Tuesday, January 31, 2012

Day 8 GMC Fitness to Practice hearing for Andrew Wakefield



Wednesday 25 July 2007

Regents Place, 350 Euston Road, London NW1 3JN

Chairman: Dr Surendra Kumar, MB BS FRCGP

Panel Members: Mrs Sylvia Dean
Ms Wendy Golding
Dr Parimala Moodley
Dr Stephen Webster

Legal Assessor: Mr Nigel Seed QC


WAKEFIELD, Dr Andrew Jeremy
WALKER-SMITH, Professor John Angus
MURCH, Professor Simon Harry


(Transcript of the shorthand notes of T. A. Reed & Co.
Tel No: 01992 465900)


MS SALLY SMITH QC and MR CHRIS MELLOR and MR OWAIN THOMAS of counsel, instructed by Messrs Field Fisher Waterhouse, solicitors, appeared on behalf of the General Medical Council.

MR KIERAN COONAN QC and MR NEIL SHELDON of counsel, instructed by Messrs RadcliffesLeBrasseur, Solicitors, appeared on behalf of Dr Wakefield who was present.

MR STEPHEN MILLER QC and MS ANDREA LINDSAY-STRUGO of counsel, instructed by Messrs Eastwoods, Solicitors, appeared on behalf of Professor Walker-Smith who was present.

MR ADRIAN HOPKINS QC and MR RICHARD PARTRIDGE of counsel, instructed by Messrs Berrymans, Solicitors, appeared on behalf of Professor Murch who was present.


Page No


Examined by MS SMITH 2
Cross-examined by MR MILLER 53

THE CHAIRMAN: Good morning to you all. Can I give my usual warning to make sure that mobile phones are switched off? Ms Smith, I think you were in the process of calling your next witness.

MS SMITH: I was, sir, yes. Before I do so, could I, first of all, just explain to you how we propose to approach the documents because from now it it is likely that many of the witnesses will have to refer to many of the documents other than patient records.

We have had some conversation about this because, as you know, the normal way is to produce them with a C or D number in respect of every document. With a case of this complexity and length that seemed not wholly the most sensible way of going about it. As you know, you have four bundles, as we are inclined rather archaically to refer to them, Bundles 1, 2, 3 and 4, and they are all paginated, and they are all on white paper. So far as the General Medical Council is concerned, any document that I ask a witness to refer to, I shall simply refer to it as Bundle 1, 2, 3 or 4 and the page number in that bundle and you will know that it is produced by the General Medical Council because it is in the bundles and on white paper.

I mention “white” paper because the defence may also be producing documents during the course of the hearing, as is the way, and they are going to colour code their documents and they are going to be inserted into the chronological bundle in chronological order, so that, for instance, if you have a document produced by Mr Coonan, it will be on one colour paper and it will go in chronologically, and if it is produced by either of the other two it will be another coloured paper and will also go in chronologically. So at the end of the case you will be able immediately to identify who has produced which document.

I ran this past the Legal Assessor and the defence – in fact it was Mr Miller’s suggestion – and we think it is the most appropriate way of going ahead if you do.

THE CHAIRMAN: It certainly sounds a very practical and sensible way of going about it. It will also make sure that we stay on track. I expected these bundles not to be given any C numbers because in your opening you referred to them as Bundles 1, 2, 3 and 4, so we expected that to be the case, but I think that is very helpful for the defence papers to go in in chronological order. I know Ms Smith said it is in accordance with the wishes of the defence as well, but just to make sure, can I check, Mr Coonan?

MR COONAN: Yes, sir.



THE CHAIRMAN: Mr Hopkins? Are you all happy?

MR HOPKINS: Yes, though we have not selected a colour yet.

THE CHAIRMAN: Well, we are not going to be colour prejudiced here. Ms Smith?

MS SMITH: In that case, sir, I will call the first witness for this morning who is Dr Pegg.

Examined by MS SMITH

(Following introductions by the Chairman)

MS SMITH: Dr Pegg, I am a long way away from you so please tell me if you find it difficult to hear me. Could I ask you to pull up your chair as close to the microphone as possible and to remember that it is a big room, so please speak up. Can I ask you, first of all, to give us your full name and address and your professional qualifications, please?
A Michael Stuart Pegg, XXX, Master B BS, BSc, LLM, FRCA, DObstCOG, MRCS, LRCP and I think that is about it, yes.

Q I think it is right that you are employed at the Royal Free Hospital as a consultant anaesthetist.
A That is right.

Q You have been a consultant since 1981, is that correct?
A Yes.

Q You are here today in your capacity as the Chairman of the ethics committee at that hospital.
A The Research, yes.

Q How long have you held that post?
A Not quite sure, since 1994 or 1995 I started, but I have not got the records.

Q Is that a sub-committee of Camden and Islington Health Authority, in fact independent of the university and the Royal Free?
A It is not a sub-committee of Camden Health. We now report to the MPSA.

Q Now.
A Yes.

Q But we are talking about a time around 1996.
A We reported then to Camden and Islington, yes.

Q I am going to have to ask you to keep your voice up a little bit. You said you have held that post since around 1994/95. Do you still hold it to this day?
A Yes.

Q If you can cast your mind back, we know it is a long time since 1996, tell us the nature of the ethics committees in those days, in broad terms, compared to your experience of them now?
A They were not regulated. Now we have a European directive above us which has created a great structure above us. In that era government were not interested in us and really as a chairman of an ethics committee at the Royal Free, you were very much on your own. You have seen the government guidance, which is about half a dozen sides of paper at that time, so that was the structure of an ethics committee at that time.

Q I am going to take you to that guidance in a moment. Can I ask you, first of all, did the trust have rules of their own in respect of a research ethics committee?
A No, not really.

Q Did you have any rules about, for instance, what the quorum was for voting members?
A We just took the quorum from the trust rules.

Q Are the trust rules now available for that period?
A No. Nothing exists like that now.

Q Do you happen to remember what the quorum was?
A One third of those eligible to vote.

Q In your experience did your research ethics committee frequently or at all vote?
A No, we never voted.

Q You did not vote?
A No.

Q So how did you manage the decision making?
A In the end everybody agreed. We did it by consensus.

Q As far as the criteria that you did have, I think you have in fact helpfully been able to find two lots of guidelines which the committee did rely on at the time. If you look at the bundles in front of you, you will find one that says, FTP4 on it, with the Ethics Guidelines in it.
A Yes, I have that.

Q Turn, please, to page 128. Is that in fact the Department of Health guidelines that you had to use at the time?
A Yes.

Q If you just keep your finger in there for the moment and go back to page 76, is that the other document that you found, which was January 1990 guidelines from the Royal College of Physicians on the contract of ethics committees in medical research?
A Yes, that is right.

Q Were they broadly the two documents that you relied upon?
A I think that is about all we had at that time.

Q Thank you. If you go back to page 128, please, and on to the first page, which is 131, so this is the Dept of Health Guidelines. I hope you will bear with me. I am just going to take you through some of the basic information in that documentation. First of all, at paragraph 1.1,

“Medical research is important, and the NHS has a key role in enabling it. The approval of research projects is an important management responsibility involving the availability of resources, financial implications, and ethical issues. Such considerations are generally best left to the local management team, but on ethical issues they need to take into account independent advice. The purpose of a local research ethics committee is to consider the ethics of proposed research projects which will involve human subjects, and which will take place broadly within the NHS. The LREC’s task is to advise the NHS body under the auspices of which the research is intended to take place. It is that NHS body which has the responsibility to decide whether or not the project should go ahead, taking account of the ethical advice of the LREC. For convenience, local research ethics committees are normally organised on a health district basis, but they exist to advise any NHS body. They are not in any sense management arms of the District Health Authority”.

Is that your understanding of the broad setup at the time?
A Yes.

Q If we go on down to 1.3,

“An LREC must be consulted about any research proposal involving:

NHS patients (ie subjects recruited by virtue of their past or present treatment by the NHS) including those treated under contracts with private sector providers”.

Is that correct?
A Yes.

Q Then if you go on to page 133,

“No NHS body should agree to such a research proposal without the approval of the relevant LREC. No such proposal should proceed without the permission of the responsible NHS body. These requirements apply equally to researchers already working within the NHS and having clinical responsibility for the patients concerned, as they do to those who have no other association with the NHS and its patients, beyond the particular research project”.

So did your remit cover all the research that was taking place in your body?
A Yes.

Q If we just go on briefly, so that we can see the setup of the research ethics committee, to page 134, paragraph 2.1,

“Although the LREC exists to provide independent advice to any NHS body within the geographical areas of a health district, it is necessary for one of the NHS bodies to take the responsibility for establishing the LREC and providing its administrative support. This task falls to the District Health Authority. However each DHA should consult all the NHS bodies which are likely to use the LREC before establishing it.

2.2 It does not follow, however, that the members of the LREC are in anyway representative of, nor beholden to, any of the NHS bodies which collaborate in its establishment, nor that the LREC as a whole is an arm of the management of any of them. The object of consultation is to ensure that all the NHS bodies which will use the LREC should have confidence in its ability to provide sound research ethics advice.”

Going down to MEMBERSHIP:

“2.4 An LREC should have eight to twelve members. This should allow for a sufficiently broad range of experience and expertise, so that the scientific and medical aspects of a research proposal can be reconciled with the welfare of research subjects, and broader ethical implications.

2.5 Members should be drawn from both sexes and from a wide range of age groups. They should include:

- hospital medical staff
- nursing staff
- general practitioners
- two or more lay persons.

2.6 Despite being drawn from groups identified with particular interests or responsibilities in connection with health issues, LREC members are not in any way the representatives of those groups. They are appointed in their own right, to participate in the work of the LREC as individuals of sound judgement and relevant experience”.

Then turning on to 2.8:

“After consultation with the relevant NHS bodies the DHA should appoint a chairman and vice-chairman from amongst the members of the committee. At least one of these posts should be filled by a lay person.”

Then on to page 136, please. At paragraph 2.13 and 2.14 there is provision for the keeping of a register of all proposals which come before the Research Ethics Committee, including the details of the organisation carrying out the research and the qualifications of the research team, the premises in which the research is to be conducted and the medical support available. Then as far as follow up is concerned:

“Once the LREC has approved a proposal, the researcher should be required to notify the Committee in advance of any significant proposed deviation from the original protocol. Reports to the Committee should also be required once the research is under way if there are any unusual or unexpected results which raise questions about the safety of the research. Reports on success (or difficulties) in recruiting subjects may also provide the LREC with a useful feedback on perceptions of the acceptability of the project among patients and volunteers.”

Then if you turn on to page 138, “Consideration of the Research Proposals.” First of all, the application:

“To arrive at its decision on whether a research proposal is acceptable on ethical grounds the LREC will need to consider a great deal of information. The proposals which reach the LREC should be of a standard to enable the committee to discharge its function without having to correct basic errors. Researchers and their supervisors are not absolved of responsibility for their work by the existence of the LREC.”

Then there are five points set out which are the minimum that the LREC need to know:

“i. Has the scientific merit of the proposal been properly assessed.
ii. How will the health of the research subjects be affects.
iii. Are there possible hazards and, if so, adequate facilities to deal with them.
iv. What degree of discomfort or distress is foreseen.
v. Is the investigation adequately supervised and is the supervisor responsible for the project adequately qualified and experienced.
vi. What monetary or other inducements are being offered to the NHS body, doctors, researchers, subjects or anyone else involved.
vii. Are there proper procedures for obtaining consent from the subjects or where necessary their parents or guardians.
viii. Has an appropriate information sheet for the subjects been prepared.”

Then going on to the type of research:

“3.3 LRECs should consider the ethical implications of all research proposals which involved human subjects, including for example questionnaires. All proposals will belong to one of two categories, therapeutic or non-therapeutic. Therapeutic carries the prospect of direct benefit to the research subject. Non-therapeutic research, whilst designed to advance scientific knowledge and therefore be of collective benefit, is not expected to give a direct benefit to the research subject. Non-therapeutic may involve ‘health’ as well as ‘patient’ volunteers.”

Then going on to paragraph 3.4 on the next page:

“Where people volunteer to take part in non-therapeutic research they should know that they cannot expect to derive any direct benefit from that participation. They LREC will therefore want to be satisfied that the risk to which they are submitting themselves can be justified by the expected collective benefit.”

Then “Recruitment”:

“No-one should be made to participate in a research study against their will. Those recruiting patients should be careful to avoid exerting any undue influence …”,

and then at the bottom of that paragraph:

“Patients who refuse to participate in research studies should be reassured that they are free to do so with no detriment to their treatment.”

Down to the bottom of the page, “Consent”:

“The procedure for obtaining consent will vary according to the nature of each research proposal. The LREC will want to be satisfied on the level and amount of information to be given to a prospective subject. Some methods of study such as randomised controlled trials need to be explained to subjects with particular are to ensure that valid consent is obtained. The LREC will want to look at such proposals particularly carefully. They will also want to check that all subjects are told that they are free to withdraw without explanation or hindrance at any stage of the procedure and with no detriment to their treatment. An information sheet, to be kept by the subject, should be required in the majority of cases.”

Then it goes on:

“Written consent should be required for all research (except where the most trivial of procedures is concerned). For therapeutic research consent should be recorded in the patient’s medical records.”

Then turning on to page 141, if you would not mind, Doctor, these were the principles so far as the financial considerations:

“The LREC should examine any financial aspect of a research proposal which may influence the patient’s judgement in consenting, or the researcher’s judgement in his/her treatment of subjects, in such a way as to call the ethics of the research into question.”

Then going down to the next paragraph:

“Payment in cash or kind to volunteers should only be for expense, time, and inconvenience reasonably incurred. It should not be at a level of inducement which would encourage people to take part in studies against their better judgement, or which would encourage them to take part in multiple studies.”

On to page 142 at paragraph 3.22:

“If it comes to the attention of a committee that research is being carried out which it has not been asked to consider or which it has considered but is recommendations have been ignored, then the LREC should bring the matter to the attention of its appointing authority, the relevant NHS body and to the appropriate professional body.”

Going on, Doctor, did you have a short bit of guidance in relation to research on children and that is on page 143? Can I ask you at this point, how often were you having to consider research proposals relating to children as opposed to adults? Was that a normal or an unusual part of your work?
A I cannot really say. I cannot really answer that question. I would need to go back to the registers to properly answer a question like that.

Q Then “Research on Children”:

“4.1 Research proposals should only involve children where it is absolutely essential to do so and the information required cannot be obtained using adult subjects.

4.2 When seeking consent to examination or treatment (which may include research which is intended to benefit the patient, ie therapeutic research) young people aged
16 and 17 are presumed … to be able to give their full consent independently of their parents or guardians. Children who are under 16 years of age may also be able to give full consent – providing they have a sufficient understanding of what is proposed, as judged by the doctor attending them. Even for therapeutic research purposes it would however be unacceptable not to have the consent of the parent or guardian where the child is under 16.”

It then deals with over 16 and under 18, and then it goes on at 4.3:

“Where the proposal is for non-therapeutic research, all the above applies but in addition the child must be subject to no more than minimal risk as a result of his or her participation”,

and lastly:

“The LREC should note that those acting for the child can only legally give their consent provided the intervention is for the benefit of the child. If they are responsible for allowing the child to be subjected to any risk (other than on so insignificant as to be negligible) which is not for the benefit of that child, it could be said they were acting illegally. It should also be noted that the giving of consent by a parent or guardian cannot override the refusal of consent by a child who is competent to make that decision.”

That chapter, which was “Special Considerations”, goes on to deal with other categories of patients to whom special rules applied, but was that broadly the information that you had when you were considering research on children?
A Yes.

Q If I may also take you on to the other document that I asked you to have a look at, page 76, I am not, you will be relieved to hear, going to take you through all this, but I do want to just establish the background for the decisions that you were making. If you go to page 87 and paragraph 2.1 please:

“The objectives of Research Ethics Committees are to maintain ethical standards of practice in research, to protect subjects of research from harm, to preserve the subjects’ rights and to provide reassurance to the public that this is being done. In achieving these objectives, Ethics Committees should remember that research benefits society and that they should take care not to hinder it without good cause. Ethics Committees also protect research workers from unjustified criticism.”

Then it sets out the World Health Organisation proposals for the matters that ethics committees should consider:

- ‘The objectives of research are directed to a justifiable advancement in biomedical knowledge that is consonant with prevailing community interests and priorities.

- ‘The interventions are justifiable in terms of these objectives; the required information cannot be obtained from animal models and the study has been designed with a view to obtaining this information …

- ‘The responsible investigator is appropriately qualified and experienced …

- ‘Adequate preliminary research and experimental studies…

- ‘Every effort will be made to inform prospective subjects of the objectives and consequences of their involvement, and particular of identifiable risks and inconvenience.

- ‘Any arrangement to delegate consent has adequate justification, and appropriate safeguards will be instituted to ensure that the rights of the subjects will in no way be abused.

- ‘Appropriate measures will be adopted to ensure the confidentiality of data generated …

2.2 In addition, every effort should be made to ensure that subjects have an opportunity to comment on and, if they wish, to withdraw easily and without penalty from a research investigation”,

and again it is underlined that the Research Ethics Committee should be aware of the need not to avoid impeding good medical research. Then it says:

“2.4 The nature of the decision that a Research Ethics Committee has to make is largely defined in para.2.1 above. But the question of the extent to which scientific quality, design and conduct should be considered continues to cause difficulty. Badly planned, poorly designed research that causes inconvenience to subjects and may carry risk, without producing useful or valid results, is unethical. Plainly, full scientific evaluation is beyond the capacity of the great majority of Ethics Committees and few will be in a position to set up a Scientific Advisory Group”,

as, it points out, is available at one centre.

“Nonetheless, Committees should approve only studies which are of good quality. Most Committees will do their best in this area, using their own knowledge and knowledge of their colleagues, but they should not hesitate to make use of external advisers for difficult problems, particularly in the areas of design and statistical evaluation of protocols.”

Then turning on, Doctor, to page 89, “Definitions and classes of research”:

“3.1 The definition of research continues to present difficulties, particularly with regard to the distinction between medical practice and medical research. The distinction derives from the intent. In medical practice the sole intention is to benefit the individual patient consulting the clinician, not to gain knowledge of general benefit, though such knowledge may incidentally emerge from the clinical experience gained. In medical research the primary intention is to advance knowledge so that patients in general may benefit; the individual patient may or may not benefit directly.”

It then deals with innovative therapy and the position where a clinician departs in a significant way from standard or accepted practice entirely for the benefit of a particular individual patient, and it then deals with “Research”:

“3.3 Any investigation in humans designed to develop or contribute to generalisable knowledge raises ethical issues, although these may be small. Because such studies may involve subordination of at least the immediate interest of the individual participate to the objective of the advancement of knowledge, they should be subject to ethical review. The College considers that this applies to non-medical as well as to medical research.

3.4 There are two major classes of research:

i that which involves making observations without any direct interference with the subject (non-intrusive or non-invasive), such as research involving the use of personal medical records.

ii that which involves interference with the subject (psychological intrusion, including intrusion on privacy, or physical invasion). Such interference, psychological or physical, raises ethical issues which may be sometimes large or very small; both should be subject to ethical review.

3.5 Research may also be classed as: (a) research which may benefit the individual participant (therapeutic research), and (b) research that will not or is unlikely to benefit the individual participant (non-therapeutic research). Whilst Ethics Committees will be concerned with both, they will naturally give particularly close attention to non-therapeutic research.”

Going on to the next page we see the provisions of “Mandatory ethical review”:

“4.1 All medical research involving human subjects should undergo ethical review before it commences, in accordance with the principal that investigators should not be the sole judge of whether their research raises significant ethical issues”,

and it then:

“4.2 The body … that sets up a Research Ethics Committee should provide that all medical research investigations involving human subjects … should come before it …

4.3 Most projects will require formal review by the full Ethics Committee, but there is a body of investigations that evidently does not pose any ethical problems …”

which can be dealt with without a full review.

Then on to page 91, “Terms of reference and scope”, and it sets out, first of all, the matter which I have already referred to in the DoH document, that a Research Ethics Committee has to advise on all proposals for research within that institution. Then going down to the bottom of the page, to “Costs of research”:

“5.7 Although the allocation of resources has ethical implications, consideration of that is beyond the scope of Research Ethics Committees. Those who distribute resources will generally require that a project has the approval of a Committee before considering it for support. The fact of approval does not carry any implication that resources ought to be provided and Committee approval should not be used to assert this …”.

On to paragraph 5.8:

“That the results of medical, social or environmental research might later give rise to demands for implementation that may be expensive is not properly a concern in the decision made by an Ethics Committee … though of course such matters are of legitimate ethical concern to those responsible for allocation of the resources.”

Then “Ethics of clinical practice”, and this is a slightly different issue, but I would like just to read it:

“From time to time a Research Ethics committee is liable to be approached by a clinician with an ethical problem of medical practice (not of research). Research Ethics Committees are not currently constituted for this purpose, and it is unwise of a Committee to respond formally to requests that are outside its terms of reference, though members may well agree to engage in informal discussion”,

and then it refers to the role played by the College in that and the importance of the issue involved.

Q Going on to page 93, at 6.1 we have a little more information in relation to the lay membership. First of all, the World Health Organisation recommendation is:

“6.1 Committees must command the technical competence and judgement to attempt to reconcile the physical and psychological consequences of participation with both the welfare of the subjects and the objectives of the investigation. They may also, with advantage, accommodate respected lay opinion in a manner that provides effective representation of community as well as medical interests.

6.2 This College considers that lay membership is essential”.

It sets out the requirements for those lay members:

“6.3 Members of Committees need to be people of goodwill, with a high regard for the human personality, for truthfulness and for the continued advance of science in the interest of society”.

Going on to 6.5,

“It is important that the community should have confidence in Ethics Committees. Such confidence should be forthcoming provided that the membership is seen to be broad and not exclusively medical, and that the lay members to be persons of responsibility and standing who will not be overawed by medical members.

6.6 Experience has shown that lay members, though they may not grasp some of the niceties of some research projects (nor may some of the medical members) are invaluable particularly on issues of consent and information to subjects. A lay member with legal training can be of great value but his role should be a general one, not solely to answer questions of law ...”

Then turning on to page 94 (viii):

“It is not practicable that a Committee should include specialists in all the fields, medical and allied, that may have a scientific or other input to all the various proposals that may come before it. The reasonable requests by specialists that members of their specialty should always be involved in assessing their applications, or at least where there is a possibility of rejection, can be met by having two members of that discipline, e.g. general practice on the Committee where applications are frequent”.

Then alternatively there is a provision for co opting specialist members.

If I can take you on to page 99, please, there is the heading, “Suggested format for applications to Research Ethics Committees”. I will not read all those out, but in broad terms they say that the application form should give the title, the question to be answered, an outline of the proposed project, the types of subjects to be involved, the likely duration of the projects, the potential hazards to subjects, the degree to which the procedure may cause discomfort or distress to subjects, and the estimated probability of that; the experience obviously of the applicant, the position as far as consent is concerned; whether the GP is to be informed and any other relevant matter including information sheets which must be in simple, non technical language, payments to subjects and the way in which the patients are recruited.

There is also a requirement at (xiii), that the application should,

“State any ‘interest’ i.e. of profit, personal or departmental, financial or otherwise, relating to the financial or otherwise relating to the study”.

It refers to a section which I am going to take you on into a moment. Going on to page 100, “Paediatric project”,

“For paediatric projects the following additional information is required:

xv In what way, if any, can the proposed investigation be expected to benefit the individual patient on whom it is to be performed. ...Non therapeutic research is unacceptable except as stated below.

xvi In the case of an investigation which cannot be expected to benefit the individual patient:

a Are the risks judged to be minimal?
b Is parental or guardian agreement to be obtained and, if so, in what form?
c Is the child capable of giving assent?”

Assent is distinguished from consent:

“(‘assent’ is used to imply a willingness that does not necessarily carry the greater understanding and legal implications that are generally understood by ‘consent’.”

If I could ask you to go on to page 104, there are the details in relation to ‘Consent to participation in research’. Again, if I can just ask you to look at the current conventional practice, the meaning of consent, remembering of course that this applies across the board and not to children.

11.3 reads:

“Potential research subjects are entitled to chose whether or not they will participate in research ...”

It sets out the various forms of consent. Then 11.5,

“There is no single preferred method of obtaining and recording consent that is appropriate to all research, but Research Ethics Committees should decide whether sufficient information has been provided, especially about potential risks and discomforts as well as any hoped for benefits, for an adequately informed choice to be possible”.

Going on to page 105, under “Information to subjects” at paragraph 11.10,

“Most research procedures should be the subject of an Information sheet written in simple language easily comprehensible by the potential research subject. It should set out the purpose of the investigation, the procedures, the risks (including psychological distress), the benefits, or absence of them, to the individual or to other future individuals or to society, a statement that the subjects may decline to participate (without incurring displeasure or any sort of penalty in the case of a dependant relationship, e.g. patient, student, employee) and will also be free to withdraw at any time without giving a reason and without in any way impairing their care …”

Then going on to paragraph 11.11:

“The subjects should be given plenty of time to study the Information Sheet, to consult their families or their general practitioners ...”

At the bottom of that paragraph it says,

“A standard hospital ‘Consent to Treatment’ form is not appropriate to research”.

Then under “Minimal risk” it reads,

“Research procedures are more or less substantial in terms of complexity, time and effort involved, but generally they should not involve more than minimal risk either to a patient volunteer or to a healthy volunteer. The term ‘minimal risk’ is used to cover two types of situation. The first is where the level of psychological distress is negligible, although there may be a small chance of a reaction where there is a very remote chance of serious injury or death…”

Then paragraph 11.14,

“There are some situations, such as the treatment of serious disease, where it is ethical for research studies to involve more than minimal risk. These would never involve healthy volunteers.”

Again, I interrupt myself to say we should remember these are general compositions.

Page 106 underlines that at paragraph 11.18,

“Where capacity to give consent is impaired, for example in children, mentally handicapped people and some psychiatric patients, special consideration is required”.

Then paragraph 11.22,

“Copies of consent documents should be kept in the case records of subjects (where these exist) as well as in research records”.

Then going on to page 111, under the heading “Special classes of research” – and again this is what the Royal College of Physicians has to say about research on children, 13.1,

“It may be appropriate to give medical treatment to give medical treatment to unwilling children if the parent or guardian consents, but the position would not necessarily be the same for research”.

Then it goes into when a child become an adult.

“Under that age [18] the capacity to consent to research probably depends on the degree of understanding on the part of the individual concerned”.

It refers to provisions that consent is between 16 and 18 which is not applicable in this case.

It then goes on,

“‘Treatment’ includes diagnostic and ancillary procedures, including the administration of an anaesthetic, and thus probably includes therapeutic research, and below the age of 18 parental consent should always be sought in addition to that of the subject”.

Again it repeats, at 13.2,

“... Non therapeutic research in children should not carry greater than minimal risk except in the rarest of circumstances”.

Paragraph 13.4 indicates where it is feasible the child will be asked:

“Children should in no circumstances be the subjects of research holding no potential benefit for them unless with the objective of elucidating psychological or pathological conditions peculiar to infancy and childhood, or of providing potential benefit to the family, and where it involves no more than minimal risk”.

It has been pointed out to me that I should have read 13.2:

“Non therapeutic research in children should not carry greater than minimal risk except in the rarest circumstances. There must be no financial or other inducement to parent, guardian or child”.

Then going back to the paragraph I was reading, 13.4,

“(Note: where a child obviously objects to such research, i.e., he or she withholds assent or agreement, or resists, this must be respected. Research should always be planned to ensure that there is negligible distress or harm to the child, e.g., a venepuncture might be accepted whereas lumbar puncture would not be in this type of work.)”

Just going on to one last paragraph, which I referred to earlier page 124 when I was dealing with financial aspects, under “Investigators, department and institutions” 17.4 reads,

“Since personal payments, both amount and nature (money, gifts, travel etc), to investigators and their pecuniary relationship with any sponsoring company have ethical implications, these should be reported to Ethics Committees or to representatives designated for that purpose, e.g., the Chairman and another member. The same applies to payments to departments and to institutions by a pharmaceutical company or a contract research company.”

Then under “Declaration of interest, 17.5,

“Personal involvement is a company is also an interest that should be declared”.

Then “Role of the Ethics Committee” paragraph 17.6, reads:

“Ethics Committees have a particular responsibility to examine closely all financial arrangement, particularly where there may be an element of inducement to recruit patients ...”

Doctor, you may feel by now that I am giving evidence rather than you, but you will understand that it is important that the Committee understands the background to the evidence that you are going to give. Are those in broad terms the principles which were guiding the ethics committee at the Royal Free in 1996?
A There was a hierarchy of guidance that we had. The most important ones are the Declaration of Helsinki sitting at the top which you have not referred to at all. That is our overriding thing. Then you come down. If you notice this one refers back to the paediatric guidelines because this guidance looks as though it has been taken out of the paediatric ones. Our problem at that time was because there was no real guidance, everybody wrote their guidance. You have a hierarchy of Helsinki at the top, and I think you probably take the Department of Health one underneath it, it is probably where things conflicted. The Department of Health’s one is probably more important. Then you have a whole lot of guidance below. Of course, this one was the only one left on my shelf and that is the one you have got here. At the time my shelf would have been thick with guidance from all sorts of bodies, so really you just have an illustration of guidelines. It was not difficult to find that conflicted with this one if you tried hard enough. You have just got an illustration, the others are all long gone.

Q In those circumstances, perhaps I should just take you to the Declaration of Helsinki which is appended the back of the Department of Health guidelines. If you go back to page 128, that is the start of that document. If you go to page 150 you will find the Declaration of Helsinki. I am going to take you briefly through this. (To the Panel) You may feel it is appropriate that you read that, and indeed the other guidelines I have referred to, carefully at some point when you retire. This was the declaration from the World Health Organisation which guided the way in which medical research was supposed to be conducted and has been subject over the various years to amendments. Is that correct?
A Yes.

Q This was the 1989 version. It sets out first of all,

“The mission of the physician to safeguard the health of the people. His or her knowledge and conscience are dedicated to the fulfilment of this mission”.

It sets out the purpose of biomedical research to improve diagnostic therapy and prophylactic procedures and the understanding of the aetiology and pathogenesis of disease.

“In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. This applies especially to biomedical research. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects”.

Then it makes the fundamental distinction between diagnostic or therapeutic and medical research,

“The essential object of which is purely scientific and without implying direct diagnostic or therapeutic value to the person subjected to the research. Special caution must be exercised in the conduct of the research ...”

Then turning on to the basic principles,

“1. Biomedical research involving human subjects must conform to generally accepted scientific principles and should be based on adequately performed laboratory experimentation ... and on a thorough knowledge of the scientific literature.”

Then it goes into the design and performance, that it should only be conducted by scientifically qualified persons.

Then 4,

“Biomedical research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject”.

Then 5,

“Every biomedical research project involving human subjects should be preceded by careful assessment of predictable risk in comparison with foreseeable benefits to the subject or to others. Concern for the interests of the subject must always prevail over the interests of science and society”.

Then 6,

“The right of the research subject to safeguard his or her integrity must always be respected. Every precaution should be taken to respect the privacy of the subject and to minimize the impact of the study on the subject’s physical and mental integrity and on the personality of the subject”.

Then 7,

“Physicians should abstain from engaging in research projects involving human subjects unless they are satisfied that the hazards involved are believed to be predictable. Physicians should cease any investigation if the hazards are found to outweigh the potential benefits”.

Then 8,

“In publication of the results of his or her research, the physician obliged to preserve the accuracy of the result. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.”

Then 9,

“In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study ... He or she must be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time”.

They should obviously give their informed consent.

Then 10,

“When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship to him or her or may consent to duress. ...”

Then 11,

“In case of legal incompetence, informed consent should be obtained form the legal guardian in accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain informed consent, or when the subject is a minor, permission from the responsible relative replaces that of the subject in accordance with national legislation”.

Then 12,

“Research protocol should always contain a statement of the ethical considerations involved and should indicate that the principles enunciated in the present Declaration are complied with”.

Then it goes into clinical research.

“1. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic measure, if in his or her judgement it offers hope of saving life, re-establishing health or alleviating suffering.

2. The potential benefit, hazards and discomfort of a new method should be weighed against the advantages of the best current diagnostic and therapeutic methods.

3. In any medical study, every patient ... should be assured of the best proven diagnostic and therapeutic method.

4. The refusal of the patient to participate in a study must never interfere with the physician patient relationship”.

There are particular provisions where consent is not necessary.

“The physician can combine medical research with professional care, the objective being the acquisition of new medical knowledge, only to the extent that medical research is justified by its potential diagnostic or therapeutic value for the patient”.

Then it deals with non-therapeutic research:

“In the purely scientific application of medical research carried out on a human being, it is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out.

The subjects should be volunteers – either healthy persons or patients for whom the experimental design is not related to the patient’s illness.

The investigator or investigating team should discontinue the research if in his/her or their judgment it may, if continued, be harmful to the individual.

In research on man, the interest of science and society should never take precedence over considerations related to the wellbeing of the subject”.

So that is the declaration of Helsinki underpinning the guidelines at that time, is that correct?
A Yes.

Q Can I ask you, Dr Pegg, in broad terms, did the make-up of your committee comply with the guidelines that were set down by the Department of Health, in broad terms?
A Yes.

Q Can we first of all hear from you about the procedure in 1996? First of all, did you have a standard application form for researchers to fill in?
A Yes.

Q Was it usual for some sort of more detailed scientific protocol to be attached to that application?
A Sometimes.

Q Did you have requirements in respect of some sort of independent review?
A Yes.

Q What exactly did that mean?
A You have already read out from the guidance that ethics committees are not expected to carry out their own scientific review, they are not empowered to do so. We require evidence that prior to submission independent scientific review has been carried out.

Q You say scientific, would that include any consideration of the ethical issues over and above the fact that obviously to be ethical it has got to be respectable science?
A No. The scientific review is supposed to say that actually it is good science. The researcher can put down that it is a worth while report, he just wants somebody else to say that this is something that needs to be researched on and that the science is good.

Q Having got that information, an application form and possibly a protocol, what happens to all the documentation?
A We circulate it and then discuss it.

Q Do members make written observations, first of all?
A Sometimes. They do not any more but they did then.

Q You say you discuss it. Is that in a formalised meeting setting?
A Yes.

Q How often do you have meetings?
A Eleven times a year.

Q Broadly speaking, how do you deal with a research project at that meeting? What do you do in respect of it?
A We discuss it and decide whether to accept it, reject it or modify it.

Q If it is possible for you to answer this in general terms, generally what is the outcome of such an application? Do they get through at first stage?
A From our records at the moment I think that we are running at about a small percentage rejected outright and about 50-50 need modification and about 50 per cent get through.

Q If the committee discuss an application and they decide that it needs changes before it is to be approved, what happens then?
A I write to the researcher.

Q Thereafter is it considered again?
A Yes.

Q If it is approved after that, or whenever the modifications that you require have been implemented, is there provision for follow up? I mean, we have seen that there should be in the DoH guidelines?
A We ask them to, but they never do.

Q When you say you ask them to.
A Ethics committees are not policemen. The policeman is the R&D committee of the hospital. The ethics committee writes a letter saying what should happen next whilst we are not charged with policing it at that time. We are just charged with setting out the conditions under which the research should take place and the R&D department of the hospital is responsible for seeing that those conditions are obeyed.

Q I want to ask you, as you know, about a particular application and protocol and that relates to a project which I think was assigned by the ethics committee number 172-96. If you would please put away bundle 4 and take out Bundle 1 and turn to page 200, please.
I want to ask you first of all, doctor, about the dates. On page 200 we see the date 6 August 1996.
A Yes.

Q But if you turn to page 233, which is the end of the application, or nearly the end, we see the date of submission as 16 September 1996.
A Yes.

Q First of all, is that a common discrepancy?
A I presume he started writing it in august and finished in September, because it takes some time to do this.

Q Can you help us at all as to when you would have received this?
A Not really.

Q Are the applications sent to you personally?
A No, they are sent to my secretary.

Q You have an administrative assistant, do you?
A Yes.

Q If we go back to page 200, first of all is this a standard form, or was it at that time?
A Well define “standard”. It is not a national form, no. I wrote it. It is standard for the Royal Free, but not standard in terms of every ethics committee has its own form.

Q But this form is the one expected to be used by researchers who applied to your ethics committee.
A Yes, the Royal Free.

Q We see at the top, “responsible consultants”. Can you tell us, first of all, in general terms what does that title denote?
A The people doing the study.

Q We see at the back of it, page 233, the signature of the investigator, which is in fact Dr Wakefield. Again, in general terms, what was the title “investigator”? How does that differentiate, if at all, from the responsible consultants?
A I think in the hierarchy you are considered the most senior one responsible. Often as you can see here, it has been signed off the by head of department. “Approved”, and
I presume that is the signature of Professor Walker-Smith. Here this is the investigator, probably signifying the person who is going to be more involved with it than the head of department. At that time any application had to be signed off by the head of department so lots of applications it was almost a formality, being signed off by the head of department.

Q In this case that is Professor Walker-Smith, who as you say was the head of department. What was your understanding of the role of Dr Wakefield in this case, in the research?
A That he was one of the investigators.

Q Were you aware of the role that was being played by then doctor, now
Professor Murch?
A That was never clear.

Q Did you in fact have any formal correspondence with Professor Murch during the course of this research application?
A No.

Q In those circumstances, who would you generally expect to be communicating with?
A Usually I send the initial correspondence to the responsible consultant. I often get replies from a researcher who I continue to correspond with.

Q As we know, we know when we look at the documentation in relation to this that there were communications both with Professor Walker-Smith and separately with
Dr Wakefield. Was there anything unusual about that?
A You corresponded with whoever was probably going to answer your question.

Q How would you know who that was?
A You got a feeling, if you did research, who was involved and who was not.

Q A review was sent at the same time as the application, and we have that on page 236. That was a review from a Dr Epstein who was consultant gastroenterologist in the Department of Medicine at the Royal Free, indicating that he had reviewed the proposal,

“The outline of the study is clear and the methodology testing the hypothesis is appropriate. This is a very important and original study which should be strongly supported on scientific grounds”.

Can I ask you, first of all, was there anything unusual about the fact that it was a member of the same hospital who was verifying the application?
A No.

Q You have already told us that the reviewer is concerned with the science of the project and would that letter have satisfied the committee in relation to that?
A Yes. I mean, this just ticks the box. When you read originally what we had to do, we had to satisfy ourselves of the science. This letter is that proof.

Q As far as the overarching ethical considerations relating to the project are concerned, whose responsibility are they?
A That is ours.

Q “Ours” meaning the ethics committee.
A Yes.

Q If we go to page 239 to follow through the story, this is the letter from your secretary of the Ethical Practices Sub-Committee, and it is a letter to Dr Wakefield acknowledging receipt of the application, code number of the project, 172-96, and he is asked to quote that from then on,

“Your application has been circulated to the members of the committee and it will be discussed at the next committee meeting. You will be advised of the outcome as soon as possible after the meeting. If any queries are raised you will be notified by the Chairman and these should be answered, in writing, at the earliest opportunity”.

Was that a standard letter?
A Yes.

Q Would the application then have been circulated in the normal way?
A Yes.

Q I would like to have a look at it with you, if I may doctor, if you would go back to page 200 for the actual application. You say you actually designed this application form. Is that correct?
A Yes.

Q We see the title of the project and the title then given and the objective, that is the research hypothesis, is that correct?
A Yes.

Q It sets out the hypothesis in relation to this particular study, and we see the design of the study and then a series of investigations set out under it,

“structured assessment for disintegrative disorder.

Routine ileocolonoscopy and upper gastrointestinal endoscopy…

A barium follow-through…

MRI, EEG…various evoked potentials.

Lumbar puncture…”,

and various blood and urine tests. Then we see the scientific background which is set out. Can I ask you in respect of that, it is in very technical terms, is that usual for an ethics committee application of this kind, to see the science set out in that sort of detail and as technical as that?
A Unfortunately yes.

Q As far as the members of your committee are concerned, how do they grapple with how to understand the science that is set out in the application?
A Half of them will and the other half usually read the information sheet to see if they can understand it from that.

Q In general terms, when you are confronted with something like this, what are you looking for to begin with?
A We are not really looking for anything. We have already had the science. This is effectively the introduction for your information, this is the science, but somebody else has looked at it, Professor Epstein and said it is OK. That is why it can be in this language, because we are not making a decision on this science. It is to help you understand the full study rather than something you are making a decision on.

Q So the decisions, so far as you as a committee are concerned, what are the basic decisions you are making?
A The risk to the patient, basically. Is it worth it? What are the risks? Patients are allowed to undergo risks, but is it properly explained? To sum up the committee, is it properly explained to the patient in the information sheet what is going to happen? If you want to sum up the ethics committee in one sentence, that is probably it.

Q Do you consider, when you are considering whether it is properly explained to the patients, I think you used the words, “Is it worth it?” Are you also considering whether what the patient is being asked to do is acceptable in research terms? I am sorry, I should not have said “asked to do”.
A I think it is different with adults than with children. Adults can often consent to some pretty horrible things in the form of science and that is up to them. So I think you have got to divide decision making into children and adults. Of course, children you have already been through the standards.

Q So we have the detailed explanation in respect of the science and they go through giving all the scientific references to page 208. Then we see the subjects with the selection criteria for the research,

“presence of disintegrative disorder
symptoms and signs of intestinal dysfunction
parental request for investigation to be undertaken”.

Then the number of subjects indicating that there are 25 to be used. Going on to the next page, all under the age of 16, all manifesting disintegrative symptoms and signs to differing extents.

“They will be accompanied at all times by a parent and will have a designated nurse(s) in attendance throughout the week. Invasive procedures and MRI will be carried out under either standard sedation or general anaesthesia (ileocolonoscopy and biopsy and the lumbar puncture will be performed on the same morning), as indicated. Parents will be aware that they can withdraw their child from the study at any stage”.

We have looked already at the principles, Dr Pegg, and there have been a number of references to that very issue. Is that a significant issue so far as the research ethics committee is concerned?
A Yes. I mean this has to be tied in with what happens next, of course, so we ask whether these are part of the study or whether they are not.

Q I will come on to that in a moment. There is a request whether there are minimum volunteers and the answer is no. Then there is “controls nil”. Can you just help us, remembering that there are lay members on the Panel, as to what “controls” are?
A A normal person.

Q A normal person for what purpose in a research project?
A You often have normal volunteers so that you know the norm. I mean if you do a colonoscopy on this child, you see a colon that is different, and you may wish to take samples from normal patients to compare it with to prove it is different. If you do not know what the normal looks like, you cannot prove the abnormal.

Q Then we see,

“How are the substances for this study being funded. How is the study being funded”.

We see,

“Clinical research at the Royal Free Hospital”,

and then “ECR”. What did you understand that to mean?
A I do not know.

Q Which bit of it?
A “ECR”. Twelve years down the line I have not the faintest idea what it means. I probably asked somebody at the time.

Q What about “clinical research at the Royal Free Hospital”?
A I presume the funds were coming from the Royal Free Hospital.

Q I am sorry, doctor, I spoke over you.
A I presume the funds were coming from the Royal Free Hospital.

Q Then we see,

“Procedures or samples to be taken from subjects…Would the procedure(s) or sample(s) be taken, especially for this investigation, or as part of normal patient care?

Yes: in view of the symptoms and signs manifested by these patients, all of the procedures and the majority of samples are clinically indicated. Additional intestinal biopsies (5 per patient) will be taken for viral analysis. DNA for genotyping will use blood cells isolated from the routine blood sample and will not require an additional sample”.

Then we go on to “Discomfort”, and the request on your form is,

“What discomfort or interference with their usual activities may be suffered in all or any of the subjects?”

The answer is,

“ileocolonoscopy, upper endoscopy and lumbar puncture are invasive procedures that are performed routinely at the Royal Free Hospital by members of the Department of Paediatric Gastroenterology. In order to avoid or reduce discomfort, ileocolonoscopy is performed under sedation given as an injection, or under a general anaesthetic. Lumbar puncture is performed under a local anaesthetic injected into the skin of the lower back. The injection itself produces a mild and brief stinging sensation. Thereafter the procedure is painless”.

Then attached to it we have a protocol and attached to that, at page 211, we see,

“The inflammatory Bowel Disease Study Group and the Department of Paediatric Gastroenterology at the Royal Free Hospital have an established record in research into inflammatory disorders of the intestine. This study hopes to add further to our understanding of the possible link between intestinal problems and behavioural disorders in a group of children who may have responded abnormally to measles and/or rubella vaccine.

If you agree to let your child take part in the study, please sign the attached consent form and return it in the enclosed envelope.

Thank you for helping us with this important work.

If you have any questions please contact Dr Wakefield”.

If I can just refer you on in the protocol, to page 223, to “practical issues”:

“First and significantly this is a demanding protocol both for the children and for those clinicians carrying out invasive procedures in particular. Due consideration should be given to this when planning the details of the admission. However, it is essential that we characterise as comprehensively as possible the pathogenesis of this condition – control of any underlying intestinal immunopathology may open up new therapeutic avenues for the treatment of affected children. Our ability to confirm or exclude a role of measles or measles/rubella vaccine also has major implications for public health”.

Going on, there were virological studies attached to the back at Appendix 1, which is at page 226. Then if we turn to page 232, this is the hand-out to parents. Would you regard this, in the light of what you previously said, as an important part of the documents that the ethics committee would be reviewing?
A Yes.

Q We see it says,

“Through parents such as you, Doctors at the Royal Free Hospital School of Medicine have been alerted to the possible existence of a new disease”.

Then it sets out what it consists of. Then,

“The problem has been associated anecdotally but consistently with measles or measles/rubella vaccination. We, at the Royal Free, have now looked into the background medical and scientific literature concerning this problem and have formulated the hypothesis that in certain (perhaps genetically susceptible children) live virus vaccines may produce long-term inflammation of the intestine and failure to absorb, in particular, vitamin B12. In the developing brain this vitamin is vital and young children are very sensitive to B12 deficiencies. Such deficiencies may lead to failure of normal brain development and regression of behaviour similar to that you have possibly observed in your own child.

We would like to carry out a series of tests which, we believe, will help us to establish the features of this possible disease. Our aim is to characterise the problem so that, for the future, we may be able to treat affected children and improve their wellbeing”.

Then it sets out the detail of what is going to happen. I will not go through it all.

“You and your child will be admitted to Malcolm Ward at the Royal Free on a Sunday, and will stay for one week. On Sunday you will be seen, interviewed, and your child examined by a paediatric doctor…On Sunday evening your child will receive a laxative that prepares the intestine for examination the following day. Your child will have water only from midnight on Sunday until Monday lunch time. On Monday morning you will both go to the endoscopy suite…ileocolonoscopy undertaken and upper endoscopy…If your child becomes distressed or the procedure proves too difficult with sedation alone, it will be performed under a light general anaesthetic. During the procedure small pieces of tissue will be taken from the bowel for analysis. This is a vital part of the procedure and is entirely painless.

Following the ileocolonoscopy and still under sedation your child will undergo a lumbar puncture”,

and it sets out the nature of that procedure.

“Over the course of the next 4 days your child, accompanied by you throughout, will have a brain scan (MRI scan) that will also be performed under sedation…EEG…Once again it is painless. Towards the end of the week your child will have a test to measure the ability of the intestine to absorb vitamin B12 [the Schilling test]…In addition it may be necessary to perform a special X-ray of your child’s intestine. This is called a barium follow-through…This examination will be performed only if the ileocolonoscopy suggests there is some abnormality of the small intestine.

Finally, you will be interviewed with your child by both a consultant neurologist and a consultant physician from the Department of Child and Adolescent Psychiatry. These experts will seek to clearly identify the features of your child’s development/behaviour problem.

On Friday your child will be discharged to be followed up in the outpatients. The tissue and blood samples will be analysed and the results reported to you, as far as they are complete, at the clinic appointment. Any further recommendation regarding treatment and follow-up will be made at this stage”.

So that is the application and the documentation, Dr Pegg, is that right, which was submitted to your secretary to be handed on to you and to be considered by the committee members?
A Yes.

MS SMITH: Sir, I see it is 11 o’clock and I am now going on to ask Dr Pegg about those considerations. I wonder if it might be appropriate to stop and give him a cup of coffee now.

THE CHAIRMAN: I am sure that will be appropriate at this stage. Can I advise you,
Dr Pegg, that you are under oath and in the middle of giving your evidence. I am sure somebody will look after you with a cup of coffee or whatever you require, but can I ask you not to discuss this case with anybody during the break because you are in the process of giving evidence. We will now adjourn and resume at 11.20.

(The Panel adjourned for a short time)


MS SMITH: Thank you, sir.

(To the witness) There is one last document that I meant to take you to, Dr Pegg, which is on the next page in the bundle you were looking in, page 234. This is the consent form which accompanied the patient handout.

“I have read and understood the aims and nature of this study and have discussed, in detail, the implications of the study with the Doctors concerned. I hereby agree to let my child ……. take part in the study. I understand that I can withdraw my child … from the study at any stage without prejudicing his/her management or treatment in any way.”

You have told us that that is the documentation that was considered by the Committee members. Could you just turn on to page 342 because I want to ask you about the identity of the Committee members at that time and there is a list on that page. We have got you as the Chairman at the top and can I just ask you, do you recall and can you tell us the respective specialism or status of each of the other members?
A Mr Carrier, lay member; Brian Davidson, Professor of Surgery; John Farrell, Chief Pharmaceutical Officer; Andrew Hilson, Nuclear Medicine.

THE CHAIRMAN: I am sorry, can you just go a little bit slowly and also can you pull the microphone closer to you?
A Andrew Hilson ---

Q I am sorry, can you start it again? “Mr Carrier is a lay member.”
A Mr Carrier is a lay member; Brian Davidson is – he was not then, he is now – Professor of Hepatic Surgery; John Farrell is the District Pharmaceutical Officer; Andrew Hilson is in nuclear medicine; Charlotte Humphrey is a general practitioner; Dr Ian James is in pharmacology; Caroline Marshall was an anaesthetist; the Reverend Mitchell speaks for himself; Dr Simon Murch is present; Miss Wendy Reid is a gynaecologist and Mr Andrew Stevens was a management representative.

MS SMITH: When you say that the Reverend Mitchell speaks for himself, was he in fact the hospital chaplain?
A Yes.

Q We have seen Dr Murch’s name on that list. Did he in fact absent himself from the parts of the ---
A He would have gone out of the room while we discussed this, yes.

Q Whilst you discussed a project with which he was involved?
A Yes.

Q Is that the standard procedure if a researcher is a member of the ethics committee?
A It was then.

Q I think it is right that when this application was circulated some members of the Committee did indeed raise queries. If we look at page 240, first of all, that was from, now, Professor Davidson, who you have told us was a Professor of Surgery, and there was approval from him. Then if you go on to page 244, please, this is from Dr Hilson, who you have told us was the doctor involved with nuclear medicine. Is that correct?
A That is right.

Q He said: “NEED ARSAC LICENCE” and can you read the rest of that?
A “CAN WE DISCUSS”, or something. No, “WE ARE DISCUSSING.”

Q Thank you. As far as the ARSAC licence he refers to, what, in brief terms, was that?
A If you need to administer radionuclear tide in a research study you need an ARSAC licence.

Q In fact, was the part of the research study that would have required an ARSAC licence the Schilling test?
A Yes. We got rid of it because the paperwork would have been too much.

Q Just so the Committee know what that is in very broad terms, I think it is right that that is the administration in some sort of substance, such as scramble egg, a small amount of radioactive ---?
A You put it in and see where it goes really sums it up. You put in radioactivity and you scan the person and see where it ends up usually

Q The last comment was from Mr Stevens and that is at page 241 and he was a lay member. Is that correct?
A That is right, yes.

Q He says:

“The project requires children to undergo an intensive regime. It would be helpful for this to …”,

and I think it should be,

“to be debated at the Committee in order to confirm that the benefits of the regime in terms of the clinical care of the individual children involved and the contribution to knowledge about the ‘syndrome’ support the proposed approach.”

Did that seem to you, as the Chairman, to be a helpful observation, Dr Pegg?
A This then prepared us for the real main debate of this study, what was clinical and what was research.

Q Tell me if you have no recollection of this, but do you recall whether that had entered your head, as well as Mr Stevens’, as being an issue when you saw the application?
A I do not know.

Q How did you react to those concerns?
A We wrote to – I think there is a letter in it – Professor Walker-Smith.

Q Can I ask you to look, before that, at page 235, please? We have got a note on there, which is the last page of the ethics application.
A Yes.

Q Is that in your handwriting?
A That is right, yes.

Q Can you read us what it says, please?

“Further discussion required. Meeting with Dr Wakefield. Remove Schilling. Modify consent form.”

Q Do you happen to remember when you made that note?
A I presume on 13 November.

Q That is November, is it, that?
A Yes.

Q Do you recall having a meeting with Dr Wakefield as was apparently then planned?
A I recall a meeting; I do not recall the detail.

Q Just so that I can be clear, I am not pressing you to try and remember things you cannot remember, but when you say you do not recall the detail ---?
A I recall that I had a meeting with him. I cannot recall the details of our discussion.

Q Can you recall when it was in this sequence that you had that meeting?
A No. It would have been after the meeting – it would be in the sequence of the notes as you have it.

Q The matter was first considered at a Committee meeting on 13 November?
A Yes.

Q We have the minutes of that meeting at page 293. Just before I go to this project, Doctor, and I am not going to read it out to you, but I want to give the Panel time to just flick through the minutes of that meeting. Are these fairly typical of the minutes that you would have from a Research Ethics Committee meeting?
A Yes.

Q They have various categories. There are applications to be discussed, which is new applications. Is that right?
A Yes.

Q Then on page 298 they have an “Adverse Effects” section?
A That is right, yes.

Q Under “Ongoing trials – items to report.” Is this researchers who come back to you to report to you some difficulty that has arisen in relation to a particular patient in a research project?
A That is right, yes.

Q Then if we go on there is a section which consists of minor amendments to protocols, page 299. There is a large number of references to the titles of studies. Is this again researchers in the hospital who are reporting to the ethics committee because they have got permission for a study but there are changes that have been made?
A Yes.

Q Is this volume of work typical of a Committee meeting at this time?
A Probably.

Q If we can look at page 294 we see project 172-96 in the middle of that page. It records the fact that Dr Murch left the room quite properly whilst the submission was discussed. It says:

“Not approved: Improvements required on patient information sheet and clarification as to whether this is a study or a normal patient investigation.”

As far as you were concerned, how important an issue was that issue as to whether it was a study or a normal patient investigation to the ethics committee?
A We wanted to know whether the investigations were part of normal care or whether the investigations would have been done for research. Had they been for research we probably would not have passed it.

Q If they were being done as part of normal care were they in fact part of the remit of the Research Ethics Committee at all?
A Not really, no.

Q When the terms are used in those minutes whether it is a study or normal patient investigation, can you explain to us what you meant by those two terms?
A Normal patient investigation is something that would be done because the patient needed it. Study would be the research.

Q Needed it as a result of what?
A Clinical need.

Q We have read through the patient information sheet, as I am sure you all did at the time. As far as you were concerned, did that make it clear whether the investigations were part of clinical treatment or being done for research purposes?
A No.

Q You are very welcome to look back at it, page 232. It sets out, as we have seen, the hypothesis in the first paragraph and it then sets out the aims in the second paragraph and the nature of the procedures in the third. Reading it as the Chairman of this Committee, Dr Pegg, did it seem to you to be more suggestive of research or of clinical care?
A We did not know, so we asked.

Q I will come on to the asking. If we look at page 291, this is a letter to you from Professor Walker-Smith, copied to Dr Wakefield and Dr Murch. It is dated 11 November 1996 and in fact the first Research Ethics Committee meeting, as we know from the minutes we have just looked at, was on 13 November. Do you recall, are you able to recall now whether you received that letter before or after the first Research Ethics Committee meeting?
A No. I presume after.

Q It says, first of all:

“Many thanks for your letter”

do you know how it came about that you wrote to Professor Walker-Smith? We do not have that letter.
A I would have written to everybody whose project was not approved at the ethics committee.

Q The reply to you says:

“Many thanks for your letter.

1. Despite extensive inquiries we could not find out what ARSAC means.

2. Clearly this is an intensive regime with procedures that could be regarded as ‘high’ risk although they are particularly used for the investigation of children with chronic inflammatory bowel disease. 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 devastating condition. In relation to their gastrointestinal symptoms which will be present in al the children we investigate, these have often been under-investigated. We have so far investigated 5 such children on a clinical need basis, all in fact have proved to have evidence of chronic bowel inflammation. One child has already had a significant response to enteral feeding. Certainly there is measurable benefit to the child:

(a) Establishing a diagnosis excluding metabolic or other causes
(b) commencing on a therapeutic regime.

The whole study is parent/patient driven as every case referred has been initiated by the GP by the parents of the child.

I can confirm that children would have these investigations even if there were not trial. I must make it clear that we would not be investigating children without gastrointestinal symptoms.

We agree that consent always involves discussion and signature of the researcher. We will change the protocol.

With Kind Regards”,

and that is from Professor Walker-Smith, and as I say, copied into the other two doctors. As far as you were concerned, Dr Pegg, as the Chairman of the ethics committee, what was the important information that was contained in that letter?
A It confirms that these children were having these investigations anyway. This therefore means that the research permission is just to collate results and publish papers.

Q When you say “have these investigations anyway”, what did you understand “have them anyway” to mean?
A They are clinically indicated.

Q You say in that case the permission was being asked in relation to the collection of information. Is there anything unusual about that, about a researcher simply coming to the ethics committee to ask for permission to collate information?
A No.

Q Once you had had that information from Professor Walker-Smith as to the children having the tests anyway, would it be part of your role as the Chairman or part of the ethics committee role to investigate further that representation? In other words, to investigate further whether these tests were indeed clinically indicated?
A No.

Q Can you tell us why that is?
A We have had a review by Professor Epstein. Professor Walker-Smith has told us something. That is it. At that time, in a year we could do a couple of hundred applications. We did not question what researchers told us. We did not have time.

Q You say you did not have time; would it be a matter that you would consider was open to any doubt?
A I can confirm that children would have these investigation even if there was no trial signed by a professor of gastroenterology. We get letters like that every day, signed by eminent people. We are not policemen. We just believed what people told us.

Q You have told us that as far as the application was concerned, you had difficulty in determining whether these were clinical or research?
A That is why we asked the question.

Q As far as you were concerned, if there was any discrepancy between Professor Walker Smith’s letter and what the original application said, how did you resolve that in your own minds?
A We asked him.

Q When you got the answer?
A The question was answered and then we approved the study.

Q What about the rest of that, letter where the children’s prognosis described as hopeless?
A It is irrelevant to the question we asked.

Q And indeed to the description of their condition as a devastating. Was that also irrelevant?
A It is irrelevant. There is only one significant sentence and that is on the second page.

Q If the tests had been research rather than clinical, would those descriptions then have become relevant?
A Yes.

Q Can you just explain to the Committee why that is?
A You have read the guidelines, you have talked about minimal risk. I do not think this is minimal risk were it to be a study.

Q If we turn on to page 313, Doctor, this is a letter from your secretary, the secretary of the ethics committee. It is addressed to Dr Wakefield. It indicates that approval had been given to the study on 13 November. It says,

“I refer to your recent application to the Ethics Committee regarding the above project and I am pleased to inform you that the project was approved at the meeting on
18 December 1996. This approval is for two years from the date of this letter...

The Ethics Committee will require an annual report on the progress of the study and a copy of the completed study together with any consequent publication. In addition, the Committee must be informed, by the completion of the relevant form, of any untoward or adverse events which must occur during the course of the study ...

The Ethics Committee must also be informed of, and approve, any proposed amendments ...

A copy of the patient consent form and information sheet must be lodged in the clinical notes.”

Then there is a warning about preserving the confidentiality of patient information used in the study. Was that letter correct in saying that the approval had been granted at the November meeting?
A It does not look like it, no.

Q If that letter was sent, what is your view as to that?
A I have a part time secretary cutting and pasting.

Q When you say cutting and pasting, is that letter otherwise in a standard form?
A Yes. This letter is a cut and paste letter. It is not written individually. I had a part time secretary who was overwhelmed. If the dates are wrong, it is probably just that she is used last month’s template, not this month’s template. If you are saying the dates are wrong, it was probably the secretary.

Q I am not giving the evidence, Doctor, you are.
A The dates are probably are not reliable then.

Q You are saying the date of the letter is not reliable?
A I am saying if the letter seems to be before the decision is made, the letter is probably wrong as we could not have written the letter without making a decision.

Q The letter could be wrong in one of a number of respects could it not?
A Yes.

Q It could be wrong simply because Mrs Carroll has made a mistake and said it was approved when it was not, or it could be wrong because the date is wrong, and I wonder whether you can assist us to that?
A Not really.

Q If we go back to the ethics committee meeting in November, that is the one I have already referred you to.
A The date at the end I have signed 18/12/96. That is what I sign when we do the final letters. That is me signing it knowing what the day of the week it is. That is the date I signed off this application. That is a proper date because I have written in writing. It is not a cut and paste date.

Q In that case, we will turn on to the minutes of the next Committee meeting if we may. We have looked at the November ones when the query was raised as to whether these tests were clinically indicated or not. We will now turn on to the December one which is on page 343. If you turn on to page 345, you will see the same project, 172-96 at the top of page. On this occasion you will see,

“Approved: Subject to modification of patient consent form and removal of Schilling test”.

You subsequently sent a letter to Professor Walker Smith on this occasion. That is on page 358 and reads,

“I refer to your recent application to the Ethics Committee regarding the above project and I am pleased to inform you that the project was approved at the meeting on
18 December 1996. This approval is for two years from the date of this letter. Extension of this period will be dependant on the submission of a brief synopsis of the progress of the project together with an estimation of the time required for its ultimate completion. As you may be aware this application was discussed at length at two committee meetings and the approval is conditional on the following:

1) Only patients enrolled after the date of the December meeting will be considered to be in the trial.

2) The Schilling test to be removed from the protocol.

3) The consent form to be modified so that the possible complications of lumbar puncture are explained.

The Ethics Committee will require an annual report on the progress of the study and a copy of the completed study together with any subsequent publication. In addition, the Committee must be informed by the completion of the relevant form, of any untoward or adverse events which occur during the course of the study. The person who provided independent review of the original protocol should also be sent information regarding adverse events.

The Ethics Committee must also be informed of, and approve, any proposed amendment to your initial application which has a bearing on the treatment or investigation of patients or volunteers. A copy of the patient consent form and information sheet must be lodged in the clinical notes.”

There again you make the warning about confidentiality of the patients and the importance of complying with the Data Protection Act. That letter is from you personally, Dr Pegg. It was sent after the December meeting. As far as you are concerned, what were you giving approval for?
A Data collection from the patients for eventual publication.

Q Can I ask you about the stipulations you have made. You say in that letter,

“Only patients enrolled after the date of the December meeting” –

that is 18 December –

“will be considered to be in the trial”.

How common was it for you to put a stipulation of that sort on?
A This is probably unique.

Q Why did you do that in this unique case?
A If you read the application, you will see they mention five patients already done. We do not give retrospect ethics approval.

Q Can you explain to the Committee, what is the importance of not giving retrospective approval?
A If you are going to be in a clinical trial, it has to be a free decision. If you have already taken part in it, you cannot really say no can you.

Q You say it was a unique.
A I had seen those five patients in the application. I had not seen that anything like that before, so we made sure that we were not giving approval for those five patients.

Q When you say you saw them in the application, do you mean the application or do you mean the letter from Professor Walker Smith?
A Somewhere in these note was a mention of five patients to clarify.

Q I read that out to you in the letter from Professor Walker Smith.
A Yes.

Q If ultimately - and, as you know, some of these children’s results were indeed written up in a paper for The Lancet journal - information obtained from investigations on children pre-18 December 1996 were included in that paper, did the authors have ethical permission to publish those results?
A No.

Q Does that apply regardless of the issue as to whether these tests were clinically indicated or not?
A It is a separate issue.

Q You ask for a consent form to be amended to involve the possible complications of lumbar puncture. Was that stipulation consistent with Professor Walker Smith saying the tests were clinically indicated?
A That condition was completely illogical.

Q Could you elaborate on that a bit for us, Doctor? First of all, can you explain clearly – remembering the Committee are lay members and this is very new to some of them – why it is logical and how it could have come about?
A If it was normal patient care, they should have had the normal consent process.
I think people thought that the normal consent form was probably not good enough, so there might have been some logic in it, but, basically, it is illogical.

Q When you say they should have the normal patient consent process, that would have been a clinical consent form?
A Yes, whatever was standard at the time.

Q That would be nothing to do with the ethics committee?
A Not if it is a normal investigation.

Q Can you just tell us in very broad terms what the distinction is between a consent form for a clinical investigation and a consent form for a research investigation; why are they different?
A A consent form for a research application has been approved by an ethics committee.

Q What about in terms of the information as to risk that it gives?
A Can you rephrase that; I do not know what you are asking.

Q I am asking you for the distinction between clinical consent forms and research consent forms. I was asking you whether there is a distinction between the two in terms of how much information they give in relation to risk?
A A research form is very much more detailed than the clinical form.

Q I am sorry if this sounds very obvious, but we need to understand it. Why do you have more information in a research consent form?
A You may well not be benefiting from the intervention.

Q With regard to the whole issue of the patient’s agreement, is there any reason why a patient should agree to research which is purely research and does not clinically benefit them, unless they wish to?
A Are there any reasons? Patients have many reasons for going into research.

Q Absolutely. Is it important that they understand the precise risk they are taking?
A Yes.

Q One further stipulation was that the Schilling test was to be removed. That was in relation to complications for ARSAC licence which you have referred to?
A Yes. The procedure to go through to get it done took so long that everybody decided to take it out.

Q As far as the requirement for the consent forms to be lodged in the clinical notes, was that a standard requirement?
A Yes, it was.

Q Again, what is its importance?
A Purely so that there is record of what the patient has agreed to. That really becomes part of the clinical notes rather than the ethics committee notes. They have agreed to something happening. You lodge an operative consent form in the patient’s notes, you lodge an ethics committee consent form in the patient’s notes.

Q You have told us that as far as you were concerned, permission was being given for the writing up of these results. I do not propose to take you to The Lancet article, but I want to ask you about in it. It was stated in The Lancet article that investigations were approved by the Ethical Practices Committee at the Royal Free. Is that statement correct if those investigations were Project 172-96?
A No, it is not correct.

Q Reverting to the history of the matter, if we look at page 362, please, this is a letter from Professor Walker Smith to you. This letter was copied to Dr Wakefield. It reads,

“Dear Dr Pegg,

Many thanks for your letter. I accept its contents and we will modify our protocol as you recommend and give an annual report of the progress of the study. We will place a copy of the patient consent form and information sheet in the clinical notes”.

What did you understand him to mean when he said, “We will modify our protocol”?
A Remove the Schilling test and explain the lumbar puncture.

Q What about the requirements as to who was to be included, in other words the start date?
A The five people.

Q This is a letter from Professor Walker Smith, Dr Pegg. What about any other doctors involved in the project; would you expect this information to be given to them and, if so, by whom?
A By Dr Walker Smith.

Q It happens to be that to that occasion that letter is from him. You have dealt already with the respective roles of the three doctors involved. Is it common for there to be a number of doctors involved in a research ethics application?
A Yes.

Q Do you have any kind of principle as to how they all know what the ethics committee needs to know?
A No. This was a final approval. It went to the person who signed off the application which was Professor Walker Smith. It is up to him how he informs his co researchers.

Q Some three months later you received correspondence from Professor Zuckerman. That was in April 1997 and the letter is at page 413 in bundle 2. This is a letter from the Dean, Professor Zuckerman, to you, Royal Free Hospital School of Medicine,

“Dear Michael

I am writing following the advice of the Ethics Department and the Legal Department of the British Medical Association, concerning research into Crohn’s Disease which
I am assured had been approved by the Ethics Committee of the Royal Free Hospital and the School of Medicine.

Professor Sir David Hull, chairman of the Joint Committee on Vaccination and Immunisation of the UK Department of Health wrote to me in February 1997 that Dawbarns Solicitors have made a submission to the House of Commons Select Committee that ‘…we are working with Mr Wakefield of the Royal Free Hospital London. He is investigating this condition (Crohn’s)…’ The difficulty is that the solicitors provided a grant to Mr Wakefield to facilitate clinical and scientific studies at a maximum cost of £55,000 and the continued maintenance of a computer database and ongoing worldwide literature searches at a maximum cost of £15,000. These funds have been authorised by the Legal Aid Board but it is not clear whether sum of £15,000 for the database was provided to Mr Wakefield or to the solicitors. The School has placed this money in a suspense account until the following issue is resolved.

The dilemma which the School faces is whether it is ethical for lawyers to fund a particular piece of research where a specific action in law is contemplated, rather than a scientifically based research project. It has been suggested that I explore with you whether the Committee considered these issue and whether the Committee will continue to monitor patient selection (particularly of children), adequate patient confidentiality in the event of possible litigation, the sources and uses of funding and of course ownership of the research findings and the potential uses of publication.

I should stress that the Medical School does not question the scientific validity of the project, the independence of research, the academic freedom of the staff and publication in learned scientific and medical journals”.

When you got that letter, doctor, did you know what Professor Zuckerman was talking about?
A I had no previous information on this subject, no.

Q Did that letter convey anything to you, other than what is on the face of it? Did you understand what he was alluding to?
A I could understand what he was alluding to, yes.

Q Did you review the applications that you had had made by Dr Wakefield?
A Yes.

Q Over the preceding two years?
A Yes.

Q I think it is right that you found four.
A Yes.

Q If I may, they are in the bundles. The first in bundle 1, page 132. If you look at 133, just so we can identify what that was, title of project,

“A case control study to examine early childhood risk factors including childhood infections in patients with inflammatory bowel disease born in XXX between 1923-1940”.

So that was a totally separate subject, but it was the first of the four that you found. If you look at page 137,

“How are the substances for this study being provided, and how is the study being funded?”

at the bottom of the page, and the answer is, “Wellcome Trust”. Is that correct?
A Yes.

Q Then if you go on to page 270, still in FTP1, there is the next application from
Dr Wakefield that you found. If we look at the title of the project at page 271, “Detection of measles virus in blood cells”. Is that correct?
A Yes.

Q If we look on to the funding section, on page 273, there is no indication given as to how that study was being funded. Is that correct?
A No.

Q Are you assisted at all, as to the funding – I do not know whether or not you will be – by looking at pages 276 and 277? That is in relation to the insurance provisions of it. Does that help you as to who was funding that proposal?
A It confirms the Medical School was funding it, I can see from 277.

Q If you go to page 94 in the same bundle, on page 95 you see an application dated April 1996, and if you look at the title of the project on page 96, “Ex-vivo appendix organ culture”. If you turn on to 98, we see under the same heading, how is the study being funded,

“Clinical research funds at the Royal Free Hospital and School of Medicine”.

A Yes.

Q Just to remind everybody, the fourth application is 172-96, that is at page 200, and if we go to page 209 we see the same heading on the form, how is the study being funded, and,

“Clinical research at the Royal Free Hospital (ECR)”,

and you told us that you cannot now recall what that meant.
A Yes.

Q Was there any possibility at that time of you personally not seeing a research application?
A No. Well, yes, there have been some.

Q Normally speaking would you expect to see all the research applications?
A I should see them.

Q Was there any research going on at the hospital which did not require ethics committee approval?
A Yes, because it is only research on patients that we were involved with.

Q That is my mis-wording, as far as research on patients is concerned?
A No.

Q So you were asked this question by Professor Zuckerman in relation to the Legal Aid Board. Were you able to find any project where Legal Aid Board funding had been referred to?
A No.

Q Have you ever seen the Legal Aid Board or the Legal Services Commission as a resource of funding on a research application?
A No.

Q If that had been a source of funding for Project 172-96, would you have expected to see that specifically referred to on the application?
A Yes, you are supposed to put down where you are getting the money from.

Q What if the funding was indirect, in the sense of only being for a part of that project?
A I think you should know where all the money is coming from, not so much from the committee’s point of view but so that patients understand who has a vested interest in the study. For example, if the drug company is sponsoring a drug trial, the patients will be told that the drug company is sponsoring the drug trial.

Q If the research was in any way associated with a legal action – the research in Project 172-96 – what would you expect in terms of the requirements of the ethics committee?
A I am sorry, I do not understand what you are asking.

Q Professor Zuckerman had written to you saying that it was his understanding that there may have been some involvement with regard to litigation. If there had been any involvement with a legal action, with litigation, is that something that the research ethics committee would want to know about?
A Yes.

Q Can you explain to us why?
A Well I have never seen it before and I probably would have done something to find out.

Q You say you would have done something to find out, how would it have affected your handling of the application?
A It is something I have never seen before. I probably would have taken advice on it and it is possible that a study could be funded that way, provided it was written on the information sheet.

Q When you say, written on the information sheet, you mean the information sheet for the parents, do you?
A Yes, for the parents.

Q Would you expect, if it was written on the information sheet, for there to be details explaining it on the information sheet?
A You would expect an explanation, yes.

Q I mean, is this from your point of view as the chairman of the committee, doctor, an ethical issue?
A It is something the committee would have looked at. They might not have turned it down but it is something they would have looked at, and the likelihood is that the information should have been given to the parents so that they knew the motives of the researchers.

Q If Project 172-96 was connected in any way with a legal action and that was not disclosed, how do you view that?
A It is information we should have had.

Q You replied, I think, to Professor Zuckerman on 15 April and that letter is in volume
2 at page 423,

“Dear Dr Zuckerman, Thank you for your letter of 2 April. You did not mention which of Mr Wakefield’s studies had received funding from the Legal Aid Board so
I have reviewed all submissions made by Mr Wakefield to the ethics committee in the last two years. I have discovered four applications”,

and then you list the applications I have referred you to, including as the second one, Project 172-96. Then you said,

“As you can see, none of the stated sources of funding include the Legal Aid Board. Thus as far as the ethics committee is concerned these are ordinary scientifically based research projects and did not raise the particular ethical questions noted in the third paragraph of your letter.

If you have evidence that Mr Wakefield has made a false statement to the ethics committee then I would be obliged if you could formally lay that evidence before this committee”.

At that stage, doctor, were you concerned about the position that had been identified to you by Professor Zuckerman?
A Yes. I just wanted to find out if he had any evidence that the statements on the application forms were incorrect.

Q He replied to you at page 425, the next page,

“You misunderstood my letter of 2 April 1997. There is absolutely no suggestion of any misconduct by Dr Wakefield.

The issue which I brought to your attention is an ethical matter on a possible conflict of interest and data protection in the case of litigation as raised by the Ethics Committee and the Legal Department of the BMA. The School’s concerns and dilemma are outlined in paragraph 3 of my letter”.

You replied to that letter on page 428,

“Dear Professor Zuckerman

To my knowledge the ethics committee has not considered any applications in which the stated source of funding was from the Legal Aid Board, neither has it considered any applications where the stated aim of the research was a specific action in law.

We have therefore not considered the issues stated in paragraph 3 of your letter of
2 April and I am unable to assist you with your dilemma”.

Was that the end of the correspondence?
A Yes, that was the end of the correspondence.

Q If those matters had been included in the application, in other words a stated source of funding “From the Legal Aid Board”, or an involvement with a specific action in law with the research, would those have been matters which the ethics committee would have regarded as part of its remit to consider?
A Yes, we would have discussed it.

Q I think the next letters which I would like to take you to also involve correspondence with Professor Zuckerman, and they are in Bundle 3, if you would turn to that, doctor. It is page 929. That is Professor Zuckerman writing to you in July 1998, so a year later,

“Dear Dr Pegg,

I would welcome your urgent comments and that of the Ethics Committee on the concerns expressed by Professor Sir David Hull Emeritus Professor of Child Health at the University of Nottingham about the investigation at the Royal Free of children with pervasive developmental disorder for bowel disorder. A copy of the letter from Professor Hull is attached.”

The letter from Professor Hull which was attached said:

“Dear Professor Zuckerman

I would welcome your help on a matter of personal concern. In February 1998,
Mr Wakefield and his colleagues reported the findings of their search for the cause of bowel disorder in children with autism. At the M RC meeting on MMR they said that many more children had been similarly investigated and still more were on the waiting list. The studies include: admission to hospital, sedation, lumbar puncture, biopsies of the bowel, MRI imaging and radiography.

In the light of the initial findings and the evidence that as a group the children do not suffer long term bowel disorder, it would seem difficult to justify such invasive studies on clinical grounds. It may be that there are arguments to perform further investigation to elucidate the nature of the brain disorder and the bowel findings. As
I cannot see what those might be, the thought of autistic children being subject to such investigation continues to trouble me, and thus my request to you.

I see that the investigations were approved by the Ethical Practices Committee of the Royal Free Hospital NHS Trust. If the studies are continuing I would be grateful if
I could see the Ethics Committee position on the investigations, especially if they have reviewed their position in the light of the reported findings. If you thought it helpful the Ethics Committee of the Royal College of Paediatrics and Child Health could give an independent view.”

What project did you understand that to be referring to, Doctor?
A The main one that we are discussing.

Q If we can turn to page 939, were you copied into a letter? We can see from the last paragraph:

“I am copying my letter to Roy Pounder Mark Berelowitz and Michael Pegg …”,

to a letter that Professor Zuckerman wrote to Professor Walker-Smith?
A I presume so.

Q The letter says:

“Dear John,

Thank you for your letter of 14th July in response to David Hull’s letter.

I am reassured that the children with autism are investigated according to the clinical need and their clinical management. Nevertheless, it would be prudent to obtain ethical approval if, as I understand it, Andy Wakefield is collecting cases for report by publication, which is therefore a research project.”

Does that accord with your understanding, that a report by publication is a research project?
A Yes.

Q Then:

“A source of some of the funding has been highly controversial … You will know that the Medical School questioned the funding through Dawbarns, Solicitors, and we sought the advice of the Ethics Committee here and subsequently advice from the Ethical Committee of the BMA. This issue must also be resolved without delay.

Please discuss these two matters with the Chairman of the Ethics Committee”,

and then the paragraph that I have just read to you. The information that Professor Walker-Smith had again given, the reassurance that the children were being investigated according to their clinical need and clinical management, did that accord with your understanding of the project?
A Yes.

Q You replied to Professor Zuckerman and that letter is on page 949. You thanked him for his letter and said:

“This matter will be discussed at the Ethics Committee Meeting on 22/7/98 and I shall write to you further after that meeting.”

It appears that there was indeed a meeting on 22 July. We do not have the minutes of that meeting, Doctor, but would the sort of general conversations anyway be recorded in them?
A They might have been.

Q You had a communication with Professor Walker-Smith on 15 July and we can see his letter to you, which is on page 940:

“Dear Dr Pegg

Re: Autism and Non-Specific Colitis and Lymphoid Nodular Hyperplasia

Further to our original study we are not continuing to see such children by clinical need and performing ileo-colonoscopy and limited blood tests in order to decide whether to give such children Mesalazine. As Dr Wakefield is carefully analysing our results and some of the biopsies taken are being used for research (we already have research permission for taking extra biopsies in children who we colonoscope)
I would like formally to request Ethics Committee approval for our clinical research analysis of these children who we are continuing to see by clinical need.”

If I can ask you about that letter, it says:

“Further to our original study …”.

What did you understand that as being a reference to?
A The original application.

Q The title has changed. Did you notice that at the time?
A No.

Q Is there anything odd in fact about your not noticing that? Would you have expected to notice necessarily?
A Not with the volume of work coming through at that time.

Q At that time were projects identified by their number?
A That is another thing. He has not put the number on, so the secretary would not have been able to refer back to it.

Q But you say that you regarded the original study as being the original application. Just so we are clear, the application for which study? Referring to what?
A 17 – is it 2?

Q Yes, thank you. If the change in title was significant in any way, if it was, whose responsibility would you regard it as being to point that out?
A I cannot really say, but a journal editor might question it if he saw that the ethics application and the paper he is publishing had different titles.

Q Did your ethics committee actively look for changes in a research project?
A No.

Q Can you explain to us, remembering again we are all starting from scratch, so in simple terms, the reference to Professor Walker-Smith saying:

“We already have research permission for taking extra biopsies in children who we colonoscope”,

is that ---?
A That is another study.

Q Can you just explain that? How does that come about? Was that a general research application?
A They had made a previous application to take extra biopsies for children who were colonoscoped, and there is an information sheet and everything for that.

Q Was that children who were being colonoscoped in the course of normal clinical practice?
A It was for every colonoscope they do they took an extra sample, I think, but they had a permission for it and an information sheet for it.

Q Was that normal practice within the hospital at that time for doctors to have a general research permission in respect of their patients?
A I think it is ahead of practice at that time. I think if you go into the College of Physicians’ guidance there was a view at that time that it was not even necessary to get consent.

Q If you were just taking an extra sample?
A Taking extra. There was a body of opinion at that time who did not even think that approval was necessary to take extra … If you were actually doing the investigation, i.e. the patient was not having any more risk, then taking extra samples you do not even need permission for, so this was almost ahead of feelings at that time, and of course we know now things have changed.

Q Yes, and that is as a result of all the ---?
A Yes, but remember this is pre the new Tissue Acts and all that sort of thing where practices were very different.

Q When you say it involved no extra risk for the patient, do you mean they were going to undergo ---
A You are going to have a colonoscope anyway, we are going to take one, can we take another one?

Q So you were taking one for clinical diagnostic purposes?
A Yes,.

Q And in addition to that you take an extra one for research purposes?
A Yes, with the risk being putting the colonoscope in, which you are already doing.

Q As far as the remainder of that letter, it clearly states that the children were being seen for clinical reasons and the investigations done for clinical reasons. The request was for ethical approval in relation to the analysis of the results, and presumably the writing up of those result. Did the ethics committee in fact approve that extension?
A Unless you have minutes of a committee to show me, I cannot answer that question.

Q I can take you on to the letter that you wrote back to Professor Zuckerman, which is on page 951:

“Dear Professor Zuckerman

The above application was first considered at the ethics committee meeting on 13/11/96”,

and I should say it now has its full title, the number 172-96, and:

“A new paediatric syndrome: Enteritis and disintegrative disorder following measles/rubella vaccination.”


“The committee was very conscious of the requirements to avoid non-therapeutic research of more than minimal risk in young children. We therefore asked for reassurance that the investigations that were to be carried out in this study were clinically indicated and were not being carried out just for research. Professor Walker-Smith gave me that written assurance”,

and then you quote the letter which we have already read, the original letter.

‘I can confirm that children would have these investigations even if there were no trial’.

Thus at the ethics meeting in December there was no real ethical issue to address. The children were having the investigations as part of normal clinical practice and the ethics committee was involved purely because the cases were being collected for report by publication. The study was therefore approved.”

Then you go on to the situation with regard to the letter I have just read to you.

“On 22/7/98 the ethics committee reviewed this study again following a report by Professor Walker-Smith. The study was now titled ‘Autism and Non-Specific Colitis and Lymphoid Nodular Hyperplasia’. Again Prof. Walker-Smith gave us reassurance that only clinically indicated investigations would be carried out”,

and you quote him again:

‘I would like formally to request Ethical Committee approval for our clinical research analysis of these children who we are continuing to see by clinical need.’

Again the ethics committee approved the study on the understanding that all that was being approved was data collection.

On 9th July you wrote to me for my comment on the letter of Professor David Hull. In his letter Professor Hull states:

‘I see that the investigations were approved by the Ethical Practices Committee of the Royal Free Hospital NHS Trust.’

This is, of course, incorrect. We did not approve the investigations. We approved data collection from clinically indicated investigations. It is not, at present, the role of an ethics committee to question clinicians judgement as to what are and what are not clinically indicated investigations. However we do not just take the word of the investigator, rather we ask for independent expert review of the applications. In this case Dr Owen Epstein provided a review and I have a letter from him ‘strongly supporting’ the study.

I hope I have answered all your questions regarding the ethical review of this study.”

Did that letter sum up your position in relation to various bits of correspondence that I have referred you to, Doctor?
A Yes.

Q You highlight, in particular, at the start of that letter the fact that the committee was very conscious of the requirement to avoid non-therapeutic research and more than minimal risk in young children. I am sorry if this is rather an obvious question, but why in particular did you put that at the start? Where was that derived from, that requirement?
A I think it just seemed a logical start to that sort of letter.

Q Yes, but the substance of it, the content of it, that you were conscious of that requirement?
A Just to show to him that we knew the guidelines.

Q So it derived from the guidelines?
A Yes.

Q Professor Zuckerman, to complete that chain of correspondence, replied to you and that is at page 954, and he said that he had replied to Professor Sir David Hull. Attached to that was a letter which set out the details. I am not going to read it through. It set out the details of what you had said. I am just going to the last paragraph:

“The Chairman of the Ethics Committee also wrote to me pointing out that our comment that: ‘I see the investigations were approved by the Ethical Practices Committee of the Royal Free Hospital NHS Trust’ was incorrect. He adds that the Committee did not approve the investigations. The Committee approved data collection from investigations that were indicated clinically and that it is not the role of an Ethics Committee to question clinicians’ judgement as to what are and what are not clinically indicated.”

and then he pointed out, as you had, that there had been an independent review of the science,

“and in this case of this particular investigation the opinion of a senior gastroenterologist was sought and a review was provided with strong support for the study.”

So did that again accurately reflect the position of the ethics committee, that they had not approved the investigations?
A Yes.

Q I want to turn on to a completely different application, Doctor, which is in bundle 3 again, so it is in the bundle you are in and it is at page 1083. (After a pause) I am not going into any detail in relation to this, Doctor. There are just some brief details that I want to ask you about in case it should become relevant at any point. This is a project which was entitled “Immunological and Virological Studies in Autistic Enterocolitis” from Dr Wakefield. It was submitted to you in May 1999. Is that correct, from that letter?
A Yes.

Q If you turn on to page 1086, the application form, the format of the application form now has changed, but we see at the bottom of page 4 who is sponsoring the study. Is that a reference to a financial sponsorship?
A Yes.

Q It refers to a particular charitable trust, Scott of Yews. Is that correct?
A Yes.

Q I think, in case it assists anybody, you have also obtained a list of the projects which were undertaken by Dr Wakefield when he was at the Royal Free Hospital from the Research and Development computer system. That is on page 1223. There are a great many projects listed there. Is it possible, Doctor, to say whether all the projects which went before the ethics committee will be included on that computer system?
A No.

Q But will they, as far as you are aware, reflect the majority of them?
A Probably

Q Is that the best that the committee can do at this late stage?
A We are not obliged to keep anything after three years.

Q I am now going to turn again to another completely different matter, which is an application which was submitted to the ethics committee in February 1998, and it is in volume 2, page 675. Doctor, just so you know where I am coming from, I simply want to take you briefly through this application to establish the facts of what the ethics committee were asked about in relation to this research project. It is a completely separate research project. It was for ‘A preliminary open label study of the effect of oral measles virus specific dialysable lymphocyte extract transfer factor in children with autistic enteropathy’. We see in the letter to you,

“One child who has received this treatment on a compassionate basis appears to have made substantial improvement without any noticeable adverse effects”.

If I may, I just want to go to the protocol starting page 676. We will see that that sets out the investigators. The principal clinical investigator responsible consultant, Professor Walker Smith. The principal scientific investigator, Dr Andrew Wakefield. Is that correct?
A Yes.

Q The title of the project is page 677. The objective:

“To assess the clinical benefit of measles virus specific transfer factor in children with development disorder and intestinal inflammation (autistic enteropathy)”

Then under “Design of the study”

“Open label open label study of children with autistic enteropathy”

If you go on to page 679, the substances to be given is set out at paragraph 10. Then under “Adverse events” it reads,

“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 on page 680, under “Discomfort” it reads,

“... There are no anticipated side effects of the drug. Virus specific transfer factor has been given in millions of doses without adverse effects, other than mild pyrexia in rare instances”.

This of course is measles specific as opposed to generally virus specific.

“Anecdotically, we have started one child with autistic enteropathy on DLE TF 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”.

What I want to ask you, Doctor, is whether you can assist us at all on what ‘approved compassionate basis’ would have meant?
A No.

Q Could it be approval by the ethics committee?
A Unlikely.

Q Would the ethics committee ever consider an application in respect of the administration of a substance for one individual patient?
A There are trials in one patient, yes.

Q But then you would expect a formal application in respect of it would you?
A Yes.

Q In so far as the remainder of the application is concerned, there is a patient information sheet at page 682. This is the information sheet that the parents would be given. Going down to the fourth paragraph,

“A possible new treatment, called measles specific virus specific Transfer Factor has been developed by NeuroImmuno Therapeutics Research Foundation, an American based Research Foundation in collaboration with workers at the Inflammatory Bowel Disease Study Group at the Royal Free Hospital School of Medicine”.

Then skipping down to the last paragraph,

“This 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 successfully treatment, has been extremely well tolerated without any adverse affects, 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 set outs what the child would have if entered into the study.

“If you agree to your child taking part in the study, your child will undergo a formal standardised behavioural assessment ...”

Then the last paragraph,

“Your child will receive DLE TF which should be collected from pharmacy before you leave hospital ...
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 ...”

At the bottom of the page under the heading, “Are there any risks involved?”

“Along with the possible desired effects, any medication can 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 is appropriate”.

Then under the heading “Are there any benefits” it reads,

“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 to the benefit could last”.

Then at page 691 there is an attached protocol. We see at the top of page 693 under the heading “Background” “Clinical study” it reads,

“We have investigated, in a pilot study a consecutive series of 12 children for a new syndrome comprising ileocolonic lymphoid nodular hyperplasia, chronic non specific colitis and regressive developmental disorder. A summary of these studies is given below. We have now completed the clinical investigation of a total of 33 children,
32 of whom show the identical syndrome”.

Then it sets out the patients, the first 12. Then at the bottom of the page, under the heading “Conclusions of Clinical study” it reads,

“We have identified significant gastrointestinal pathology in association with developmental regression in a selected group of previously, apparently normal children. In the majority there is a clear temporal association with possible environmental triggers. 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”.

That was the protocol attached. Could I ask you, Doctor, to turn to page 817. That is a letter from Professor Walker Smith to you, apparently in relation to some communication between you saying,

“Since this is an open labelled trial with no placebo group, no DDX is required.
I have consulted with both the Dept of Health and their handbook on trials with respect to this”.

He talks about the fact that they were not going to be using a control group, the comparative group that you have told us about and the reasons for that. It is not an issue in this case, Doctor, but for reasons which will become clear, just so that we are clear about it, can you just tell us in very broad terms what a DDX is?
A It is like the MHRA now. It is permission to use not from us, from the Department of Health a drug in a drug trial. Obviously we questioned whether such permission would be needed and he has obviously consulted with the Department of Health as to whether that permission was required and it was not.

Q As I say, it is not an issue.
A DDX stands for doctors and dentists exception certificate.

Q I am only asking you to look at this correspondence because it just sets out the history and reminds you and the Committee. If you go to page 822, which is in bundle 3, this is a letter from you to Professor Walker Smith saying you have taken some advice and you thought that a DDX was necessary and you enclosed with that at page 823 the reason why you thought a DDX was required. Then if we go on to page 959, there is a letter to Professor Walker Smith because, apparently, there had been some delay in relation to the application and you were asking about a reply. That is no criticism of anyone of course. Professor Walker Smith wrote back to you on page 960, saying,

“Many thanks for your letter. I apologise for not replying before but there has been some time involved in determining details of European Safety Standards requirements. We have no doubt that the transfer factor 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. It will not thus be possible for us to have the information ready for the October Ethical Committee meeting, but it will be for the following ...”

Then he writes on page 961,

“I now have the safety details concerning the European standards and Regulations on Drug Safety. I enclose the relevant correspondence and hope this meets the Ethical Committee’s concerns”.

Enclosed with it was a letter at page 962 from Dr Wakefield to Professor Walker Smith,

“Please find enclosed a summary of safety and efficacy evaluation from Professor Charles Kirkpatrick, Professor of Immunology at the University of Colorado in Denver. Both Professor Kirkpatrick and I have now had time to review extensively the EU regulations on drug safety, and concur that transfer factors comply with these safety regulations. Professor Kirkpatrick has gone to the trouble of enumerating the trials that he has 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 give subcutaneously. The plan for our trial, as you are aware, is to deliver the drug orally. In conclusion, therefore, we are confident that the drug and the protocol comply with the European Standards and Regulations on Drug Safety”.

That was enclosed to you. Then on page 969, there is a letter from Professor Walker Smith enclosing the exception from the Medicines Controls Agency. That is the DDX. In fact if you keep your finger in there and look back at page 944 in the bundle, you will see that that is the DDX exemption certificate. We will see the remark at the bottom which reads,

“It is assumed that the Transfer Factor is produced in accordance with the principle contained in ‘The Rules Governing Medicinal Products in the European Community”

and then there is the reference to it. That of course ties in with the safety investigations that have been carried out.

Then, just for the sake of completeness, on page 970, Doctor, we see that the application was approved because if you look at the top of the page, there are the words, “approved 18 December 1998”. Is that correct?
A Yes. Just looking at this trial, we obviously did not want to give permission for a drug to be used. We had no evidence that it was safe and we did not approve this until we got the letter from the MCA.

Q Can I take you to page 1223 of volume 3 that you are in. It is a computer print out of the ethics committee. You told us you were not able to say whether all the applications were there. Can you just tell us this: all the applications which are on that list, would they necessarily have gone before the ethics committee?
A You cannot tell from this whether it is research on patients or, you might say, bits of patients. So the answer to your question is no, I think.

Q If it is research involving patients?
A It should come to us, yes. Some of this might be test tube research.

MS SMITH: Sir, that concludes my examination in chief, and I can see the time.

THE CHAIRMAN: Thank you very much indeed. It is the appropriate time to adjourn for lunch. It has been a long morning. We will resume at 2 o’clock. I need to remind you,
Dr Pegg, once again that you are still under oath and therefore should not discuss this case with anyone, including any of the lawyers. We will resume at 2 o’clock.

(Luncheon Adjournment)

THE CHAIRMAN: Good afternoon. Mr Miller, you are going to start with cross-examination.

Cross-examined by MR MILLER

MR MILLER: Dr Pegg, you gave us a span of years. Do you remember when you became Chairman of the local research ethics committee?
A Not definitely, no.

Q Before you became Chairman, what was your experience on the committee?
A I think I had done about seven years in the eighties.

Q Was there then a break and you came back in the nineties?
A Yes.

Q In terms of chairman, was your predecessor Baroness Gardner?
A No.

Q Was there a Baroness Gardner who was the chairman?
A No.

MR MILLER: I would like you to look at a document from about that time in 1995, and I will just ask for your comments on it. We are going to start our process, sir, of introducing documents into the chronological bundle. By default I seem to have got green and shall remain green for the rest of this case. There is still some considerable debate about the colours which have been used by others which will be resolved overnight, I hope, but it is only me who will be introducing documents today. Can I hand in a clip of correspondence. It has already been numbered. I will hand in the whole clip now and we can insert it at the appropriate time.

MS SMITH: Can I make it clear – this is not a complaint; it is just an observation – that this will be the first time that we too have seen any documents that Mr Miller is producing.

THE CHAIRMAN: That observation has been noted. So we are not going to give these documents any numbers, but put them in, for example, 86a after page 86.

MR MILLER: Exactly, sir. They will either have an “a” number, a “b” number or a “c” number. Turn to the first page, if you would, Dr Pegg. The letter comes from the Academic Department of Paediatric Gastroenterology. Do not go all the way down, just look at the first page. It is from Professor Walker-Smith. It is addressed to Baroness Gardner, Chairperson of the Ethics Committee, Royal Free Hospital.
A She is the chairman of the whole hospital, not the ethics committee.

Q But it is dated 24 August,

“Dear Baroness Gardner,

Re Paediatric Gastroenterology: As you know my department transfers to the Royal Free on 1 September. For some years at Barts during the course of colonoscopy in children we have had ethical permission to take two extra mucosal biopsies for research purposes. During colonoscopy children routinely have multiple biopsies taken for diagnostic purpose (4-6). The parents have signed a form as attached granting permission. These biopsies are used for a variety of ‘research’ investigations such as cytokine production where on occasion information of direct and immediate importance to the child’s illness has been obtained as well as of research importance.

I would be very grateful if you would grant permission for this to continue after our move to the Royal Free”.

Maybe he addressed it to the wrong person, but what he got back at page 86c is a response from somebody whose name we are familiar with, Maureen Carroll, the secretary of the Ethical Practices Sub-Committee, dated 5 September 1995,

“Re The taking of two extra mucosal biopsies for research purposes during the course of colonoscopy in children

I am pleased to be able to inform you that your recent submission to the Ethical Practices Sub-Committee has now received approval by Chairman’s Action.

This approval will be formally documented at the next meeting of the full committee and meanwhile you are free to carry out the above procedure at the Royal Free.

Please note the code number 162-95 that the submission has been given and quote this in all correspondence”.

So whether it went to the right person, it ended up with yourselves, the secretary of the committee saying it had been approved by chairman’s action. Is that fair?
A It would appear to say that, yes.

Q We can see at 86b, it may be relevant to this case, that there is a consent form, a proforma consent form for research biopsies to parents:

“Your child has been referred for diagnostic colonoscopy. Several small pieces of tissue (biopsies) are taken during the procedure for diagnostic purposes. Chronic inflammatory bowel diseases are still little understood and their cause is unknown. It is therefore of great value for laboratory research to have such biopsies available to study how inflammation in the bowel develops and is influenced by treatment. Your permission is asked to agree for two extra biopsies to be taken for these purposes.

Whether or not you agree to this will in no way influence your assessment or treatment”.

Then the permission given, the patient’s name, parents’ signature, etc., and the signature of the doctor. So it encloses a draft consent form for research biopsies, which presumably would be expected to be discussed and ultimately signed by the parents and the medical practitioner concerned. Is this the application procedure which you described earlier as being forward thinking at that time in 1995?
A Yes.

Q I think if we really did a bit more work, which is not necessary, later in 1997 Professor Walker-Smith asked for similar permission in respect of upper GI endoscopy as well and received permission for that.
A Sorry, the question is?

Q Were you aware of that, that he applied to your committee in 1997 for permission in relation to upper GI endoscopy?
A I have no way of knowing that.

Q The only way you could know it is because the files of the committee --
A We need to see them. Is there a file here because I cannot remember these things.

Q This one is the one to which you were referring earlier, is it?
A Yes.

Q Can I ask you about your ethics committee in 1996? Were you given any training or advice as to how you were to approach applications placed before you?
A No, there was no training. We trained on the job.

Q It is fair to say in 1996 there was not the same degree of rigour applied to research and research applications for ethical permissions as there might be in 2007, is it not?
A I think the rigour that the members of the committee applied then is probably comparable with that that they apply today. What does not have the same rigour is the bureaucratic infrastructure.

Q I think you described local research ethics committees as isolated, unpoliced entities within hospitals.
A Yes. But I did not say that the members of those committees acted with any less rigour when they saw an application. They might not have had the same formal training, the procedures of the committee might not be so well defined, but thinking back over my decade as a chairman, the type of discussion we have about applications in 2007 is not a dissimilar discussion to that we would have had in 1997.

Q What about your dialogue with the clinicians and the researchers involved in making applications?
A The only thing that we really changed is that we now encourage researchers to attend meetings for direct dialogue rather than having a written type.

Q So if a point arises during a meeting, they can address it.
A Yes.

Q You also say at that time in 1996 they were in their infancy and you had only just started to hold meetings.
A Yes. I think – I do not know quite what the date was – in the early nineties ethics committees did everything by post. They never actually formally met. The Royal Free committee I think had four – I am guessing here – a couple of years before this time, and started to actually formally meet.

Q We see some of the minutes of the meetings in this and I think you said earlier that you had 11 meetings a year.
A That is right.

Q A large number of applications to be considered at those meetings.
A Yes, but for example at last week’s meeting one application took half the meeting, all the other applications took the other half of the meeting. There is a large number of what
I would call mundane technical applications that can be dismissed in a couple of minutes and you tend to find that each committee meeting is dominated by one or two major studies.

Q In terms of guidance from on high, you were taken at length this morning through the Royal College of Physicians guidelines, and I think you said the advantage of that was that it remained on your shelf after all these years, and there have been many others at the time to which you had access at the same time.
A Yes.

Q We are not to read it as an Act of Parliament, that piece of guidance; it was part of a number of sources of guidance which was available to ethics committees.
A That is correct.

Q You explained the procedure in 1996. You receive an application for approval. As we have seen with other documents in the bundle, it is in a standard form, set up in a proforma way which you had devised. Is that right?
A Yes.

Q Fourteen sections, the one with which we are concerned, to which may or may not have been attached a copy of a protocol which was intended to be followed, probably there would have been.
A Probably.

Q The person submitting the application, before it is submitted, has to provide an independent review of that protocol.
A That is correct.

Q Because it has to go to the committee not only with the substance of what is proposed, but also somebody else who is independent saying why it is a good idea.
A Yes.

Q Again it starts off with paper and the application is sent round to the individual members before the meeting, and they would have the opportunity, if they considered it appropriate, to make comments on particular aspects of it.
A Yes.

Q We have seen three comments in this case, in terms of 172-96, one from the Professor of Surgery saying approved as far as he was concerned, and then two comments. Dr Hilson was saying what about the ARC-AC we are discussing and then the substantive matter raised by one of the lay members of the Panel.
A Yes.

Q Could you turn up your copy please of 172-96, FTP1, page 200. You say that you received this from Professor Walker-Smith. Why do you say you received it from him?
A Because his name is at the top of it. It might have come from his secretary. It might have come from anybody.

Q Your secretary wrote back to Dr Wakefield acknowledging receipt of the application.
A Yes.

Q That is page 239 in the bundle. Just turn to that. That has the date of 1 October 1996,

“Dear Dr Wakefield, I acknowledge receipt of your application for ethical approval of your research project”.

Then there is the code number. So she wrote that to him and as I understood your evidence, what you are saying was because you have on page 200, under the first paragraph, “responsible consultants”, three people’s names, Professor Walker-Smith, Dr Simon Murch, both from the Department of Paediatric and Gastroenterology, and Dr Wakefield from the Academic Department of Medicine, you assumed it was Professor Walker-Smith who was the lead in this. Is that right?
A Yes.

Q One of the things you said led you to that conclusion was that he had signed off this application. Where do we find that?
A Section 1, signature donating approval “Head of Department”.

Q I think you know that is Professor Pounder’s signature, not Professor Walker-Smith.
A I do not know who it is. You can never read signatures.

Q But that is Professor Pounder who was the head of Dr Wakefield’s department, and you were familiar, presumably, with Professor Pounder because indeed on the first meeting there were two applications by him for ethics committee approval.
A It is the first time anybody has brought that to my attention. I assumed that was Professor Walker-Smith’s signature.

Q Will you accept from me for the moment that that is not Professor Walker-Smith’s signature, it is Professor Pounder’s?
A It is just two squiggles really. It could be anybody’s.

Q But the head of the department is the approval of the head of department from which the application emanates, is it not? That is what it is supposed to be.
A It is never quite defined.

Q You said you knew nothing about what Dr Murch’s position in the study was, for instance. In terms of division of the work involved, what if anything did you understand to be the roles of those mentioned in Section 1?
A My understanding was that Professor Walker-Smith was the head of department. In applications heads of department have variable amounts of commitment to a piece of research. Some just sign it, almost without reading it sometimes. Others have an active part in it. Whether he had a greater or lesser part in the study, there is no evidence to show. Simon Murch, there was never any correspondence with him and his name is not mentioned in any other correspondence and therefore I cannot say what his involvement was.
Dr Wakefield we assumed was the major researcher. He answered the letters and did most of the correspondence.

Q I would just like to know, when you talk about, “answered the letters” and did most of the correspondence, are those letters to which we have already referred today?
A Yes.

Q Do you have in mind any particular letters which were his letters?
A You allude to a meeting between me and Dr Wakefield which gives the impression that any practical sorting out was his responsibility.

Q I alluded to that?
A Sorry, no, Ms Smith did.

Q Apart from that, as yet we have not seen any other correspondence I think between you or between the committee apart from Mrs Carroll writing a letter acknowledging that there was a lodged application.
A She sent it to Dr Wakefield, yes.

Q And also you pointed out earlier this morning, on 14 November I think she wrote saying it had approval.
A Yes.

Q In terms of your correspondence, do you have any letters from you to Dr Wakefield?
A No, I think I only have my notes about a meeting.

Q In fairness to you, Dr Pegg, it may be that you simply looked at the man whose name was at the top of the list and chose to correspond with him until somebody else steps in and takes over, because there does not seem to be any other clue from the application itself.
A I mean, you have three people. You know who the three people are. As long as somebody answers the questions you are not going to worry who does. They are all involved in the study and you presume they talk to each other.

Q I was hoping I was helping you out. There was nothing about the study itself. You simply went to the person who seemed to be the most senior. If somebody else had intervened in the correspondence and taken over, you would have corresponded with him.
A Yes.

Q But you cannot say what, if anything you had in mind as to the roles of the various people concerned.
A No, everything was an assumption. There was no evidence who did what.

Q There are a whole lot of other people mentioned on that page, page 200. There is
Dr Peter Harvey who signed the document, who I imagine if you looked at the Department of Neurology you would have thought had something to do with the neurological side of things, and Dr Berelowitz, Department of Child Health (Child Psychiatry), psychiatric.
A You would not necessarily assume that. It means that their departments are collaborating in some way. This again is the heads of the departments. You do not know whether they are doing it personally or they have other people doing it.

Q Certainly, apart from being nominated as a responsible consultant there is no other reference to Professor Walker-Smith playing any particular part in this study, is there?
A There is no evidence of who did what, no.

Q Did you know Dr Wakefield at that time?
A Not in a personal manner, no.

Q Professionally did you know him?
A Our paths I do not think have ever crossed prior to this.

Q Indirectly they may have in previous applications for ethics committee approval, but that would not involve crossing of paths?
A Could you define “no” and I will answer the question?

Q Did you know of him as a doctor involved in research ---
A I know all the names of all the doctors at the Royal Free involved in research, yes.

Q You had obviously been there for some time?
A Yes.

Q And he had been there for some time?
A I would not know when he started.

Q But certainly well before 1996?
A If you say so.

Q What about Professor Walker-Smith? Did you know him? Have you ever met him?
A I think I may have passed by.

Q Had he made any application for ethics committee approval apart from the one that we have looked at earlier?
A I do not know. I know he had only recently joined the Free, transferring from Barts and the London.

Q Can we look at the application itself? It was supported by Dr Epstein in a short letter addressed to Dr Wakefield which we looked at earlier on. What is the purpose of a letter such as the letter which Dr Epstein wrote? It is on page 236 in the bundle.
A To provide independent advice on the scientific merit of the study.

Q The outline of the study is clear, so it is clear what it is about, and the methodology, testing the hypothesis as appropriate. That, presumably, would involve what was going to be done, the investigations and the testing that was going to be used to try to arrive at a conclusion?
A Yes.

Q He is a gastroenterologist, so had some insight into that aspect of the studies, whatever it was?
A Yes.

Q You were content, presumably, having received that, at least to know that there was somebody else there who had looked at it as a gastroenterologist and appeared to approve the study?
A Yes. I was more familiar with Dr Epstein than any other of the researchers.

Q Is he another gastroenterologist, do you know?
A Yes.

Q Turn back then to page 200 and 201. The title of the project, paragraph 2:

“A New Paediatric Syndrome: Enteritis And Disintegrative Disorder following Measles/Rubella Vaccination.”

What did you understand at the time by the term “disintegrative disorder”?
A I do not know what we thought of that.

Q Do you have any thoughts about it now?
A At this point now I could not define to you “disintegrative disorder”, no.

Q Can you give us a rough idea about it?
A We discuss a study. You mug up on it like you would mug up a case, but 12 years down the line you do not know what it is.

Q There is no intended criticism there, Dr Pegg, I just want to know what, either now or then – then and now I suppose ---
A All I remember is that at the time I was quite well up on this because I remember looking up what this was all about, but with the passing of years I cannot work out – I cannot remember. I actually remember getting it clear in my head what it was about at the time, but I cannot tell you now.

Q Did you understand that it was something that was not on the face of it related to gastrointestinal disease?
A I remember the study, that I actually did get on board with the background and I did understand it, because of all these questions; but I could not answer any questions on it now.

Q Under the design you have what on the face of it is going to be (paragraph 4) where the patients come from, or the route by which they get to the Royal Free, and then the sort of investigations that are going to be carried out or may be carried out, the bullet points, all of those down to the bottom of the page. It is clear on the face of it that they may include routine ileocolonoscopy and upper gastrointestinal endoscopy, barium follow-through, MRI, EEG, and lumbar puncture. So it is clear on the face of it that the design of the study includes those investigations?
A Yes.

Q Then if you turn to page 209, taking up really the same point, paragraph 11:


(Venepunctures, arterial blood, urine, tissue biopsy, etc.) State type, frequency and amount.”

is that part of the proforma, that first part of paragraph 11, or is that something that the team has put in?
A How do you mean, part of the proforma?

Q This is a proforma which you have developed ---?
A Yes.

Q -- which includes headings and what appears anyway here to be a question.
A This is just another – as you say, 10, things given to the patient, 11, things taken from the patient. It is just asking what will be taken from the patient.

Q I wonder whether this is a pre-prepared question, if you like, because they know the answers, but those are the questions:

“State type, frequency and amount”,

and then there is another question after the four sub-topics:

“Would the procedure(s) or sample(s) be taken, especially for this investigation, or as part of normal patient care?”

I just wonder whether those are built into the proforma and the answers are there. The questions are on the form as it is prepared?
A My blank will say:


(Venepunctures …”,

and there is a gap where he has put in the things (1) to (4). The words:

“Would the procedure(s) …”,

is part of my proforma, and his answer “Yes” is what he has written. So, the two middle bits he as written and the other bits I have written.

Q That is all I was asking. These are prepared questions, to which he responds:

“(1) Two venepunctures of 10-20 ml each …”?

A Yes. No, those four things he wrote. I did not write those.

Q No, obviously not, but it is your question.

“(2) Ileocolonic tissue biopsies 10 per patient
(3) One 24-hour urine collection
(4) Cerebrospinal fluid 3 ml.”

A We always then ask which ones are specially for the study and which ones … We want to know everything that is done. We then ask which is for the study and which is for normal care, and of course then he has got the second answer.

Q Yes.

“Yes: in view of the symptoms and signs manifested by these patients, all of the procedures and the majority of samples are clinically indicated. Additional intestinal biopsies (5 per patient ) will be taken for viral analysis. DNA for genotyping will use blood cells isolated from the routine blood sample, and will not require an additional sample.”

So there it is being asserted that the procedures would have been effectively clinically indicated?
A Yes.

Q Just turning 20 pages further on to page 233, this is the patient handout, is it not, starting on page 232?
A Yes.

Q Which you regard as an important part of the application, do you not, the patient handout, because it has got to be comprehensible to the parents in this case because it is a child case?
A Yes.

Q What the draftsman of this has done is go through what is likely or may happen and the reasons for it, ending up on page 233 in the last paragraph:

“On Friday your child will be discharged, to be followed up in the outpatients. The tissue and blood samples will be analysed, and the results reported to you, as far as they are complete, at the clinic appointment. Any further recommendations regarding treatment and follow-up will be made at this stage.”

So this is the part that it is intended will go to the parents at the time that the child comes in or agrees to come in, which gives the description not only of what happens while he is in there, but what will happen when the testing is finished.
A Yes.

Q You stressed – and I will come back to it later – that the patient information sheet is important because the parents have to make an informed decision about whether or not their child is going to be investigated?
A Yes.

Q It does not look from what happened as if you were prepared to take the assertion in the application form at face value, or at least the committee was not prepared to do that, because at least one of your colleagues on the committee, Mr Stevens, made the suggestion on 4 October 1996 which we have got at page 241. Let us just turn that up, please. This is the method by which your committee members communicate to you that they have a query or a problem with what is begin proposed in any particular application.
A They also communicate at the … They often add things at the meeting. This was always so that I could see what was coming up and organise the meeting.

Q Also, in terms of the timing in this case, the application appears to have been submitted in September and it does not look as though the next meeting was coming up until 13 November. Is that right?
A That was the scheduled meeting, yes, 13 November.

Q It is distributed to the proposed members of that committee and whether they wish to or not they will put in some advance warning to you of matters that they might like to consider at that meeting?
A Yes.

Q One is an approval, which is from Mr Davidson. There is the ARSAC, which we may come back to, and then there is this one from Mr Stevens. What he is flagging up here, despite the fact that it is said in the application that these will be clinically indicated, is that this is an intensive regime and it would be worth debating at the meeting the benefits of that regime in terms of clinical care of the individual children and the contribution to knowledge about the “syndrome.” In other words, is it worth doing these for that purpose. Is that a fair summary?
A Yes.

Q I do not think that Mr Stevens identifies the procedures which he has in mind. He says it is an intensive regime as described, going on over a period of a week, as an inpatient at the Royal Free.
A Yes.

Q Do you have your statements there, Dr Pegg?
A I was told not to bring them.

Q I wonder if you could have copies of your statements there. I am not going to ask you to look at them, just to have them by you if any dispute arises between us. (Same handed) Would you just confirm that both your statements are there?
A No.

Q The second one is following. (Same handed) I am just trying to get the sequence correct. This query is raised by Mr Stevens on 4 October. In your first statement at paragraph 23 you said:

“Following receipt of these queries I met with Dr Wakefield in order to discuss with him the nature of the members’ concerns*”,

* document not available for checking

and you point to a handwritten note on page 235 in the bundle, which is in your handwriting. It is the note of 13 November, so that would be five weeks further on, which says:

“Meeting with Dr Wakefield. Remove Schilling. Modify consent form.”

I think you told us this morning that you would take that as being your note of something that you wrote on 13 November?
A Yes

Q As to whether a discussion took place on that date or on some other date you cannot say?
A It is likely to be the date. When I am doing this, if you think of the number of studies, I would not remember that to write another day. It is likely it would have been in front of me.

Q Then you go on to say in your statement, I think, that you had a committee meeting on 13 November, which we know, which is minuted, if we go to page 294:

“Not approved. Improvements required on patient information sheet and clarification as to whether this is a study or a normal patient investigation.”

So if you had a conversation with Dr Wakefield on the 13th , it does not look as though it is addressing either of those issues from the way in which you have written it?
A I am addressing, sorry, which issues?

Q The patient information sheet and clarification as to whether this is a study or a normal patient investigation, because the note ---?
A I did not make any reference to that. I have written to Walker-Smith about that. I did not discuss that with Wakefield. As far as my note is concerned, it looks as though we talked about Schilling and modifying the consent form. With Wakefield it looks as though I wrote to Walker-Smith about whether the studies were clinically indicated.

Q I think the difficulty, which we can clear up in a moment, is the fact that the sequence is distorted by the fact that your letter to Professor Walker-Smith is not in the bundle, so we go straight to his letter of 11 November. That is right, is it not?
A I am lost on that one. I have lost you. Can you say it again?

Q What we have got is Mr Stevens raising his concerns and then as far as our documentation is concerned, although we have got a note of the fact that this was not approved at the meeting, the next document in sequence we get is Professor Walker-Smith’s response to your letter. What we do not have in the bundle is the letter to which it was a response.
A Well, if it is not, it is not.

Q Could you turn in that little clip – and perhaps you can insert it – to page 265a and following? Can you put that in the bundle, or somebody can do it for you. Do you have that there?
A Yes.

Q Just before we look at the letter itself, if you would look at your supplementary statement in paragraph 14, you state,

“I have stated in my first statement (paragraph 23) that I met Dr Wakefield to discuss the nature of the members’ concerns. I cannot recall the content of this conversation and I do not know if the letter from Professor Walker Smith to me dated 11 November 1996 followed on from this conversation”.

That clearly cannot be right, can it, because the letter from Professor Walker Smith is dated 11 November and you say your conversation was on the 13th, so in your supplementary statement you simply cannot be right can you?
A Let me clear in my mind before I can answer. It was obviously written on 15 October. Can you start the question again?

Q Paragraph 14, you have it there in front of you, I will read it to you,

“I have stated in my first statement that I met with Dr Wakefield to discuss the nature of the members’ concerns. I cannot recall the content of this conversation and I do not know if the letter from Professor Walker Smith to me dated 11 November 1996 followed on from this conversation”.

A Yes.

Q That cannot be right, because one is dated the 11th and you say that conversation took place on the 13th?
A Well then it cannot be right.

Q The sequence is clear when you put that letter in its correct position that Mr Stephens raises his concerns in advance of the meeting that was due to take place on the 13th and, as a result of those concerns, you write to Professor Walker Smith on 15 October and so what the Committee has seen previously, namely his response, is a response to specific points that you have raised in your letter to him. That is right is it not?
A This would have been after Stephen’s thing but before the Committee.

Q Exactly so. It is not a question of Professor Walker Smith writing to you out of the blue volunteering various things. It is a point by point response, as we will see, to the particular concerns raised by you in your letter. Is that right?
A Yes.

Q If you look at the letter at page 265A,

“I am writing to you to inform you of the reservations I have received and to invite your comments.

1 No ARSAC licence.
2 It is a very intensive regime involving some unpleasant investigations”

and unlike Mr Stephens you identify those:

“Lumbar puncture, endoscopy, MRI etcetera, some of which may require general anaesthetic. I would consider the risk of such procedures to be high, BPA guidelines classification”.

A Yes.

Q We will look at that in a moment. For his information you supplied him with one page of the BPA guidelines, which we have at 265c, which you considered appropriate for this case. We will come to this in a minute. You go on say,

“The guidelines state ‘It would be unethical to submit child subjects to more than minimal risk when the procedure offers no benefit to them, or only a slight or very uncertain one.’

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

(a) Confirm that the child would undergo this regimen even if it was not in a trial.
(b) Indicate what benefit the child will receive from having been investigated in this way. Will the benefit be more than ‘slight or uncertain’?

I enclose the relevant sections of the guidelines in case my comments have lost some meaning in my paraphrasing”.

In fact, what you were doing was taking up the points which were clear on the face of the BPA guidelines were you not?
A Yes.

Q You see on 265c under “High risk” It reads,

“High risk procedures such as lung or liver biopsy, arterial puncture, and cardiac catheterisation are not justified for research purposes alone. They should be carried out only when research is combined with diagnosis or treatment intended to benefit the child concerned”.

That was what that paragraph was addressing. You were asserting that these were high risk in your view and a benefit of that high risk procedure had to be justified?
A Yes.

Q That is what it is saying, is it not?
A If it was high risk you have to justify it, yes.

Q In accordance with the BPA guidelines?
A Yes.

Q We have looked at 2. Then 3,

“Page one of the consent forms states ‘Please sign the attached form and return in the enclosed envelope”.

That is a reference to the proforma consent form that was at the back of the protocol, is it not?
A Yes.

Q Then,

“The consent form does however require discussion with and the signature of the research. Please clarify.”

This is obviously an important letter is it not, Dr Pegg?
A Yes.

Q It may be because you have a part time secretary, but it is not the letter which you appear to have retained in the records.
A I personally wrote my letters at that time. I can see how this one would get left out. This one would have been written at my desk when I had to write a proper letter I had to do it myself. The secretary could deal with the proforma stuff, but this is a real letter which a secretary which my secretary could not write which means that this was written at my desk in the office. You can see how it would get separated from the main ethics bundle things which is another office miles away.

Q We have seen demonstrated in other areas, and indeed in relation to this application, that Mrs Carroll wrote notification of things, either having been received or approved, but this is one where you have to apply your mind to the content of the letter.
A She had many other jobs.

Q However it happened, it did not remain with the other documentation. It is important because it gives context to what is clearly a reply letter point by point from Professor Walker Smith in his letter of 11 November.
A Yes.

Q If we turn to page 291 – just keep a finger in your letter – he says,

“Despite extensive enquiries we could not find out what ARSAC means.”

We will leave that for the moment. He is responding specifically to your paragraph 2 when he says,

“Clearly this is an intensive regime with procedures that could be regarded as ‘high’ risk although they are particularly used for the investigation of children with chronic inflammatory bowel disease”.

It goes on in the letter to deal with the other aspects, the disintegrative disorder and says,

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

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

Again, to make the point, Dr Pegg, these are a direct response to your question as to what the benefit might be to the child to be involved in this?
A Yes.

Q Then,

“This whole study is parent/patient driven as every case referred has been initiated by the GP by the parents of the child”,

and confirmation of what he said earlier:

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

This is a direct response to the second part of your sub paragraph 2, is it not, on page 265a?

A Yes.

Q This is being written by a professor of paediatric gastroenterology about investigations on children whom he said had gastrointestinal symptoms. He is addressing the point from the point of view of his expertise that they would not have been investigating them unless they had evidence of bowel disease. That is right, is it not?
A Yes.

Q Then turning to the second matter which you raise,

“We agree that consent always involves discussion and signature of the researcher. We will change the protocol”.

That is a reference to your final point in your letter, which is that merely signing the consent form is not enough. There needs to be discussion with a doctor as to what was involved?
A The other one gave the impression that the parent was signing it and sending back in the post which is not something that we approve of.

Q And he reassures you about that, “... consent always involves discussion and signature” and therefore that is what is going to happen, and that they will make it clear in the protocol. You will see from the bottom of that letter that it was copied to the other two named responsible consultants in paragraph 1 of the application. It is in embracing the three responsible consultants nominated in the application. That letter is dated 11 November. I do not know what the post system is externally or internally.
A If I am allowed to make a comment, if that was the same day as the meeting, I would presume we did not have that at the meeting.

Q You interrupted what I was going to say. I do not know what your arrangements were internally or externally as far as post was concerned, but it may be that some letters came quickly, some letters did not come so quickly to their intended destination. Is that right?
A Yes.

Q You were not all on one site were you?
A Everything is on one site at the Royal Free, yes.

Q Was it then?
A Yes.

Q Rightly or wrongly, Dr Pegg, the Committee secretary sent a letter to Dr Wakefield, dated 14 November 1996, so three days after this, and one day after the meeting on 13 November which is at page 313.

THE LEGAL ASSESSOR: Before we move to that, I think it is an appropriate moment to interrupt you if we are trying to sort out chronology. The prelude to the two letters you have just read, the one you have inserted at page 265a, and the response which you have just dealt with, as a preclude to that topic, you were questioning this witness about page 235 in the bundle a reference to a meeting with Dr Wakefield and a date of 13 November.


THE LEGAL ASSESSOR: It seems to me that a lot of confusion has come about – and
I hope somebody will correct me if I am wrong – I do not think page 234 should be where it is because it seems to me that page 235 follows on directly from page 233. I deduce that comparing that form with a similar form later in the bundle which you need not look at.

MR MILLER: You are right.

THE LEGAL ASSESSOR: It is 16 and then 16A and 16B.


THE LEGAL ASSESSOR: It would appear, and this is only my conjecture, for you to put to this witness that what is inserted there under “comments” should more properly go under 16A “Consideration deferred for the following reasons” because we know that the decision was deferred until the December meeting. It seems to me that a great deal of confusion has been generated by page 234 being where it is and that last page not being seen as part and parcel of page 233. I do know if I have made it worse or if I have clarified things.

MR MILLER: You have certainly clarified the documentation. We had all the reached the position that 235 as it stands now that any discussion must have post dated the documents we were looking at there. Clearly further discussion cannot come in after project approved registration. It has to come in after deferred or not approved and deferred for following reasons. Clearly that is something that must have occurred on or after 13 November and could not have had anything to do with what happened in October.

THE LEGAL ASSESSOR: My suggestion, either for you to put to the witness or not, is that he is wrong when he says that that note means he had a meeting with Dr Wakefield on
13 November. My assessment of these minutes is that he made a note on 13 November at the meeting, but Dr Wakefield needed to be spoken to. That date, 13 November, is indeed the day of the meeting when reservations were expressed and approval was not given. Then, of course, approval was given on 18 December at the next meeting.

MR MILLER: My only reason for introducing it was because he had said that the decision we got, the discussion took place with Dr Wakefield and then the letter came.

THE LEGAL ASSESSOR: I agree it probably matters not, but it is going to look wrong on the transcript when we get it.

MR COONAN: I am slightly concerned and worried if we change the numbering on the documents to make 234 235 and vice versa. Then having done that, I will put that point to this witness.

MS SMITH: So far as the secretary is concerned, the number does have to be changed. They simply need swapping round.

MR COONAN: I am sorry to interrupt. On the question of numbering, in due course I am going to have something to say about the whole sequencing of these series of documents from page 200 to page 231. So whatever solution is adopted at the moment, I hope it is sufficiently reflectable to accommodate this line of inquiry. I do not know whether any substantial will turn on it, but I do know need to raise this point later.

THE CHAIRMAN: Can I make a suggestion that this issue is dealt with and when we have finished for the day and the three counsel, along with the Legal Assessor, can meet with the secretary and resolve this issue of numbering.

MR MILLER: Certainly, sir.
A If it would help you, I think 234 is in the right place. We have got handout to parent/guardian. After that would come the consent form. Those two pieces of paper go together. It is not cut and paste. It is one piece of paper so he could not stuff it in just above the number 15 so he has put it after that page. Information sheets and consent forms live together, so that is in the right place and I think 13/11/96 is me making notes at the meeting to remind myself what to do.

Q Can I just take things up with you. I am sure we are not going to fall out about this, but there are two paragraphs 16, as they stand, on page 233.
A We have been into secretaries already.

Q So logically it may well be, and as you would expect, that the consent form would follow the first of those, or follow 15.
A The consent form should follow the patient handout, but because of technology in those days it does not, and he just stuck it in here.

Q There is the signature of the investigator, Dr Wakefield, and then these are the sort of wrapping up of the application with its outcome, whether it was passed, whether it was deferred and if it did for what reasons, and finally when it gets through, product approved and registration and any comments there might be there. The only point being made, which with respect is a good one, is that the handwritten bit, 13 November, looks as if it ought properly to be under the second paragraph 16 on page 233; in other words, a prospective meeting noted on 13November.
A I think 13/11 is me writing a note to myself on the date of the meeting, what I am going to do with it.

Q Yes, “We need to have a meeting”. I was going to take you to 313. This is a letter from Maureen Carroll to Dr Wakefield dated 14 November 1996. In paragraph 28 of your original statement you said a letter was sent to Dr Wakefield by the secretary of the LREC dated 14 November informing him that the application 172-95 – that should be 96 – had been approved. That approval was subject to the various reservations made by members. We know now that it was not approved, but a letter was sent by Mrs Carroll saying that it had been approved without any apparent reservation and that may have been a mistake.
A I would say that this is an error.

MS SMITH: I am sorry to interrupt Mr Miller, but he should point out Dr Pegg’s second statement where he makes that very point, that there is an error in the first statement.

MR MILLER: I think we all recognise that it must have been an error because you had not passed it by 13 November, but for some reason administratively it was communicated to
Dr Wakefield that approval had been given. As I say, now looking back and seeing the whole sequence you had not finished your deliberations and your concerns as to whether or not it should be passed. That is right, is it not?
A Yes.

Q If that letter was sent, Dr Pegg, and on the face of it there is no reason to believe it was not, it would have led the applicants to believe that approval had been granted on
13 November.
A It would for a short length of time, yes.

Q There is no communication from you to Professor Walker-Smith between that date – 14 November 1996 – and 7 January 1997 when you informed him that approval had been given. So there is no communication with him to disabuse any of them of the fact that permission had not been given.
A I am just trying to think whether this is in the right place or not. The meeting is
11 November. He writes me a letter.

Q The meeting was 13 November.
A I approved by chairman’s action and then bring it back to the committee.

Q It is a mistake.
A Yes. I am trying to rationalise it, but it will not rationalise.

Q Yes, unfortunately the letter went out, or appears to have gone out – we will hear evidence about it – and the jury was still out at that stage because you had not at that stage clearly received the letter that had been sent by Professor Walker-Smith on 11 November.
A Yes.

MS SMITH: I am sorry to persist, but I have asked Mr Miller this once. He has gone to
Dr Pegg’s first statement and I think in fairness to Dr Pegg he should also refer him to paragraph 25 of his second statement.

MR MILLER: I will put it to you because it is just what we were discussing a moment ago, Dr Pegg. You say,

“I do not know why the letter dated 14 November was sent to Dr Wakefield. If the letter was sent, it was sent in error”,

which we are all agreeing about.

“The LREC did not intend to give final approval at that stage because the outstanding matters had not yet been resolved in correspondence with Professor Walker-Smith”.

That is what you and I have just been discussing, is it not?
A Yes.

MR MILLER: Sir, are you going to have a break this afternoon, because I am coming on to the letter of 7 January and it is a much longer topic.

THE CHAIRMAN: I think so. If you want us to have it now that will be appropriate at this stage. We will resume at 3.30. Again, Dr Pegg, I have to give you the same reminder that you are still under oath so please do not discuss this case with anyone.

(The Panel adjourned for a short time)

THE CHAIRMAN: I think we are ready to start.

MR MILLER: Could you turn, Dr Pegg, to page 358 in Bundle 1, please? This is your letter addressed to Professor Walker-Smith dated 7 January 1997, and although the meeting I think was on 18 December, probably because of the time of year you are not writing to him until later.
A I think Christmas intervened.

Q So you are actually writing to him on 7 January, although for the purposes of your approval, the date of the meeting is important and we will come to that, but the notification, formal notification comes from you this time, dated 7 January.
A Yes.

Q In your second paragraph you have,

“As you may be aware, this application was discussed at length at two committee meetings”.

Just a point, how would he have been aware that it had been discussed at length at two committee meetings?
A He would have been aware it was discussed at two committee meetings. He might not have been aware that it was discussed at length.

Q You say,

“Approval is conditional upon the following”,

and you number them 1, 2 and 3. First,

“Only patients enrolled after the date of the December meeting, 18 December, will be considered to be in the trial”.

Was that because of the modification to the consent form which you were insisting upon in paragraph 3?
A No, it was because we were aware that they had done this procedure on five previous patients.

Q Where do we find that in the letter?
A I did not say that. I did not give my reasons. I just said only patients – are you asking me what my thought processes in making that statement or are you asking me what I told them?

Q The 18 December is the date of the meeting.
A Yes.

Q I wondered why you picked the 18 December.
A Because that is the date of approval of the study.

Q Right.
A So they could actually do it after then, even though my letter did not get there until
7 January.

Q Why would patients using your word, “enrolled” before that date not be eligible?
A Because they did not get an information sheet before they were enrolled into a study. They did not sign a consent form before they were enrolled into a study.

Q It does not go to the question necessarily of the lumbar puncture risks, but it goes to the final draft of any consent form or any information sheet.
A Or any consent form at all.

Q But there was a draft of the consent form attached to the original protocols, was there not?
A The details do not matter. The thing is that only people enrolled after the 18th would be allowed to be in the study.

Q Would be considered to be in the trial is what you say.
A Yes. We do not give retrospective ethical approval.

Q So anybody who was going to join the trial had to have signed the consent form and seen a patient information sheet after the date of the December meeting.
A Yes, that is right.

Q As far as you were concerned, the five patients about whom Professor Walker-Smith had spoken in his letter of 11 December could not, as far as you were concerned, be considered to be in the trial.
A That is right.

Q Nor could any others who may have been investigated in between the 11 November and 18 December.
A That is correct.

Q The second condition is that the Schilling test should be removed from the protocol. This was a clinical diagnostic test, was it not?
A That is right.

Q Quite sophisticated but nonetheless a clinical diagnostic test. If you look at paragraph 13 of your supplemental statement, please,

“I understand that the researchers got rid of the Schilling test because of the high volume of paperwork involved in obtaining a licence”.

A That is right.

Q Where do we get that from? Where do we find the information in the documentation about that?
A About what?

Q About the fact that the researchers got rid of it because of the high volume of paperwork involved in obtaining a licence.
A You do not.

Q Where did it come from?
A It is just something I remember from the study. It is not just this study. It is all studies. ARSAC licences take months to come and people used to take out things needing them.

Q So it would apply to all studies in which that particular test was required to be carried out.
A An ARSAC licence is for any test involving radioactive materials.

Q But you are not saying it is just this study, but any study.
A It makes you think twice before using them.

Q Are you saying that the decision to remove this from the protocol was in fact the decision of the researchers?
A Yes.

Q So you would not have needed to make approval conditional upon that clinical test being removed from the protocol; it would simply have been superfluous to the protocol, would it not?
A As we had not been shown an ARSAC licence it had to be removed from the protocol.

Q But that is not what you said. I thought it was a decision, you told us, because the researchers thought there was too much paperwork involved and that is why they were not interested in doing it.
A That is right, yes.

Q So the removal of the protocol cannot have been a condition for granting approval because you were asking them to take it out.
A We were just confirming it was going to be taken out. You can go around in circles with semantics but we were just confirming that it was being taken out.

Q You had imposed three conditions, had you not? The approval was conditional upon three things.
A Yes.

Q You have explained the first and you say this in fact was not the committee flexing its muscles; it was the researchers themselves deciding they did not want it. You say nonetheless you imposed that condition about the removal of a clinical test from the protocol as a precondition to granting approval.
A Yes.

Q The third precondition to the grant of approval, the consent form to be modified so possible complications of lumbar puncture are explained. I think you accept that that is a clinical matter, is it not?
A Yes.

Q There is an illogicality, given the stance you have taken, about imposing that condition because you had by then been satisfied that these investigations were clinically given.
A I think we are agreed it is illogical.

Q Because it has nothing to do with research. It is normal clinical practice that you would expect there to be some sort of dialogue about the risks of any procedure.
A Yes.

Q If one looks at these three conditions together, one involves, if you like, informed consent to enter the study; two and three are clinical matters, albeit two you say was at the request of the researchers rather than being imposed by the committee.
A The researchers request it when they realise the paperwork involved.

Q That you can remember, can you, from a conversation with somebody?
A Yes.

Q It cannot be with Professor Walker-Smith because you never spoke to him.
A No.

Q We have seen all the correspondence now between you and him.
A It is likely to be the conversation between me and Dr Wakefield.

Q Again, in your original witness statement, can I just ask you to consider this aspect, paragraph 20 – sorry your supplemental statement – assurance was requested from Professor Walker-Smith and this was obtained about the clinical need aspect.

“Once LREC was assured that all of the tests were clinically indicated, they requested that the patient information sheet reflected this”.

Where do we see that request that the patient information sheet reflected that “all” of the tests were clinically indicated?
A You do not.

Q What was it you were intending should be in the patient information sheet?
A We put that in an earlier letter, I think, to Professor Walker-Smith.

Q You identified certain tests, and that is why I stressed the word “all”. You identified certain tests which you described as “high risk” and they were I think lumbar puncture, MRI and endoscopy. This is at page 265a. So those were three things which you nominated and also said “etc” which may have covered others. That is where it is spelt out. But there were many more tests than that, were there not, included in the protocol?
A Yes.

Q Obviously if there were tests which were purely on the specimens taken as part of the endoscopy and the biopsies and work done on those, or the bloods and things like that, you would not have expected all those to be clinically indicated, would you?
A We have been into the extra samples taken with the consent form that you have already shown me at the beginning of this session, that there was a separate consent form in use for the extra biopsies which were not clinically indicated. That was part of a previous ethics committee submission.

Q But we do not see any request for all of these matters to be covered in the patient information sheet. As far as we have been shown, there is no amended patient information sheet which expressly says that, is there?
A No.

Q So this is the position, Dr Pegg: Having had an application submitted to you in September about which you correspond with Professor Walker-Smith about the clinical aspect of these investigations, approval was given subject to these three conditions.
A Yes.

Q You say in paragraph 23 of your supplemental statement,

“Even if the paperwork submitted by the other researchers appeared to be seeking ethical permission to do research-based investigation, the LREC understood that what they granted” –

I think you emphasised that –

“was ethical permission to undertake data collection and publication of results from clinically indicated tests”.

Is that fair? Is that what you say?
A Yes.

Q Could you identify where in your letter of approval on page 358 you say that?
A It is not in the letter of approval. It is in the letter of Professor Walker-Smith that assures me. The decision was based on information provided to us by Professor Walker-Smith.

Q That is a different point. He is saying, “I will carry out these investigations anyway as part of clinical need”.
A So he has already assured us of that.

Q But you are granting ethics committee approval in the terms that you can see there, which include clinical matters. I asked you where in any communication to these investigators you say that you were only giving ethical permission to undertake data collection and publication of results in clinically indicated tests?
A We approved the application on the understanding that the high risk, whatever you call them, procedures were clinically indicated.

Q That may have been what was passing through your minds. I am asking you where in the documents, where in your notification of approval you say that that is all you are doing; that you are only interested in data collection and publication of results.
A It is not in that. It is related to the assurances by Professor Walker-Smith. Professor Walker-Smith assures us that everything is clinically indicated. Right? Therefore the decision is based on the fact that Professor Walker-Smith assured us that all the investigations were clinically indicated. So there is no need to put a condition on the thing. That is already agreed. That is a piece of evidence given by Professor Walker-Smith to the committee. We asked him, “Are they clinically indicated?” “Yes, they are”, therefore he has given evidence to us that they are clinically indicated and therefore there is no further discussion about the high risk procedures.

Q But my point, and I still come back to it, is that there is nothing on the face of this document that says --
A You are taking that document in isolation.

Q Please ---
A I will agree with you on that one. It is not on that document but the document … You have had Walker-Smith saying to the committee, “These …”.

THE CHAIRMAN: I am sorry, Dr Pegg, I think you will need to wait until the question has been completed by counsel. Mr Miller?

MR MILLER: I was asking you about the document which you sent which gave approval for the study, which is what this document is, and I asked you where we find ---
A You do not.

Q No, and granted it might have been open to you to say, on what you considered to be your powers at the time, “Given our assurance that all of the investigations will be clinically indicated, we are prepared to grant permission for the undertaking of data collection and publication of results from this study.”
A We could have done.

Q You could have done that, which would have made it perfectly clear that you were only considering that aspect of the study. That is right, is it not?
A Yes.

Q You accept that that is not what you say in this letter. You also accept, I imagine, that in relation to (1), (2) and (3), the conditions which you were imposing on the approval,
(2) and (3) certainly relate to clinical investigations?
A Yes

Q At the end of the page, going on below the fact that you want a report, you say:

“The ethics committee must also be informed of, and approve, any proposed amendment to your initial application which has a bearing on the treatment of investigation of patients or volunteers”,

which of course would relate to the clinical matters on which you had asked for assurances from Professor Walker-Smith?
A Yes.

Q So you were inviting them to tell you if there was any change in any of the clinical aspects which had been discussed between you and Professor Walker-Smith, which you say was of no concern to you now?
A The sentence is a stock sentence. That is how it gets there, from cut and paste.

Q Thank you very much for the information, but in terms of what you are saying that explains how it got there, it does not explain the fact that it is clearly dealing again with the clinical nature of the investigations and treatment, does it?
A Yes.

Q Do you understand, Dr Pegg, how those involved could have believed that you had approved the investigations upon which a large part of this protocol was based?
A I cannot see how Professor Walker-Smith could have come to that conclusion after writing to me that the investigations were clinically indicated.

Q But even so, he was making an application for the whole study, not simply the investigations, the whole study, which included the investigations, to have ethical approval?
A Yes, but he said that the investigations were clinically indicated investigations. He did not say they were research things, therefore the ethics committee is reassured that the investigations that he is including in it is something that he would have done whether we were there or not.

Q So is this your position, that in relation to clinical ---
A Even if we were approving the clinical studies, these are … If I take your line of reasoning that we are approving the whole thing, the whole thing is based on an assumption that the studies are clinically indicated studies, they are not research studies.

Q I am not departing from that, because clearly you must have realised at the time, to the extent that you read it in detail, that there were different aspects to this study, a fairly hefty clinical involvement, which is set out in the paragraph bullet points that we saw at the beginning, and some research which did not involve invasive treatment of the patients. So there was a combination of the two, was there not, in the study?
A Yes

Q And the division of labour – and it may be that others will take it up with you – as between the various doctors is clearly set out in the study, explaining exactly what role each had. That is right, is it not?
A We had inferred which role they had from ---

Q It may be that others, as I say, will take it up.
A It does not come in the study. We worked out what the roles of various doctors were.

Q So is this your evidence, Dr Pegg, that having had this discussion or exchange of correspondence, the position is reached that when a senior clinician tells an ethics committee that in his judgement these children presented in such a way as they would have been investigated anyway in accordance with the protocol, that you accept that as being the end of the matter as far as clinical investigations are concerned?
A If he, a senior professor at the Royal Free, says these are clinically indicated, I do not see we have any place questioning that.

Q Of course, you had got Dr Epstein’s contribution for the framework of the studies, a fellow gastroenterologist, saying that the methodology was correct?
A Yes.

Q You saw your role solely as being able to give permission, given that background, for data collection and writing up the case study?
A Yes.

Q But you accept that there is nothing to that effect in any of the correspondence?
A He has put in his application that they are clinically indicated.

Q Please answer the question. There is nothing in any of the correspondence to that effect, is there?
A No.

Q If one looks to the state of mind of the researchers, if it is possible to derive it from the materials we have got … Have you got the last two pieces of green paper there? They are pages 366aa and bb?
A a and b, yes.

Q I think yours will have to be amended after the end of the day, but the rest of us are now “aa” because there already is a 366a. This is a letter to you as Chairman of the ethics committee, dated 3 February 1997, from Dr Wakefield:

“Dear Dr Pegg

Further to your recent letter”,

and unless I am told otherwise I am taking that to be the letter we have just been looking at of 7 January,

“and our response regarding the granting of Ethics Committee approval for our study … we would request that the following amendments be made:-

The pilot study has demonstrated that the MRI and EEG studies are all normal and therefore we feel there is no need to continue these unless specifically indicated. Eight out of the 9 children examined so far have an indeterminate inflammatory bowel disease [is] clearly present both histologically and endoscopically. Therefore, we feel that gastrointestinal inflammation may be, in part, the source of the underlying problem in these children and we would like to investigate this in more detail by studying intestinal permeability.”

Then he gives a description of a non-invasive test involving a drink and a urine sample, and there is a copy of an explanatory letter to the parents and a suggestion that the parents might be able to deal with it at home or at an outpatient appointment. Dr Pegg, that, on the face of it, is notification to you as Chairman of the ethics committee of a decision to discontinue two of the test which had been considered to be high risk but clinically necessary investigations.
A It would be a letter to me, yes.

Q With Dr Wakefield telling you that they had decided, because of what they had discovered in the pilot study, that MRI and EEG were normal, and you may remember that when you wrote to Professor Walker-Smith in October 2006 MRI was specifically chosen by you as an invasive test which must be considered to be high risk. Do you remember that?
A I can remember that part, but I cannot remember this letter because it is not in my bundle from the Royal Free. Did we approve this?

Q I have not seen an approval. I have not seen ---
A Do we know that I got this?

Q We are suggesting that it was sent.
A Yes, it might be sent, but I have not found it in my files.

Q You have actually missed quite an important letter already in your files, have you not?
A It could be in our files, it could not. I have no evidence that I have got it.

Q No, you may not have looked, I do not know, but we know that you did not have in your files the letter written by you to Professor Walker-Smith?
A Yes. I might have received it, I might not have received it, but I cannot prove that
I did.

Q Can I just tell you the purpose of asking you this?
A Yes.

Q Let us see if we can do it in sequence; it will be easier, and we are near the end of the day and we are all tired. Look back at page 265a, that is your letter to
Professor Walker-Smith.
A Yes.

Q When you were asking him about the investigations in subparagraph (2) you say:

“It is a very intensive regime involving some unpleasant investigations – LP, endoscopy, MRI etc. some of which may require a general anaesthetic. I would consider the risk of such procedures to be ‘High’ …”.

That is the starting point, and you would accept, would you not, that LP, endoscopy and MRI are clinical investigations?
A Yes. We have said that before.

Q Turn back to page 366aa. In the second paragraph Dr Wakefield is saying:

“The pilot study has demonstrated that the MRI”,

which is one of those high risk investigations to which you had referred earlier,

“and EEG studies are all normal and therefore we feel there is no need to continue these unless specifically indicated.”

A Yes.

Q So, again, making the assumption that this letter was sent to you, Dr Wakefield is applying to you to remove from the protocol what you had been satisfied were clinically indicated investigations
A Yes.

Q As I say, if one needs any evidence or is looking for evidence as to the state of mind of the researchers, this is one of the researchers feeling that he has to come back to you to get permission to remove these investigations from the protocol, although you have said, well, it is nothing to do with you because you had been convinced that all of these investigations were clinically indicated.
A You say that his state of mind is such that he thinks the study (sic) has approved non-clinically indicated studies?

Q No, he thinks that he has to go back to the ethics committee to get approval to delete clinically indicated examinations. That is the only point I am making.
A I cannot think his mindset, but if he has ---

Q That is what it looks like.
A Yes, but he is saying that he is deleting clinically indicated things. He might be doing this out of completeness for the study or because of his mindset. We cannot say what it is .

Q You had told him that he had to do that. You told him at the end of your letter of
7 December that he had to do it.
A Yes.

Q Although it was a clinically indicated investigation, you told him, “If you want to change any of these investigations, clinically indicated or not, you have to come back to the ethics committee to tell them about it.”
A Yes. He has done that.

Q That is my point, Dr Pegg, that you say, “Oh, we had no interest in anything else except data collection and writing up case studies”, but in fact you were keeping control of the whole of this study, clinically indicated or not, and in fact that is the basis on which the approval was given?
A He has taken these out because he would have been collecting data on MRI and EEG, therefore he will take them out and not collect data on them.

Q He is also saying, “We don’t want to do the tests”, and he is being told ---
A Yes, if you are taking a test out you do not get the data from it, yes, but he could just be saying that “We wanted data collection for ten points. We now only want data collection for eight points.”

Q If that is right, then by colonoscopy he collects data as well, does he not?
A He has not taken that out, has he?

Q But still if you are making a distinction between data collection and clinically indicated observations or investigations, this falls fairly and squarely in the category of a clinically indicated investigation?
A He is collecting data from clinically indicated investigations, is he not? These are two investigations, therefore he is not collecting data from them, therefore he is telling us that he is no longer collecting data from MRI and EEG.

Q Does he say that?
A He obviously cannot be collecting data if he is not doing it.

Q My point is a simple one, Dr Pegg, which I do not know whether you have ---
A I actually cannot quite get your point, because he is collecting data on MRI and EEG, he has taken them out, therefore he is not collecting data on MRI and EEG.

Q But you told him that he had to.
A He had to tell us if his data collection is changed.

Q If there is any change in the investigations, is what you said?
A Yes. He is collecting the data from his investigations, is he not? If he changed the investigations, he changes data set.

Q Dr Pegg, can we go back to your approval letter?
A Yes

Q Do you have the page?
A No, I have lost it.

Q It is page 358, the penultimate paragraph?
A Yes.

Q It says:

“The ethics committee must also be informed of, and approve, any proposed amendment to your initial application which has a bearing on the treatment or investigation of patients or volunteers.”

Does it say “has a bearing on data collected from investigation of patients or volunteers”?
A No.

Q You are insisting in that letter that you are told to come back for approval for any amendment which has a bearing on the treatment or investigation.
A Yes.

Q Nothing to do with data.
A Yes.

Q If you go back to Dr Wakefield’s letter just for a moment, in the second paragraph, the second line, the last word in that line:

“Eight out of the 9 children examined so far have an indeterminate inflammatory bowel disease …”,

and just leave it there for the moment. This is an echo, is it not, of what Professor Walker-Smith had written in November about, at that time, five children, because in the letter which Professor Walker-Smith wrote on 11 November by that time five children had been investigated, had they not?
A Yes.

Q By the time we get to this letter, which is just under a month after the approval had been notified, by that stage nine children had already been examined, had they not?
A Yes.

Q We do not know when they were examined, but if they were examined before
18 December then on your understanding they could not be entered in the study:
A That is right, yes.

Q Just on that point, I say it is clear from Professor Walker-Smith that by that date when he wrote to you they had already investigated those five. It has risen to eight or nine.
A You cannot extrapolate. They might have done eight new patients. You do not know that the five are in that. They could have done eight since my permission. So, there is no evidence that the five is in that eight. They could have done eight new patients since we gave them permission.

Q That obviously is a matter which will be taken up by those who had access to the individual case records, but what ---
A From reading this letter it does not imply that the five before 18 December were in those eight.

Q I think you may leave us to deal with the chronology. It may be that it was badly put by me to you, but if you were to assume that nine children had been investigated and had been investigated before 18 December, then they would be not entitled to be put into any trial?
A That is right.

Q It will be a matter of just looking at the dates of investigation and decide whether or not that is the case.
A That is right.

Q Certainly what Dr Wakefield describes this as is a pilot study does he not?
A Yes.

Q Presumably if you have spent as much time in ethics committees as you appear to have done, you will know that in many cases involving clinical investigation there may be preliminary studies in which a small number of patients are investigated before they decide to make it into a formal trial?
A People still ask ethics permission for pilot studies. We get them every month.

Q But they may not do so if they feel that they are clinically indicated examinations?
A That is right.

Q You would have experienced both, presumably; people who, on the one hand, say, ‘Let’s do a pilot study” and others who think, ‘Let’s just get the thing together and then do a proper trial’?
A It depends what you are doing. If you are doing research in your pilot study, therefore you need permission for a pilot study. It is as simple as that. You cannot do any study without an ethics committee, be it pilot study nor definitive study. You cannot have a go at giving the drug to a few people and see if it works before it comes to the ethics committee.

Q Of course. That is a different situation from what we have been considering here, where there is undoubtedly and I think you would accept this a hefty clinical investigation part of this trial.
A The five were not a study. They were just five people being properly investigated for a disease that they presented at their doctor’s. You get information all the time from normal patients which you can then create a study from, but these five were just normal patients having investigations.

Q As far as you are concerned, you have told us, although it is not clear from the documentation, that that was the reason for imposing the cut off time that these five children, who had been mentioned on 11 November, could not properly be part of the study because they had not been subject to the same consents as had been approved by the Committee?
A Yes.

Q Therefore, whatever their status, they were not part of 172-96?
A That is right.

Q It would follow that if all of these nine children had been investigated before 18 December, or they had their clinical investigations clinically before that, they could not be part of 172-96 either?
A Yes.

Q Could we come to the following year, to 1998.

THE CHAIRMAN: Mr Miller, I am sorry to interrupt. I am getting the impression that the witness is getting quite tired. Whenever you find the normal break, I think it will be appropriate to call it a day at that stage.

MR MILLER: I have moved on, and I will take it this second bit relatively shortly, but I will not finish in the next quarter of an hour.

THE CHAIRMAN: I will leave it entirely in your hands.

MR MILLER: That is a perfect spot. You saw me hesitate.

THE CHAIRMAN: In that case, we will now adjourn for the day. Dr Pegg, I know that it is never the right thing to leave the witness under oath overnight, but unfortunately we have come to a stage where I believe that we have no choice. I have to remind you again that you are still under oath and you are still in the middle of giving your evidence. Therefore, please do not discuss this case with anyone, including your lawyers or your Trust’s lawyers, or anybody on these issues. We will resume at nine thirty tomorrow morning.

(The Panel adjourned until 9.30 a.m. on Thursday, 26 July 2007)

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