-term aim is providing treatment if the suspicion is well-founded, that would be a relatively standard approach, would it not?
A When I see patients in my out-patients clinic, for example, I do not have a lack of clarity in my mind if I am seeing them for clinical reasons or as part of a research study – if that answers your question? I am not quite sure if I have addressed the points you are making.

Q The mere fact that you choose to have a child referred to you at your out-patients clinic, but you choose to have that child admitted as an in-patient with a view to carrying out a full range of tests, does not make it of itself a research project if the fundamental aim is to make a diagnosis for the benefit of the individual patient.
A I think it would depend on the investigations you were planning on performing. If they were clinically indicated investigations then there would not be an issue. If you were planning on using indications for doing the investigations that were not within normally accepted clinical practice and guidelines, then I think you would need to put the matter before a research ethics committee.

Q Yes, but that would depend on the nature of the investigations that you were carrying out, and you would have to look at the proposed investigations and say “Is this something which is clearly directed towards diagnosis and treatment of the patient?”
A Yes, that would be one of the criteria that you would adopt, but if for example you are wanting to perform an innovative surgical technique on a patient that has not been tried before, then it is good practice to put it before an ethics committee. The point of the intervention on the patient would be to provide benefit, but if it was a novel procedure then you would need to get some outside confirmation that it was ethically appropriate – in other words that the patient was likely to get some degree of benefit as compared with any possible risk.

Q Yes, and that would follow, because it cannot be simply up to the surgeon to decide “Well, I’d quite like to do it this way round this time to see whether I get a better result”, if there is no question of a balance of risks as between the benefit of the patient or not. In that example you would run it past the ethics committee because you would have to say “I’ve got no idea whether or not it is going to work and whether or not the patient is going to be made better”.
A But I do not think you can just use the argument of patient benefit as the sole arbiter of whether you can carry out procedures or investigations on patients without referral to an ethics committee. Everything that one does as a paediatrician, whether you are a researcher or just a committed clinician, is designed I imagine for patient benefit. That is the long-term outcome of one’s activities. So we are all interested in patient benefit.

Q There is a significant difference, is there not, between overall benefit and understanding of a condition, and looking at the benefit of the individual patient who has been referred to you? If you are just saying “I’d like to see as many people as I can to see whether I can get a better understanding of the condition”, that is not tailored to the individual need of the patient, it is in order to find a way in which medical knowledge can be advanced.
A Yes. If you just aim to see patients, to characterise them, but without any intention of providing any therapeutic intervention, then it is not of much benefit to that particular patient or that particular group of patients.

Q Can we just look at your proposition for a moment. One of the problems about asserting that this was a clinical trial from the outset, which has to be from sometime at the beginning or mid part of 1996 ---
A I do not think I said that it is a clinical trial

Q It is research, sorry.
A A clinical trial would be a study where you had intervention A and intervention B, and B might be a placebo or a known drug. So I am not suggesting ---

Q No, no, I am sorry – you are entirely right. This is research from the outset. You have made the point many times, the apparent lack of a uniform approach to either admission to that study, investigation, or treatment. You make the point that it is not a uniform approach in the case of each child. Because if you are right, the clinicians and researchers had an idea for a study which involved strict inclusion criteria for those to be recruited – and I use the work I think appropriately, on your theory – so there were strict criteria for inclusion.
A There was a protocol and an application that went to the research ethics committee where there were strict inclusion criteria defined, yes.

Q Secondly, they started seeing patients in a haphazard way, most without patient clinic assessments, the two, as you have observed, without any effort to identify either those who had the necessary developmental condition, or had had the necessary environmental influence – namely measles vaccination or measles/rubella vaccination rather than MMR. That is the factual position, is it not, that even if they were about to embark on a research study, in fact these patients reported in The Lancet failed for a number of reasons to be investigated in a scientific manner?
A Are you suggesting to me that because the departures from the protocol were so massive, that this could not possibly have been related to the research ethics committee application?

Q I am saying that this is not a research – these patients seen in this case were not part of the research application to which 172/96 applied, for a variety of reasons which we will go into, because if you are right, these patients did not meet, you say, the fundamental requirement of having disintegrative disorder.
A Yes, they failed to meet that key inclusion criterion.

Q If you are right, most of the patients did not even meet the requirement of having bowel symptoms at the point of referral. That is right, is it not, on your analysis of the presenting signs and symptoms at the point of referral, most of these children did not have the bowel symptoms which were said to underlie the condition described in the protocol?
A Some of them did, some of them did not, I think.

Q I think in most cases you say they did not, at the time of referral.
A At the time of referral they did not have symptoms that would lead you to think that a colonoscopy in most cases was clinically indicated. I think I have pointed out in one instance that I could not find any evidence that the patient had fulfilled the research criteria with regard to gastrointestinal symptoms.

Q As a matter of fact, all 12 of The Lancet children were referred, and all but three had been investigated, before the ethics committee gave its approval for a study, and incidentally disabled them from taking part.
A Yes.

Q But you say that the documentation suggests that this was effectively a non-therapeutic research study from start to finish.
A That is based on having seen the application to the research ethics committee, 172/96, having compared in the case of each patient the investigations that were included in 172/96 with the investigations that the patients subsequently had. It is arrived at by considering whether the investigations that the patients had – for example, lumbar puncture, MRI scan and EEG, would have been clinically indicated and not being able to define a clinical purpose for those investigations. Also, by looking at the clinical notes of those patients, which contained references to admission for disintegrative disorder studies or intensive programme therefore for needing ethics committee permission.

Q You say, and you were taken to it on each occasion in relation to each child, that what was fundamental to what was going to be 172/96 was missing in all of these children, so they failed in limine because they did not have the condition which was contained in the protocol.
A Well, yes, if they did not have the condition that was contained in the protocol, and yet appeared to have been investigated according to the terms of the protocol.

Q In advance of any application in some cases being made.
A So they were having research-driven investigations in the absence of a research ethical committee permission.

Q That is your take on it, if you put it in the category of being a research-driven investigation.
A As I have said, the investigations that were carried out on these children conformed to the investigations that were defined in the protocol, and the investigations that these children had would not have been part of the routine clinical investigations of patients with suspected inflammatory bowel disease. So one would conclude therefore that they were research-driven.

Q Can I ask you about your view of the ethics committee approval, because you deal with it at the top of page 14 of your overview report. Do I understand you to be saying there – that is the paragraph where you deal with the application or the permission, is it not?
A This is in the section about the ethics committee, yes.

Q I am not going to read it out, but it starts “I find”. Do you see that?
A Yes, I do, yes.

Q It looks as though it is your view that the ethics committee was granting permission for the whole study rather than the more limited approval for collecting data and writing it up, which was Dr Pegg’s explanation after the event. You find his view difficult to understand. Your own opinion is that the ethics committee did provide approval for the investigation of the children. Is that still your view?
A Yes.

Q Could we then just look at the relevant documents surrounding the application for approval in FTP1, starting at page 200. Professor Booth, we were told by Dr Pegg that this document followed a pro-forma set of questions which he had devised, and it is not particularly easy to follow the sections of it, but it is starting at page 200, all sections to be completed, and there follows a series of questions which are left to be filled in by those making the application. Is that an approach with which you are familiar?
A Yes, I think that would be a fairly standard approach.

Q So the ethics committee chairman is asking a series of questions and getting the results which have been put in by whoever it is who has made up the application. It describes a series of proposed investigations, at page 201; it gives a timetable for the carrying out of those investigations, which we see at the back of the document, page 231. Do you see that?
A Sorry?

Q 231.
A Yes.

Q That is the timetable, starting on a Monday and finishing on a Friday. It is clearly contemplated that a colonoscopy would precede any psychiatric or neurological assessment, and barium meal and follow-through would follow colonoscopy, by which one imagines that the clinician would know what the pathology was that had been seen at colonoscopy?
A Yes.

Q It also contemplates the involvement of the consultant psychiatrist on the Wednesday and the consultant neurologist on the Thursday. So that is made clear on the face of the document, is it not?
A Yes.

Q If you just go back to paragraph 11 which is at the bottom of page 209, that paragraph expressly states that the investigations would effectively have been done:

“… all the procedures and the majority of the samples are clinically indicated.”

We have seen this before.
A Yes.

Q So again, whoever is putting forward this application to the research ethics committee is saying “the procedures” – for which we are to read the procedures which have been dealt with on page 221 – “are clinically indicated”.
A Yes.

Q Then there are a number of research elements to do with the analysis of samples, which are unlikely to have any bearing on the management of the patient, which would be said to be research, would they not?
A Yes.

Q So at the outset what was contemplated was that there would be a study with research elements to it, but that it would arise out of ordinary clinical care; that is what paragraph 11 says effectively, is it not?
A It says that the procedures are clinically indicated, yes.

Q And clinically indicated means indicated for the benefit of the patient.
A No, it means indicated within the constraints of normal clinical practice at that time.

Q But the ethics committee were not obliged to accept ---
A In fact one could argue that the whole of this, including the research investigations on the biopsies, would be for patient benefit, as I have said, so it is all about patient benefit. So I do not think that is a satisfactory guideline or the equivalent of saying that they are clinically indicated, which is very specifically what it says here.

Q We do not need to worry too much, because the ethics committee was not obliged to accept that assertion without enquiry. They might have done so, but they were not obliged to if they were carrying out their function, and they do not appear to have accepted it without enquiry, do they? If you look later in the bundle, at page 265A, this is a letter from Dr Pegg which I do not think you have seen when you first looked at these papers.
A That is correct.

Q But clearly it arises out of discussions that had taken place within the Committee and in the second numbered paragraph he points to the fact that:

“It is a very intensive regime involving some unpleasant investigations – LP [lumbar puncture], endoscopy, MRI etc. some of which may require a general anaesthetic. I would consider the risk of such procedures to be ‘High’ (BPA guidelines classification). The guidelines state ‘It would be unethical to submit child subjects to more than minimal risk when the procedure offers no benefit to them, or only a slight or very uncertain one’.”

That paragraph, the second sentence onward, is lifted directly from the British Paediatric Association’s guidance on ethical conduct of medical research, is it not?
A Yes.

Q It would have no relevance to procedures carried out as part of clinical care. It is all to do with research, is it not?
A That is correct, yes.

Q So on the face of it, Dr Pegg was questioning the suitability of appropriateness of such investigations in a research context? Otherwise he would have no remit, would he?
A That is correct.

Q High risk as against benefit, are the counterbalances when considering the ethical nature of research, not clinical care?
A Yes.

Q Dr Pegg goes on in the next paragraph:

“Your submission indicates that all these tests would be carried out (apart from 5 extra biopsies and some extra blood) in the normal care of the child. I would therefore like you to:

a) Confirm that the child would undergo this regimen even if it was not in a trial
b) Indicate what benefit”

by which I imagine he means “explain” –

“what benefit the child will receive from having been investigated in this way. Will the benefit be more than ‘slight’ or ‘uncertain’.”

Again, that harks back to the BPA guidelines on research?
A Yes.

Q Professor Walker-Smith replied on page 291. If we look at the second paragraph, it clearly responds to the second paragraph of Dr Pegg’s letter, does it not?
A Yes.

Q He agrees with the proposition that the procedures could be regarded as “high”. Again, that is taken from the guidelines?
A Yes.

Q You said in evidence last Monday that if Professor Walker-Smith was asserting that the bowel disease which these children had had a hopeless prognosis, in your judgment, having looked at the cases, he would not be correct, but may I suggest, Professor, that is a false point, if you look at the whole of the letter because the “hopeless prognosis”, in quotations, is said to relate to their cerebral disintegrative disorder, is it not?
A Yes, absolutely.

Q Six lines down in that paragraph he deals with the gastrointestinal symptoms.

“In relation to their gastrointestinal symptoms which will be present in all the children we investigate, these have often been under-investigated. We have so far investigated 5 such children on a clinical need basis, all in fact have proved to have evidence of chronic bowel inflammation. One child has already had a significant response to enteral feeding.”

So he clearly did separate the two, did he not, and he gives an account of the experience that they have had, with five children already seen on the clinical need basis?
A I think he is justifying the investigations on the basis of these children, as he says, who have often not had a level of investigation “which we would regard as adequate” for a child presenting with such a devastating condition.” That would suggest that they are referring the gastrointestinal symptoms. Or he is certainly not excluding from that sentence the issues relating to the cerebral disintegrative disorder.

Q No. He deals with them separately because he says, in relation to their gastrointestinal symptoms,

“which will be present in all the children we investigate, these have often been under-investigated”.

So how do you read “in relation to the gastrointestinal symptoms … these have often been under-investigated”. There is clear reference to that?
A He refers in the previous sentence to investigations, and the devastating condition, and then goes on to enlarge on the gastrointestinal symptoms and the investigations.

Q And says that they have been under-investigated.
A Yes.

Q And then points to the fact that one child has already had a significant response to enteral feeding.

“Certainly there is a measurable benefit to the child.”

If that is what he is saying, he can hardly be saying that he is asserting that they have a hopeless prognosis, because he is telling them about significant response to enteral feeding?
A He is saying that as a result of their investigation, they seem to have turned things round for this patient.

Q Yes.
A Who had a devastating disorder initially.

Q That is your reading, is it?
A That is how I read that letter, yes.

Q He identifies the measurable benefit to the children, accepting that by then five had already been investigated. And the measurable benefit is:

“(a) Establishing a diagnosis and excluding metabolic and other causes
(b) Commencing on a therapeutic regime.”

What do you understand by the term “therapeutic regime”?
A It is difficult to say in the context of a research study like this. It could be that patients are going to start on an open label study of an agent. It could be that they are going to be entered in a randomised clinical trial.

Q Where do we find that in the application?
A It is not in the application.

Q There is not a treatment arm in 172/96, is there?
A No. It is non-therapeutic.

Q So this is something that might have, despite the fact that the measurable benefit commencing on a therapeutic regime, you say that is a hidden reference to the fact that they were going to be involved in another trial?
A No. It is just not clear. That is all I am saying. It is a very broad statement.

Q He has identified ---
A In the context of a research study, where you are saying that you are investigating a novel association, when you then say, “We are going to commence on a therapeutic regime”, it could mean that you are going to try established agents for a new indication; it could mean that you are going to set up a clinical trial. I could not say.

Q It is a perfectly reasonable proposition, if you go across to the top of page 292,

“I can confirm that children would have these investigations even if there were no trial. I must make clear that we would not be investigating children without gastrointestinal symptoms.”

A He is confirming there that there is a trial.

Q But he is also saying he is seeing them and investigating them in a way that would occur despite the fact that there is a proposed trial?
A He is saying there, the patients are in a trial.

Q Even if there were no trial, the children would have these investigations, so that must be a reference back to what is said in the protocol, that they are having these investigations on the basis of clinical need?
A He is saying, “These patients are in the trial. Even if they were not in the trial, I would be investigating them.”

Q As part of clinical care?
A Yes, but the patients are in the trial.

Q It is difficult to see how they are in the trial, because they have already been investigated now, and we are talking about a time before any trial has been approved?
A I think that is one of the issues of the hearing, is it not?

Q But the commencement on a therapeutic regime equally follows, if they are investigated on the basis of clinical need, of having identified some bowel disorder which is susceptible to treatment?
A Yes. It would not be unreasonable to offer these patients treatment. But going back to your earlier point, he is saying that there is a trial here.

Q Help me about this, will you, Professor Booth? Why would there need to be a trial if as a gastroenterology unit dealing with children, you identify bowel pathology would be helped by anti-inflammatory drugs. Why do they need to have a trial? Why can they not simply prescribe anti-inflammatory drugs to deal with that pathology?
A Because at this stage, the nature of the inflammatory changes that they were seeing in these patients were undefined.

Q That does not stop them being treated?
A It would depend on diagnosis that had been arrived at, and what treatment you would institute.

Q But that is in fact exactly what they do. They treated with anti-inflammatories of different types, which you have already explained in your publications are standard forms of therapy for inflammatory bowel disease. They do not need to have a trial for that. They can do that as part of ordinary clinical practice?
A The notion here is that they are defining a new disorder. That is the point of the reference to the trial. Therefore they are using an established agent for a novel indication.

Q It is not a novel indication to prescribe anti-inflammatories, as was done, for inflammatory changes in the bowel, is it?
A It would depend on what was causing inflammatory changes. At this point, they were not aware what was causing the inflammatory change. They were assuming it was a version of inflammatory bowel disease, but there were alternative possibilities.

Q In most cases, Professor Booth, you make no criticism of the prescription of anti-inflammatories in the children whose cases you have considered. If you are right, they should not have received any treatment because it was being done for a novel purpose linked to some other condition, and therefore it needed a clinical trial in order for treatment to be given. Is that right?
A I have pointed out in my evidence that that when treatment is given for a novel indication, the normal process would be that it would be given as part of a clinical trial.

Q Let us take that stage by stage. The novel indication would be to treat neuro-developmental disorder. Is that right – in this context?
A With associated lymphoid nodular hyperplasia.

Q So that is the novel aspect of it, is it? Does one know what the cause of Crohn's disease is in every case?
A I do not think you know the cause of Crohn's disease in any case.

Q So in every case of Crohn's you do not know what has caused it, but you are treating the presence of inflammation within the bowel?
A Yes. You are treating patients with a clear diagnosis usually of Crohn's disease. It is frequently the case that we effectively treat patients with well characterised disorders, of which Crohn's would be a good example, without knowing the cause.

Q Presumably you do not treat merely on symptoms of that disease. You would have identified inflammation within the bowel but which you thought would be susceptible to treat with anti-inflammatories?
A Yes. You would consider a range of possibilities, of factors that might be causing the inflammation and there may be several that you would need to consider.

Q Do you recognise any other form of treatable inflammation apart from Crohn's disease and ulcerative colitis?
A Yes.

Q What other types of inflammatory bowel disease are there?
A One that springs to mind is allergic inflammatory diseases – allergic colitis, for example, that affects principally infants and toddlers. That would be one example.

Q What about indeterminate colitis? Do you recognise that as an entity?
A Yes.

Q In one of the pieces of literature – I think it was the one which you were the sole author of – when it was suggested that there was microscopic colitis as something which was only identified histologically. You said that that was susceptible to conventional treatment?
A Yes, that is correct.

Q What is that conventional treatment?
A Conventional treatment would be prednisolone, in the first instance, followed up with other anti-inflammatory agents.

Q So there you are not treating, and you would not be treating, Crohn's disease or ulcerative colitis; you would be treating a condition of the bowel for which you had no explanation but which you would assume or hope might respond well to conventional treatment?
A Yes. Equally well, if you thought you were dealing with an inflammatory of the gut that was caused by food allergy, prescribing anti-inflammatory agents would be contra-indicated. You would approach the patient with food avoidance. Equally well, if the patient has inflammatory disease of the colon because if Hirschsprung’s disease, it would be entirely inappropriate to treat the patient with anti-inflammatory agent as well. I think it is not entirely appropriate to say that every time you see inflammation in the colon, would you automatically reach for anti-inflammatory agents without considering a differential diagnosis.

Q I was not suggesting that, but I was taking you up on the proposition that in fact it required in this particular instance, even though you were identifying bowel pathology, a research trial to see whether or not conventional anti-inflammatory treatment would deal with the signs and symptoms of that condition?
A I am sorry. Can you just re-state the question? I do not follow.

Q I was taking you up the suggestion that because in some way it was being suggested that these might be linked to a neurodevelopment condition, these bowel abnormalities, it required those investigating to carry out a clinical trial rather than simply treat, as they did, with anti-inflammatories?
A I think they felt that they had a novel disorder. That is how it was subsequently published in The Lancet. This was not being portrayed as standard inflammatory bowel disease. That was not the impact of The Lancet publication. This was being portrayed as a novel disorder.

Q I want to make sure I do not misrepresent you at some later stage. Are you saying that in those circumstances, if you were making that link, then it was inappropriate to treat the signs and symptoms as manifest from the pathology you found during the investigation, there should not have been treatment with standard anti inflammatory drugs?
A No, I am not saying that they should not have been treatments. The treatment should have been tailored by the clinical endoscopic and histological findings on each patient. Each merited treatment in their own right on an individualised basis. For example, after the first three patients had been investigated, it was clear that severe constipation was a problem in these patients. The point I am making is that to home in on some inflammatory cells is to the exclusion of the overall clinical management of the patient.

Q Can I ask you this before we move on to the patients: Would you carry out a colonoscopy on a child without there being signs or symptoms present that merited that colonoscopy?
A No.

Q The only reason for doing it would be because you believed that a colonoscopy was necessary in the interests of the child.
A Yes.

Q You would make that judgment, presumably, on the basis of the child as presented to you, first of all, by the referring general practitioner and, secondly, from your own observations at an out patient clinic appointment judging what the signs and symptoms were?
A And, quite often, as a result of some other investigations.

Q It is your judgment that matters, is it not? You would have the patient in front of you and you would know something of the history or as much as you could of the history.
A Yes.

Q That is the standard approach is it not?
A Yes. You would take the history and examine the patient. You may well do some preliminary investigations. Often in a patient who has bloody diarrhoea you would arrange for an early colonoscopy.

Q For runny diarrhoea, even if you do it, you do not need to wait, but it is a judgment that you would make on the basis of all the information with which you were provided.
A Yes, that is the basis of clinical medicine.

Q That is not just your position; you would imagine it is the same for all paediatricians and paediatric gastroenterologists.
A They would make a judgment based on the assessment of the patient, yes.

Q They would only make a judgment based on that, would they not?
A Yes.

MR MILLER: Sir, I am going to deal with the individual patients. It might be convenient if we break off now and start them after the short adjournment.

THE CHAIRMAN: I am sure that is. Professor Booth will also be relieved to have a break at this stage. We will adjourn now and resume at one forty-five. Professor Booth, once again, can I give you my usual reminder: please do not discuss this case.

(The luncheon adjournment)


MR MILLER: Sir, can I give you a progress report. I sensed a sinking feeling as you came back in again to face the afternoon session! What I propose to do this afternoon, subject to your approval, is to deal with the first two children, starting with Child 2 who takes a little bit longer than others, and finish when I have dealt with Child 1- I am not behind – and then deal with the children in quite short order, simply picking up the points that I want to make about their individual conditions. I anticipate finishing cross examining this witness by lunchtime tomorrow. Then, if Mr Hopkins has any questions, he seems to think that is sufficient for him tomorrow. We are not falling behind the timetable. The only other witness we have is tabled for Friday in any event. I think you may have had enough by the time we get to the end of Child 1.

THE CHAIRMAN: I am sure Professor Booth may be relieved to hear that.

THE WITNESS: I could not possibly comment!

MR MILLER: He has not had the opportunity of going through it five times yet as you have, so we will see if we can go through it a sixth time and that will be the end.

THE CHAIRMAN: Mr Miller is quite right that the last expert is scheduled for Friday, but obviously we will make inquiries as to whether there is any possible chance of bringing him forward if it is appropriate, so we will just have to see how we get on.

MR MILLER: I had no intention of filling up the time until Friday. That is the only one who is on the horizon.

THE CHAIRMAN: I was talking to the Legal Assessor about trying to handle the situation for January, so he is going to articulate those feelings and may have some observations from you. Legal Assessor?

THE LEGAL ASSESSOR: We have these days in January which are going to be used if there were to be any submissions. What I have agreed with the Chairman I will do is I will discuss it with counsel before Friday to put people on a timetable so that the doctors’ submissions are in by a particular date, probably about the end of November I would have thought was the latest, and then any response from the General Medical Council by the end of December so that the Panel have twenty one days to look at the doctor’s submissions. Then they will have another two weeks to look at the GMC’s responses. We will talk about that. If there are to be submissions, they will need skeletons in advance.

THE CHAIRMAN: I hope that clarifies the situation. As the Legal Assessor has said, I am sure he will be able to have a conversation with you all before the end of the week so that we all agree on what is going to happen. Mr Miller?

MR MILLER: Professor Booth, turning to Child 2’s case, for which we will need the Royal Free Hospital notes, general practice and local records, you were asked to start with a referral to Professor Walker Smith at St Bartholomew’s Hospital on 29 June 1995 in a letter from Dr Wozencroft. I would like to start at the same point. If you look that referral letter which is at page 197, this is a letter from a consultant in child and family psychiatry written to Professor Walker Smith. You do not say that that is a research referral do you, Professor Booth?
A I just comment that Dr Wozencroft is making a referral to a specialist paediatric gastroenterologist.

Q Exactly.
A Which, as far as I can see, does not contain any reference to gastrointestinal

Q You are making my point for me, Professor Booth: this letter, which nobody has characterised as having anything to do with research, there is no reference by Dr Wozencroft to any gastrointestinal signs or symptoms although, as one might expect, he deals with the psychiatric diagnosis of autistic spectrum disorder.
A For a clinical referral you would anticipate that there would be some outlining of the reason for gastrological referral that would list what the gastrointestinal problems were. He goes on to say in the final paragraph,

“... I am not familiar with the research evidence which connects immunisation with difficulties like [2]”.

It is not entirely clear to me that this is unrelated to research. It would be an unusual referral to a tertiary level gastroenterologist.

Q Merely because it does not refer to the symptoms; is that feature?

A There are two features. One is it does not refer to any gastrointestinal symptoms which would be unusual in a referral to a gastroenterologist. It also talks about research evidence in the final paragraph.

Q What are you saying?
A I am saying that this is not a typical clinical letter of referral.

Q Up to now you have not said that this is directed at any research which is going on. We know when we look at what happened that upon receiving it Professor Walker Smith did examine the gastroenterological history that this child had.
A We do not know what the nature of the interaction was between the parents and Dr Wakefield, for example.

Q I am not sure what the point – you are obviously trying to make a point, Professor Booth – is. The fact is that there was a letter here sent by somebody who does not specify gastrointestinal symptoms but who sends the letter to a gastroenterologist who we know promptly investigates what that child’s gastrointestinal condition is. What is your point? What point are you trying to make? You are obviously trying to make a point.
A Could you restate your question?

Q My question is what is the evidence of this being a research referral by Dr Wozencroft?
A My answer is that, firstly, there is reference in the final paragraph to research evidence and, secondly, it would be an unusual letter of referral for clinical purposes if we are just considering a binary decision: is this clinical or is it research, and saying it is unusual as a clinical referral not to enumerate the reasons for referral to a paediatric gastroenterologist in clinical terms.

Q So it merely depends on upon the precise terms of the referral letter. You told us when you gave your evidence that if there was no reference to gastrointestinal symptoms, you would write back to the GP or the referral doctor and say, “Are you sure you have got the right department” is that right?
A If I had a referral that made no mention of symptoms or signs within in my clinical discipline, I would want to make sure that the referral had come to the correct place, yes.

“I write to ask you to see [2] and to express an opinion upon him. I know that his parents have contacted you and your colleague ... The family doctor, Dr Cartmel, also wants the benefit of your opinion”.

You say the proper response to that was to write back and say, “Are you sure you have got the right department because I see no reference to gastrointestinal symptoms”.
A I would be very interested to know what gastrointestinal problem the patient had. Presumably it was made clear to Dr Wakefield.

Q It was made clear to Professor Walker Smith when he saw the child in the out patient clinic.
A We are just considering this referral letter at the moment.

Q I do not want to take up cudgels with you, Professor Booth, but it look as though you are looking for evidence of research at every turn and at every stage. This is in June 1995.
A I am merely pointing out that it is very unusual to obtain a referral letter to a tertiary specialist that contains no reference to symptoms within that particular clinical discipline.

Q The fault may be was on the part of Dr Wozencroft in failing to specify what those symptoms were, because you do not criticise the investigations that Professor Walker Smith carried out when the child came to him.
A I am just saying that it is unusual in a referral letter for prior discussions to have taken place with another colleague in the institution, not to contain any reference to the reason for the referral and, as I say, for reference to be made to research evidence if it is just an ordinary clinical referral.

Q Let me just deal with it one more time. Are you inviting the Panel to consider this as being a research referral because of the involvement in advance by the parents and the mention of Dr Wakefield?
A No. You cannot either way. It does not say “I want you to carry out research investigations on my patient” that is perfectly correct.

Q It seems a very wooden approach, if I may say so, because you have to assume that the referring doctor, whoever he or she is, wants your help as gastroenterologist otherwise you would not have sent the child. That must be your assumption.
A The alternative is that the parents want to be involved in a research project.

Q Can we have a look at page 196 please. This is the way in which Professor Walker Smith responded,

“Many thanks for referring this child. Clearly this is a very difficult problem. I am left somewhat confused as to what the evidence is of B12 deficiency in this child. On examination there is no evidence of Crohn’s disease which concerned the mother, in view of the possible association between measles and Crohn’s disease. Apparently there has been a gastrointestinal problem in the past and I am writing to the various professionals to try and find what has been done in the past and I plan to see [2] again in 2 months’ time.

One of my former research fellows, Dr Mark Beattie, as you know, has come to Peterborough as a consultant paediatrician. Mother is saying that she has not had a consultant paediatrician concerned with the overall management of [2] and I think it might be very helpful in due course for Mark Beattie to see [2].
However, I plan to see him myself again in 2 months’ time when I have more information available. I have done some routine blood tests”.

It does not look as though Professor Walker Smith considered that he was expected to do other than look at the gastrointestinal problems that this child had and to examine him and to take appropriate blood tests. He did not seem to be confused about his role on the basis of that letter.

A That is correct. In reference to your former question about the referral, there is reference in that letter to why the parents may have been seeking a referral to this particular department.

Q It is all very well to say that because now you look at it and try to establish and you are, if I may so, straining to find research at every turn, it is clear from the way in which this child was managed at the stage in 1995 that a the head of a tertiary centre took it upon himself to make full investigation of his gastrointestinal symptoms which was the reason, on the face of it, when you look at the correspondence for referral.
A I would not say I was straining in any particular direction, Mr Miller; I am just trying to answer your questions as honestly as I can.

Q You said there are two ways of doing it, you could simply write back and say “Until you tell me what the symptoms and signs are, I am not prepared to see the child in clinic” or alternatively he sees the child and examines and investigates him which is in fact what happened is it not?
A Yes. There is evidence in the referral that Professor Walker Smith may have had some information from Dr Wakefield that has not transmitted in the referral letter.

Q And from the parents?
A The parents also may have had a particular reason for seeking a referral.

Q Information from them as opposed merely to Dr Wakefield?
A It would suggest that the parents had not communicated directly with Professor Walker Smith, but had contacted Dr Wakefield.

Q Why do you say that? Look at page 197, the first paragraph.
A Because it says “The parents have contacted you and your colleague, Dr Wakefield”.

Q Do you stand by your answer?
A So the parents had contacted both of them in fact.

Q You said it does not look as though there is any evidence that the parents contacted him. That is wrong, is it not?
A The parents have contacted both Dr Wakefield and Professor Walker-Smith.

Q Yes. Again we do not know what was said by the parents to Professor Walker-Smith.
A We do not.

Q And it does not look as though Professor Walker-Smith chose not to elicit symptoms which demonstrated this child’s gastrointestinal problems, does it?
A That is correct.

Q It is clear, however, Professor Booth, that this referral initially came about because Mrs 2 wanted the referral to take place; that appears clear, does it not?
A Yes; it looks as if the parents have initiated the referral.

Q That would not be unusual, if the parents had heard of particular expertise in a particular area?
A No, not at all.

Q The mere fact that the parents say to a doctor “I would rather like you to send my child to Dr or Professor X or Y” does not undermine the fact that they may want to get proper clinical care from the person to whom the child is referred.
A That could be one of several reasons why they wanted to be referred, yes.

Q If you look again back at the bottom of page 197, the penultimate paragraph:

“I think it entirely legitimate for [Mr & Mrs 2] to be seeking your expertise” –

expertise as a gastroenterologist.
A Sorry, I cannot find it.

Q The penultimate paragraph on 197.
A Yes. Sorry, can you direct me to the paragraph where it says “seeking your expertise as” ---

Q The penultimate paragraph on page 197, the last sentence:

“I think it entirely legitimate for [Mr & Mrs 2] to be seeking your expertise.”

A Yes, it does. You cited “expertise as a gastroenterologist”.

Q It was being sent to the gastroenterology department.
A Yes.

Q It does not look from that letter as though this is a referral that was initiated by a consultant psychiatrist for the benefit of his elucidation, does it? It looks as though it is because the parents want the referral to be made, and the GP would like help as well.
A Yes.

Q But the mere fact that it is not the referring doctor applying his own mind to the question of the referral does not make it any different, if it is the parents who are asking him to make the referral. In other words, in order for it to be a proper referral, he does not have to be the person who thought of it, if the parents have approached him to say “Please will you send my child to Professor Walker-Smith”.
A No, that is correct.

Q We have been through the out-patients clinic note and the investigations that were carried out. The blood results were normal on that occasion, and Professor Walker-Smith decided against further investigations at that time. We can go through the individual notes if you like, but that seems to be the sequence. Have you found some point you want to make, Professor?
A Can I just check my notes for one second. (Short pause) It is just that I had a note of page 193 in the Royal Free Hospital record. In the penultimate paragraph, Professor Walker-Smith’s letter to Dr Nick Cavanagh at the Chelsea and Westminster, it goes a little more fully into his thoughts on the likely diagnosis.

Q Why did you raise that?
A Because you took me to Professor Walker-Smith’s comments about what he thought the diagnosis was, and I think there is a clearer statement of his views in this letter.

Q I was going to take you to 13 September 1995, to the referring doctor, Dr Wozencroft, page 179. Interesting though it may be to revert to the Chelsea and Westminster, this was the doctor who had referred the child to him in the first place, is that right?
A That is correct, yes.

“After reviewing [2], I don’t really believe there is any evidence of chronic inflammatory bowel disease …”.

So are you happy with that as a description of his thoughts?
A It summarises part of his thinking, yes.

Q “I think the next way forward is to do a Schilling test”. What is a Schilling test?
A It is a test of the ability of the gut to absorb vitamin B12.

Q Would it be regarded as a clinical investigation?
A It would be unusual to ask for a Schilling test in a patient on whom you did not have any previous information with regard to vitamin B12 malabsorption. I am aware that Professor Walker-Smith had been in correspondence with Dr Cavanagh at the Chelsea and Westminster, but on the face of it it is a little unusual.

Q There had been a great deal of correspondence which, because we have been through it already, I have not gone to, but there is correspondence with a number of different people who have seen this child in the past, including Dr Bhatt and Dr Cavanagh at the Chelsea and Westminster. In fact as we see in the next line on 13 September letter, this apparently had already been planned by Dr Bhatt, who is at the Chelsea and Westminster. “That is a copy of a letter that I have written to Dr Bhatt”.

“Rather than make this seem too complicated I think it would be best if the Schilling Test was done, as planned, at the Chelsea and Westminster …

I have not made an appointment to see [him] again, but I should be happy to do so again in the future and I have left the line of communication open with [Mrs 2].”

So it looks from that letter to the referring doctor as if he is saying there should be, in his judgement, a Schilling test, but it is better done at the Chelsea and Westminster.
A Yes, that is correct.

Q And although he has not made further plans to see the child, he has left a line of communication open with them. What do you think that means?
A That if the parents – I would interpret that as if the parents or the GP or Dr Wozencroft wanted the patient reviewed again, he would be happy to see them again.

Q Professor Booth, you have no information about what, if anything, happened in 1996 to reopen lines of communication between the family and Professor Walker-Smith?
A No.

Q As far as you are aware, was the Schilling test ever carried out at the Chelsea and Westminster Hospital?
A I am not aware.

Q Have you seen the Chelsea and Westminster notes? I have not asked you to look at them, but have you seen them in the past?
A No, I think I have only seen the GP records and the local hospital and the Royal Free.

Q If the mother made contact and asked for the child to be seen again because of concerns about him and about his condition, that would be consistent with the lines being left open to Professor Walker-Smith to see him again, would it not?
A It would, absolutely, yes.

Q We know after all that the original referral had come about at the mother’s instigation.
A Yes.

Q Could you look in Royal Free page 28 at the out-patients clinic note, which some have struggled to interpret, but may I just invite you to consider if I am correct that this is what it says. It is the top of page 28, the first entry. This is Professor Walker-Smith. 21 June 1996:

“In school play … Ate some… in school, began to vomit several times. Admitted to XXX General [Hospital]. Lost some weight.

Under care of Dr Beattie in Peterborough. After seen last had diarrhoea, weight loss, very ill. Saw Dr Hunter on acidophilus mixture. On an exclusion diet, on milk-free, yeast-free, additive-free etc.

When has food to which he is intolerant he develops diarrhoea.

Behaviour stable now – diagnosis autistic spectrum disorder.”

That as I understand it is the note. I know when you went through it before, my recollection is “After last seen had diarrhoea, weight loss, very ill”, but that appears on the note about five or six lines down. So those reported signs and symptoms are important, are they not?
A Yes, I think they would be entirely consistent with Professor Walker-Smith’s preferred diagnosis when he saw this patient previously in August 1995, when he said the gastrointestinal story sounds very much like multiple food allergy/irritable bowel syndrome, rather than inflammatory bowel disease.

Q Help me again about irritable bowel syndrome. That is the functional condition, is it, described by the Americans in the paper we read this morning?
A That is a disorder in which recurrent abdominal pain is associated with an alteration in bowel habit, which is either diarrhoea predominantly, or constipation predominantly, or a combination of those two interspersed with periods of normal bowel, and also associated with other symptoms like bloating and feeling of incomplete defecation.

Q If it is persistent, if it is diarrhoea there is no reference to pain, but that obviously does not mean that it is one thing or another, and if the child has been very ill and there has been weight loss, these are different features, are they not?
A It is difficult to know where the severe diarrhoea and weight loss comes in the chronology. It would appear that it happened before he saw Dr Hunter at Addenbrooke’s and went on to an exclusion diet, because subsequently it says when he has food to which he – I cannot read that word – he develops diarrhoea.

Q So that is your detective work on the note; that is your interpretation, looking at the note now? That would be your interpretation of what Professor Walker-Smith’s note meant?
A Yes.

Q So as far as you are concerned there is no difference, the fact that if the mother came back, that really would not be a matter that you could comment about without knowing the terms on which she came back?
A She seems to be coming back and saying that he has been referred to Dr Beattie, he is also seeing Dr Hunter, that he had an episode of diarrhoea and was very ill, that he is on an exclusion diet which avoids a number of foods, and that he gets diarrhoea when he eats a particular food.

Q You do not see that history as being anything which would suggest the need for a colonoscopy; you have made that perfectly clear.
A That is correct.

Q You see it and expressed the view, that the reason for the child having a colonoscopy was for research purposes, and nothing to do with clinical need, so contrary to your own practice and your understanding of what most people would consider appropriate, it had nothing to do with the child’s interests?
A I think it is influenced by the observation that three days after the out-patients consultation, Professor Walker-Smith writes to Dr Wakefield “I think he is now the most appropriate child to begin our programme”.

Q The mere fact that Professor Walker-Smith’s team, which does not include Dr Wakefield, were interested in seeing whether autistic children had something wrong with their bowels as well, does not mean of itself that they cannot be seeing children for their own benefit on the basis of clinical need.
A I cannot understand why Professor Walker-Smith would write to Dr Wakefield in those terms, mentioning specifically a programme.

Q A programme of investigation. If the children have symptoms that merit investigation and treatment, that is perfectly consistent with seeing them on a clinical need basis.
A But why would Professor Walker-Smith write to someone who was not clinically involved?

Q He may have interest alongside, but that is not the same thing as saying that he is involved in their clinical care.
A No, I am not suggesting at this stage that Dr Wakefield is involved in their clinical care; I am just interested in the fact that Dr Wakefield and Professor Walker-Smith are considering beginning a programme.

Q I am not sure – you seem to take, if I may say so, a very rigid view, that children cannot be seen because they are being referred for investigation and treatment if they are having a protocol or a series of investigations which are set out in advance. You seem to say “Well, if that’s right, then they can’t be being seen on the basis of clinical need”.
A There is a protocol that we have seen that was set out in advance.

Q My point, the question I asked, is you do not seem to contemplate the possibility that children can be seen and investigated according to a list of investigations for their own clinical need as well as for research purposes in relation to some of the investigations or some of the results that are obtained.
A Yes, that is perfectly feasible. The point I am making is that in the context of Patient 2, there was discussion about entering this patient into a programme.

Q It is a programme of investigation, is it not?
A If it was just a programme of clinical investigation why would someone who has an appointment in experimental gastroenterology be involved?

Q He may get the benefit of some of the results of that investigation. He is not going to be carrying out the investigation?
A Why would Professor Walker-Smith write to him in terms of “beginning the programme”?

Q Because he is seeing the children, and some benefit from the research may occur as a result of the samples that are obtained as part of clinical need. Because that is, in fact, what happened, is it not?
A I think we have not discussed that yet – clinical need.

Q No, but as far as all of these children are concerned. They were investigated by colonoscopy, and biopsies were obtained, and they were all treated on the one hand by the clinicians and research material was obtained, which was used by Dr Wakefield’s team?
A Research material was obtained that was used by Dr Wakefield’s team, yes.

Q Again, I struggle to understand what this actual study is – whatever may be there on paper. You say there is a research protocol in a series of investigations which you attach to all of these children, most of whom are in fact investigated before it is approved. I want to find out what it is, the nature of the research trial in which you say these children were involved; your starting point is, it must have been 172/96 because that was a study for which application was made in September 1996 for local research ethics committee approval. Is that right?
A Yes. My basis, as I have already explained, is that firstly the investigations that these children had were the investigations that were outlined in 172/96. Secondly, the order in which the investigations were carried out by and large was consistent with the defined protocol; and the clinical notes of these children contain a lot of references to their being admitted for a disintegrative disorder study. The request for some of the investigations allude to disintegrative disorder study. There are references to the children being exposed to an intensive programme and therefore needing ethical committee permission ---

Q You take that ---
A There are references to exploring possible links, beginning the programme, the protocol being worked out, investigations being performed because of disintegrative disorder variant of autism. So it is on those several bases that I am taking a view that these children were taking part in a research study. Whether or not the research ethics committee permission had been obtained in a timely and appropriate way is another matter.

Q But you pick these things. You pick features. We will come to look at the individual cases. Take the individual cases. You say, “I found the reference to study in case 2; I found the reference to protocol in case 4.” You put them all together, and say the whole thing therefore becomes a research study. It must have been a research study from the outset.
A As I have just said, references to turns, such as the one that is enumerated, is but one of the reasons why I am taking the view that these children were taking part in a research study.

Q But it is not ---
A The other reasons were adherence to a protocol that was defined in the ethical committee application and, second, that the children were exposed to a number of investigations that were also very clearly defined in a research ethical committee application.

Q But it is 172/96 that you have in mind as being the research study, not any other one which is undeclared?
A I have not seen anything that has been undeclared. That is correct. If there is another study, I have not seen it.

Q And you see as a core component of that study first that the children, in order to enter it, had to have disintegrative disorder?
A Yes,.

Q So those involved, if this is the running of a scientific study, have to have disintegrative disorder?
A Yes.

Q By implication diagnosed as such before they entered the study?
A Yes.

Q Secondly, they have to have had measles immunisation or measles/rubella immunisation rather than on the face of it MMR because there is a distinction, we are told, between the three.
A Uh-hum.

Q So they need to have a diagnosis of disintegrative disorder and they need to have been immunised with measles or measles/rubella?
A Yes.

Q And were you aware of any distinction between measles and measles/rubella and MMR at the time?
A No.

Q And they have to have had bowel symptoms of some sort, at least to set up the proposition that there was a linked bowel condition which went with the disintegrative disorder?
A That is correct.

Q And the MMR?
A Yes.

Q And the simple hypothesis from the title of 172/96, if this was a pure research trial, was to see if there was a link between disintegrative disorder, enterocolitis and measles or measles/rubella vaccine? That is what the title says.
A Yes.

Q And I think that is what the aim is. So it would follow that for such a trial to have any scientific value that the children investigated would have to have disintegrative disorder, bowel symptoms which led to enterocolitis and measles or measles/rubella vaccine?
A If the applicants were adhering to their submitted protocol.

Q And since the only purpose would have been to establish a link, or to try to see whether there was a link between all three, you would have to recruit patients who satisfied all three. You would not know, obviously, until you investigated them, whether there was indeed a pathology, but they would have to have the symptoms which would suggest the need to investigate?
A Yes. They would have to have disintegrative disorder and also gastrointestinal symptoms.

Q It is not a question of trying to establish whether or not the symptoms are there. The purpose of this is to establish whether there is a condition in the gut described as enterocolitis, so that would require finding evidence of a condition in the bowel which was the result of the symptoms which were being displayed?
A If you were investigating patients as part of the research protocol, that is what you would be seeking to establish, yes.

Q My point is one step further back. That is (a) you have to have disintegrative disorder as an established diagnosis before they are ever seen; and (b) you have to have the fact that they have had measles or measles/rubella vaccination rather than MMR and they would have to have signs and symptoms which would give rise to a suspicion that they had some form of irritable bowel disease demonstrable either endoscopically or histologically?
A If you were adhering to the protocol, yes.

Q The protocol is meaningless except to show or to establish whether or not such a link can be made. It is purely a framework of investigation to see whether these three coincide, is it not?
A It is giving the investigators, or the investigators are seeking ethical committee permission to carry out a number of investigations on these children. I think it is a bit more than a framework.

Q Yes but the point is, if that is the purpose then you have to have those three features present before these children ever get considered to be part of any trial. Otherwise, the whole hypothesis disappears if what you are seeking to do is to find 25 children with these features present ---
A If you ---

Q --- to demonstrate your hypothesis.
A If you were adhering to the terms of the research ethical committee application, yes. If you were not adhering to the terms of the ethical committee application the study, as well as being ethically unproved, would also lack scientific credibility.

Q Yes, because there is no point, if you have these criteria, ignoring them because you are never going to establish the hypothesis you start out with.
A That is correct.

Q Looking at the individual cases, which the Panel had to do, you have been at pains to point out that in fact you could not anywhere with the 12 Lancet children find a confirmed diagnosis of disintegrative disorder at the beginning or subsequently. In other words, when they came to the outpatient clinic first time round, or subsequently when they were seen by a psychiatrist or a neurologist?
A Yes.

Q So what you say is, the primary feature of this proposed trial was not there for any of these children at any stage?
A That is correct.

Q And all but one or two children, you say, on your reading of the notes, did not have abdominal or gastrointestinal symptoms that merited investigation other than by blood testing, or other non-invasive means?
A No. I have not said that.

Q At the outset?
A I am saying that at the time that these patients were first seen, colonoscopy as being the first and, in general, only clinical investigation was not appropriate, looking at the patients overall. A theme emerges that whatever the symptoms were that the patient had, even though a view had previously been expressed, for example as we have been considering that inflammatory bowel disease was most unlikely ---

Q But is that not ---
A --- the patient still ended up having a colonoscopy as one of their very first investigations.

Q That is what I am saying. I think in all but one, or possibly two, they did not have signs and symptoms that merited investigation other than by non-invasive means. Is that not the same point?
A Yes. The terms of the research ethical committee application with regard to gastrointestinal symptoms, however, were drawn much more loosely.

Q How do you mean?
A The gastrointestinal symptoms that were enumerated in that research ethical committee application were not those symptoms that would immediately make you think that this patient probably had inflammatory bowel disease, so they were not strictly drawn, in that sense. There are differences between the indications as set out in the research ethical committee application for undertaking gastrointestinal investigations on the one hand, and on the other hand, clinically accepted indications for investigating inflammatory bowel disease that was present at the time.

Q I am sorry – forgive me if I have not followed it. You are saying that the suggestive symptoms in the application to the ethics committee were widely drawn and were wider than one would accept, or you would accept, as being those signs and symptoms that would generally lead to invasive investigation by colonoscopy?
A I think they were very non-specific, yes.

Q So although they said non-specific symptoms, your own view is that even those, as non-specific as they were, they were not a benchmark for the need for colonoscopy in the first instance?
A That is correct.

Q Again, so we get back to the same point, but as far as the symptomatology is concerned, the considerable majority of the children in your judgment did not have signs and symptoms that merited other than non-invasive testing in the first instance?
A In the first instance.

Q And thirdly, I think all but one of the children reported in The Lancet had had MMR rather than measles or measles/rubella immunisation?
A Yes, I think that is correct.

Q And we were told by Professor Salisbury earlier in this hearing, that they involved a very different patient population. So if this was 172/96 from the outset, a pure research project, the recruitment to it seemed to fall at every level?
A It is therefore difficult to understand why the patient notes contain statements that they were admitted for the disintegrative disorder study, and that the requests for investigations on these patients make reference to the disintegrative disorder study.

Q Can I repeat the question? You have made your comment. Can I repeat the question. If this was 172/96 from the outset, from the time that the first child was investigated, they did not do terribly well in selecting the children for that study because they failed almost entirely on all aspects of it? That is the question. I do not need the comment. I just want the answer.
A Yes.

Q We know from evidence already given in the hearing which you may have seen, probably have seen, that although the cases of the 11 English children in The Lancet paper have in effect been put under the microscope, and every nuance of their care has been examined and re-examined, you know that children continued to be admitted after these twelve were seen, and were investigated in the paediatric gastroenterology department, with colonoscopy and barium studies, for years after 1997, seen by Dr Berelowitz to assess what, if anything, their development disorder was. You know that?
A Yes. I think the subsequent investigation in these patients led to a very useful observation by Professor Murch – that the majority of them are constipated.

Q But were they all part of 172/96?
A I do not know. There were twenty-five subjects enumerated in the original application.

Q We have seen that by the time that the publication of The Lancet article, I think 50 had been seen, and we see from other references a number of others who continued to be seen because in 1999 Dr Berelowitz was seeing them on a regular basis. Are they part of another study, or are they part of 172/96?
A I do not know. It would depend on the nature of the investigations that they had and whether they all had lumbar puncture, EEGs, MRI scans and so on, and whether the notes indicated that they were admitted for a disintegrative disorder study. I have not seen those data, so I find it difficult to comment, I am afraid.

Q Beyond 25 they could not be 172/96, could they, because it was limited to 25 patients?
A One would assume not.

Q Have you seen any where a report of the study 172/96 with 25 patients with disintegrative disorder enter a colitis following measles or measles/rubella?
A No, I have not.

Q The Lancet paper cannot be the result of that because of the features which we have already seen are absent: disintegrative disorder, measles and rubella, although enterocolitis is shown to be there.
A The patients who were published in the Lancet study in their clinical notes had reference to the disintegrative disorder study. That is why they were admitted to hospital for investigation in some cases. It was quite clear.

Q But you have already met the point I do not need to remind you of how many times that these children could not be part of that because they did not have disintegrative disorder.
A Either that or the applicants did not bother to confirm the diagnosis before investigating them.

Q It was not even confirmed afterwards was it?
A That is correct.

Q Can we just return to Child 2, please, and to the Royal Free notes at page 160. This is a letter to the general practitioner who had been involved in the original referral who had wanted Professor Walker Smith’s opinion at the time:

“I duly saw [2] in clinic. As you know I first met Mrs 2 via Dr Andy Wakefield who is concerned with measles immunisation and possible Crohn’s disease. Crohn’s disease is unlikely. Dr Wakefield has the view that there may be some kind of other inflammation which may be a relevant factor in [2’s] illness and we now have a programme for investigating children who have an association with autism and a possible reaction to immunisation. I am arranging for [2] to come in for investigation in September”.

You pointed out during your evidence in chief that Dr Wakefield is not a clinician, but I think you accept that he has a great deal of accumulated knowledge about inflammatory bowel disease and has published widely on it.
A I am not aware that he had accumulated knowledge of inflammatory bowel disease in children.

Q What was the registry that you were setting up in 1996/1997?
A That was related to a register of children with inflammatory bowel disease.

Q Was he part of the Committee of that?
A He was part of the Committee. The issue in this letter is the clinical investigation of this patient, not whether he is going to be registered for inflammatory bowel disease registry.

Q We know that he was the director of the inflammatory bowel disease study group at the Royal Free. What would be wrong with him having a view that there may be some kind of inflammation other than Crohn’s which might be a relevant factor in the child’s illness? Why would he be disabled from having that knowledge or at least that view merely because he did not have any clinical contract?
A I do not have an issue with Dr Wakefield having a view about some kind of other inflammation as it is expressed here, but I do have a view about Dr Wakefield influencing clinical decisions.

Q If he says, “I think that there may be some kind of other inflammation”, if that is his view from his experience, why is Professor Walker Smith not in a position to say that that is an interesting theory, particularly if, on the account given to him, the child’s condition has worsened. Why, merely because Dr Wakefield is not a clinician, should he not have a valid view about what might be going on?
A Because Professor Walker Smith has already expressed very clearly in previous correspondence that we have looked at that he does not think that this patient had Crohn’s disease. He says that he thinks it is likely that the patient has got multi food intolerances and/or irritability bowel syndrome. I cannot understand what new information of a clinical nature has been made available that leads Professor Walker Smith to change his mind about whether this patient is going to be investigated or not, unless the intent is to carry out research driven investigations.

Q We know perfectly well that by the time the child is investigated there is a finding of bowel pathology there and you say you are not allowed to take that into account in making your decision, but, in fact, quite a few of these children, not all of the children who are reported, did have a form of inflammation in their bowel which was not Crohn’s and was not ulcerative colitis.
A I do not think you can validly in this context use the subsequent result of an investigation as a justification serially carrying out invasive investigations on children outside accepted clinical indications as we have said. You do not know what you are going to find before you do it. Clinically accepted practice is based on the premise that one does investigations that are likely to benefit the patient in terms of a meaningful diagnostic yield, otherwise you could justify doing any investigation on any patient on the remote possibility that you might find some abnormality.

A The other point is that if you are then going to start using novel research investigations of a somewhat anonymised source in patient management, the clinical validity of those investigations absolutely has to be confirmed. In other words, in retrospect, are the observations valid; in retrospect were there appropriate controls studied alongside the patients that were being investigated. In other words, for example, were patients being investigated who did not have autistic spectrum disorder but who were equally constipated. If you are going to say, “In retrospect we can justify the investigation” you have to say, “In retrospect was the interpretation of the investigations valid” which opens up a whole new area.

Q You may say that in retrospect Professor Walker Smith missed it when he saw the child in 1995 and on re presentation decided that it would be appropriate to investigate. The mere fact that he made a decision in 1995 does not mean that there is no going back on that if the position has not improved and in fact has got worse in 1996.
A The handwritten clerking that you took me was actually 1996 with reference to “only has diarrhoea when eats particular foods”. I cannot understand why a conversation with Dr Wakefield leads to a change in Professor Walker Smith’s view that this patient needs to be investigated.

Q We may never agree about this Professor Booth, but there can be nothing wrong with somebody with considerable expertise in inflammatory bowel disease discussing what might be something other than Crohn’s disease, which is what Professor Walker Smith was considering in 1995.
A I have no knowledge that Dr Wakefield had considerable experience in the clinical management of children with inflammatory bowel disease.

Q I am sorry, I missed that answer.
A You are putting to me, as I understand it, that is reasonable for Professor Walker Smith to change his mind in the light of suggestions being made by Dr Wakefield in the light of Professor Wakefield’s immense experience of managing patients with inflammatory bowel disease. My reply is I am not aware that Dr Wakefield has any such immense experience in the clinical management of children with gastrointestinal disease.

Q I am not suggesting that. He suggested
A Particularly when the differential diagnosis here as we have already heard is food intolerance or irritable bowel syndrome. Professor Walker Smith’s preferred diagnosis when he had seen the patient was not actually inflammatory bowel disease.

Q But he was wrong was he not? As he turns out he was wrong in 1995.
A I would like to look at the evidence then that this patient did have inflammatory bowel disease. I do not think there is any convincing evidence that this person had inflammatory bowel disease in the terms in which we use that term inflammatory bowel disease.

Q Let us shall me have a look at the colonoscopy and the histology results, please.

MR MILLER: Sir, shall we come back to that after a break.

THE CHAIRMAN: I am entirely in your hands.

MR MILLER: If we have our break now, we will dig out the results.

THE CHAIRMAN: We will have our mid afternoon break at this stage and we will resume at three fifteen. Professor Booth, please do not discuss the case.

(The Panel adjourned for a short time)

MR MILLER: (To the witness) Can you turn to page 247 in the Royal Free notes, please. This is Dr Murch’s colonoscopy report.

“This colonoscopy was performed in the further investigation of disintegrative disorder, and was in fact abnormal. The rectum showed very minor abnormalities of the vascular pattern, without frank ulceration, friability or contact bleeding. The appearances were largely normal (although the procedure technically difficult) until the ascending colon. One definite aphthoid ulcer was seen near to the hepatic flexure. Towards the caecum there were multiple prominent colonic lymphoid follicles, each with an erythematous rim and a central pale swollen core. These were densely aggregated in the caecum. The terminal ileum was also abnormal, showing lymphoid nodular hyperplasia although no ulceration or other abnormality”.

Those were the findings at colonoscopy which were considered abnormal. Do you agree that those are a true account of what was encountered?
A Yes. That is the observation. This would be an example of what we were discussing before the break about a patient being investigated for investigation of degenerative disorder.

Q Where do
A It says,

“This colonoscopy was performed in the further investigation of disintegrative disorder”

and the history is given as disintegrative disorder.

Q Can we have a look at the findings; where are the findings referable to disintegrative disorder?
A None of the findings are referable to disintegrative disorder because this is a gastrointestinal investigation and disintegrative disorder is a neuro psychiatric disorder.

Q So you are underscoring the point a point which you have made on a number of occasions that your reading of the documentation suggests that there is a history of disintegrative disorder, but once we get beyond that as the history, I am asking you, as I said that I would, about the findings at colonoscopy. Clearly that has no relevance to colonoscopy findings.

A It says,

“The colonoscopy was performed in the further investigation of disintegrative disorder”

so I cannot see how that could not be the reason for carrying out the colonoscopy.

Q Do you want to make the point again?
A If you would like me to.

Q That is the point that you are determined to deal with and yet, as I said, we wanted to look at the colonoscopy findings about which you had some expertise. It is in relation to those findings as gastroenterologist that I invite you to consider what Dr Murch, as he then was, was describing?
A Before the break you were making the point to me that this could not have been an investigation of part of 172/96. Because disintegrative disorder formed no part of the thinking about this patient and, therefore, by definition, it could not have been part of the investigations carried out under 172/96. I am just

Q Arguing the point again?
A Yes.

Q Do you want to do it again, or can we deal with findings in that colonoscopy?
A I am at your disposal, Mr Miller.

Q That is what I am asking you as a gastroenterologist; the findings at colonoscopy. What is an aphthoid ulcer?
A It is a small defect in the lining of the colon that is often slightly raised and surrounded by some reddening as well.

Q So it is small and surrounded by some reddening?
A Yes. They have some superficial resemblance to ulcers that occur in the mouth.

Q What is the significance of an aphthoid ulcer?
A They are often seen in patients who have Crohn’s disease.

Q What about,

“Prominent colonic lymphoid follicles, each with an erythematous rim and a central pale swollen core ... densely aggregated in the caecum”.

What does that say? Are these normal findings in the colon? I am asking you to concentrate on the colon.

A I think there is debate about whether this sort of aggregation is within normal limits or not.

Q “With a central pale swollen core” is that within normal limits?
A Normality or abnormality within a definition of lymphoid nodular hyperplasia is very controversial, but it looks from this report as though it was very pronounced, yes.

Q It looks as though the decision was made at the time to treat this as evidence of Crohn’s disease was it not?
A Yes.

Q That would be reasonable before you got any other information to do so would it not?
A I think you would want to see the histology first.

Q Let us have a look at the histology, page 264. It appears twice because some of the copies are not very clear. You cannot just simply go to the comment, can you, because if you are looking at the histology report you have to identify what it is that is being described. Each of these paragraphs with Roman numerals are related to a different biopsy sample are they not?
A That is correct, yes.

Q I is,

“Small bowel mucosa with mild chronic inflammation within the lamina propria. No granulomas are identified”.

Small bowel, we have looked at before, is not the same as colon is it?

A No, they are different parts of the gut.

Q Then II,

“These are fragments of large bowel mucosa with a moderate chronic inflammatory infiltrate within the lamina propria. No granulomas are identified.”

We are talking there about the colon are we not?

A That is correct, yes.

Q Then III IV V,

“All these specimens show fragments of large bowel mucosa”

- again colon –

“with patchy increase of chronic inflammatory cells within the lamina propria and occasional prominent lymphoid follicle with a germinal centre within the ascending and transverse colon biopsies”.

What is a germinal centre?
A It means that there is an area within that collection of lymphoid cells where there is active proliferation.

Q Proliferation means what?
A Division of the cells actively.

Q Why did they divide?
A It is normal; it is a normal finding in lymphoid tissue in the colon, and is also interpreted as being related to antigenic stimulation – in other words, the response of the mucosa to some substance in the gut, lumen.

Q So it can either be normal or it can be the response to something happening in the gut?
A Something like food allergy, for example.

“An occasional focus of acute cryptitis is present within the ascending colon specimen and there is mild crypt distortion.”

We have had evidence from Dr Davies about this, but what would your interpretation be about acute cryptitis?
A (Pause).

Q If you do not feel you are able to say so, as I say, we have had a histopathologist ---
A Sorry, I am just finding the wording. It is an inflammatory change involving particular parts of the mucosa called the crypt, which are sort of pits in the lining of the colon.

Q And ‘acute’ means what?
A ‘Acute’ means something that is happening short term, and it is characterised by a particular type of inflammatory cell infiltrate.

Q Does that imply current inflammation?
A Yes.

Q “Mild crypt distortion”?
A Normally the crypts when they are cut in section histologically go straight up and down; sometimes they are slightly crooked or sometimes branched. I think this is referring to a mild departure from their being straight.

Q Again, the cause or potential cause?
A It is sometimes seen in inflammatory states in the colon.

Q Then, VI:

“... fragment of large bowel mucosa with mild chronic inflammation of the lamina propria and very focal cryptitis.”

So again the same points there.
A Yes.

Q Chronic inflammation and focal cryptitis. So it looks as though there were abnormalities noted at all levels of the bowel or parts of the bowel where biopsies were taken.
A That is correct, yes.

Q We do not know about the particular expertise of Dr Quaglia as a paediatric histopathologist, but the comment of him and Dr Crow:

“The mild patchy generalised increase in inflammatory cells with lymphoid aggregates and follicles is not very specific but could be in keeping with low grade quiescent inflammatory bowel disease.”

A Yes, that is correct.

Q So receiving that report and knowing what Dr Murch had seen at colonoscopy, it was reasonable to treat this child as having inflammatory bowel disease?
A Yes.

Q And reasonable to start the child on enteral feeding?
A Yes.

Q If we look at page 14 in that bundle, this is Professor Walker-Smith’s ward round. Provisional diagnosis, Crohn’s disease, and then the plan: eight weeks of enteral feeding, then “gradual [something]] reintroduction”. My copy is extremely poor, but I think “gradual food reintroduction”. Could you confirm that with enteral feeding, if it is wholly enteral feeding it is all liquid, is it not?
A Yes, that is correct.

Q The idea is to stabilise the child and then try to get back to an acceptable diet after that?
A Yes, that would be the usual way of using it, yes.

Q So if you look at Dr Casson’s discharge letter of 16 September, which is in the same bundle at page 145, to Dr Cartmell, who is the general practitioner, we get the information that effectively he is being treated as somebody who has Crohn’s disease and had been started on enteral feeding because that is what the diagnosis is, is it not?
A That was the working diagnosis at the time, yes.

Q Just one small point. Can you go back to page 264, please, under “Clinical details” at the top of page 264:

“Autistic/hyperactivity. Diarrhoea intermittent for many years.
3 x obstructive jaundice episodes. ? Crohn's disease.”

So those clinical details are presumably given by the clinical team, because at that stage the histopathologist would not have any idea what the background was; they would have to be told that by somebody?
A Yes, it is something which is non-attributed; it is not clear who has written that. It would be a member of the clinical team, yes.

Q There is a long letter from Dr Casson explaining really everything that had happened, with a long history, explaining the various investigations at various stages and how it had been approached by the Royal Free at the time that he had been investigated by them.
A Could you just remind me what page you are on. I lost my place when we went back to 264.

Q I am sorry, it is my fault. 145.
A Yes.

Q Just standing back from the points in this case, I imagine you would be fairly content if your lecturer had written such a detailed discharge summary to the general practitioner explaining the history of this child’s condition and what had happened?
A Yes, it is a very good discharge summary.

Q It makes it clear that they had put him on enteral feeding, explaining what that was. This is at page 148, two-thirds of the way down the page. Do you have that?
A Yes.

In view of the colonic inflammation it was decided to treat him with an enteral feeding regime using CT3211. This is a casein based formula with which we have had extremely good results in children with Crohn's disease. It requires that he has CT3211 alone for 8 weeks. At this time we will consider re-introduction of food. We will review him regularly throughout this period and subsequently to assess his progress.”

That is in fact what happened, is it not, that he was maintained on that regime for the eight weeks?
A Yes, I think so.

Q And his progress was monitored. You do not have any criticism about that?
A No, I think if the team thought that he had Crohn's disease that would be an entirely rational form of treatment.

Q Would it also, having got the findings that they had from colonoscopy, have been reasonable to do the barium meal and follow-through as well?
A Yes.

Q Equally it would be reasonable just to see if there had been any improvement, to do a repeat colonoscopy at the end of the period of enteral feeding?
A The use of a feed by the term ‘CT3211’ would suggest that this was a feed that was undergoing evaluation as part of a clinical trial, and I would need to know whether or not repeat colonoscopy was part of the trial protocol, before being able to comment.

Q It may not matter very much, because it is not an issue as to what happened, but I am more interested in the treatment aspect which you considered to be appropriate.
A Yes.

Q And consistent with good clinical care.
A Yes.

Q They were on to it quite quickly and they started the child quickly on something which they thought might help him.
A Yes.

Q There was, as the Panel have seen, having gone through the evidence with the general practitioner, a long follow-up which is charted in the notes, with this child being seen at the out-patient clinic and subsequently treated with anti-inflammatories.
A Initially, yes, that is correct.

Q Certainly at the outset, at the time that he was first investigated, indeed up to the time we have just looked at, there is no evidence that constipation was at the heart of his problems, is there, from the various investigations that were carried out?
A There is a reference at page 12 in this bundle where it says:

“Ward round SHO
Mum worried as [2] last BO” –

Q Bowels open?
A “bowels open Wednesday evening. She thinks he is uncomfortable”.

Q I think that is the day after the colonoscopy, is it not? The date is cut off in the one we have.
A Yes. It is difficult to say, because the next entry is the 9th.

Q The 5th of the 9th is the heading “Neurology”, and we know that the 2nd is the date of admission. There is an admission note by Dr Casson. But up to that point do we have any evidence ---
A I have the colonoscopy as 2 September.

Q That is the Monday, which is the day I think on which Dr Casson does his clerking note.
A Right.

Q Although there had been the admission I think the day before. This is a reference, as you say, to “bowels last open Wednesday p.m.” but we do not have the date of that.
A I would agree that the subsequent references to constipation do not occur until about 12 months after this.

Q We know from the recipients of this discharge letter amongst others that a number of people were being kept informed of what had happened, including Dr Hunter, who is an adult gastroenterologist, is he not?
A At Addenbrooke’s in Cambridge, yes.

Q And Dr Beattie, who is a paediatrician at Peterborough?
A That is correct, yes.

Q As far as that is concerned, we have in this child a very long period of treatment after these investigations were carried out, and there is not any indication – I take your point about enteral feeding, but as far as the long-term follow-up and the out-patient clinics and the treatment with anti-inflammatories, there is no indication from the papers anyway that they were part of a research study.
A Sorry, could you repeat the question again?

Q I take your point about the enteral feeding regime, which may or may not have been part of a research trial; but as far as the long-term follow-up for a number of years which occurred in this case, the out-patient clinics and the treatment with anti-inflammatories, there is no indication in the papers that that was as a result of being involved in any research trial as far as treatment is concerned?
A No, that is right. The relevance of a presumed diagnosis of Crohn's disease becomes increasingly questionable as the follow-up evolves, and it is clear that in fact this patient has constipation.

Q What is the status of that long-term follow-up, because it seems to carry on virtually from the moment that he comes back in his first out-patient clinic appointment, that he is seen then for many years in this department and is treated and is investigated. What is the status of that? Are you saying that is anything to do with research or is that just part of normal clinical care?
A No, I think the relevance is – you made the point to me that the investigations on this patient were justified on the basis of making a diagnosis of Crohn's disease. The point I am making is that as the history evolves it becomes clear that the focus shifts towards a diagnosis of constipation.

Q But it is still a diagnosis that is being made as part of ongoing involvement with the child as a patient.
A There is no question that this patient was followed up. I am just saying that the original working diagnosis of Crohn's disease was not substantiated when the long-term history of this patient is considered.

Q I am asking you a different point, which is what if this was just part of a research study, to get these children in and investigate them? We know he is a good example, in that for many, many years he is seen and looked after by this unit, and they try to treat whatever the underlying condition might be. I am asking you what you say the status of that treatment is. Are you saying it is part of ongoing research or it is simply part of clinical care? That is the question I asked you.
A No, I do not think there is any evidence that this it not just part of ongoing clinical care.

Q Which starts, apparently, from the moment that a diagnosis of some form of inflammatory bowel disease is made at the time of endoscopy in this case.
A Yes. I think that the evidence in the clinical notes up until the point that this patient has a working diagnosis of Crohn's disease suggests that he was – and I am sorry to labour the point, Mr Miller – investigated for investigation of disintegrative disorder. Two of the applicants on the research ethics committee documentation have had their names on documents that say “disintegrative disorder”. That is Professor Murch at 247 and Dr Wakefield at 257.

Q Can I ask you about Dr Davies? Can I also just before we get there assure you that I have used this case as a vehicle for dealing with wider issues simply than strictly pertain to his case, so you may be relieved to know that we are not going through any of the other cases with the same degree of detail. Just as far as Dr Davies is concerned, how does she fit in? If this is a research-driven investigation, if the colonoscopy is a research-driven investigation, what is the need for having the service component provided by Dr Davies? She told the Panel that as far as she was concerned, she was doing the histological work, the histopathology in this case, as part of NHS care of the children. So where does she fit in if this colonoscopy is research-driven?
A One reason for involving her department would be that you could not get the biopsies processes and sectioned and stained without the involvement of her department. But it would be very unusual if a patient came in for research investigations and it included histological examination, whatever other studies you were going to be carrying out on the material, not to put it through the routine clinical department.

Q Her role, as she described it, is of simply the service investigation of the biopsies and reporting back to the clinicians with a view to dealing with the management and possible treatment of the child. That is within that one week turn-around. That is what her role is.
A That is undoubtedly her role. If the only issue with the biopsies was clinical interpretation and clinical care, then there would have been no need for other people to comment upon them as appears to have been the case.

Q It is always the other way, Professor Booth. If this is purely a question of identifying what pathology is there without it being for the benefit of the patient, or his or her clinical care, then you do not need to have the service requirement because you can identify from the research biopsies all you need to know about what is to be found in the bowel. You can cut out the NHS histopathologist because she does not have any role to play. This is purely being dealt with on the basis of research.
A We have no idea at this stage about the expertise of the histopathologists who were making the research observations. I have not seen any signed reports. I cannot comment on their clinical competence.

Q I am not getting my point across. If this is research-driven, and you are saying the colonoscopy is research-driven, it is nothing to do with whether or not it is going to assist in the management of the patient. It is purely to obtain information to make the link between those three parameters in the study. You do not need the NHS component there at all. You simply get your biopsy from the colonoscopy and then identify what the pathology is from that. You do not need to have any service involvement at all, or any clinico-pathological meeting to discuss how best to deal with the child.
A It would be a very unusual research investigation if you were not aiming for there to be some patient benefit as well, and that is what proved to be the case here. A diagnosis was made.

Q It was a diagnosis and treatment. It is not just simply diagnosis. Dr Davies’s evidence was that the whole purpose was for her having these meetings on a Friday, and it was not simply for these children. It was all the children who were seen during that week, but was in order to deal with the management and treatment of the children.
A I think it would be completely unethical to exclude the clinical histopathologist and send all the material to a research department who may have no particular accreditation for clinical reporting, who may be (as appeared to be the case) under no pressure to provide signed reports in a timely way, so I think that not to put the material through the clinical department would be completely inappropriate for a number of reasons.

Q This all goes to the question of the clinical care of the patient, because clearly if you are going to have results discussed which are going to benefit that individual patient, you need to have them there and discussed before the patient leaves the hospital in this instance, and discussed between the clinicians on the one side, and the histopathologists on the other. That one could well understand if the children are being brought in by their parents and staying for a week there with their parents in order to investigate their symptoms. If the purpose of the colonoscopy has nothing to do with their well-being, it is purely to make a research finding, then that constraint does not need to be there because it is only a question of identifying histologically what the pathology is.
A That would be true if patients who were taking part in research studies were doing so to the exclusion of any possible clinical benefit to them. As we have discussed earlier, it would be unethical to enrol patients in a study where there was absolutely no prospect of clinical benefit to them. The two components of their participation in these investigations, clinical and research, are not mutually exclusive, and never could or should be.

Q Similarly, I suppose, the same would apply to Dr Casson’s involvement not only in admitting the children to the hospital, but also in the detailed follow-up letters; that you could not divorce the fact of their diagnosis and proposed treatment, from the fact that they had had a colonoscopy and subsequent biopsies taken. The fact that he writes a four-page discharge summary to the general practitioner and every single doctor who appears to have been involved in the last two years would just be consistent with good clinical care, which you could not do without merely because they were part of a research trial.
A No, the discharge summary serves two purposes. It summarises those aspects of the investigations that were clinically relevant, and also it summarises the results of the investigations that were in the research ethical application 172/96.

Q So his discharge summary in every case is part and parcel of the research study?
A He is summarising the results of ---

Q All investigations.
A --- of the investigations that were included in the research ethical committee application. You would not expect him not to.

Q I am not going to debate with you about the entry criteria for the trial because we have been over that, I think, sufficient times not to have to go back to it, but I want to ask you about the slightly laboured point which you have been asked to deal with about the consent forms. In each case, when you were asked to look at the notes of an individual child, you were asked to go to the consent form, and in each case you solemnly told the Panel that there was a standard form, a National Health Service consent form on the one hand, and in effect a standard research biopsy consent form on the other. That is your observation.
A There were standard consent forms for the endoscopies, yes.

Q There were standard consent forms for the endoscopy and what appears to be a standard research biopsy consent form?
A Yes.

Q Alongside it.
A Yes.

Q And I think if you were not taken to every patient that consent form is not there, but for all of the patients which you were asked to look at, that was the form which the consent forms took?
A Yes.

Q So those taking consent from the parent of each child was, as far as the consent form is concerned, treating them as ordinary NHS patients by getting them to sign ordinary trust consent forms?
A Yes.

Q That is standard, I think, throughout all of the notes that you have seen?
A Yes. There were no….

Q Research?
A There were no research consent forms, nor were there in any of the notes that I saw any copies of patient information documentation.

Q Which by January 1997 had become a stipulation of the ethics committee, that they should be imported into each child’s notes?
A Yes.

Q Or any child taking part in the trial?
A Yes.

Q Could you put away Child 2, please. I think we can manage with the Royal Free Hospital notes throughout with this child.

THE CHAIRMAN: Which child?

MR MILLER: Child 1. I am sorry. I am taking them in the order that Ms Smith took them.

MS SMITH: I am sorry to interrupt for a minute, but I am just a little concerned that Professor Booth is just asked whether he is happy to start another child at 4 o’clock. I am very conscious that being cross-examined really is very tiring – much more so than in chief.

MR MILLER: I can deal with it tomorrow. As I said, having used Child 2 as a vehicle, the children who follow take a very much shorter course because we have canvassed the general issues as we have gone along. If we wish to stop there, I do not mind.

THE CHAIRMAN: I think the best course of action might be to ask Professor Booth. Professor Booth, are you happy to continue or do you wish to have a break now?

THE WITNESS: No, I am happy to continue. It is tiring and stressful but ---

THE CHAIRMAN: This is the reason. In that case, I think we will actually have a break now that he has used those words. That will probably be appropriate. We will now adjourn and resume at 9.30 tomorrow morning. Professor Booth, once again you are under oath and please do not discuss this case with anyone overnight.


THE CHAIRMAN: We will see you in the morning.

(The Panel adjourned until Wednesday 16 October 2007 at 9.30 a.m.)

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