GENERAL MEDICAL COUNCIL
FITNESS TO PRACTISE PANEL (MISCONDUCT)
Monday 1 October 2007
Regents Place, 350 Euston Road, London NW1 3JN
Chairman: Dr Surendra Kumar, MB BS FRCGP
Panel Members: Mrs Sylvia Dean
Ms Wendy Golding
Dr Parimala Moodley
Dr Stephen Webster
Legal Assessor: Mr Nigel Seed QC
WAKEFIELD, Dr Andrew Jeremy
WALKER-SMITH, Professor John Angus
MURCH, Professor Simon Harry
(Transcript of the shorthand notes of T. A. Reed & Co.
Tel No: 01992 465900)
A P P E A R A N C E S
MS SALLY SMITH QC and MR CHRIS MELLOR and MR OWAIN THOMAS of counsel, instructed by Messrs Field Fisher Waterhouse, solicitors, appeared on behalf of the General Medical Council.
MR KIERAN COONAN QC and MR NEIL SHELDON of counsel, instructed by Messrs RadcliffesLeBrasseur, Solicitors, appeared on behalf of Dr Wakefield, who was present.
MR STEPHEN MILLER QC and MS ANDREA LINDSAY-STRUGO of counsel, instructed by Messrs Eastwoods, Solicitors, appeared on behalf of Professor Walker-Smith, who was present.
MR ADRIAN HOPKINS QC and MR RICHARD PARTRIDGE of counsel, instructed by Messrs Berrymans, Solicitors, appeared on behalf of Professor Murch, who was present.
I N D E X
PROFESSOR SIR MICHAEL RUTTER
Examined by MS SMITH, contd 1
THE CHAIRMAN: Good morning, Professor Rutter. Good morning to you all, good morning, Ms Smith.
MS SMITH: Good morning, sir.
THE CHAIRMAN: You are continuing the examination in chief of Professor Rutter.
PROFESSOR SIR MICHAEL RUTTER,
Examination in chief by MS SMITH contd.
MS SMITH: Yes, sir. Good morning, Professor Rutter, we are going to be turning to child 8 next, page 3 in your report so that you know. Sir, as far as the Panel is concerned we are going to be needing the GP and the Royal Free records for that child. If we could just look at the circumstances of how this child came to the Royal Free first, Professor Rutter, the first note that we have is in the GP records at page 28. The reference is just above the middle of the page, 30 September 1996 and we see a “T” which the GP has told us stands for telephone call, and she could not recall any more than that this is what the mother told her.
“Mum taking her to Dr Wakefield Royal Free Hospital for CT scans/gut biopsies ? Crohn’s. Will need ref [stands for referral] letter – Dr [Wakefield] to phone me. Funded through legal aid.”
That was the first note and if we can then go into the Royal Free records where we will be remaining for some time, page 21, it is a letter to Dr Wakefield dated 3 October 1996.
“Dear Dr Wakefield
’s mother has been into see me and said that you need a referral letter from me in order to accept  into your investigation programme. I gather this is a specific area of expertise relating to the possible effects of vaccine damage and her ongoing GI tract symptoms. As far as I am concerned if [Mrs 8] is happy to proceed with this and it gives her any further information and peace of mind I am sure it would be beneficial for both her and .”
She enclosed photocopies of recent correspondence giving an idea of ’s current state.
“I would simply reiterate Dr Houlsby’s recent comment that both the hospital and members of the primary care team involved with  had significant concerns about her development some months before she had her MMR vaccination. I take ’s point that she has video evidence of  saying a few words prior to this vaccination being given and her vocal abilities are now nil but I don’t think we can be entirely convinced as yet the vaccine is the central cause of her current difficulties. However I am quite prepared to support [Mrs 8] in her quest for further information …”
She hopes that useful results will come from the tests.
Following on from that we have a letter from Dr Wakefield to whom that letter was addressed to Professor Walker-Smith which is at page 35, dated 9 October.
Please find enclosed some details of the girl who was referred to me with secondary autism and bowel problems. I requested a letter of referral be sent to you and I hope that this has been done. Nonetheless, here is confirmation of the referral and some further details.”
Just in passing, Professor Rutter, does the term “secondary autism” mean anything to you and if so what?
A Yes, it is a term that actually is not used very much nowadays and has not been for some time, but what it means is that autism is secondary to some other condition.
Q A physical condition?
A Yes, usually a physical condition but it could be some psychological one, I suppose.
Q Then after that Professor Walker-Smith writes to Mrs 8 direct and we have a letter at page 22.
“Dear [Mrs 8]
I have had documentation concerning  and I have heard that you would like us to go ahead with the investigations. I have arranged for  to be admitted to Malcolm Ward on the afternoon of Sunday, 19 January. The colonoscopy will be the next day and other investigations will be arranged during the week. [She] would be able to go home on the Friday or Saturday.”
She was indeed admitted to the Royal Free Hospital on 19 January. I have already asked you this question in relation to child 4, but leaving aside the gastroenterological aspects, generally speaking would you have expected, if a GP makes a clinical referral to a consultant, an outpatient appointment prior to an admission for a procedure?
A Yes, I would, that would be the usual.
Q Does it lend any support to the overall observations that you have made in relation to these children being admitted as part of a research project/
A Yes, the initial letter talks about the child being admitted for the investigative programme, which is research talk. It also makes direct reference there to the litigation as if that was connected with the need for the investigative programme, so it does not come across as a straightforward clinical referral. The kind of problem is not actually specified very much in these early letters but it does not seem to fall into the characteristics of a disintegrative disorder.
Q If we go to the discharge summary – as I say she was admitted on the 19th – we can see the investigations that were performed during that admission which is at page 15, please. I should just say in passing, although no particular criticism is made in relation to this, that the discharge summary is very much later in November 1997. It says:
“ was admitted to our ward at the Royal Free on 20 January 1997 for further investigation of possible association between developmental delay, gastrointestinal symptoms and vaccination.”
It sets out her developmental history as was ascertained at the Royal Free.
“It was notable that by 18 months of age she was able to say two to three words and was walking. At 18 months of age she had a MMR immunisation and within two weeks she had developed diarrhoea and … temperature … febrile convulsion and had a hospital stay of five days. Subsequent to that, her parents noted dramatic deterioration. She stopped vocalising and had some myeclonic jerks at night. She also started giving screaming episodes. Co-incidentally … developed diarrhoea (continuing) …”
I will not go into the gastrointestinal aspects. It says she had a colonoscopy, a barium meal and follow-through which was normal, an MRI scan which was normal, the blood results are set out and we see at the bottom –
“These results therefore are not indicative of marked ongoing inflammation. The results from Dr Wakefield’s specific investigations concerning the measles antibody would be available from him.”
If this had been an ordinary clinical admission and if there had been an ordinary clinical, psychological or neurological assessment, Professor Rutter, and we will look to see whether there in fact was, would you expect it to be included in the discharge summary?
A Yes, certainly.
Q If we can look at the rest of the records for the nature of the investigations, at page 93 is the colonoscopy report, and we can see at the top of the page, rather faintly, that that took place on 20 January, the day after her admission, and under “Plan” that it was in accordance with Dr Wakefield’s protocol. Then if we go to the clinical records at page 9, please, at the top of the page, 23 January, “Ward round with Professor. Behaviour deteriorating since evening primrose stopped. Awaiting MRI EEG Dr Berelowitz, histology.” Then underneath that we see that she then had her barium meal and follow-through which looked normal. Bloods were taken and if we look at page 82 the samples were stored for virology and the plan that had been made for MRI was carried through, because we can see that at page 89. The result, which is at page 9, on 27 January was normal and it is not clear if she had an EEG or not in that the records certainly envisaged that she would have one post MRI, but we do not have the results. We know at some point she saw Dr Berelowitz because we have a subsequent letter from him and that is at page 18. It was written on 28 January 1997 to Professor Walker-Smith:
“Thank you for referring  to me. There is a detailed history in the correspondence in the file and I will not go over it all that history but will summarise certain key features.”
Then it sets out for  and her older sister their parentage.
“After an uneventful first few months of life, ’s mother noticed that  was developing more slowly than her sister when she was about 11 months old and showed no progress towards walking. She had a few words at 14 months. She was taken to see a developmental paediatrician who noted a heart problem and she was found to have a coarctation of the aorta which was operated on successfully when she was about 14 months old.”
She had her MMR at 19 months.
“Mother reports that following the MMR there was a catastrophic deterioration in her level of functioning. She lost all language, became docile, with poor co-ordination and was, from her mother’s point of view, a different person.”
Then there is reference to her gastrointestinal symptoms and it was said there was no direct or obvious correlation between her gut symptoms and behavioural problems. She now has no language. However she is affectionate and responsive and makes good eye contact. She tried hard to communicate with him when he saw her. He noticed that following vaccination there was a period of fever, diarrhoea and developmental regression. It may have been relevant that she was in hospital for five days for febrile convulsions.
“I am therefore left wondering whether in fact she had post vaccination encephalitis rather than anything more complicated than that. I don’t think autistic spectrum diagnosis is merited here. I am sure that Andrew Lloyd Evans’s opinion would be valuable.
She is seeing Professor Anne le Couteur and I will ask Professor le Couteur to send us the results of her assessment.”
Pausing there, Professor Rutter, first of all if you know, Dr Lloyd-Evans was a developmental paediatrician at the Royal Free Hospital, the nearest they had a paediatric neurologist at that time. Given the suggestion of a possible encephalitis would you have expected that that suggestion of the child seeing Dr Lloyd-Evans to be followed on?
A Yes. It would seem a reasonable next step.
Q Why would that be? Can you tell us what the significance of an encephalitis is, how that is distinguished from the disintegrative disorder we have been talking about from autism?
A Disintegrative disorder does not have a known pathology and therefore gets into the area of needing investigation to see whether there is a progressive neurological disorder of some kind. Encephalitis here would be the acute condition, and therefore is a somewhat different phenomenon. I must say, I am unpersuaded from Dr Berelowitz’ account that that is in fact the case but certainly that suggestion, having been made, it would be reasonable to get an expert in that area to give an opinion.
Q In fairness, I should point out that at page 9 some attempt does seem to have been made to ask Dr Lloyd-Evans to play a part, because we see on page 9:
“Discussed with Dr Lloyd-Evans he cannot possibly see her today.”
Q Would it be satisfactory if the matter remained there, if this was a serious clinical investigation into the possibility of an encephalopathy?
A Not really, because if the suggestion has been made one needs to follow through in order to resolve one way or the other so that, as I say, I am unpersuaded that that was likely to be the diagnosis but, obviously, I can only go on what is in the notes and that the ordinary course of events is that if Dr Lloyd-Evans was not free on that day – which might well ordinarily be the case with competing commitments – that a later appointment would be made.
Q Now you have said that you do not think, you are not persuaded, that Dr Berelowitz’ assessment was in fact correct, and I will revert to the developmental history if I may at this stage. Previously we have heard there were concerns about her developmental delay. Could we go to the GP records for a moment at page 164? This echoes in more detail what was contained in the referral letter. It is a letter considerably earlier, 1994, and the first indication of a problem asking for an early appointment with a paediatrician in XXX. The mother …
“… is expressing considerable concern about her health and development generally and in particular relating this to her performance compared to her older sister…”
and relating her delay to her having a moderate ear infection which might be contributing.
Then could we go to page 162. We see the response to that from Dr Houlsby, which is referred to in the referral letter, setting out in the first two paragraphs her general condition, and the fact that the doctor had some concerns about a heart condition.
“My impression was that she is a child w ho is developing within normal limits, but in whom I thought I may have found congenital heart disease as an incidental finding. I arranged an E.E.G. which was of very poor quality but probably within normal limits. A chest X-ray however showed an unusual cardiac contour. I am therefore referring her to the Paediatric Cardiologists for a further opinion.”
She was indeed, as we already know, referred on and ultimately had to undergo coarctation of her aorta. The earlier reports on her behaviour said it was not autistic spectrum disorder. If we go back to the GP records at page 137, this is the consultant paediatrician, Dr Shabde, in November 1995.
“ has global developmental delay. At the age of 10½ months it was discovered that she had coarctation of the aorta which was repaired (19.9.94). She has rather unusual appearance with a bossed forehead and deep set eyes which could be familial. However, there is no doubt that this young lady has dysmorphism and with her developmental delay and congenital heart merits your expert opinion. I should add that she has had her chromosomes checked, the results are awaited. There have been a number of other investigations done – so far nothing positive has been found.”
Can we go to page 128 in the same volume, please? It is 19 January 1996 from Dr Houlsby again. She is now two and a half.
“No further progress has been made towards establishing an underlying diagnosis for her problems but I note that she will be seen by the geneticists again in the Spring.”
Then it deals with various behavioural problems. Can you just help us, Professor Rutter, as to what is dysmorphism, which is referred to?
A Dysmorphism means an unusual facial appearance. It could go beyond the face but that is usually what is referred to. That is something that alerts you to some kind of congenital abnormality, possibly a chromosomal one, but possibly something else. It is an early indicator of something having gone wrong in development, assuming that it is not a familial thing. Sometimes people do have unusual appearances simply because all the family have unusual appearances, which is the possibility that was raised although, as far as I can see, not confirmed.
Q Absolutely. If there were that concern or suspicion that there might be a genetic origin, might that be contraindicative of the condition being something like autism. Is that correct?
A No. It would not rule out autism, but it would indicate that if there were autism it was likely to be associated with some somatic disorder involving congenital abnormalities. The fact that there is a coarctation of the aorta is, as it were, another element in that. That is an abnormality that can occur in complete isolation. It does not have to be part of a broader pattern of congenital anomalies, but if you do find one, you obviously wonder about others.
Q If you go to page 122 in the GP records. This is a letter relating to a special needs team meeting in June 1996, so shortly before referral to the Royal Free. ’s mother deals with the gastrointestinal symptoms that she was suffering from. It says:
“There is no recognisable diagnosis for her difficulty. She will continue to be reviewed by the Geneticist … and a diagnosis at a later date may become clear.”
Then, in the next paragraph:
“[Her] behaviour has improved a lot and … particularly, since commencing the nursery. …. She is under review by the Clinical Psychologist … regarding her behaviour difficulties.”
Then in the last paragraph on the page:
“’s mother was concerned that she noticed a definite regression of ’s skills since her MMR injection! Presently, [she] has no speech only vocalization.”
And it sets out details of her ability to play by herself, and that she is going to have speech therapy, and her referral to a dietician with mother to keep a food diary. So there is no firm diagnosis at that stage. Later on, post the Royal Free admission, if you look at page 59 in the GP records, you see the involvement of Dr Berney, the consultant child and adolescent psychiatrist. He says:
“I last say  a year ago…”
- and this is October 1999 –
“Apparently mesalazine did not help either her bowel or her behaviour”
- that is the prescription from the Royal Free. Then, in the second paragraph:
“I found  much as I had a year ago – constantly on the go, provocatively testing those around her and not persisting at any single task; in short exhausting. As before, I think the primary diagnosis is Attention Deficit Hyperactivity Disorder in a child who has a language (and in particular speech) delay and probably has other specific learning difficulties as well. She may well have a generalised mild learning disability but I am not sure that it would be possible to identify this at present.”
That letter, referring to that diagnosis, we know was enclosed with the referral letter to the Royal Free. Then the last one I want to take you to is page 54. This is a report in June 2000 to the GP from Dr Berney at page 55. I will not give you the whole report, but he says:
“Overall,  has a Pervasive Developmental Disorder. Although she is too sociable and responsive for a diagnosis of ‘autism’ she would fall into the category of ‘autism spectrum disorder’. I have discussed this with [Mrs 8] and, in particular, the difficulty that arises that where a disorder shades into normality. I reaffirmed that  has, in addition, an Attention Deficit Disorder, a moderate learning disability and a severe language disorder.”
There is some suggestion of an actual developmental regression, as you can see from some of the comments that were made by [Mrs 8]. May we go to page 120, Professor Rutter, in this bundle, please. You can see the letter refers specifically to that and which you highlight in your report. This is a letter to the GP in 1996 from Dr Houlsby. I am at the third paragraph down.
“Her mother showed me a video of her progress over the years. In summary, at the age of 18 months she appeared to vocalise having two or three recognisable words. One year later there appears to be no vocalisation and she displays some behavioural features suggesting hyperacusis. More recently she was filmed in the bath where she seemed to be very happy and demonstrated plenty of symbolic play. Finally I watched a period when she was asleep. During this time she had some myoclonic jerking. Although it seems very unlikely that she is having seizures, I am arranging for her to have a further EEG.”
“On reviewing her records I find that the concern about ’s developmental delay was expressed by her mother and yourself in May 1994, long before the MMR was given in January or February 1995. The fever associated convulsion which she had in February 1995 was in the context of a diarrhoeal illness associated with fever two weeks after her MMR immunisation. I feel therefore that [it] is extremely unlikely that the MMR was the cause of her present problems.”
Leaving that aside for a moment, what I really wanted to ask you about overall, Professor Rutter, is the account of the regression that is included in that letter. Is it a kind of account that you would regard as being of clinical significance?
A It is the kind of account that one often gets with an autism spectrum disorder. The fact that the child had only two to three words would make one uncertain as to whether this is a true bill or not, in that that is a very small amount of language to lose, but this is the kind of thing that one often sees so that the picture that comes out of all of these records is of a developmental problem that began early, involves language, involves some autistic-like features, quite a lot of hyperactivity, so that there does not seem much doubt that there was some sort of pervasive developmental disorder that could be regarded as falling on the autism spectrum at an earlier point.
Given that that is so, then it would not be unexpected to see this sort of regression described here. As I say, it is not a very convincing account because of the small amount of language but nevertheless it is consistent with that. It is that which makes me a bit sceptical about a further diagnosis of an encephalitis. Of course children, like adults, can have two totally unconnected conditions but, other things being equal, one wants to see whether in fact it is all part of the same thing, so that bringing him a diagnosis of encephalitis, which is unconnected with what happened before is possible, did not seem to me very plausible.
Q Was there any indication at the Royal Free of the investigations or assessments there, or in the background, which could have led to any diagnosis of disintegrative disorder?
A No, none at all.
Q In those circumstances can you see any justification for the inclusion of her in a study of children with disintegrative disorder?
A No, I cannot.
Q And just to remind the Panel, because we have had a weekend in between although I am sure they do not need reminding, but the fact of some degree of regression in the clinical history, would that of itself take you any further towards the diagnosis of disintegrative disorder?
A No, because there are so many much more common causes and no, it is not in itself. In order to diagnose a disintegrative disorder you have to have much more extensive evidence, usually at a later age (although not always), and you would not expect to have prior developmental abnormalities and you would expect a much more global regression.
Q. What, again, is your overall view, Professor Rutter, just pulling together the various things you have already told us in relation to the admission of this child without an outpatient assessment for the investigations, the nature of which we have gone through, what is your overall view as to whether this was a research or a clinical admission?
A The overall picture is certainly of a research-driven referral. As always, it is difficult to understand exactly what the motivations of everything were, but the key things are that the referral is in terms of a concern re MMR; mention is made of the litigation; mention is made of the plan of investigation that Dr Wakefield had developed rather than a particular clinical problem for which advice and help was being sought.
Q Thank you. Lastly, the standard question I have been asking you: Did you see any sign of the patient information leaflet and research consent forms that were envisaged?
A No, I think I did not find that.
Q Could you excuse me for one moment. I want to check back with one record because it has been pointed out to me that I may not have been as clear as I had hoped. What was available to the Royal Free at the time that Child 8 was referred to them? Obviously we have to look at what they would have known. If we go back to page 23 in the Royal Free records, these are the letters which accompanied the referral. Professor Walker-Smith says on page 22 that he had had the documentation concerning Child 8. We see that was the letters to which I have taken you between pages 23 and 28: March 1995 from Dr Houlsby; September 1996 from Dr Houlsby; and then the minutes of the special needs meeting.
Q They would have had the information that I have taken you through as to her behavioural development and the element of regression that he had examined.
A Yes, indeed. As you point out, the question of a general developmental problem and its timing are repeated several times in this series of letters.
Q Thank you, Professor Rutter. I am going to turn on to the next child at page 23 of your report, Child 7. Sir, we are going to need the GP and Royal Free records for Child 7. Professor Rutter, you raised some doubts in this case about whether this child had an MMR immunisation. I should tell you that we have established from the general practitioner that he did indeed have MMR in November 1995.
Q I will not take everybody to it, but in case you want a note of that it is in the GP records at page 296. To remind everybody, this is the sibling of Child 6. We can deal with this case relatively briefly because there was a limit to the amount of assistance you could give us. He was referred to the Royal Free Hospital in December 1996. If you go to the GP records at page 282, there is a letter with a manuscript date of 5 December 1996 to Professor Walker-Smith. It comes after the investigation of Child 6, so the family were by then known to the Royal Free Hospital .
“I would be grateful if you could see this boy who is a child whose sibling you have recently investigated as part of your programme for colonoscopy for children with autistic problems. He himself probably does not have autism, although this is not certain at present but he does have convulsions which I believe may make him eligible for your study. He also suffers with bowel problems similar to his sibling who is autistic.”
That led to an outpatient appointment with Professor Walker-Smith, who then wrote to the general practitioner at page 279. The letter was dated 23 January 1997 after a clinic on 15 January.
“Many thanks for referring [Child 7]. I was very interested to hear the history of this child in which there does seem to be a clear relationship between symptomatology and the MMR. He had the MMR rather later than usual at the age of 21 months. His mother tells me 24 hours afterwards he had a fit like episode and slept poorly thereafter and she attributes changes in his behaviour to this event. I understand that he has not been fully investigated although I understand it is your opinion he could be within the autistic spectrum although it is not your view that he does have autism. I understand that he had had an abnormal EEG in the past and was for a period of time on anticonvulsants but he is no longer on any kind of medication.”
He sets out his gastrointestinal symptoms and then says:
“Particularly in view of the findings in his sibling, I think it would be appropriate for this child to be investigated particularly by colonoscopy and I am arranging for him to be admitted on Sunday 26 January 1997 and he will be having other investigations as part of the protocol. We will let you know the results of these investigations in due course.”
As far as that letter is concerned, Professor Rutter, again leaving aside, in so far as it is possible, the gastrointestinal aspects of the case, do you have any comments to make about the basis upon which this child seems to have been being admitted behaviourally?
A The initial referral letter deals with it in terms of the epilepsy, which, as far as I understand it, was not part of the plan. That was not an inclusion criterion. There is a clear statement: thought not to have autism/might or might not have a autism spectrum disorder, so it is not at all clear how that would fit in.
Q He was subsequently admitted to the Royal Free Hospital. We know that because there is a note in the computerised records at page 4 of the Royal Free records, if we could just look at that. We see there that he was dealt with with an inpatient appointment, 26 January to 1 February 1997, and he was admitted under the care of Professor Walker-Smith. Subsequently, we see there is an outpatient appointment on 29 May 1997 with Dr Berelowitz. There are some difficulties as to the nature and the reason for the investigations that were carried out on this child because we do not have a formal discharge summary. There is a letter which was sent which is in the Royal Free records on page 59 from Professor Walker-Smith dated 17 April 1997.
“I am sorry that we have not yet had the discharge summary sent to you for [Child 7]. Basically though, he had lymphoid nodular hyperplasia but on this occasion no evidence of inflammation in the distal bowel. Nevertheless he continues to have symptoms, although these are chiefly behavioural. When I reviewed him in the clinic I thought it would be helpful to try a therapeutic trial of olsalazine in the same dose as for his sibling ... and then assess whether we need to continue.”
He then refers to blood results and says that he is going to review them again in four months time. If we go on to page 57, in May 1997 there is a rather fuller communication in respect of both of these children, but still not setting out all the detail. This is to Dr Bennett, the community paediatrician, from Dr Casson, a lecturer at the Royal Free. If we go to page 58, just dealing with Child 7 – the first part of the letter deals with Child 6 – he was referred to Professor Walker-Smith by his GP.
“He is not thought to have features of autism. There was concern over a previous fit-like episode which occurred 24 hours following his measles vaccination. There was also concern that form the age of 2 years he had intermittent passage of blood PR …”
Then it goes into the gastrointestinal complications.
“It was decided in view of the findings in his sibling to investigate [Child 7] further. He was therefore admitted for a colonoscopy …”
Then it refers to very mild abnormalities.
“When [Child 7] was seen subsequently seen by Professor Walker-Smith in clinic, he felt that a therapeutic trial of olsalazine was indicated. This was empirical treatment chosen as mum had reported a marked improvement in [Child 6 – the sibling].
I hope this is sufficient information and would be extremely pleased to keep in close contact with yourself, and let you know of any further developments.”
That is the nearest we get. It does not deal with the circumstances of the other investigations, but if we look in the Royal Free records at page 6 we see:
“Admitted to Malcolm Ward for colonoscopy and investigations as part of the disintegrative disorder/colitis study”
and on page 7 we see the plan for what was to be done: “Colonoscopy mane [tomorrow]” and then there is a tick by the preparation for the colonoscopy. “Autism protocol. Consent” and then it says “Venfon, bloods mane”. The same day there was a ward round with Professor Walker-Smith: “Colonoscopy today” for barium meal and follow-through Wednesday. “To see Dr Berelowitz RE autism. MRI, EEG” and then it says “Dr Lloyd-Evans RE development”.
In fact those investigations were indeed carried out. There is a colonoscopy report on page 109, and that took place on 27 January. If you look at page 157, that is a request form which is signed by Dr Wakefield for an EEG and evoked potentials and specifying the type of evoked potentials, giving the reason for the request as disintegrative disorder and inflammatory bowel disease. I have asked you this question in relation to a number of the other patients, Professor Rutter: if these were clinical investigations, would you expect to see Dr Wakefield ordering them?
Q Was there any basis at all for him to indicate that his child needed this investigation for disintegrative disorder?
A No, I could find no evidence of disintegrative disorder.
Q We know he had an MRI, because it is set out at page 82, with the procedure undertaken on the brief discharge notification: “colonoscopy”. Also, he had a lumbar puncture. That is at page 10. That is that procedure. We have heard from Dr Lloyd-Evans that he may well have been asked to see this child because of the association with convulsions or what he said were then referred to as “petit mal attacks” but he said he would not have been happy to do a full developmental assessment. He was uncertain if he in fact saw this child or not. Again, is the reference to the suitability of his seeing a developmental paediatrician one that you would understand in view of the history of convulsions?
Q And which you would expect?
A Yes, that would be perfectly reasonable.
Q In passing, because you referred to it and we may need to look later at the litigation background of some of these children, could I just ask you to look in the local hospital records at page 413. This is a local newspaper article which is included in the child’s medical records at the local hospital with a manuscript date on it of 1 March 1997. It refers to the fact that these two siblings [Child 6 and Child 7] have joined 600 other youngsters fighting for compensation. That appears in the second paragraph down. In the second column:
“[Child 6 and 7] have been granted legal aid and their case is being fought by Kings Lynn-based solicitor [Mr] Barr.”
That is the chronology of that and you can put away the local hospital records.
With regard to Dr Berelowitz, we know he did see the child because we have a much later record of the letter he wrote to Dr Wakefield. This is another letter which has to be included in FTP bundle 2 and which I now have to hand in to you. I handed one in in respect of Child 6, you will recall, and this is the same document in respect of Child 7. (Document circulated) It will be 605G. I remind you that this is a document that is on yellow paper because it was provided by Professor Murch’s team. It is dated 3 June 1997 from Dr Berelowitz, addressed to Dr Wakefield and copied to Professor Walker-Smith and Professor Murch.
“Dear Andy, thank you for referring [Child 7] to me.”
Then there is details of mum’s background.
“…he developed well, had social smiling and was responsive to his mother. But he began to have pale episodes and ? petit mal and had an EEG done at 15 months, which was abnormal. Following the EEG, he was put on Epilim, which turned him into a robot.
He walked at 10 months and began speaking at about a year. At 18 months he had a febrile fit during a chicken pox programme. He was unconscious for about 20 minutes and lost the use of one side for a while. He then had his MMR at 20 months. On the same night as his MMR he had what his mother thought was another fit, but I am not sure about this. From then on he became quiet with a decrease in spontaneous speech, less social engagement, less eye contact and poor language.
Since going on to olsalazine, he is very much better and has started to improve quite significantly …He continues, however, to be socially withdrawn, difficult to comfort and has little make-believe play.
Mother is somewhat at loggerheads with the local services” –
I do not think that is of relevance.
“In fact, [Child 7] played very little while he was in my office and made no eye contact.”
He says that he and Child 6 engaged in some lovely imaginative play, lining up the chairs in the office and pretending that they were a train and playing hide-and-seek.
“Mother took the lining up of the chairs to be an allegation of the children’s obsessionality, but in fact I did not think this and I thought it was a good example of imaginative play. I should add that there were other aspects of what mother called [Child 7’s] repetitive play which I thought was probably normal toddler behaviour.
Notwithstanding these comments, I do think that [Child 7] suffers from a developmental disorder, perhaps somewhere between Asperger’s and Autism. However, I would want Andrew Lloyd Evans’ view on the development following the febrile convulsion. I also retain some uncertainties about the strength of the conclusion that we should draw from some of the historical features.”
Reading between the lines of some of what Dr Berelowitz has said about some of the mother’s interpretation of the way these children reacted to things, what do you understand him to mean by:
“I also retain some uncertainties about the strength of the conclusion that we should draw from some of the historical features.”
A I presume he is referring to the fact that in the behaviour that he could observe – which the mother also could observe during the clinical assessment – what he regarded within normal limits, she was reporting as repetitive and abnormal, and I presume that he is using that as a way of inferring that possibly there may be doubts about some of the other inferences that had been made by the mother with respect to development.
Q I will take you back to this when I have looked a little at the developmental history of this child, Professor Rutter, but, at this stage, on the basis of what Dr Berelowitz says, is there anything that you can assist us with as to the appropriateness of a label either of autism or of disintegrative disorder?
A Certainly there is no evidence of disintegrative disorder; there are flavours of possible autism but it is no more than a flavour.
Q Then we have Dr Wakefield writing directly to the mother of children 6 and 7 in your FTP 2 bundle at page 605D, just flipping back from the page you are at. It is dated 6 September 1997:
“Dear [Mrs 6 and 7]
Further to our conversation the other day, I am writing to confirm that following assessment of your children at the Royal Free, in particular by Dr Berelowitz, the consultant child psychiatrist, the behavioural diagnosis in  is of a developmental disorder on the autistic spectrum between Asperger’s and autism.”
Then there is a reference to child 6. That then is a reflection of his overall view of somewhere between Asperger’s and autism.
Q Just taking things on chronologically, bloods seem to have been taken for measles testing much later, back in the Royal Free Hospital records at page 92, and we see that that was from a sample received on 6 May 1998 and there is reference to the testing for measles virus antibodies. I would like if I may just to revert to the background of this child’s behavioural history, if I can do it briefly. In 1995 he was investigated to begin with for epilepsy, if you go to the GP records at page 331. That is the first reference to some sort of convulsions, floppy and unresponsive and a diagnosis of a febrile convulsion, and it was thought at that stage [query] to be secondary to an ear infection. Then if we go on to 330, which is also in relation to the Royal Alexandra Hospital, there is a prescription for sodium valproate for febrile convulsions, and we can see in the notes: “Recommendation: query history of complex seizures. Commenced on sodium valproate, awaiting EEG.” Then at 329 we are now May 1995 for the same hospital, a concern that the child had some drag in one leg and it says:
“His turns have improved on sodium valproate but he had an episode when he clung to his mother’s leg, went a little blue with shallow breathing and slept afterwards. His first turn for some time. He has been on a low dose of sodium valproate and I would increase this to 18 mg twice daily.”
Then that history is summarised in the GP records at page 24, at the bottom of the page, “Past medical history. Being investigated for epilepsy. EEG. Normal brain scan.” We can see the prescription in the GP records at the bottom of the page for October 1995.
The MRI or the brain scan was apparently normal but the EEG was abnormal, and we can see that from page 103 in the GP records. Under “Patient summary” 1 June 1999 under “Significant problems” there is a reference to “Abnormal EEG.” In September 1998 he had a clinical psychology report from the Newcomen Centre which we have looked at in respect of another child, at page 224. You highlight this report because if you look to page 225 we see in the middle of the page that on that assessment he had a full-scale IQ of 124 on the 95th percentile, is that correct?
Q That is a high IQ.
A It is a high IQ, yes.
Q Again, Professor Rutter, if the psychiatric assessments at the Royal Free had been part of a clinical psychiatric admission, would you have expected to see details of it in the discharge summary?
Q What is your view about the fact that although we have looked at these two children separately, and indeed with a gap between them because they were seen at different times, from the point of view of a clinician seeing these children, if he is indeed seeing them for clinical reasons, would you expect any significance to be attached to the fact that there were two of them?
A That there were two in the same family?
Q Yes, two siblings.
A Yes, there are of course a variety of reasons why that might be the case but that would undoubtedly be a clinically significant element and one would expect to see some discussion as to what that meant.
Q I think in view of the absence of any details of the neuropsychiatric assessments in the discharge summary you do not feel able to express a view as to whether this lumbar puncture was clinically indicated or not?
Q Is there any indication at the Royal Free of investigations or assessments which could have led them in your view to a diagnosis of disintegrative disorder being an appropriate one?
A No, to the contrary, such evidence as is available – and as you point out it is rather limited – is to the contrary, so here is a child of above average intelligence, which would be almost unknown in a case of disintegrative disorder, there is not a history that shows a pattern at all similar to disintegrative disorder and there is a clear history of epilepsy that preceded all of this. On the evidence available in the records there is nothing to indicate a pointer in that direction at all and therefore nothing to justify lumbar puncture or the other investigations. The reason that I expressed caution on that is simply that there is such limited evidence available and of course one never knows whether there is evidence that was important that just is not recorded there, but in terms of what is recorded not only does it not point to disintegrative disorder, there are several elements that point decisively against it.
Q On that basis is there anything that you can see which would justify inclusion of this child in a study on children specifically with disintegrative disorder?
Q You expressed some views when I asked you about the method of referral, which as you will recall was through the sibling and with references to the similarity of the bowel symptoms with those of the sibling, but a different behavioural history. Again, can I ask you the question I am asking you in respect of the others, does it seem to you that this admission is consistent with a clinical admission and investigation of the child’s behavioural disorder?
A No, because that is not highlighted and as we have discussed the discharge letters do not deal with that, so what might have been seen as a clinical reason is significant by the absence.
Q Is your response the same in relation to the absence of the research information for the parents?
A It is.
MS SMITH: Sir, that is all I have to ask about child 7 and you have only one remaining child, child 10, who is a little longer because there are other charges relating to him. Would you like to have a coffee break at this point?
THE CHAIRMAN: Yes, it is close to quarter to eleven so we will now adjourn for a short mid-morning break and resume at five past eleven. Professor Rutter, you are still under oath and still in the middle of giving your evidence so please do not discuss this case. Thank you.
THE CHAIRMAN: Ms Smith, I believe you were going to start with child 10. Which notes are we going to need?
MS SMITH: The Royal Free and the GP records, page 19 in your report, Professor Rutter. If we can turn at once to the referral letter at page 35 in the Royal Free hospital records. This is a letter to Professor Walker-Smith dated 14 October 1996, from the GP, Dr Hopkins.
“Dear Professor Walker-Smith,
Thank you for seeing this unfortunate 3½ year old boy who has been extensively investigated by our local paediatricians.
He was presented by his mother in late February 1995 with a history of loss of acquired skills. This appeared to follow on from a viral-type illness which  caught while visiting his grandparents in XXX. This was apparently accompanied by a rash and thought to be a measles-type illness. Unfortunately he was not seen by any doctor from this practice and we have no documentation on this.
He had been given the MMR vaccine on 21.2.94. Of all the investigations performed by Dr Paul Davis, community paediatrician locally, the only thing of significance was that his ‘measles antibody was significantly raised’.”
It then goes on to deal with his ear infections.
“No actual diagnosis has been given for ’s condition but the most recent report states ‘severe speech and language disorder with some autistic features’ – 2.9.96.
Mr  – who holds a PhD – has heard of your work and is keen for  to be assessed by yourself.
The situation is obviously much more complex than I am able to outline in a brief introductory letter and  has been seen by a consultant paediatric neurologist and a principal clinical psychologist in addition to the community paediatrician and ENT surgeon.
However, the situation is so difficult and complex that I’ll be grateful for any help you can give. I would be happy to forward copies of any letters in my possession or of course you could liaise with the consultants directly.”
As far as that referral letter is concerned, Professor Rutter, I have asked you this in relation to other cases. Does anything strike you as being of particular relevance, given that this is a referral to a gastroenterology unit?
A The absence of reference to gastroenterological problems.
Q This may be a somewhat obvious question, but we have of course heard from the GP in relation to this. When a doctor has a patient referred obviously they are going to have the information that is in the referral letter and any other documentation that is enclosed with that referral letter, but will they have any other source of information as to what the GP may or may not have been thinking about the case, except for what they derive later from the parents in outpatients or any admission?
A No, that is what you would have to rely on.
Q The child has attended an outpatient appointment with Professor Walker-Smith and Professor Walker-Smith then writes to the GP, if you go back to page 32, please. It is 11 November 1996,
“Dear Dr Hopkins
Thank you so much for referring this very difficult problem with ’s history of loss of acquired skills, and somewhat autistic features which have improved. From a gastroenterological point of view …”
Then it sets out the symptoms that Professor Walker-Smith apparently elicited in relation to the gastroenterology, and then he says:
“The parents are keen that I should investigate him for a possible gastrointestinal disease, it is very interesting that he has a high measles antibody and I think this needs to be taken into account with the possible relationship of measles immunisation and inflammatory bowel disease. I am therefore arranging for him to come in to have a colonoscopy on Sunday, 12 January … Many thanks for referring him …”
Prior to the admission there was some information sent to Professor Walker-Smith by the consultant paediatrician involved in the case and we have got that at page 31. That is a Dr Davis who is at the hospital in Cardiff:
“I gather  is coming to see you next week for investigations in connection with his severe speech and language disorder and possible food intolerances. His father has asked me to forward ’s MRI scan films which were reported as normal. Our x-ray department is sending these to you. I thought you may also be interested to know that we did some blood tests in August last year which were reported as normal, specifically the results were as follows …”
Then he gives them.
“ still has a total lack of speech and some autistic features although not enough to amount to a diagnosis of autism per se. He has never presented as having an overt gastroenterological problem, although his parents in retrospect do report some loose motions.”
Then it refers to various dietary exclusions and says that his parents have noticed some improvement in his social skills. “I would be interested to know your findings and look forward to the outcome of the research in due course.”
That was from Dr Davis and then the child was admitted on 16 February 1997 and discharged on the 19th. If we go to the discharge summary to see the investigations he had, they are in the Royal Free records at page 26, 17 March 1997 from Dr Casson, the registrar.
“ was admitted for other investigations of his bowel symptoms in association with possible disintegrative neurological disorder and possible association with measles vaccination.”
He then sets out his birth history:
“Mum reports that he was well until 16 months of age when he had a viral infection which was diagnosed by a GP as some form of measles. The exact history of this episode is somewhat confused. Mum was unsure as to the nature of the rash in association with a pyrexial illness. [It] lasted four days and he seemed to recover well … over the next few months the person that she had previously known began to gradually disappear. She cites a very specific period between September and December of that year during which he appeared to lose eye contact, lose the basic verbal skills he had developed and generally become less happy and outgoing. She notes no loss of motor skills. She notes that following this period he had episodes where he appeared to improve, however with each viral infection he contracted he reverted to his previous condition. In the summer of 1996 he appeared to deteriorate once again …”
There is reference to bowel symptoms and it then says that he appeared to show some comprehension of language and sense of humour but he had no speech. He never had any bowel control or urinary control.
Then it sets out the details of his bowel habit. He has been investigated in Cardiff. Under Dr Davies an MRI, EEG and various blood tests have all been reported as normal, but a measles antibody was noted to be quite elevated. We see the tests he had carried out at the colonoscopy. We know about a lumbar puncture from the fact that there is a record of his CSF being normal. Also during this admission he was reviewed by the child psychiatrists who will be forward a report. In view of the inflammatory changes it was felt that he was going to be prescribed anti-inflammatories.
Reverting to the records, we can see when they were carried out. The colonoscopy was on 17 December, if you look at the Royal Free records at page 64, which gives the result with the date of the sample. The sample was taken on 17 February 1997. In fact, that is the same day as the colonoscopy, and the day after his admission to hospital. Then, the day after that, he sees Dr Berelowitz, so that is at page 16. At the bottom of the page:
“Seen by child psychiatrist
Detailed report to follow”
That, as I say, on the 18th, so the day after the investigations, and the subsequent report is available and is on page 28. This letter, in fact, contains an express acknowledgement that this is a research interview by Dr Berelowitz. He writes to Professor Walker-Smith:
I saw  on 18th February 1997. In fact I saw ’s father only as  was sleeping, and father said mother would not wish to participate in a research interview.
In terms of ’s present state, he does not talk …. He is not yet potty trained and according to his father, appears to have no bowel control and virtually no bladder control. He is friendly and affectionate, recognising his parents, seeking them out, and enjoying cuddling with them. His sleep is now good.”
And it refers to the various activities that he has.
“He has no reciprocal play or make-believe play …”.
It says that he appears to be perfectly normal.
“Father said  was a brilliant child up to about 18 months. … He never got to use any clear words.
Then, according to father, he ‘just disappeared’. This was in June when he was about 15 months old. He had had his MMR at 12 months. In June he had a febrile illness, with fever, rash, vomiting and a low level, of consciousness for three days.”
The doctor diagnosed German measles.
“Following this illness, he avoided eye contact and physical contact, his sleep became poor, his behaviour became obsessive. He lost interest in toys, parents and everything else except videos. There was no rocking or head banging.
He has begun to improve quite dramatically over the last six months.”
That had been attributed to dietary exclusions.
“You will see from the above account that  has certain features of autism, and certain of the features of disintegrative disorder. However, in fact he does not meet the criteria for either of these two conditions. He is far too affectionate, by his father’s account, for a child with full-blown autism, and a clinical cause, apart from the bowel and bladder problems does not rally fit with disintegrative disorder. Furthermore it is possible that he does not truly lack bowel and bladder control, but has merely not yet been successfully toilet trained. Only time will tell.
I was very troubled by certain things that father said to me. He said that I should not mention the [word] autism to mother, as she hated that word, and she was convinced that  had disintegrative disorder. The father did not know that disintegrative disorder is a condition with a very much worse prognosis than autism. He said that they had been in considerable communication with [Mrs 2]”
- the mother of Child 2 –
“and they may have picked up this misinformation from her. He did not say that but I wondered if that were the case.
I must say that I thought the most likely diagnosis was in fact an encephalitic episode, which led to some low grade generalised brain damage. You will see above that in the acute episode he had fever, rash, vomiting and a low level of consciousness for at least three days. Father deeply regrets not having had him admitted to hospital at that time.”
As I said, that was a letter that was address to Professor Walker-Smith, copy to Dr Wakefield.
The first paragraph, Professor Rutter, we see a reference to the fact that Dr Berelowitz talked only to ’s father because  was asleep, and an express reference which Dr Berelowitz acknowledges to the fact that he was regarding this as a research interview. Would it have been possible to do any serious clinical assessment of this child through his father when he was asleep?
A You could certainly get a history.
A But in terms of an assessment of current behaviour you would have to see the child as well as getting a report.
Q Could you excuse me for a moment – I am sorry. (After a pause) I am going to take you on just to look back at the behavioural history. I should make it clear that the records to which I am going to refer you were in fact available to the Royal Free Hospital as regards his behavioural history, so they had not only Dr Berelowitz’s letter but the documents we are going to now. They start in March 1995. Could you turn to the GP records, please, at page 110. This is from a consultant paediatrician, Dr Hodges, at the BUPA Hospital in Cardiff.
“… the family were quite happy with ’s progress up until June 1994.”
Then it sets out the history that I have already referred you to, so I will not go through it again, of him becoming unwell after some sort of viral illness. Mum describes him as going into a shell, with a stopping of speech and communication, and little eye to eye contact. At the bottom of the page the doctor says:
“I observed  playing in my room. He was interested in books, turning the pages over and taking some interest in what was on the pages. In addition he built several towers of cubes and did this quite efficiently. There was a degree of eye to eye contact with myself and more so with Mother during the consultation. He was certainly able to get over … what he wanted without actually speaking. …
It was difficult to do a full assessment on  in such a short period of time but I thought his play, although not entirely normal for a child of two, was not that far outside the normal range.”
Then, at the end of the letter:
“I am always very concerned when children develop what appears to be a simple viral illness and lose acquired skills. I think Mum has been quite right to be worried about  although I did give her an optimistic prognosis … I have told Mum that if she remains concerned about 10’s lack of progress then I would gladly see him again but I must have a longer period of time with him in order to do a more formal assessment.”
So that is way back, the start of the problems in March 1995. Then, if we go on to pages 106-108. This is the Children’s Centre in Cardiff and, again, a letter from Dr Davis, the Community Paediatrician. This is May 1995. He says:
“I discussed him with the Speech Therapist … She tells me that  has become rather detached from every day life and doesn’t interact well. He has delayed sounds acquisition and poor retention of learnt communication skills. … They saw … ENT Surgeon … You told me over the phone about the previous consultation with Dr Ian Hodges who linked his developmental problems possibly with a previous measles illness.”
He then sets out the facts. He had no neo-natal problems. There was a brief episode of fever at two weeks for which he was admitted to hospital but settled spontaneously.
“Despite having had MMR he had an illness in June 1994…”
And he sets out the history. Then it goes to a family history and the difficulties following the episode of measles. He began to lose eye contact, went into his own world, lost interest in his toys and books, and ceased interaction with other people. Early vocalisation ceased. He developed a habit of bouncing up and down, jiggling and running in circles. Since Christmas he has been improving.
“He attempts communication using physical contact and gesture. His eye contact is beginning to improve. … Following another viral illness early this year he regressed somewhat and went back to the way he had been in June but is now improving again. He rarely responds to commands, sometimes takes the initiative in games, but often ignores strangers. He is inconsistent in his response to his parents and tends to lose interest in new skills as soon as he has acquired them.”
Going on to page 108:
“He certainly appears to have had a developmental regression particularly in communication and social skills … coincident with the illness which may or may not have been measles. There is also a history of some trivial head injuries.
I think it is worth investigating him at this stage. I will arrange a hearing assessment …. I will arrange a vision assessment … I have taken blood for CPK, chromosomes, thyroid function and viral titres. I will arrange a head scan and EEG and next time he comes we will take some urine to look for organic and amino acids.
His father after some open ended questioning asked if he could be autistic and I had to spend a considerable time talking them through what autism is.  certainly has a number of features at the moment which are characteristic of autistic children but his score on the Autism Behaviour Check list was certainly not in the autistic range i.e. he has some autistic features but is not autistic. I told his parents that I couldn’t guarantee that he wouldn’t be labelled autistic later in his life but I felt it was extremely unlikely. I felt it was more likely that he has a transient developmental regression due to a set back, presumably a viral illness and is already making good progress towards recovery and I hope will continue to do so. His mother was rather shocked because she thought that we could totally rule out autism by virtue of the fact that he had been normal during the first year of life, but this is not the case.
I plan to review him in six weeks by which time I hope to have most of the results and I will talk with the parents some more. If the question regarding autism is still prominent I may ask Professor Bill Frazer to see him and at some time it may be appropriate to get an opinion from the Paediatric Neurologists. I will also write to the parents summarising our discussions today.”
That was the view that was being expressed there. Given that this was a consultant community paediatrician, Professor Rutter, rather than anyone who was more specialist, would you regard that as a thorough assessment at that stage?
A Yes. Thorough and thoughtful.
Q Just to make it clear, because we have already read in Dr Berelowitz’s letter later that the mother apparently had some concept that disintegrative disorder was a preferable diagnosis – none of us can speculate any more than Dr Berelowitz could – as to where she got that notion. But when it says his mother was shocked because she thought “we could totally rule out autism by virtue of the fact that he had been normal during the first year of life,” that is incorrect in that case?
A Yes, it certainly is incorrect.
Q Whatever the problem, whether it be truly disintegrative disorder in the terms that you have already discussed with us, or autism?
A Yes, that is right. It does not help either way.
Q Then, if we go on to page 102 and see what came out of that, Dr Davis is writing in June 1995 after another review.
“Since I last saw him he had a significant regression for about 2 weeks precipitated by a cold. His opthalmalogical assessment was unsuccessful and is to be repeated under GA [general anaesthetic] when he comes in for his MRI scan in July.”
Then it refers to his ear problems. It says:
“[He] is responding to some extent to speech therapy although his skills are quite fragile and easily lost.”
It goes into his various abilities. The impression:
“He is still exhibiting a number of autistic features but at this stage I would certainly fall short of labelling him as autistic. All his problems could be explained by a specific speech and language disorder aggravated by transient deafness due to glue ear. The role of the precipitating measles illness in June in causing his current problems is rather unclear although his measles antibody titre was significantly raised.
Other investigations have been unremarkable. His DNA studies and chromosomes were normal as were his CPK and EEG. We still have not obtained urine for organic acid estimation and I will try to do this next time …”.
Then he says at the bottom:
“I will ask Professor Bill Fraser to see the family to give a clear view on the autistic elements of his behaviour. I will ask Dr Sheila Wallace to comment on his neurology. I discussed with the parents the pros and cons of referral to the Education Department but we decided to leave this until the next time I see him.”
He said he is likely to have special education needs and that he would review him in three months. Dr Sheila Wallace, Professor Rutter – do you know what her specialism is?
A Yes. She is a paediatric neurologist.
Q Do you know any thing of hr expertise and would you describe her as experienced?
A Yes. She is both experienced and knowledgeable.
Q Then at page 100 there was an admission to the University Hospital of Wales for an MRI and page 96 there is an assessment by Dr Sheila Wallace.
“Thank you for asking me to see .”
This is on the 3 August 1995.
“ has many autistic features but he seems to have had a rather more acute loss of social and communication skills than usual, and I wonder whether the more appropriate diagnosis would be disintegrative psychosis. I note that you are referring  to Professor Fraser and I should be very interested to have a copy of Professor Fraser’s report.
At the moment,  is not talking, though he will take his parents hands and lead them to things.”
Then it goes through his behaviour.
“He has lots of rituals at home. … He becomes agitated in strange places, is not interested in toys and will sit for long periods of time in a sandpit … He has poor eye contact…. Some interest in his mother and father … He also has books that he likes …. Currently at home he is interacting with [his mother] and she feels that his interaction is at a level that would be normal for a 1 year old.”
Then she took refers to the behaviour starting after the illness, thought to have been measles, in June 1994. She sets out in considerable detail at page 97 the nature of that illness.
She says that he is currently seeing a speech therapist and then she sets out the family history. She says,
“It was difficult to tether [Child 10] for a formal examination and I realised after he had left that I had not measured his head circumference. I made no attempt to look at his optic fundi. His head circumference however did not look out of proportion to the rest of him.”
She sets out how he behaved in her surgery while she was talking to his parents. She says,
“In summary, [Child 10] appears to have been progressing entirely normally until June 1994 when he had an illness which consisted of a rash, a fever and listlessness. This could have been measles since he subsequently had a rather higher than expected measles titre. Since then [child 10]’s behaviour has been unusual and his ability to communicate at a very simple level. I feel that many of the features that he displays could be autistic in nature but I am not sure whether they are sufficient to make the diagnosis of infantile autism. On the other hand, [he] seems to have become behaviourally disturbed after an illness and this behavioural disturbance seems to have come on rather rapidly and I wonder whether the term disintegrative disorder would be more appropriate for him. [Child 10’s] parents were extremely upset that I did not have the result of his MRI of the brain when they came to my clinic. I explained that the result would be sent to you since you have requested the MRI. I was however able to get the result off the computer screen in the MRI office and I was able to tell [Mr and Mrs 10] that [Child 10’s] MRI of the brain did not show any abnormalities. If sudden episodes of stillness and quietness become a regular feature of [Child 10’s] behaviour, it could be worth repeating his EEG.”
You have told us that Dr Wallace was an experienced paediatric neurologist. During this child’s admissions to the Royal Free, could you find any evidence of any neurological assessment?
A No, I do not think I did find any.
Q As far as that letter from Dr Wallace, do you regard it as being a definitive diagnosis of what is the matter with the child?
A No, it is a thoughtful account of a somewhat unusual picture and expressing uncertainties that it does not quite fit an autism spectrum disorder as ordinarily understood, but nevertheless has features of that kind. It raises the question of a disintegrative disorder, in view of the set back, as described. It is a good clinical opinion, making clear a definite view in so far as she was able to come to it, but also making clear the uncertainties that surround that.
Q We see that she did not, at that stage, suggest that there were any other investigations that were appropriate, other than saying, if there was some evidence of stillness and quietness -- by which I understand she might have been fearing minor fits, is that correct?
A Yes, indeed. That is my assumption.
Q -- that it would then be appropriate to repeat his EEG. When he arrives at the Royal Free – and you have told us you could not find any evidence of any neurological assessment – he is given a lumbar puncture the day after his admission, and the day after that he sees Dr Berelowitz. We have looked at what Dr Berelowitz had to say about him, which was of course another diagnostic conclusion, albeit again not a certain one. Given the lack of a neurological assessment, was the carrying out of that lumbar puncture an acceptable decision in your view?
A I do not think it was, because this was a child where there had been quite extensive assessment both by development paediatricians and by paediatric neurologists. To take a decision on that, without looking carefully as to what had been found previously and whether there was anything now (meaning at the time of admission) which meant that something different had to be done. As far as I could tell, it was simply: that was in the protocol, and therefore that is what had to be done.
Q You have told us at the outset of your evidence, before we looked at the children, of the circumstances in which you would have done a lumbar puncture and we have seen that Dr Wallace apparently did not think it was appropriate, but was it a justifiable clinical decision to make on the evidence that was available to you on this child?
A Not in my view; it was not.
Q In relation both to Dr Wallace’s information and Dr Berelowitz’s assessment, in so far as it assisted, was there any indication that it was justifiable to make a firm diagnosis of disintegrative disorder in this child?
A No. As comes out in the reports, there are elements that are consistent with that, although there are also elements that are different. It is not so much whether that was a correct diagnosis but that, as far as I could see, there was no new evidence, as it were, that led to a reappraisal subsequent to the much more detailed assessments by Dr Sheila Wallace and by the others who had been involved in the child’s care, so that whether or not that was an appropriate term I think is not really the key issue. The issue is: Was there any evidence that took it beyond what had happened before and where Dr Sheila Wallace, who is very experienced in this area of work, had not thought it appropriate to do a lumbar puncture? One needs to think carefully why would one go over that or, if you like, go against that. Ordinarily, in those circumstances, my practice would be – which I think is pretty typical – if I felt something was needed beyond that, that I would then contact the expert who had seen the child before I had and say, “Because of x, y and z, I wonder whether it might not be better to proceed by doing some further investigations. What are your views?” As far as I could see, nothing of that kind happened.
Q As far as the inclusion of this child in a study of children, which, as far as we can ascertain, purported to be a study of children with disintegrative disorder, do you think there was sufficient to justify that diagnosis firmly being made in relation to this child?
A No, I think it is rather dubious.
Q Lastly, again, does the same answer as you have given previously relate to any information as to consenting for research purposes?
A It does.
Q Before we leave Child 10, Professor Rutter, as you know, you were asked to deal with a separate matter. In order to make sense of the questions that I am going to ask you, I am going to have to take you first to some of the documentation. To assist you, I am at paragraph 80, which is at page 41 of your report. I think I should preface this by saying that you would not pretend to be an expert in transfer factor, is that correct?
A That is certainly correct.
Q Indeed, we are going to be calling an expert to assist us on that, but I want to ask about the more general matters relating to a prescription to this child, and, firstly, the evidence that the child was being given it. If you go back to the GP records at page 65, this is a letter form Dr Davis, a community paediatrician, to the GP. It is dated 7 August 1997. The only bit with which we are concerned is the end of the first paragraph:
“He is on Salazopyrin” –
which we know is an anti-inflammatory –
“for bowel inflammation and is awaiting some new treatment with measles transfer factor.”
In December 1997 we have further indications of that. That is in the Royal Free Hospital records at page 181. This is part of what is known, as we can see at page 178, as an Aberrant Behaviour Checklist, a document which was filled in by Child 10’s mother. If we go back to the very bottom of page 181, it says:
“He is not as good as he has been recently. Over Christmas and the New Year, we felt very optimistic about the apparent effect of Transfer Factor – there seemed to be such a noticeable change in [Child 10]. But this week we feel pessimistic. This may be a stupid question, but is it possible that the dose now needs to be increased?”
Subsequently, in February 1998 we have a vaccine damage questionnaire for the Medical Controls Agency. That is at pages 21-22 of the Royal Free records. It is a Questionnaire to Obtain Information About Possible Adverse Effects. It concludes on page 22 and is signed by Dr Wakefield on 3 February 1998. On page 21we see:
“(b) What were your findings when you first examined the child? Has there been any chance since?
Examined by Professor Walker-Smith. Autistic features; otherwise nil of note.
(c) has any treatment been given for this possible adverse effect?
Yes. In view of the colonic inflammation [Child 10] was commenced on mesalazine. When measles virus antigen was detected in his bowel biopsy he was started on measles virus-specific transfer factor (details available on request).”
That is the evidence, Professor Rutter – filling you in on a rather lengthy background, I am afraid, in order to ask you some questions – that this child was indeed given this substance. I now want to look at the other documentation that we have in relation to transfer factor before I ask you some questions I have. Could you look in your FTP bundle 2, please. At the same time as the vaccine damage questionnaire of February 1998 to which I have just taken you, there was an application submitted to the ethics committee at the Royal Free in relation to transfer factor. Would you look at page 675, please, which is a letter to Dr Pegg – who, as you know, is the Chairman. The trial is a preliminary open-label study of the effect of oral measles virus-specific dialyzable lymphocyte extract transfer factor (DLE-TFmv) in children with autistic enteropathy and asking the Committee to consider the application.
“One child who has received this treatment on a compassionate basis appears to have made substantial improvement without any noticeable adverse effects. I look forward to hearing from you.”
That is Dr Wakefield’s letter. If we look at the application at page 676, we see, under “Principal Clinical Investigators” “Responsible Consultant(s)”, that Professor Walker-Smith is included and the “Principal Scientific Investigator” is Dr Wakefield. If we look at page 679, we see, under “SUBSTANCES TO BE GIVEN TO SUBJECTS”:
“Adverse events associated with use of DLE-TF
DLE-TF is virtually free from adverse side effects (reviewed by Fudenberg & Pizza; see full protocol). When given intramuscularly or subcutaneously, it may cause pain at the injection site for 10-20 minutes. Transient low-grade pyrexia may occur but there have been no reports of either hypersensitivity reactions or of long-term adverse effects.”
Then going on to 680, under the paragraph 12, “Discomfort”:
“There are no anticipated side effects of the drug. [It] has been given in millions of doses without adverse effects, other than mild pyrexia in rare instances.
Anecdotally, we have started one child with autistic enteropathy on [transfer factor] on an approved compassionate basis; he has tolerated the therapy, for one month so far, without any adverse effects and according to his parents has shown definite improvement.”
Then on to 682, this is the information sheet which it was proposed would be given to the parents if this study went ahead, i.e. after ethics committee approval had been granted, and we see the explanation that has been given and the novelty of this drug.
“A possible new treatment, called … Transfer Factor has been developed by NeuroImmuno Therapeutics Research Foundation, an American-based research foundation in collaboration with workers at the IBD Study Group at the Royal Free …”
Then it says how it works.
“This is the first study of a measles-virus specific transfer factor in patients with this syndrome. There are no guarantees that it will work. To date, Transfer Factor against other viruses, bacteria and tumours has been given and as well as being an apparently successful treatment has been extremely well-tolerated without any adverse effects other than a mildly raised temperature in rare instances. If this occurs, it usually lasts only a day or two and is easily controlled with paracetamol.”
Then it sets out what would be entailed in a study of this treatment.
“If you agree to your child taking part in the study, your child will undergo a formal, standardised behavioural assessment … Your child will receive transfer factor …”
Then at the bottom of the page:
“During this time or any time after starting the treatment, you can call the hospital to discuss the trial, and any concerns that you might have … you will be provided with a sublingual mineral supplement to help [the] immune system respond …”
At the bottom of the page, under the questions which parents might pose:
“Are there any risks involved?
Along with possible desired effects, any medication may cause unwanted effects. If your child feels unwell or has any unusual discomfort during the study, it is important that you tell the doctor as soon as possible. Your doctor can withdraw you from the study at any time if he/she feels it appropriate.
Are there any benefits?
It is hoped that your child will benefit from the study drug, in terms of both intestinal and behavioural symptoms, but it is not known how long this benefit could last.”
Then it sets out all the other questions that parents may have and there is prospective consent form at page 686. Then at 691 you will see there is an attached scientific protocol, a clinical research protocol, and we see the background to the case with a clear reference under “Clinical Study” to The Lancet children, if I can refer to them in that way:
“We have investigated, in a pilot study, a consecutive series of 12 children for a new syndrome … summary below” and setting out the details of what they have suffered from. At the bottom paragraph page 693:
“We are aware of some 554 children who require investigation for similar symptoms, many of whom have been or are in the process of being referred.”
Can I just pause there? This is peripheral to the matters I am asking about, Professor Rutter, but normally speaking would you expect clinicians to be aware of a precise number as large as that, 554 children, who were in the process of being referred for ordinary clinical investigations?
Q You have told us you see patients, could you see how many are in the pipeline for being referred to you?
A Yes, but it would not be a number of that kind, so in that it is a precise sort of number it must be based on some sort of documentation outside the ordinary clinical referral system.
Q As I say, that was something I wanted to ask you about in passing, and then we see the entire scientific protocol relating to how it is hoped transfer factor might assist. There was correspondence with the dean in relation to this trial in July 1998, six months after it had been given to child 10, and we can see that if you just go to FTP3, please, page 941. This is a letter that was sent in July 1998, as I say, to Professor Zuckerman from Professor Walker-Smith and he says:
“I have now written to Dudley Dumonde whom I have known for many years concerning the safety aspects of ‘transfer factor proposal’. I attach copies of these.
If it is regarded as safe I do feel in duty bound to the parents of these unfortunate children (where there are three pieces of evidence in favour of measles: lymphocyte PCR, serology and tissue immunohistochemistry) to proceed with initially an open trial evaluated by a psychologist or psychiatrist. Andy has promised me that this would not be published as such but would be a vital preliminary to a placebo controlled trial. Such a trial would not proceed if the first study were entirely without effect. I understand that Roy [a reference to Professor Pounder, head of department] and Andy are planning a trial in adults with Crohn’s disease.”
In fact we have, for other reasons, looked at the documentation relating to that. Just pausing there, that is suggesting some sort of pilot trial, is that correct, and saying that that was a vital preliminary to a trial involving controls, in other words comparators?
A Yes, that would be a fairly straightforward ordinary way of approaching it. You do not want to go into a full randomised control trial unless there is some reason for supposing it might be valuable, and an open trial would be a reasonable beginning.
Q You would expect as, I hasten to add, was indeed the case that an application would be made to the ethics committee before that open trial was embarked upon.
A Certainly, yes.
Q Then attached at 943 was the letter that Professor Walker-Smith sent to Professor Dumonde:
You doubtless will have heard about the controversial findings that Wakefield et al have reported concerning the possible role of measles in children with autism. A study is proposed to give a group of such children who have evidence of measles antigen in tissue, positive measles serology and PCR positivity … transfer factor. These will be patients under my care and I will be responsible for safety aspects.
As I have known you so long and always valued your advice I would much appreciate your confidential opinion of the safety of this extract as will be supplied to us by Dr Charles Kirkpatrick, Professor of Medicine and Immunology at University of Colorado, USA.
I have discussed this matter confidentially with our dean, Professor Zuckerman, and we both would value very much your advice, which I could pass on in confidence to Dr Pegg, chairman of the ethics committee if you were willing for me to do that. Or else you could give me your own opinion in confidence.
I would be happy to discuss this if appropriate on the telephone.”
Then just completing the story, in September 1998 Dr Pegg writes enquiring what has happened to transfer factor trial and Professor Walker-Smith responds, and we have got his letter at page 960.
“… there has been some time involved in determining details of European Safety Standards requirements. We have no doubt that the transfer factor produced is safe but Dr Andy Wakefield will be flying shortly to Denver, Colorado to see the manufacturers to ensure that all the details of the European Safety Standards are met.”
He explains that it would not be possible to have the information until the following ethics committee meeting.
Then at 961 he sends the safety details concerning the European Standards as promised and at 962 the letter that he encloses was from Dr Wakefield to him, Professor Walker-Smith:
Please find enclosed a summary of safety and efficacy evaluation from Professor Kirkpatrick … Both Professor Kirkpatrick and I have now had time review extensively the EU Regulations on Drug Safety and concur that transfer factors comply with [them]. Professor Kirkpatrick has gone to the trouble of enumerating the trials that he has been conducting and the adverse events, such as they are, that have been recorded. These are remarkably few and consist of pain on the injection site when given subcutaneously and pointing out that in [their] trial they ate proposing to give the drug orally. In conclusion, therefore, we are confident that the drug and the protocol comply with the European Standards and Regulations on Drug Safety.”
Following on from that, which I will not go through now with you, is a long summary from Professor Kirkpatrick setting out the various trials that he has done using transfer factor in other clinical circumstances and the effects of those.
I am sorry to give you that long introduction, Professor Rutter, but you appreciate it is necessary for the Panel to understand the factual background.
If I can revert to child 10 you will recall that the claim that was made, which is the first thing I want to deal with, was that the substance was given to child 10 prior to all the ethics committee involvement as a compassionate treatment. First of all, what do you understand that term, giving it for compassionate reasons, to mean?
A It is not a term that I would have used in my own clinical practice but I am assuming that is simply saying that they have got a new treatment and that it seemed worthwhile to try it out and that this is being done as a way of exploring clinical value on a one-off basis, so this comes back to what I was saying the other day, that as an ordinary part of hospital or for that matter general practice it would be common for the person in charge to explore new approaches and that this is, I assume, what is meant by compassionate here.
Q Right. On that basis if you are using an experimental – and I do not mean that in a pejorative sense but something that is not usually used – for an individual patient, is that in broad terms acceptable?
A Yes, it is, as long as appropriate enquiries are being made re possible value and safety. If that is within your own expertise that is fine, if it is not then you consult the appropriate experts.
Q If you are simply doing it on the basis of an individual patient, and you wanted to consult, who would you consult?
A You would consult whoever you felt was the most appropriate authority in that field.
Q Just so we are absolutely clear, you refer in your report to the possibility of a clinician being able to consult a clinical ethics committee.
Q That is a particular animal that I think it is right did not exist in very many hospitals in 1996.
A I think that is probably correct.
Q But it is a completely different sort of committee from the research ethics committee with which we have so far been concerned.
A Entirely so, yes.
Q And that would be a committee which, if it had existed, might have been able to give some advice on a novel treatment on a one-off basis.
Q In the absence of that – and we have no idea, we have had no evidence that the Royal Free had one of those committees – you say you would consult a colleague who you believed might know something about whatever it is you wished to know.
Q You cannot, I know, comment on transfer factor itself but you have been able to look at the neuropsychiatric condition of all the patients that I have taken you through. Is there anything about child 10 neuropsychiatrically which might single him out for an individualised treatment?
A There is nothing that I could see. As I have mentioned before, the group of cases that we have been looking at are quite heterogeneous so saying is one child different from the others, the answer in virtually all cases is yes because they are all different, but as far as I could see in terms of what I knew about the situation there was nothing that would have picked this child out as requiring some special approach that differed from that in the others.
Q Of course you were looking at the records, but is there anything that you can see why he more than the others might require compassionate treatment?
A Not that I could see.
Q If you are going to give an innovative or an experimental treatment to an individual patient, tailored to their individual needs, whose responsibility is that?
A The consultant in charge.
Q We know that the position was that in the application that I have taken you to subsequently Professor Walker-Smith and Dr Wakefield were named as the principal clinical and scientific investigators and the application says “We have started this child …” We know from the evidence, and you have seen Dr Berelowitz’s transcript, that he is named on it but has told us that he declined in fact to be involved in the study; would you expect Dr Wakefield to have anything to do with the prescription of a substance for any reason, compassionate or otherwise, to a child patient?
A No, certainly not on the compassionate level because as I understand it the criteria of his appointment meant that he could not be involved in clinical care. The situation when moving to an open trial is different, of course, in the sense that then that is a piece of research and will have been looked at by the ethics committee as a research proposal, and it would be entirely reasonable then for that to be jointly concerned between Dr Wakefield and Professor Walker-Smith.
Q We of course, as you appreciated in that answer, are concerned with a child who was apparently given this substance prior to the ethics committee application; if Dr Wakefield was involved in the giving of that substance to this child, are you critical of that?
A Yes, because that is not part of what his job is supposed to cover.
Q Who would you expect to have been the decision-maker with regard to that prescription?
A I would presume Professor Walker-Smith.
Q If it was being given, this substance, on a compassionate basis which related to behavioural symptoms, would you expect there to be some sort of neuropsychiatric input into the decision to give it?
A Oh yes.
Q We have seen that subsequently enquiries were made, both for Professor Zuckerman and the ethics committee, as to the safety of this substance; does that cause you any concerns?
A I think it is entirely proper to make enquiry of acknowledged experts in the field regarding safety. What is unusual is to have done that after the compassionate treatment rather than before. Unless Professor Walker-Smith felt that he had sufficient expertise to go ahead, I am surprised that he then did not seek advice at that stage. It is possible of course that he was simply being ultra-cautious when moving to an open trial, but you would expect if you were not clear in your own mind that you have the expertise that on the first occasion of using it you consult with a colleague, not in a formal way but just saying as far as I can see this seems a reasonable thing to be doing, but you have much more experience on this than I have, what do you think?
Q Which indeed, in fairness, is what happened when Professor Dumonde was consulted afterwards.
A Yes, indeed.
Q Are you critical, Professor Rutter, from what you can tell on the documentation, of this prescription in these circumstances?
A I think only in the sense that the enquiry about safety came after the event rather than before the event and so, as I was saying, if that was being ultra cautious, but Professor Walker-Smith felt that he actually had sufficient experience to take that decision on his own, then that would be okay. The way it comes across – and I can only go on what I have seen in the records – he felt relatively lacking in adequate detailed experience of the use of transfer factor and therefore appropriately sought advice. My concern then is why afterwards, not before?
Q Reverting for a moment to Dr Wakefield’s position, you said if he was involved you would be critical of that for all the circumstances you have said. With regard to Dr Wakefield’s completion of the vaccine damage questionnaire, would you expect that to be a role that he would fulfil?
A Not ordinarily because that is a clinical assessment, admittedly in relation to potential litigation, but nevertheless it is a clinical assessment that is being asked of the person completing it and ordinarily that would be completed by somebody who had clinical responsibility for the individual about whom the questionnaire is being completed.
Q Thank you very much. That is all I have to ask you about the individual patients and I am now going to revert, as I told you that I would, to ask you again about some of the overall views you have expressed now that you have got some examples on which to draw. You can put away your clinical records.
THE CHAIRMAN: Are we still going to require our FTP2 and FTP3?
MS SMITH: I think not, sir, but I do not make any rash promises; not at any rate for a little while. Professor Rutter, if it assists you I was going to ask you in a moment about the handling of the decisions on the basis that they were clinical investigations, which is paragraph 53 of your report.
Q Before I ask it, can I ask just one general question? Having looked at all the records in these cases can you assist us as to whether it is your view that these children were indeed investigated, albeit perhaps not as a rigid timetable, but were investigated in a way which complied with the list of investigations which are set out in the ethics committee application?
A You mean whether the investigations carried out were in relation to the protocol as submitted?
A Yes, yes. They were.
Q In so far as the handling of the decisions, just on the basis for a moment that they were clinical investigations which you have told us you think on the whole they were not, but if they were – as I say, I am on paragraph 53 of your report – did they seem to you to follow the normal pattern in relation to clinical decision-making?
A No, because they are sort of back to front, so that ordinarily you decide on investigations after a thorough clinical assessment, which is appropriate to what the particular problem was, but in this case that did not seem to be the usual practice. In some cases there had been an outpatient assessment. In other cases there had not, and the assessment by the additional expert, or Dr Berelowitz or Dr Harvey, did not precede the planning of the investigations; they followed it. So that is not the way one would ordinarily undertake things in relation to a clinical case.
Q At the point at which it was apparently decided that these children were going to have this plan of investigations, do you regard the experience of the clinicians neuro-psychiatrically as being sufficient?
A Not really because each of them has some relevant experience but not really particularly in relation to these issues, so that if we deal with those who are not being considered in the case here, Dr Berelowitz in his own evidence makes clear he is not an expert in this field. He is not trained in the use of research instruments that one might apply in this situation. So he is giving the opinion of an experienced child psychiatrist who has some knowledge of the area, but it is not his main area of expertise. If one turns to Dr Harvey, again the same would be said. He is an adult neurologist with a limited experience in the field of paediatrics and the sort of way he approached the case, very much as an adult neurologist, not as the way a paediatric neurologist would do it. If we turn to the paediatrician’s concern, the gastroenterologist, obviously as part of the paediatric training they will have experience in some aspects of this, and I imagine that all of them had some experience with neuro-psychiatric of one sort or another, so that is partially within their expertise, but if you ask the question a different way and say, “Has their experience particularly been in the difficult area of deciding what you do with a disintegrative disorder,” then at least so far as I can see on the documents that were made available to me, I do not find that there really for any of them.
Q That leaves really one doctor, I think, because I assumed from the paediatric gastroenterologists you were referring to Professor Murch and Professor Walker-Smith. As far as Dr Wakefield is concerned, you have told us already that you had considerable difficulty in sorting out in fact what role he did play ---
Q --- in all this from the records. But would you have regarded him as being appropriate if he were involved in any clinical decision-making about the investigations that were to be carried out on these children?
A As far as I can see, he similarly has some experience but not a lot. I think again that is on the evidence available to me.
Q Of course. In those cases where Dr Harvey was involved, since he is the nearest we get to a neurological assessment – I think you have answered this but if we can just make it clear – what would be the usual expectation as to the timing of the assessment but he did, if he was to be relevant to the nature of the investigations being undertaken?
A It would have to be before they were decided upon, otherwise it makes no sense. That often was not the case.
Q We have seen that at least two of these children had had previous assessments by paediatric neurologists, and a number of them, of course, by psychiatrists as well, but I am thinking in particular of Child 3, whose was assessed by Dr Rosenbloom, and Child 10, who was assessed by Dr Wallace. What course would you have expected to have taken with those children if there were not specific specialists involved previously?
A I would expect some kind of discussion with them. Both are acknowledged experts in the field, and if the plan of investigations is to go beyond what they did, as I was indicating in relation to the last child, one would expect to give them a telephone, or contact in some way to say, “This child has been referred, and I note that you have been involved and have read your very helpful summary letter. I note that you did not include such-and-such investigation. We are thinking of including it. We would welcome your views.”
Q If there had been experienced assessment by a paediatric neurologist, and that that individual had not ordered an invasive investigation such as the lumbar puncture, obviously that does not preclude another doctor taking another view, but would you expect it to give less specialist doctors pause for thought?
A No. One would assume, other things being equal, that the more experienced, more specialised, view would have precedence.
Q Generally, Professor Rutter, if we assume for the moment that it is the case – and we are all, to some degree in the dark, that an assessment was done on an individual basis, and the investigation of lumbar puncture was decided on in relation to the individual child, would you expect to be able such find in the clinical records the reasons as to why that decision had been reached?
A Yes, I think I would in this particular instance, because it would clearly be an unusual thing to do. So you would not expect to find in the clinical records a rationale and detailed arguments for each and every investigation that is being planned. If they are the ones that any expert in the field would be doing, then that would seem redundant. If, however, you are doing something which is rather unusual and particularly if it is out of your own area of expertise as a main thing, yes, you would expect to see something in the notes as to why that was being done.
Q And were you able to find in respect of any of these children any kind of reasoning as to the procedural ---
A No, not at all.
Q I am turning on, just so you know, to your paragraph 54. With regard to the list of investigations that was undertaken, what is your view as to their nature?
A You mean in terms of their focus or their invasiveness or ---
Q Sorry. No. In terms, as I say, of paragraph 54 of your report. You say that as a set of investigations which is undertaken on all cases they have a particular flavour about them?
A Yes. I am making the point in my report that these are quite heterogeneous group of cases. In some cases there is some evidence of regression. In Child 2’s case it is quite marked and repeated. That in itself was unusual, does not fit in with a disintegrative disorder, but it is certainly clinically significant, and that the cases also vary greatly in intellectual level. There are some that are of above average intelligence, and there are some who are profoundly intellectually impaired, and then there are a number in the middle. There are variations in terms of the extent to which there is a straightforward set of features like in autism that fit the criteria for autism spectrum disorder, and there are others in which one can say, there are some features but it is a bit mixed. So they are very heterogeneous. It is not that that is unusual in itself if you are dealing with developmental problems, neuro-developmental problems, that would be pretty much par for the course. But what it does mean is, when you have an individual case, you would not approach it by a set of fixed procedures. You would be asking yourself, what is special about this child in relation to the overall mixture that one sees.
Similarly in relation to findings, you would want to follow through. So you do not just do a set of investigations, write a report and then leave it at that. In the course of the last few days, we have noted high lead levels in several of the children, and one was thoroughly followed up locally; in the others, as far as one could see, it was left pretty much up in the air. So that would be an example where something unexpected, although actually fairly common, was found and you would expect that to lead on to whatever is thought appropriate. There are a number of unusual and in my view unsatisfactory aspects of imposing a set of pre-determined investigations on a heterogeneous group of children. That would be so irrespective of whether they are meeting criteria as previously laid down. It is the heterogeneity which is striking.
Q If, as you have told us you think these admissions were, they were research admissions, does that make the standard nature of the investigations to be carried out more explicable?
A Yes, it does, but only if you are dealing with a relatively homogenous group of disorders, so that the protocol has put to the ethics committee right at the beginning was in terms of a particular disorder, disintegrative disorder, which is uncommon, as we have heard, and as we have been referred to various research studies which clearly indicated it is an uncommon disorder. There is, though, a kind of unity to this and where I think all experienced people would recognise that it raises the possibility of a progressive neurological disorder. In the event, one does not usually find that, but the point is you have to be careful you do not miss it when it is present. So that I would see as perfectly acceptable.
In the event the cases do not meet the criteria that had been put in that protocol, so even if it was a research study having a uniform set of investigations it would seem somewhat unsatisfactory.
Q Just arising out of that, if we are looking at the cases from a clinical viewpoint, you told us when I first started asking you questions about the correlation of bowel and behavioural disorders?
Q Do you see any evidence that that was taken into account?
A No, because in relation to several of the cases I commented that there are issues in terms of the extent to which the bowel problem reflected a failure to gain continence, rather than an acquired bowel disorder. In some of the cases there was the question of the effects of PICA and so there are a range of different aspects which would be well understood by any one dealing with autism spectrum disorders. Those do not feature very much in the way the case notes are written up.
Q If this had been a series of clinical admissions, as opposed to submitting the children to a particular set, research protocol, would you have expected to see those issues?
A Oh yes, I certainly would.
Q You would?
A Yes, because that was the expressed rationale for what was being done.
Q As far as the condition of disintegrative disorder is concerned, you dealt very clearly – if I may say so – with the classification in your opinion. We know it was the express entry criteria for the study, if one goes by the ethics committee application. Is it your understanding that in fact a diagnosis of disintegrative disorder was necessary to the hypothesis that was being set out in the ethics committee application? When I say “necessary”, was there a link between the disintegrative disorder particularly, as opposed to any better language?
A Oh yes, there were two main hypotheses put forward. Both of them referred to a lot of skills which are thought to be linked, so that in that sense, yes, this was central.
Q You have told us, I think, there is only one child whose presentation with periods of regression you described as very unusual, and that was the first child, Child 2?
Q I think even with respect to him, you said that if that was a closer picture, which is why you have not criticised the lumbar puncture, but nonetheless you were not sure it actually amounted to disintegrative disorder?
Q Because it was unusual. Collectively, did these children fulfil in your view to any degree that criteria that it had apparently been set down for the ethics committee application?
A No, not at all.
Q We have looked at Professor Walker-Smith’s description of children, and at that time, of course, he was talking to Dr Pegg in the context of the ethics committee application, and he described them as children with a hopeless prognosis. If he had indeed been looking at children with true disintegrative disorder, would that description have been, albeit a rather depressing one, perhaps a legitimate one to make?
A Yes. It is a bit one-sided, but disintegrative disorders do indeed have a poor prognosis, so I would not demur from that being a reasonable description of disintegrative disorder.
Q I realise I am asking you to generalise, and it is never wholly satisfactory, but collectively these children, as you have told us, had different degrees of severity of condition and different conditions, but would you regard the description of them having a hopeless prognosis as being an appropriate one?
A No, it is manifestly wrong in that follow-up studies, not only the ones I have been involved with but really all follow-up studies, have indicated the marked heterogeneity in outcome. Autism spectrum disorders as a whole obviously do not have a good outcome, in that the number of individuals who obtain fully normal functioning by the time they are adult is very few. On the other hand, there is certainly a number who become independent, who are able to hold a job, and to describe them as having a hopeless prognosis is clearly wrong. They are functioning in society.
Q Could I ask you to turn to FTP bundle 1, page 291, in the middle of paragraph 2,
“These children suffer from a disease with a ‘hopeless prognosis’ in relation to their cerebral disintegrative disorder. They have often not had the level of investigation which we would regard as adequate for a child presenting with such a devastating condition.”
He also goes on to deal with the gastrointestinal symptoms and says they too have been under-investigated. I do not want to ask you about that but I do want to ask you about his observation that the children have not had an adequate neuro-developmental level of investigation. Obviously the amount of consultation varies enormously between these children, but, in those cases where it might be correct to say that they required further neuro-psychiatric assessment, is it your view that that was remedied in any way by the investigations that they underwent at the Royal Free?
A Unfortunately not because they were not followed through. The lead levels would be one example of that. The lack of attention to family history – and there are a couple of cases where that seems likely, possibly, to be relevant. No, it does not carry through in that sort of way, so that even when there are positive findings of that kind those do not feature very much in the feedback that has been given.
Q The ages of these children vary but the vast number of them were very young. Is there anything unusual about the fact that, with some sort of developmental problem having been recognised by the parents, we then see them going through the series of paediatricians, child psychiatrists. Is there anything unusual about not having a definitive diagnosis about them at that stage in their lives?
A No, it would be quite common – for two rather separate reasons. The first is that, early on, differential diagnosis is more difficult than it when the course is well established, so that it would be quite common for even experienced clinicians in this area to express uncertainty. We saw this in the report, for example, from Dr Sheila Wallace in relation to one of the last children we discussed. The other is that parents look around for possible answers for their concerns over the terrible things that seem to be happening to their children in their development. Of course they quite naturally look for solutions, and if they do not get the answers that they feel they want or that might be helpful they search elsewhere. That is pretty normal and very understandable.
Q Those are the questions I had to ask you about those aspects of the clinical nature of the way these children were looked at, but, turning to the research issues – and I am at page 60 of your report, just so that you know – I would like you to look at FTP bundle 2 again, to remind ourselves of what was said in The Lancet paper. At page 783 is the paper which I know you are familiar with, the writing up of these children in The Lancet. On page 784, under the heading “Ethical Approval and Consent”
“Investigations were approved by the Ethical Practices Committee of the Royal Free Hospital and the NHS Trust, and parents gave informed consent.”
If you would turn back to page 783, we see the investigations which were carried out: colonoscopy, neurological and psychiatric assessments, Barium meal and follow-through, MRI, EEG, evoked potentials and lumbar punctures. I have asked you in respect of the individual children whom we have looked at, so forgive me if I am repeating myself, but overall what is your view as to whether this series of admissions was of research or clinical admissions?
A I think this was research.
Q Do you feel much doubt about it?
Q Is it standard practice for a scientific paper about a research project to make a reference to the fact of the relevant hospital having given ethics committee approval?
A Yes, indeed. That has been usual for a very long time and nowadays it would be required by most journals.
Q To an informed reader of a scientific paper, by which in this context I mean you, what would you understand it to mean in terms of the investigation referred to?
A I think it has to mean the investigations listed in the paragraph “Clinical Investigations” on page 783, which include, amongst other things, lumbar puncture, MRI and so on. So the statement in the paper is to my mind quite explicit and easily understood, which is saying those investigations were approved by the ethics committee – which would have to mean that they were specified as being performed for a research purpose and had been approved for that purpose. In fact, as we know, that is not the way it was presented.
Q May I interrupt you for a moment, before you come on to that. You have told us that it is now required practice and it was then relatively standard practice to mention ethics committee approval. What is the purpose of that? Why do scientific editors want papers to refer to that particular issue?
A Because of a concern that research that has not been undertaken in an ethical manner is unacceptable, and where that has been proven to be the case the journal would ordinarily refuse publication.
Q You were going on to look at the ethics committee position, and I will do that with you in one moment, but, before we look at the detail, could I ask you, broadly speaking, from your knowledge of the ethics committee documentation, was that representation in The Lancet paper an accurate one?
Q Does that cause you concern?
A Yes, it does, because what is being stated is clearly that the approval had been given for the investigations, whereas the application for the ethics committee had not been for that at all. The statement to the contrary had been made. These would have been done anyway. The approval is being given simply for the research use of additional specimens. That is a perfectly acceptable thing to be doing, if that is the way it works. That is to say, if this truly is routine clinical work, then getting ethics permission for additional specimens is fine. That is standard practice. But what is different here is that the claim was made that these investigations would have been undertaken anyway and the statement in the paper is that those investigations had been approved by the ethics committee, and that is not correct.
Q As far as responsibility is concerned, whose responsibility would you regard it to ensure the accuracy of representations of that kind which are made in a paper that is submitted to The Lancet?
A The prime responsibility would the first author, in that, ordinarily, unless it is specified differently, that is the person who is responsible for the correspondence with the journal. But it is the joint responsibility of all authors. It is up to the team to have sorted out how they are going to do that, but, although it is the first author who has the prime responsibility as the coordinator, it is something that all have to sign up to.
Q Obviously there are, as we have heard, differing roles in relation to any study that is written up.
Q And there are a great many people involved in this. Do you differentiate between the role of the clinicians – the senior clinicians, if you like – and those who are involved in a more minor aspect of it?
A Yes. This is a report of a clinical series and therefore the consultants who were responsible for care would be the key people. Of course they are also the people who are named in relation to the application to the ethics committee, so that, whether you are viewing it one way or the other, it still lands up the same way.
Q We have looked at the documentation earlier on and you have had the opportunity to see the evidence that Dr Pegg has given, but you have expressed some views even before that in your report. Is it your view that the handling of this application by the ethics committee was not wholly satisfactory?
A No, it was not wholly satisfactory, but the ethics committee can only deal with what is submitted to it. Now, as then, ethics committees cannot be involved in policing everything. They have to deal with what is sent to them and they have to assume, unless there is evidence to the contrary, that what has been submitted to them is accurate and honest.
Q Yes. You said it was not wholly satisfactory. Could you just make the assumption for the moment that the doctors had ethics committee approval for their study. First of all, what are the obligations of the responsible consultants in relation to the admission of children who have complied with the entry criteria, if they set out entry criteria in the application form?
A It is expected that those would be met, of course.
Q As far as the conditions that are imposed by the committee, whose obligation is it to make sure they are complied with?
A Again the people who made the application, but, in any case, if they are different – although in this case they are not – the responsible consultants.
Q You have just said to us that in the end the ethics committee has to be dependent upon the information that they are given in relation to the study.
Q I want to revert to the basics. I hope you will forgive me for repeating things, but it is important, and I want to go through it just with reference to this study. You have told us, firstly, that if a doctor wants to embark upon research he has to ask for ethics committee approval.
Q Does that apply – indeed, I asked you this in the context of the transfer factor trial as well – whether they are doing a preliminary pilot study or whether they are doing a more formalised trial with controls?
A No, it would apply to pilot studies as well as to full studies.
Q As far as invasive investigations are concerned, if an application is made to a research ethics committee with regards to children, what is the most important thing about the nature of those invasive investigations for the ethics committee to know?
A They would need to be assured that they are within the degree of risk that is acceptable in relation to whatever is being done. The various documents, the Royal College of Physicians, paediatricians and so on, talk about minimal risk, slight risk and so on, so that would always be a key feature. They would also be concerned with the scientific justification, so that if the scientific justification is very poor then the invasiveness would certainly be looked at much more critically.
Q We know in fact that the scientific evaluation, which was done independently, was done by Dr Epstein, who was a gastroenterologist at the hospital. I think that is one of the aspects which you regard as unsatisfactory from the ethics committee point of view, that there was nobody other than him looking at the science of this project. Is that correct?
A That is correct. So that I presume that he interpreted his brief in terms of the gastroenterology, but the application, of course, was as much involved with neuro-developmental disorder as with gastroenterology. Certainly there is nothing said about that being justifiable scientifically, and I do regard that as unsatisfactory, that with a complicated protocol like this you want somebody who knows about both aspects. If necessary, you get two experts. This was pretty cursory.
Q Having said that, you have told us what are the basic things that the ethics committee will look at in regard to invasive investigations on children if an application is made. If they are told that those invasive investigations are dictated by clinical need, will they embark on that process at all in relation to an assessment of risk and benefit for the procedure?
A No, I think they will have to go by what they are told. It seems to me that they had some doubts about that because of the repeated request that came as to whether this was really clinically justifiable. They asked for that, not once, but several times – and that was an appropriate thing to be doing – and, being given the unequivocal statement that this was clinically required – and the letter we looked at a few moments ago would be an example of that kind – I think they had no alternative but to accept that.
Q If they did accept it, would they then go any further into considering the nature of those investigations and whether it was appropriate?
Q I am really asking whether they are in any position to evaluate clinical need.
Q We know the ethics committee application indicated that the “procedures” were clinically indicated and that the research element applied only to the obtaining of some extra samples.
Q Do you think that accurately represented what in fact these doctors were doing?
A No, I do not.
Q Professor Rutter, I have asked you rather tediously, I am afraid, in respect of the absence of consent forms throughout these cases. You said, very fairly, when I asked you in the first case, that you had limited concern about it because it was easy, as you said, for a form to become mislaid. Given their total absence in all the sets of records which you have looked at, do you feel a greater degree of concern in relation to that matter?
A Yes, I do, because I think obtaining proper informed consent is crucially important. My answer in relation to that first case was simply to say that even in the best organised record systems things occasionally go astray, so that its failure to be located in one case is unfortunate but I would not place a lot of weight on it. For it to be absent throughout, as far as I can see, that is a different matter, because it cannot be coincidental that they are all missing. One has to assume in one way or another that the obtaining of informed consent was not given the priority that it should have been. Why, I do not know.
Q As far as the nature of consent, you told us that it is important for parents to know that it is a research project.
Q If I can just refresh your memory, you will recall that in the case of Mrs 12 we have a letter from her which actually expressly makes reference to the fact that if it did not help her child it would help other children, and you said that was the language of research. Is it that kind of matter which it is important for the parents to understand?
A Yes, it is.
Q They are being asked to make a decision about whether to submit to the trial – I do not mean submit in any pejorative sense, but to put the child into a research project or not.
Q Do they have to understand that the risks that you might take in a clinical investigation would be different in a research investigation?
A Yes, they need to understand that this, as you say, is to increase knowledge that certainly one hopes will be of benefit generally, and it is on a disorder which is being shown by your child. If such knowledge happens to provide benefits for your child, that is a plus, but that actually is not why it is being done and you must not expect that to happen.
Q Thank you. Lastly on this subject, I am going to paragraph 78 of your report, Professor Rutter. That is where you have overall given four reasons in fact why it is your view that the investigations were undertaken for research reasons. I want to ask you, if the claim is made that these investigations were undertaken solely on clinical grounds, is it in your view a remotely sustainable contention?
A In my view it is not.
Q Would you just run through the reasons particularly, amongst the many you have given, why you say that?
A I think as you say there are many reasons why I conclude that. One would be the heterogeneity so that when you have got heterogeneous conditions you need to respond on the basis of individual variation as well as what the conditions have in common with those shown by others, so that would be one feature. The second would be the timing of it, that is to say that you do a thorough assessment and then on the basis of that thorough assessment you decide what investigations are needed and in this instance firstly the assessments were far from systematic and thorough and they were often preceded by the investigations rather than the other way around. The issue of the referral being prompted by the investigative programme would be a further feature – it is of course always difficult to know precisely why patients are referred but, as indicated in discussion in individual cases, reference is made from time to time about the trial, as many of the individuals referred to it, and wanting to participate in that. That is not ordinarily the way I would put things.
The content of the referral letter sometimes made no mention of gastroenterological problems, even though it was to a department of gastroenterology. It is true that the systematic assessment by the gastroenterologists sometimes gave indications that there were gastroenterological features that have not been mentioned in the referral, so I am not as it were commenting on that but, rather, the nature of the referral which did not mention that.
Q Can I just at that point interrupt your flow for a second, Professor Rutter, to say that I made an error on Friday which I ought to put right because I referred to the fact that you had had the transcripts of the GPs’ evidence and I am told in fact by my solicitors that you were sent the main Royal Free witnesses but not the GPs. It was for that reason that I asked you this morning, what we are concerned about is what the clinicians at the Royal Free Hospital would have known at the time from the referral letters with regard to the referring presentation of the child.
Q You have already told us that they are not going to know the background which we have gone through in great detail, except where those records were included with the GP referral letters.
A Yes, indeed.
Q I interrupted you, but I think you had dealt with the referral; was there anything else?
A As I mention in my report the justification given to the ethics committee was seriously at odds with the disorders actually shown by the children so that the application was for a disintegrative disorder that was going to be assessed by a standardised assessment of deterioration, but not only was there not any kind of systematic assessment of deterioration, but none of the children clearly fall into the criteria of disintegrative disorder and, with one possible exception, they do not even come close to it. There are really so many multiple reasons and, as always in coming to clinical decisions like scientific decisions, one needs to focus on a pattern as a whole rather than any individual bit, and that is what I have tried to do here.
MS SMITH: Thank you. Sir, I am now going to turn with Professor Rutter to a totally different subject and I see it is five past one, so I wonder if this is a convenient moment to break for lunch.
THE CHAIRMAN: Yes, we will now break for lunch and resume at five minutes past two. Professor Rutter, you are still under oath and still in the middle of giving evidence so please do not discuss the case.
THE CHAIRMAN: Good afternoon to all of you. Professor Rutter, I know you have now been sitting on that chair for rather a long time. If at any stage you feel you are feeling the pressure and you would want a little break, give me a little hint of some kind and I am sure we will be very sympathetic.
A I appreciate that; I have got quite a lot of energy, I think I will be fine.
Q I hope you will continue with that energy, but if at any stage you do feel it, please give us a signal.
A Thank you.
MS SMITH: Professor Rutter, I wanted to turn in fact to a completely different topic relating to the descriptions that were given, particularly in the context of the referral of these patients in the ultimate Lancet paper in which they were written up. Before I actually turn to the paper, I want to ask you what I appreciate are some rather big questions about the fundamentals of the way in which scientific knowledge is disseminated and remembering in particular that there are lay members of the Panel. Can you just tell us in broad terms, what is the role that is played by the production of peer reviewed scientific papers in the practice of medicine and the way in which knowledge develops?
A It is a way of trying to ensure the quality of what is published so that by peer review it means simply review by the peers, i.e. the equal colleagues of the workers writing up the paper, and the usual approach is that two or three reviewers will be allocated for each paper and the job of the reviewers is to look carefully at whether the science or clinical description is of a high quality and also as to whether, as far as they can tell, it is portrayed in a straightforward and acceptable manner.
Q As far as its ultimate publication in scientific journals, is there a spectrum of quality in relation to scientific journals themselves?
A Yes, there is. It is an imperfect index of course but by and large a higher prestige is given to journals with a much more general circulation on the grounds that if you are writing to an audience that goes beyond a narrow specialty you have to be particularly careful that you are getting it right and putting it in ways which are understandable. Such journals tend to have a higher impact factor which means that there are more of their articles that are referenced by other people than would be the case in more specialised journals, so yes there is a hierarchy; it is not a perfect one but it is quite an important one.
Q We have asked Dr Horton this question, but obviously it is a bit difficult for him to say since he is the editor, or to be taken as giving an independent view, but the reputation of The Lancet in this country, can you just tell us what it is?
A It is high. It is a high impact journal as measured by any of the usual indices, it is a journal for a general medical audience so it has the sort of requirements that I have just put forward, and it is generally well-regarded.
Q We have heard that some doctors do not do any research medicine at all, but amongst those who do do research medicine, is it important not only to the development of science but the development of their own personal reputation, the scientific papers that they submit and which are ultimately published?
A Certainly, for anybody who is in an academic position publishing good papers in good journals is very much what they are judged by.
Q As far as the actual writing up of a research study is concerned, we know about the one in The Lancet and we are going to look at that in a moment, but I have referred you to numerous bits of scientific literature when you were talking generally and when you first began to give your evidence, and they all follow roughly a certain format of describing what scientists are going to do and then going through the investigations and reaching conclusions as a result of it. Is that the basic way in which scientific knowledge is added to?
A Yes. The general rule throughout the whole of science is that although one looks carefully at the quality of any individual article, the value has to be judged by the extent to which other people are able to find the same thing, using roughly comparable methods. That is a key feature.
Q Following on from that, as how important does the scientific community regard the integrity and the accuracy of papers?
A Very highly. Science that cannot be relied upon because it is inaccurate, biased or distorted fails science and so the integrity of science is taken very seriously by, I would have thought, the whole community. Applying that of course is not an easy matter but the need to do so would certainly be universally accepted.
Q Ultimately, what does the integrity of a scientific paper rely upon? Upon what is it founded?
A It is founded upon doing good science; that is to say what is being done, whether it is clinical or whether it is laboratory studies, is done well within the general canons that are applied to that; whether it is honestly and straightforwardly reported and whether the limitations are adequately expressed and whether alternative views are put forward. Science is always concerned with probabilities, there is almost nothing in science that is certain and, therefore, looking at alternatives is what it has to be all about. Obviously, any writer of a scientific paper will want to emphasise the positive in what they have done, that is regarded as entirely proper, but they also need to be sensitive to the fact that there are other views and have those been properly taken into account.
Q Can you tell us: how important is the description of what I think is called the patient population, in other words the actual subjects that you are investigating. How important is the detail that is provided in relation to those, to those trying to make judgments about the scientific paper and how it helps science?
A Oh, absolutely crucial, because unless that is done well, you have no idea to what group of patients the findings refer. Can I refer back to an earlier era that involved me more personally, at the time I first worked in the United States in 1961. In the United States in psychiatry virtually everybody was diagnosed as having schizophrenia. That was quite different to the rest of the world. It meant that papers in the United States were unusable outside because everybody had the same diagnosis. That completely changed with the introduction, as it were, of rules for diagnosis. That has had its downside, with some of the rigidities that go with it, but it has been a plus in the recognition that both clinicians and researchers have to know as best they can to whom these findings refer, what sort of people, what sort of problems in what sort of circumstances.
Q That deals with the circumstances of the patient. The circumstances in which they came to be investigated by the doctors who are writing up the paper – how important is that?
A Oh, very much so. One of the major problems in research, looking back in history, not referring to the particular issues concerned here, is where conclusions have been drawn from samples that are very biased in terms of the particular way in which groups have been accumulated. So there is a general recognition that you do have to know about that, because it is so easy inadvertently to land up with samples, groups of patients, who are unrepresentative because they have come in a particular kind of way.
Q Given that background, could I just turn again to The Lancet paper, please, which is in your FTP2 at page 783. I am going to first of all go to the summary, where it says “Background”. We see the words:
“We investigated a consecutive series of children with chronic enterocolitis and regressive developmental disorder.”
Then going to “Patients and methods”, which is in the right-hand column:
“12 children, consecutively referred to the department of paediatric gastroenterology with a history of a pervasive developmental disorder with loss of acquired skills and intestinal symptoms”
which are then set out –
“(diarrhoea, abdominal pain, bloating and food intolerance), were investigated. All children were admitted to the ward for 1 week, accompanied by their parents.”
Going on, if we could, I am looking for all the descriptions of the way in which the children came in. Page 785, under “Discussion”.
“We describe a pattern of colitis and ileal-lymphoid-nodular hyperplasia in children with developmental disorders. Intestinal and behavioural pathologies may have occurred together by chance, reflecting a selection bias in a self-referred group; however, the uniformity of the intestinal pathological changes and the fact that previous studies have found intestinal dysfunction in children with autistic-spectrum disorders, suggests the connection is real and reflects a unique disease process.”
I want to ask you this first of all as a generality, Professor Rutter. Do you think the description which is given in the “Patients and methods” section on page 783 is one which properly describes the way in which these children came to be investigated at the Royal Free, with reference to the circumstances that we have been looking at on the individual children?
A Well, not really. To begin with, a consecutive series has to mean in relation to something specific, and the difficulty, I think, one has as a reader of this paper is to know what it is a consecutive series of. So it says of children with chronic entero-colitis, but of course that is not true, in that they (inaudible due to non-functioning microphone) children with intestinal symptoms.
Q You are cracking up a bit on your microphone. I think you are a little bit too close.
A Sorry. The chronic enterocolitis is, as it were, an inference based on findings. The series has to be in terms of what was present at the time of referral, so it is the referral in relation to symptoms referable to the gastrointestinal tract. We know from the individual cases that they are actually quite varied, so that it involves a mixture of constipation, a failure to gain bowel control, diarrhoea – a great mixture. I am not a gastroenterologist, so I cannot comment on the meaning of the heterogeneity but, as a reader, as it were, I am left uncertain as to what is meant by consecutive series on that side. There is then the statement that it is the combination of it and regressive developmental disorder but actually the referrals do not deal with regression, other than in some of the cases. It is therefore not a consecutive series of regression and, indeed, they have a developmental disorder, but one of the children seems to have been included in this series on the basis of epilepsy rather than any other kind of developmental disorder. One is left uncertain as to quite what that means. Even if, as it were, one assumes that there are no biases in the way that cases are collected, there is still a problem with knowing quite what it means. There is then the additional issue of the matter that was discussed in relation to several cases – that the prompting of the referral has come sometimes because the parents have been concerned about MMR and were involved in litigation. The issue of how far the litigation played a role is a separate sort of issue, but certainly it was in the minds of the parents at that time and that some of the parents also refer to wishing to be involved in a clinical trial, which would ordinarily mean a piece of research. So no, I do not find that very helpful, I have to say.
Q Just looking at those two aspects you refer first of all to the description of what the actual presenting picture was in these children?
Q And, of course, we have gone to some cases where at least the referral letter does not refer to the presence of gastrointestinal symptoms.
Q Do you think that that description makes that fact clear – the description that is used in The Lancet paper?
Q And I have asked you – when we have been through the referral circumstances of the child, where it is relevant I have asked you whether the method of referral was a usual or an unusual one. I deliberately did not ask you to go any further than that on the individual basis of these children. You said, in relation to those that I have asked you, that it was a very unusual method of referral. Whether or not that is acceptable on an individual basis, does this description make clear in your view that unusual method of referral in respect of some of these children?
A No, it does not.
Q And do you think it should have done?
A Yes, I do.
Q You have also mentioned as another issue the fact, as we know, that many of these referral letters indicate that the parents have a view, to which they are perfectly entitled, of course, that MMR is implicated in the condition that their child suffers from, and they are being specifically referred to the Royal Free for the investigation of that possible association?
Q It would appear – and I do not think there will be any argument about it – that the doctors were investigating that issue to some degree at least. In those circumstances should that have been conveyed, given the conclusions that are set out in the paper, in relation to both the gastrointestinal behavioural disorder link and also the reporting of the temporal association with MMR?
A Yes. The difficulty is that it is described as a consecutive series without any thing about MMR coming in, although it is clear that at least in the parents’ minds and in the research protocol outline, MMR plays a key role. So it is not a straightforward way of describing it. No. I do find that problematic, I have to say.
Q When I asked you about the individual examples, and you said, “Well, these were not unusual referrals”, can you tell us just in brief terms what a “usual referral” means? What would you expect of the normal referral of a child with symptoms relevant to that department? How do they get to that department in a specialist hospital?
A The referrals ordinarily can come either from a general practitioner or from another hospital colleague, and the referral would usually present a problem, asking about the diagnosis, or it might quite properly ask about the combination of two patterns, so I do not find anything unusual in that being the case. What is unusual is that it does not for the most part focus on what the clinical issue is, and in several of the referrals, although it is to a gastroenterology department, it does not mention any gastroenterological problem. Sometimes the gastroenterologists agree that there was not any significant problem. In others they thought that there was, but it was not present in the referral. That is the thing that is unusual. You are asking the referral doctor for an opinion and that might be simply on diagnosis; it might be on a combination of patterns as to whether that had a particular meaning, or it might be leading more directly to wanting advice on a therapeutic intervention. It could be any of those, but it would be focused on the problems of a particular child. Quite often, where the referring doctor’s views are somewhat different from those of the parent, that might be made explicit – “That Mrs X and her husband are concerned about so-and-so’s developmental, are thinking that it might be. As far as I can see it does not actually fit that sort of pattern, but I would much welcome your advice on that.” That would be quite a common feature, particularly with complicated problems.
Q That is the actual referral letter from the doctor. I have asked you, and you have said, it has been unusual in those cases which we have identified, about cases where it would appear that the initial contact was from the doctors at the Royal Free, either Professor Walker-Smith or Dr Wakefield to the GP who then, in response to that, refers the child?
Q Again, you said that is unusual and I assume that there might be circumstances in which than can arise?
Q But if it does arise, would it be relevant in a paper of this kind to make that fact apparent?
A Yes, I think probably would. I am stuck with thinking of an example where that has occurred, but if you are claiming it is a consecutive series, then this departs from that in a significant way, so I guess I would expect that to be mentioned.
Q Bearing in mind what you helpfully told us generally about the important of the description of the patient population, those matters which you said you would expect to be mentioned, and which you think are concerning, are they important in the context of this paper?
Q Do you have particular reasons for saying that?
A Sorry? Do I have particular ---
Q Yes. Why is the description of the patient population important in the context of this particular paper?
A Because the conclusions are expressed as if this were – as we have said – a consecutive series of patients, so that in reading the paper, it would not enter your mind that the association might be biased by, for example, the involvement with litigation, because there is nothing there to indicate that. The weight that you attach would be influenced by that. Now whether it should be or should not be is a separate matter, but you would need to know that. Similarly in relation to other matters involved with selection, it is routine that you want to know where patients come from so that, for example, in some of the historical examples in medicine where individual clinicians have highlighted particular problems, for example the damage associated with thalidomide ---
Q You are too close to the microphone! You are breaking up.
A Sorry. The problems associated with thalidomide, or the problems associated with rubella, both of which we now know had devastating effects, the original reports needed to make clear, as it were, how this came their way.
A And then there was a question of needing to follow up by a series of cases, as it were, that did not have that particular bias in the way they had come. Not that there is anything wrong with the bias. In one case it is to an ophthalmologist, and that was relevant in what was picked up, although the disorders were much more widespread. So yes, this sort of accuracy in how patients come into the group that you are reporting on is a critical matter throughout the whole of medicine.
Q Thank you. Could you excuse me for one moment. (After a pause) Just one other matter, but also relevant to The Lancet, Professor Rutter, how much resemblance, in your view, did the study that is written up in The Lancet bear to the original ethics application? I want to ask you this particularly in relation to the change from “disintegrative disorder” in the ethics committee application to what is now called “pervasive developmental disorder”. Pervasive developmental disorder covers what?
A It would be a term that nowadays would usually be referred to as “autism spectrum disorders”; in other words, it is quite a wide range of problems, most of which do not involve anything you would describe as disintegration, and vary from mild to severe, with a whole mixture in the middle. The change is undoubtedly a highly significant one from a scientific point of view. It is also a highly significant change in terms of the justification for the more invasive investigations that were done.
Q In that context, we know that there was a draft of the paper which referred to a “regressive behaviour disorder” and Dr Berelowitz took issue with that. In FTP 2 at page 504 is a letter dated 5 August 1997 to Professor Walker-Smith, but, if you turn on to page 505, it is copied in to Dr Wakefield and Professor Murch, amongst others. It says:
“Lastly, I have had some second thoughts about our title. I think that we should call this condition a ‘developmental disorder’ rather than a regressive behavioural disorder. This title is technically more correct, and will cut off in advance one potential area of criticism.”
As we know, that was indeed reflected in the ultimate title that was published, “Pervasive Developmental Disorder”. From a neuro-psychiatric point of view, would you agree with Dr Berelowitz, in fact, that, given the condition of these children, it would be unwise to call it a regressive developmental disorder.
A Yes, I do agree with that. I think that the title, as amended, was better and, unfortunately, was out of synchrony with what had been put to the ethics committee.
Q That is all I wish to ask you about that. Thank you very much. I am now going to turn to a completely different subject, which involves issues relating to Dr Wakefield’s involvement in the MMR litigation. There are two aspects of that: first, the fact of his involvement and the advice that he was giving to the solicitors in that litigation as an expert, and, secondly, the funding. Having considered the nature and degree of his involvement as an expert, I then want to explore with you issues which may arise in relation to a potential conflict of interest. I hope you will bear with me, Professor Rutter, but it is a long time since both you and the Panel have looked at the documentation and I am going to have to take you back to the basic documentation relating to the Legal Aid Board, particularly to remind you of the timeline. The first reference to Dr Wakefield’s involvement as an expert is in FTP 1 at page 90, a newsletter from Dawbarns, Solicitors, to possible litigants in relation to the MMR and MR vaccine litigation. It is dated February 1996, which you will find on the second page, page 91, at the top of the page.
A Yes, I see that.
Q Under the heading “Dr Andrew Wakefield” it reads:
“As you may have read in the Sunday Times of December 1995 Dr Andrew Wakefield has published some very disturbing material which indicates a clear link between the measles element of the vaccine and Crohn’s disease”
which it then identifies.
“He has deeply depressing views about the effects of vaccines on the nation’s children. He is also anxious to arrange for tests to be carried out on any children vaccinated with the MR or MMR vaccine who are showing symptoms of possible Crohn’s disease. The following are signs to look for. If your child has suffered some or all of these symptoms could you please contact us and it may be appropriate to put you in touch with Dr Wakefield.”
They then set out a series of gastrointestinal symptoms. That is, as I say, the first letter. If we go on to page 101, this is a letter that was sent by Dawbarns, Solicitors, to a lady who at that time was in charge of funding at the Legal Aid Board. In the third paragraph of the letter, dated 21 May 1996, the solicitors say,
“There does seem at last to be an increasing acknowledgement among the medical profession that these vaccines actually are causing damage. Dr Andrew Wakefield (who has been mentioned to you in Counsel’s Opinion and by me several times) is actually quite astonished at the evidence that he is uncovering and feels that objective tests may well establish conclusively that the measles vaccine is causing a wide range of these injuries.
I am waiting for his protocol proposals but a significant part of the costing will be in a proposal for testing a significant number of children to try to establish the link. I should emphasise that the hope is that the tests will be so positive that they will actually find the measles vaccine virus (as opposed to the wild type) in the areas of inflammation in the children. If that can be done it must be rather like catching a burglar red handed!”
It then goes on with the fact that they are continuing with their researches and the time constraints on the solicitors.
“There are experts that we would like to continue to correspond with both in this country and in the USA and we would also like to start to see as many as we can in this country. We have already had several constructive meetings with Dr Wakefield but there are other experts that we would like to involve covering a variety of different fields ...”
and that they are making requests as to the funding. Then we come on to page 103. This is June 1996, so two months prior to the date of the ethics committee application in August, and again it is a letter from the solicitors to the Legal Aid Board. The only paragraph you need to be concerned with is the second paragraph:
“To give you further information on the costing proposals I enclose a copy of a draft (not entirely finished yet) of Dr Wakefield’s proposed protocol for the study and his costing proposals.”
Attached to that, at page 104, was the proposed clinical and scientific study. I am not going to take you through all the detail of that because I think it would probably be accepted by all that it is almost identical in wording to the clinical and scientific study that was exhibited to the ethics committee application that we looked at.
A Yes. I agree.
Q Indeed, as I say, quoting your own chapter at page 108 in exactly the same form. The responsibilities of the doctor are the same. At page 113 are the investigations that it was intended to carry out, including the same investigations, albeit the explanations are a little more detailed than in the ethics committee application. At page 115, going on to a paragraph we have already looked at, are the practical issues relating to the protocol for the children. We see the plan as to the referrals to be coordinated on page 116. Are you with me?
A Yes, I am with you.
Q You have subsequently been taken to the child who was the first child admitted for investigation, who was admitted on 21 July 1996; in other words, after the protocol went to the Legal Aid Board. The next document is at page 121, which is the proposed protocol and costing proposals for testing a selected number of children. Perhaps we can have a look at that document, just to remind you, Professor Rutter, and the Panel.
“A protocol giving the detailed technical specification is attached.”
That is what we have just looked at.
“The objective is to seek evidence which will be acceptable in a court of law of the causative connection between either the mumps, measles and rubella vaccine or the measles/rubella vaccine and certain conditions which have been reported with considerable frequency by families of children who are seeking compensation.
It is hoped that using the testing protocol attached it will be possible to establish a causal link between the administration of the vaccines and the conditions outlined in this proposed protocol and costing proposal. The standard of proof aimed for will be at least the balance of probabilities but it is hoped that in many respects the level of proof will reach certainty or near certainty.
Briefly these conditions consist of: Crohn’s disease … children suffering from symptoms akin to autism (here described as disintegrative disorder) coupled with inflammatory bowel disease.”
At the bottom of the page 121, we see the heading “Costings” and there are the setting up costs. Then, on page 122 at paragraph 3:
“… children with enteritis/disintegrative disorder form part of a new syndrome. Nonetheless the evidence is undeniably in favour of a specific vaccine induced pathology. Many more tests have to be carried out for investigating these conditions and accordingly the costs of investigation are considerably higher.
The children will come into the Paediatric Gastroenterology Ward under the care of Professor Walker-Smith. Costs for four nights stay for the child and the parent …” –
and the figures are given.
“The magnetic resonance imaging … will cost …” –
and the figures are given –
“and the combination of molecular, immunohistochemical, vitamin B12 and complement studies will cost …” –
and the figures are given. There is also the envisaging of medical reports from the individual experts in those disciplines. If we go on to page 123, we see the total figures, and then “Conclusion”:
“It is not of course possible to anticipate the conclusions that will be reached but the indicators are that it should be possible to establish a clear causative link between the vaccines and the two sets of conditions mentioned above.”
Going on in the chronology, at page 147 of FTP 1 is another letter, in this case to [Mother 12], the mother of Child 12, from the solicitors, Dawbarns, stating in the fourth paragraph down:
“We are also in touch with other experts and together they are hoping to establish a link between the vaccine, inflammatory bowel disease and autism. There is a clear cut biological mechanism for linking the two conditions. I suggest it might be worth your while to contact Dr Wakefield. If you would like me to do so I will be happy to make the introduction for you. May I have permission to send him a copy of the statement that I have prepared for [Child 12]?”
I should have said that that letter was dated 14 August 1996 and, as I say, Child 1 had been admitted for investigations on 21 July 1996.
At page 183, there is the Legal Aid Board, Authority to do Contract Work. This is the Legal Aid Board’s authority in contract with the solicitors. We see at number 2:
“To facilitate the setting up of the clinical and scientific study proposed by Dr AJ Wakefield in respect of 10 assisted persons at a maximum cost of ₤55,000 and to cover the work necessary by the solicitors in so doing …”
At page 189 there is a newsletter, this time September 1996. If we look at page 190, under “Pilot Study”:
“If we can prove a clear link between the vaccines and autism/inflammatory bowel disease this will be exceedingly useful not only for cases involving those conditions, but also for other types of damage such as epilepsy.
To obtain the evidence to do this, we will be running a pilot study. Around 10 children with symptoms which are closely linked to the vaccine will be extensively tested by a team of doctors headed by Dr Wakefield at the Royal Free Hospital in London.
We will be selecting children to take part in the study from details and medical notes we already have. The investigations will involve a whole battery of tests, to be carried out by a number of leading experts in their fields. We will of course be liaising closely with the families concerned; and the doctors will be giving very full details of what will be involved.”
At page 237 we see a letter from Dr Wakefield to the solicitor.
“We are now in a position to start work on this study on behalf of affected children identified by yourselves and approved by the Legal Aid Board. I would be grateful if the initial sum … could be transferred …. for the purposes of initiating and carrying out the initial phase of this analysis. I will write to you once again when the remainder of the funding is required. Naturally, we will keep you appraised of progress and let you have the results and reports as soon as they are complete.”
Lastly, at page 317 there is another letter from the solicitors to the Legal Aid Board. I would like to remind you of the contents of paragraph 2.
“We have seen an absolute explosion in the number of autism cases … far and away the greatest number of cases now and it is very important to try to establish a level of proof that the autism is connected with the vaccine. Dr Wakefield has suggested that one way of producing quite convincing evidence is to do a survey of the autism cases.”
He then gives the figures. Going on to page 318, the sixth paragraph down:
“It very much appears that autism is associated with the triple MMR vaccine. It is not showing at all in any of our MR cases (though the reason may be that children vaccinated with that vaccine are older).”
“I would like to try to establish that there is a fairly consistent time link between the administration of the vaccine (MMR) and the onset of autistic features. To achieve this we have prepared a survey questionnaire. This has been approved by Dr Wakefield. The aim is to send it out to all … families ….”
“We would then collate the data and in particular we would be looking very closely at the date of onset of the beginning of the autistic condition.”
It sets out the details. At the bottom of the page:
“Dr Wakefield feels that if we can show a clear time link between the vaccination and the onset of symptoms we should be able to dispose of the suggestion that it is simply a chance encounter.”
Then on to page 319, it sets out the solicitors’ costs in relation to the questionnaire and in the third paragraph down, after analysis and collation of the report by the lawyers plus discussions with Dr Wakefield and then details as to Dr Wakefield’s fees.
The last thing I want to remind the Panel and you of, Professor Rutter, before I ask you the questions is you will know from your reading that around that time concerns were also being raised by Professor Zuckerman, the Dean at the Royal Free, to the British medical Association, that they had been consulted. I want to ask you this, Professor Zuckerman has told us that he had not previously encountered the provision of funds for research by the Legal Aid Board. Have you, in your experience of research science, ever come across that as a source?
A No, I have not.
Q If I can just remind you of the letters between Professor Zuckerman and Dr Wakefield, the first is in FTP2 at page 393. This is a letter about two separate issues and you need not trouble yourself with the first one, but the last paragraph on page 393, this is Dr Wakefield to Professor Zuckerman, dated 10 March 1997.
“You mentioned a conflict of interest when we spoke. This is something which has exercised my mind greatly in the interim. I feel I must go on record as stating that I do not see how any conflict of interest exists. It is, as I am sure you would agree, our joint and several responsibility as members of the medical profession to use our training and expertise appropriately, In the context of the current measles vaccine safety/consequences debate, I am providing independent expert guidance based on facts available to me. I do this in common with colleagues worldwide. The fair legal assessment of potential claims relies on high-calibre expert advice. The GMC and the Royal Colleges have long accepted this premise.
In the particular circumstances with which I am dealing, there is, I believe, an even higher moral obligation to act as an expert adviser. We are faced with a situation where the most vulnerable category of patients, i.e. children, may be put at risk. It is right and proper therefore to review the facts, assess them and offer guidance.”
The next letter is at 397 and this is Professor Zuckerman’s reply to Dr Wakefield. This is dated 13 March 1997, the last paragraph:
“I do not think that there is any conflict between duty of care to patients or the provision of independent expert advice to lawyers. However, it is a different matter when lawyers fund a particular piece of research where a specific action is contemplated. This surely suggests that some preliminary legal discussions have taken place and that a specific action is contemplated. If so, then the interpretation must surely be that a conflict of interest may well exist. The School must, therefore, seek expert advice, but in the meantime you should know of my concern.”
Lastly, page 401 is a letter back from Dr Wakefield to Professor Zuckerman of 24 March 1997.
“Further to our exchanges regarding the investigation of children with enterocolitis and autism, and especially the involvement of Dawbarns … and the Legal Aid Board, please find enclosed all documentation relating to this matter. This includes a letter to Dawbarns from the Legal Aid Board specifying the conditions for making the award. These conditions were based upon the enclosed protocol which has been approved by the ethics committee … I got the impression from Roy [Professor Pounder] that you were concerned that we were being contracted to provide a specific answer – that is, that measles vaccine or the MMR vaccine was the cause of this disease. That is absolutely not the case. We are being funded to conduct a piece of scientific research to establish or refute the link between MMR vaccine and the disease. There are absolutely no preconditions concerning the outcome. If this were the case, you may rest assured I would never have been involved in the first instance. The science must lead and everything else follows. As with medical experts opinion elsewhere, I am being asked to provide my opinion, whether that opinion is positive or negative. It is on this basis and only on this basis that I have agreed to assist in this matter. I hope that this issue can be resolved as quickly as possible and my group are working to achieve this end.”
I remind you that that letter in fact has a handwritten note from Professor Zuckerman. “This does confirm my worst fears” and as you may be aware the money was ultimately refused by the medical school and paid into the special trustees account at the hospital NHS trust.
There is one other letter which is at page 420. It is a transcript of handwritten notes of a meeting with Dr Wakefield and the solicitors and a representative from the Legal Aid Board. If we look at the second paragraph down:
“Dr Wakefield was enthusiastic about his investigation. He is a gastroenterologist and didn’t enter these investigations on a crusade and in fact gas been completely convinced by his subsequent studies and tests of a link between the vaccine and the gastroenterological effects showing as various bowel disorders. He referred to them as indeterminate colitis …”
He goes through the detail of those.
“He mentioned that they had also managed to identify the measles virus in the affected tissues …”
Going on to the next paragraph:
“All three were keen to stress that they had to get the science right first before launching into new steps. They feel confident that they can now show a temporal association at work at least.”
I apologise to both you and the Panel for taking you through that long preamble before the questions, Professor Rutter, but I think no one can remember the details of these documents unless they are taken to them. With that background I want to ask you first of all this, and I am at paragraph 61 in your report if it assists you.
In 1996 if you were a research doctor formulating a research project and subsequently when you submit it for publication, would any possible conflict of interest – and I underline we are in 1996 – would it be a subject to which you would have given consideration?
A Yes, it would be routine to have done so and it is in terms not of the individual investigators actual conflict of interest as they think but of perceptions. There are umpteen documents on ethical issues and they all make clear that it is perceived conflicts which are important, and that in 1996 as well as now that would have to be seen as potentially relevant in the way that people would read and interpret the findings of a paper. So, yes, it would have to be made explicit.
Q I know this is a huge subject but you say it would be something in 1996 that should have been given consideration to. Just in broad terms first, what is its relevance to scientific research, why is it regarded as something that should be considered and declared if there is a possible perception?
A Because there is actually a vet substantial research literature which shows that everybody, that is all of us as well as the rest of the world outside, whether we like it or not is influenced in our judgments by what we think might be the case, so if there is a reason for favouring one interpretation than another you have to assume that although you may not be conscious of it, it will do so. That is the reason why these things have to be made transparent, made overt, so that people can judge for themselves is the science of such high quality that really the perceived possible conflict of interest can be cast aside because the evidence is so strong or is this open to a variety of interpretations where the fact that one answer will lead to one sort of outcome and another to a different sort of outcome may influence judgment.
Q Is that in your view, in fact, however brilliant you may be as a scientist, a judgement that a researcher is necessarily able to make for himself?
A No, in fact the rules are perfectly clear-cut that they cannot so that, for example, in scientific committees deciding on funding of projects the rule is that if you are in any way connected you have to withdraw while a decision is being made, and it has been made explicit lots of times, you cannot decide that for yourself, you cannot say that is another part of the university and actually I know nothing about it. You have to assume that if you are from the same organisation you will be conflicted and it is up to the chairman of the committee to decide whether to overrule that as it were and say “I am glad that you mentioned it, I note the possible conflict but I actually want you here because of whatever the reason is” so the individual investigator cannot take that decision; all of us are bound to be influenced a bit, whether we recognise it or not, by our own position.
Q Given the background that I have just run you quickly through, if we can deal first of all with the application to the ethics committee at the time that it was submitted, so that is in September 1996, what is your view as to whether or not Dr Wakefield should have declared his involvement in the litigation?
A I think he should have. What comes out of the documents that you have just carefully taken us through is that it is not simply that Dr Wakefield was involved in litigation as an expert. Like everyone else I see nothing wrong in that in principle; most experienced researchers do serve as experts from time to time. What is relevant is that, firstly, the way the cases are collected is influenced by that so that the news sheet or letter, I have forgotten which it is now, from the solicitors makes clear that the pilot study of ten cases is to be decided on cases in which there is a link with MMR so that unless the ten cases are entirely separate from those reported in the paper, the consecutive series is neither here nor there. The solicitor’s view is that they are selected because of the MMR involvement. The other feature is that it is clear from the way things are put, particularly in what the solicitors say, and Dr Wakefield will have to give his own view as to how far they are accurately representing his opinion, that he had already made up his mind in advance of the ten cases that there was a link. Science is not involved in proving a hypothesis, science is involved in testing a hypothesis. That sounds a minor distinction but it is an absolutely fundamental one in the way that science is all about.
The issue of whether the funding was relevant to coming up with a particular answer seems to me to sort of miss the point really. Of course it is true that as an expert witness in this country you, as an expert witness, are responsible to the court, you are not responsible to whoever it is who has called you as an expert witness. The United States I have to say is different in that connection, but in this country that is quite clear. If you have already made up your mind in relation to a sample which is involved in litigation, and we know from the papers that Mrs 12 that it was very much involved at that point, then that is relevant.
The issue in relation to the use of funds brings in another issue.
Q Can I stop you just for a moment at that point? Before we go away from this, with regard to the general involvement, before we come on to the funding, you have said you think it should have been declared to the ethics committee and you have told us why; do you have any concerns, given the involvement in the litigation, in Dr Wakefield having been apparently involved, if we accept what the ethics committee application says, with the actual planning of the investigations on the children?
A Yes, because it is difficult to see how you can keep them apart.
Q Going on to the funding, if I can just ask you this question, Professor Rutter, because as you rightly identified everyone wants to be fair to Dr Wakefield and we do not know exactly what he is going to say in relation to this, but if the funding provided by the Legal Aid Board was funding for the study which is the subject of the ethics committee application, should it in your view in those circumstances have been declared?
A Yes, but I actually have a broader concern than that and that is that the application both to the Legal Aid Board and in the communication back is funding a four day stay in hospital plus the costs of the brain imaging, plus the costs of evoke potentials. If these are individuals who are being seen for clinical need, all of that is covered by the NHS so that the funds that are being requested could not be relevant if it is on clinical need because the NHS does that and as far as I know did cover the costs in relation to these cases.
Q You have said it should have been declared to the ethics committee, is the answer you have just given the reason why you say it should have been declared?
Q I want to just turn to The Lancet if I may and go to the test which is formulated by that journal in respect of conflicts of interest. That is in your FTP2 at 616. If you look on the left hand side, do you see these are notes for people writing to The Lancet, authorship and then underneath “A conflict of interest in funding”, are you with me?
A Yes, I am.
Q It says:
“The conflict of interest test is a simple one. Is there anything, e.g. a shareholding in or receipt of a grant or consultancy fees from a pharmaceutical company or a contract from a medical devices manufacturer that would embarrass you if it were to emerge after publication and you had not declared it. The editor needs to be informed and will discuss with you whether or not disclosure in the journal is necessary. All sources of funding must be disclosed as an acknowledgement in the text.”
I want to ask you this, putting yourself in the shoes of a reasonably responsible and experienced submitter to medical journals would you regard that test as triggering disclosure in relation to Dr Wakefield’s involvement in the litigation?
A Yes, I would, for the reasons I have already given.
Q Would you regard it as a matter about which a doctor should have any hesitation?
A No hesitation I would have thought.
Q As a separate question, although obviously closely related, would you regard that test as triggering disclosure in relation to the actual monies received from the Legal Aid Board in respect of the research project which is apparently the subject of a Lancet paper?
A Yes, because it says explicitly about receipt of a grant. There was a grant for a pilot study of ten cases and it was not just funding for the extra analyses to be done on the basis of the extra specimens obtained for research purposes, the grant was given to cover the admission to hospital and tests that were said to be given for clinical need alone. It seems to me impossible to see that as other than involving something that should be declared.
Q You have told us that legal aid monies are not a source of monies for research in medicine that you have come across; does the novelty of the source in your view give the author of the paper any excuse for not disclosing?
Q If you had uncertainties in your own mind – you say you would not in fact but if you did – as to the novelty of the monies and whether that did constitute a conflict of interest, what should you have done about it?
A I suppose consult with colleagues if you like, but it seems to me that the rule throughout all of this is transparency is the aim. Whether there is an actual conflict, whether there is an actual bias is neither here nor there, and that was so in that era as well as today so that in relation to the ethics committee in my own institution we had a case – I do not remember the exact year but it would have been actually before 1996 – where a researcher was in fact forced to hand back monies because of its source.
Q Just because it is an interesting example for the Panel can you tell us, without identifying any source in particular, what the problem in that case was?
A The problem was that it was an investigation of so-called cultural differences in intelligence that was funded by a racist organisation.
Q And the ethics committee were informed?
A No, they were not, as it happens.
Q They found out!
A They found out later.
Q And insisted on the moneys being returned?
MS SMITH: Sir, I have one other topic to cover with Professor Rutter. I do not know whether you would regard that as an appropriate moment to have a short break?
THE CHAIRMAN: Yes, I think it probably would be. We will now take a short break again, Professor Rutter, and we will resume at twenty to four. Once again my usual warning and a reminder that you are still under oath. Please do not discuss the case.
THE WITNESS: Yes, indeed.
THE CHAIRMAN: Let us resume at twenty to four.
(The Panel adjourned for a short time)
THE CHAIRMAN: Ms Smith?
MS SMITH: Thank you, sir. Professor Rutter, just before we leave this subject I just wanted to pick up one thing you said with one other document. When I was asking you generally about the possibilities of the conflicts of interest you said that you could not say, “Of course”, which is correct, but what the solicitor said reflected Dr Wakefield’s view, but it did rather appear you said as though he had made up his mind. I just want to take you to one document which I did not refer to, which is in FTP1. This is a letter that was produced ---
THE CHAIRMAN: What page, please?
MS SMITH: Sorry. FTP1, page 193. This is a letter which was written, produced, by Dr Salisbury from the Department of Health and it is a letter written to Dr Calman, who was the Chief Medical Officer at that time directly from Dr Wakefield, its relevance being its date, which is September 1996, so at a time with which you are concerned. It is a lengthy letter. I am not going to read it all, but you will see from the first paragraph what it is about.
“I am writing to you in order to express formally, my anxieties over your intention to re-vaccinate all pre-school children prior to school entry. I will not go over the history of our exchanges on this subject; this will emerge at the appropriate time.”
Then he sets out the science on which he is relying, and some significant criticisms of the government’s experts on this issue. Can we go on to the end at page 196, at the bottom of the page:
“It is my concern that the expert advice that you have received has been deficient, and far from independent. If and when the dam bursts it will be you and your department that is standing in the way. We, for our part, have tried to help, only to have our work denigrated and misrepresented. We went into this with our eyes open and will continue to generate peer-reviewed, published data in the true scientific spirit; there is a vast gulf between this and opinion. You may wish to ask your experts what are the longest prospective safety trials of measles vaccine, MMR, and measles re-vaccination at any time, anywhere in the world. The result may surprise you.”
And then the last words:
“Do not re-vaccinate.”
Does that bear out the impression that you were given via the newsletters as to Dr Wakefield at that time having views?
A Yes, it does. He also incidentally raises a different point, which is Dr Wakefield’s awareness that professional connections may raise perceived conflicts of interest. He is raising it in relation to the government experts at that time, but of course that has to apply equally to himself.
Q I now just want to turn on. I said I had one topic, sir, and I am afraid I have spotted another in the tea-break, but they are two short matters. The first arises directly out of the issue that we are discussing, Professor Rutter, on which you express views in your reports. That is the issue relating to the patents that Dr Wakefield had applied for at the time. In June 1997, we know that Dr Wakefield instructed patent agents in relation to the patenting of his idea as to the proposed use of transfer factor. I would like you to go, if you will, to FTP2 at page 479. This is the registration of the transfer factor patent from the Patent Office, and attached to it at 480 is a description of that patent. Can I just refer you to the relevant parts. On page 1:
“The present invention relates to a new vaccine for the elimination of MMR and measles virus and to a pharmaceutical or therapeutic composition for the treatment of IBD …; particularly Crohn’s Disease and Ulcerative Colitis and regressive behavioural disease.”
He refers to an earlier patent that he had made, which I will not take you to but which fore-ran this one and examined the use of transfer factor for inflammatory bowel disease. If we go down to line 22, we see:
“At present vaccination is used for the prophylactic prevention of measles virus and as a public health measure has proved to be generally effective.”
Then the next paragraph:
“Unfortunately as I have shown previously in the above mentioned patent application the use of this vaccine has been shown to be instrumental in development of Crohn’s Disease and others forms of IBD over the ensuing 30 to 40 years…
The Physician is therefore confronted with a difficulty at the individual level in that whereas as a public health measure measles vaccination is called for, it can have unwanted effects in those subjects who are unable to immunologically eliminate the virus so introduced.”
Then going down to line 8:
“What is needed therefore is a safer vaccine which does not give rise to these problems, and a treatment for those with existing IBD. I have now discovered a combined vaccine/therapeutic agent which is not only most probably safer to administer to neonates and others by way of vaccination, but which can also be used to treat IBD whether as a complete cure or to alleviate symptoms.”
Then going on to page 482 at line 3:
“The compositions of the present invention have the ability not only to condition the recipient to raise a specific immune response to MMR and measles virus when used as a vaccine, but also to re-establish the appropriate antiviral immune response of an immune system to persistent measles virus infection in IBD.
I have also found that regressive behavioural disorder (RBD) in children is associated with measles, mumps and rubella (MMR) vaccination.”
He then goes through the evidence in relation to that, and then goes on to 488. He set out two separate examples at the bottom of the page, line 28:
“The results of Examples 1 and 2 show anecdotally that TF [transfer factor] is an effective agent for the treatment of IBD and as a vaccine for measles virus.”
In order to investigate a consecutive series of children for a new syndrome comprising chronic enterocolitis and regressive behavioural disorder (RBD) 12 children with a mean age of 6 years … all but one of whom were male, were referred with a history of achievement of normal developmental milestones followed by loss of acquired skills …”
And going on on the next page, line 4:
“The children underwent gastroenterological, neurological and developmental assessment including review of prospective in developmental records. Under sedation, ileo-colonoscopy and biopsy, MRI, EEG, and lumbar puncture …”.
Then at line 10:
“It was found that the onset of behavioural symptoms were associated with MMR … in 8 of the 12 children and with measles infections one child … All 12 children had significant intestinal pathology ….”.
Then we go to line 19:
“Behaviourally, they all formed a heterogeneous diagnostic group … All the children exhibited features of severe developmental regression.”
At the bottom of the page:
“Accordingly a significant gastrointestinal pathology has been identified in association with behavioural regression in a selected group of previously, apparently normal children.”
The only other matter I want to take you to is at page 490 is the “Claims”, which is above the patent application.
“1. A pharmaceutical composition for the treatment of an MMR virus mediated disease comprising … transfer factor (TF)…”
And then it says how it is created.
“2. A composition according to Claim 1 adapted for use as a vaccine for the prophylaxis of measles virus.
3. A composition according to Claim 1 adapted for use as therapy for IBD and/or RBD.”
I want to ask you, in the light of the fact that that application was submitted and, indeed, registered by the Patent Office prior to the publication of The Lancet article, and in light of what it appears to be envisaging – in other words, both a treatment and a vaccine instead of MMR, what is your view as to whether the existence of that patent should have been disclosed to The Lancet?
A I think on the same sort of grounds as already discussed that it should have been because it is dealing with the same issue, admittedly from a different perspective in a way but in terms of reading the paper, the fact that a patent which includes the prophylaxis has to be seen as relevant in my view. I do not see how you could view it otherwise.
Q As far as the envisaging, at least, of an alternative vaccine to the MMR vaccine, given one of the themes, at least, of The Lancet paper which is, there may be a problem with MMR, albeit an anecdotal one at that point – is that something that you as a member of the scientific community would wish to know when reading that paper?
Q Again, I have asked you this in relation to the other matters, Professor Rutter. Are you critical of the omission of that declaration?
A Yes, I am because I think it does raise a perceived conflict of interest, if you like, in exactly the same way as Dr Wakefield was worrying about in terms of government experts. They may or may not have influenced their views, and this may or may not have influenced his views, but the point is that unless one knows that you have to worry. The rule is that you declare whatever the relevant interest is. The problem is not on conflicts. All of us have conflicts of various kinds through our employment, through our funding and so on. The problem is not making those known to other people.
Q In relation to that, because you have raised it as being a significant issue, can I just take you back to that letter for a moment. It is in FTP1, page 193, at the bottom paragraph of that page:
“In the future you may have cause to reflect on the ‘independence’ of your appointed experts.”
Then he refers to the two individuals particularly and says:
“… [they] cannot be considered independent. If I and my colleagues are right, then they are wrong. Their scientific and professional standing and credibility is inextricably linked to the success of measles vaccination. You may also wish to consider the value of their advice with respect to the depth of their knowledge about measles virus.”
Leaving aside that second matter, about depth of knowledge, is it that criticism that you are referring to when you say, as I understand it, in effect what is sauce for the goose is sauce for the gander?
A Yes, it is. Exactly.
Q As far as the patent application is concerned, Professor Rutter, of course The Lancet paper is suggesting at least an association between MMR and behavioural disorders, and expressly refers to that. Is that a matter directly relevant to the nature of the patent that had been registered by Dr Wakefield?
A I am not sure I quite understand the question.
MR COONAN: I am sorry just to interrupt. My learned friend – not a criticism – prefaced that on a directly leading basis, that this paper demonstrated an association as she set out. I think we had better look at the paper.
MS SMITH: Yes. I am quite happy to take Mr Coonan to the line. I did not say “demonstrated”; I said “suggested”. I will take Professor Rutter to the line I am referring to.
MR COONAN: There are dangers without actually looking at the precise passage.
MS SMITH: Let us look at the passage, Professor Rutter. It is at 482. I am sorry – excuse me. The point we are trying to make is a slightly different one. The Lancet
paper does not suggest that there is an express association. It simply gives the evidence. It gives the observation that there was anecdotal evidence from the parents, and that a causal connection had not at that point been associated. If we look at page 482, Professor Rutter, which is indeed the patent, line 9, Dr Wakefield is saying:
“I have also found that regressive behavioural disorder (RBD) in children is associated with measles, mumps and rubella (MMR) vaccination.”
In contrast to what is said in The Lancet article, have you any observations in relation to what he is there saying?
A He is making a clear claim of an association. It is not just simply parents have suggested; it is his statement that there is an association.
A The implication, as is clear from what follows, is that is causal although he goes on to indicate it is not clear which element, as it were, provides the causal effect.
Q And is that fact, that view that he expresses in the patent application, relevant to your views that this was at least a potential conflict of interest?
Q Which should have been referred to?
A Yes, it is.
Q Thank you. Now I want to turn on to one last matter with you, Professor Rutter. It is at paragraph 79 of your report, where you deal with your views on the Mind video. Have you had the opportunity to look at and listen to the video of a lecture which Dr Wakefield gave to the Mind Institute in 1999, when he gave an explanation as to the obtaining of blood from normal children for controls?
A Yes. I have not seen the whole lecture but I have seen the segment that deals with that and the surrounding text.
Q Perhaps I could ask you, first of all, this as a general question. Assume that the incident occurred as it is recounted in that video. This was blood from normal children being used for control purposes; in other words, as comparators.
Q What does that mean as far as whether this blood was being used for research or clinical reasons?
A It has to mean that it is involved with research and the context of the story is in terms of a case control study.
Q What does that mean?
A That is research.
Q Can blood ever be taken from normal volunteering patients without ethics committee approval?
Q You have given a categorical answer. If we add in the word “child” patients and ask the same question, is the answer the same?
Q You raise a number of concerns with regard to the story that has been told and I would like to go through those with you. If it is indeed the case that blood was taken from normal children and that the venue was a birthday party, as Dr Wakefield says it was, do you regard that as a suitable venue?
A No, I think it clearly is not, in that it is a situation with implicit pressures. Whether that is intended or not is beside the point. If children are invited along and that is the sort of expectation, it is true they are not forced to do it but, on the other hand, the social context provides pressures. No, I would see that as an inappropriate context for obtaining blood.
Q When you say “implicit pressures” can you explain what you mean. You mean pressures on whom?
A On the child. Children are influenced very much – as, to an extent, so are adults – by group pressures, so if everybody else is going along with this, and that is what you are expected to do, you can refuse, you can stand out, but, on the other hand, there are implicit pressures saying “It’s okay, everybody else is doing it, surely you’re likely to want to do so too.”
Q If, as would appear to be the case – and we are in 1999 – payment of ₤5 was given to young children, do you regard that as appropriate or acceptable?
A No. The British Paediatric Association guidelines are absolutely explicit: there cannot be inducement for children to participate in research. ₤5 of course is not a large sum of money, even at that time, but the rules are that you can recompense people for the time involved but the time involved here is absolutely trivial and one would have to see this as a way of encouraging the child to give blood (that is, it is an inducement) and the guidelines are quite explicit that that is not allowed.
Q Obviously the guidelines are highly relevant to that but, from your position as a consultant child psychiatrist and a member of an ethics committee, do you yourself think there are significant ethical implications about giving money to a child in exchange for giving blood at a birthday party?
A Yes. It would not have been passed by my ethics committee.
Q If the episode took place in the face of children’s distress, as we have heard – namely, children in tears and children being sick – what do you think of that?
A That is not really an appropriate source of amusement. Young children are sensitive creatures and the fact that two fainted and one vomited over the mother is a clear indication that at least at that moment they were distressed by it. So I found that upsetting.
Q All in all, Professor Rutter, as I say, assuming that this incident took place as it is recounted that it did, what is your view of a doctor lending himself to this particular episode?
A As you say, if it is true, and all I have is the video and the transcript of it – then it does seem to suggest a disregard of the sensitivity to young children and disregard of the ethical expectations in dealing with children who are participating in a piece of research.
Q Turning perhaps to the other aspect of it, what is your view of a doctor telling this apparently as a funny story in the context of a scientific lecture?
A I think that is not acceptable.
MS SMITH: Thank you very much, Professor Rutter.
That concludes my examination-in-chief of this expert, sir.
THE CHAIRMAN: Thank you very much indeed, Ms Smith.
Professor Rutter, this was the examination-in-chief. There would now be cross-examination by the representative counsel of the three doctors who are facing this inquiry if they wish to cross-examine you on any of the issues that have been raised. I am looking at the time. It is ten-past four and I do not believe, after having spent the whole day sitting on that chair giving examination-in-chief, it is the right time to start with your cross-examination. Therefore, we will now adjourn and resume at 9.30 tomorrow morning.
Mr Coonan and Mr Hopkins, would you be able to give me some indication of the order in which you are going to cross-examine?
MR COONAN: Sir, I shall probably go first. As you know, I am making arrangements for the transcript today to be emailed to the USA. If everything works according to plan – and I must say the shorthand writers have been extremely helpful – I do not think there is going to be a problem.
THE CHAIRMAN: That is precisely the reason I asked that question because I anticipated there may be some difficulties for you to get the instructions.
MR COONAN: Difficulties but not an impossibility.
THE CHAIRMAN: If possible, Mr Coonan.
MR HOPKINS: I draw the next straw.
THE CHAIRMAN: If Mr Coonan is not able to start in the morning then you will be able to start.
MR HOPKINS: Yes.
MS SMITH: Might I say, so that Professor Rutter can hear me, I mentioned to you that we were having to talk to him about his availability on Friday evening and he has very kindly indicated what that is. I am not going to talk about it now because I think tomorrow afternoon we will be in a very clear position as to how much further we have to go with him, whereas tonight it is a little bit speculative. We will revisit the subject tomorrow afternoon.
THE CHAIRMAN: Thank you. That would be very helpful. I am sure the Panel would like to know that information as well whenever you can inform us.
We will now adjourn and resume at 9.30 tomorrow morning.
Professor Rutter, once again, my usual reminder: you are still in the middle of giving the evidence so please do not discuss this case overnight with anyone, including any lawyers.
(Adjourned until 9.30 am on Tuesday 2 October 2007)