GENERAL MEDICAL COUNCIL

Transcription

1 NRL MICL COUNCIL ITNSS TO PRCTIS PNL (applying the eneral Medial Counil's Preliminary Proeedings and Professional Condut Committee (Proedure Rules) 1988) On: Wednesday, 8 ugust 2007 eld at: St James's uildings 79 Oxford Street Manhester M1 6 Case of: JYN LVINI MRY ONN M S 1983 Lond Registration No: (ay Two) Panel Members: Mrs S ewitt (Chairman) MrJ rown Ms J oulding rmoodman Mr R rey C (Legal ssessor) MR I STRN, C, and MR S SIN, Counsel, instruted by Clifford Miller, Soliitors, appeared on behalf of the dotor, who was present. MR T KRK, Counsel, instruted by ield isher Waterhouse, Soliitors, appeared on behalf of the eneral Medial Counil. Transript of the shorthand notes of Transribe UK Ltd Tel No:

2 INX ITNSS TO PRCTIS LLIMN, avid, sworn xamined by MR KRK Cross-examined by MR STRN 1 51

3 T CIRMN: ood morning, everybody. Mr Kark, you were going to all your first witness. We have taken all of yesterday and a bit of this morning to do the reading that we were assigned to do. It is for you to all your first witness. MR KRK: May I all r lliman, please? VI LLIMN, sworn xamined by MR KRK It is r avid lliman. Is that right? It is. Just to make sure, you have got available to you a opy, first of all, of your own report, a opy of the r onegan file, and also your referenes and her referenes? Ido. ehind tab, I think it is, of Panel bundle 4, we have your urriulum vitae. I am not going to ask you to go into great detail about that. Would you tell us a little bit, please, about your bakground and experiene? I qualified in 1973 from medial shool in London and for the first two or three years did general jobs and then, from 1977, my posts were exlusively in paediatris, initially within the hospital setting and then as a ommunity paediatriian. My interest in immunisation started in about 1977 when I worked at reat Ormond Street. My urrent role as a ommunity paediatriian is jointly between the loal Primary Care Trust and reat Ormond Street ospital. Islington? Islington. I have worked there now for three or four years. mongst my roles is an oversight of the immunisation programme in Islington and in aringey, whih is onneted to reat Ormond Street. I think you were asked to onsider the reports that had been written by r onegan, and you onsidered those. You also read the reports of r Conway and Professor Kroll? That is so. nd onsidered a number of the referenes? s a result of that work, you produed the report that we know the Panel have now read, whih appears behind tab 1. Is that right? Transribe UK Lld You an take it, first of all, that the Panel have read that. I am not going to take you through that report word by word, but, as you know, as I indiated to the Panel yesterday, what I propose to do is to take one or two examples in eah disease that r onegan dealt with and just ask you to assist the Panel by giving a little expanded explanation. Now, first of all, I think you have also had the opportunity of reading the report of r lether, who is the expert witness instruted by the defene? I have, yes. aving read that report, we will look at it but in no great detail, but do you stand by your report? 2/l

4 Transribe UK Lld There were a ouple ofpage numberings that were inorret in my report, but apart from that, I do, yes. Can we start then, please? I think the most useful doument for the Panel now to have open would be r onegan's first report, whih the Panel knows it will find in Panel bundle 1, behind tab C. It is really that doument that I am going to onentrate on. r onegan began by dealing with the disease of diphtheria. She sets out, at page 10, a brief summary of the disease. I am using the pagination in the bottom right-hand orner, just so it is lear for everybody, of r onegan's reports. Could I ask you to turn to page 11, please? We are going to look at the third paragraph down beginning, "iptheria inreased." s our first example of some of the omplaints that you have made about r onegan's report, let us look at this: "iptheria inreased in prevalene and malignany in the middle of nineteenth entury and delined before the introdution of the antitoxin. ntitoxin beame available in the 1890s and redued the ase fatality rate so that mortality from diphtheria began to fall from that point, in a similar fashion to whooping ough and measles. y the 1940s when a national immunisation ampaign began, the death rate in hildren had dropped by two thirds and ontinued to drop." Now, first of all, was that in fat orret, in your view, in what it said? The desription of the disease falling is as you have on page 13, and this is death rates from the disease. There is a graph that is a nationally aeptable graph showing the number of deaths whih ourred over the last hundred years, plus or minus. The interpretation of that graph, I think, is more ontentious, beause I would suggest that what it does indeed show is a fall in deaths from the middle of 1890s to 1920, and then that fall slowed and almost finished. There is no further signifiant fall. There is a down - a little blip downwards, whih would be 1938, 1939, whih, I imagine, and I annot support this, is probably artefatual. Just stop for a moment. What does that mean? It is not genuine. It seems out of keeping with the rest of the pattern. Of ourse that was the beginning of the Seond WorId War and so reporting may not have been as good as it was previously. That, I have to say, is supposition. I would have diffiulty produing the evidene to support that partiular point. owever, that mayor may not be so. What I would suggest is very lear is that there had been a plateau then with the introdution of diphtheria in the early 1940s. There is a preipitous fall in the number of deaths. That of itself is not proving ausal assoiation. It is an assoiation in time and it is highly suggestive of a link, but it is one piee of evidene. ll right. It does suggest that the immunisation had a signifiant effet. Can we look, please, at r onegan's referene that she was relying on. It is her referene two, and we an see from her referenes at page 12, it omes from "The Role of Mediine," Thomas MKeown. I think we find that behind tab 2 of r onegan's referenes. I am afraid we are going to have to have a number ofbundles open as we go through this proess. It is Panel bundle 2, tab 2. The quote at the top of the artile on diphtheria is: 2/2

5 "Mortality from diphtheria in ngland and Wales has fallen fairly ontinuously sine the late nineteenth entury, when treatment by antitoxin was introdued. The rate slightly inreased at the beginning of the last war" - and that is the blip you were just referring to - "but fell rapidly from about the time when a national programme of immunization began. iptheria is now a rare disease, and many dotors trained sine the Seond World War have never seen it. In the six years from 1965 to 1970, there were only nine deaths from diphtheria in ngland and Wales." Now that quote, as we saw yesterday, I think, stops at the words, "May also have been at." We will have to turn, I am afraid, to your referenes as well. Can I just ask you to take up Panel bundle 5, whih are r lliman's referenes, just to see how that artile would have ontinued. Tab 6, if we look for the page numbers from the original artile itself, we an find page 98, and that seems to be the same page that r onegan was referring to and whih r onegan opied. lso opied, as we an see, if we have both open now, r onegan's referene was the top part of page 99. I am just going to pause. T CIRMN: We will get onfused beause the numbers are at the bottom left as well as the top. MR KRK: I am referring at the moment to the original page numbers of the artile itself. If we look at r onegan's tab 2, the first page behind tab 2. oes everybody have it? We an see that page 98 has been opied, I think, and then underneath that, where you see the graph, that is atually the top of page 99. If we go to r lliman's referenes, he is atually -- r lliman, you have opied both pages fully? If we go to your tab 6, and we an see page 99, we an see how the words of the author in fat ontinue in this way: "With due regard for this reservation it seems probable that immunisation had more effet on the ontrol of this disease than of any other, with the exeptions of poliomyelitis and, possibly, small pox. This onlusion is supported by the high level of immunity whih follows the use of a good antigen. videne for ngland and Wales in indiated that the risk of an attak of diphtheria was about six times greater, and the risk of a fatal attak ten times greater, in those not immunized than in those immunized." It looks as though that is the same page that r onegan opied or had opied. Transribe UK Lld Let me move on then, going bak to r onegan's report, to the seond that I am going to use in relation to diphtheria and it is, in fat, in the next paragraph: "In the US, of the few ases reported, throat involvement is dereasing and 2/3

6 C Then this: symptomati skin lesion make up a higher perentage, espeially amongst indigenous people suh as Native merians and Paifi Islanders, where males living in rowded onditions with poor personal and ommunity hygiene have the highest attak rate." "Most ases are in adults, as in the former Soviet Union where most of the ases are in vainated adults, not unvainated hildren." Can you just help the Panel first of all with that? If you take an extreme example of 100 per ent of the population immunised with a 99 per ent effetive vaine, every person who develops the disease will be immunised. That does not mean to say the immunisation is ineffetive beause without the vaination many, many more people would have developed the disease. What you need, to be able to interpret suh figures, is to know what proportion of the population were immunised, what proportion of that group, what proportion of the unimmunised group developed the disease. rom that you an then alulate how well the vaine works. I think it is ited in some of the other bits and piees later on and in various reports from r Conway and Professor Kroll, a whole series of papers that ame out of the experiene in the Soviet Union when indeed they did have an enormous reurrene of diphtheria at the time that the Soviet Union broke up. ll those papers ome to the same onlusion that the vaine of itself works well, but there were problems with delivery of the vaine and so you did get this, what seems a paradoxial situation, where a large proportion of the people developing the disease had been vainated. There is another issue on top of that and that is that it is known that the diphtheria vaine does wear off as you get older, hene the reommendation in just about every industrialised ountry that you have routine boosters up to a ertain age. Now, in fat, r onegan did not give that further explanation, as it were, it is left in this way: "Most ases are in adults, as in the former Soviet Union where most of the ases are in vainated adults, not unvainated hildren." Transribe UKLld Now she has not atually given the referene for that, I do not think, but you do have it ertainly or we appear to have it behind tab 1 of her referenes. Could I ask the Panel again to go bak to r onegan's referenes in tab 1. Now the point that she was making was that most of the ases in the Soviet Union of this disease were in those who had been vainated. Can we just have a look at tab 1, the seond page, page 910, of the atual artile? I do not think we atually see the phrase that r onegan has used, but it may well be right, but let us have a look at what the artile atually says. Page 910, if everyone has it, and it is the seond paragraph down: 2/4

7 " massive diphtheria epidemi ourred reently in the states ofthe former Soviet Union and aounted for> 80% of diphtheria ases reported worldwide during that interval. The epidemi began in 1990 with 1,436 ases (0.49 per 100,000 population), peaked in 1995 for 50,425 ases and waned by 1998 with 2,720 ases as the result of a mass immunization program." Then further down the page there is referene to the most important risk fator for diphtheria in the Republi of eorgia with the lak of vaination. lthough it is right to say that r onegan inluded that referene material in her two large volumes of referene material, did those sentiments find their way into her report? I think she aurately said that the majority were unvainated adults and in fat in the beginning of the third paragraph that is the message that omes aross at the beginning, the majority of ases were in --- ut the explanation for why that should have ourred was not there, no. Can we move on, please, to pertussis and she writes a great deal about pertussis and again I am just going to take a ouple of examples of what she has written. I know the Panel will understand first of all I am herry-piking and seondly, I am not abandoning the rest of what r lliman has said, but these are just examples of the omplaints that r lliman makes and indeed the MC makes. (To the witness) Will you go to page 19 ofr onegan's report, bottom right-hand orner. This is dealing with pertussis or whooping ough and the bottom paragraph, large paragraph at the bottom of that page, she wrote: "oes the vaine ause brain damage? paperpublished in 1974 desribed neurologial ompliations of pertussis vaination. This aused widespread pani among parents and some health professionals. In order to investigate the matter, the National Childhood nephalopathy Study was set whih looked at all 'serious neurologial events' ourring in hildren aged two to thirty five months between and mathed them with 'ontrols' who had not had suh an event. The study did not look at the number of the hildren in the 'event' or 'ontrol' group who had been vainated against pertussis ompared with those who had not, but only at the numbers who had been vainated against pertussis in the seven days before the neurologial events. This means that a hild ould have had a serious neurologial reation two or three weeks after pertussis vaination and this would not have been inluded in the 'pertussis vaine' figures." Then she goes on: Transribe UK Lld "owever, even with this timeframe, it was shown that those with severe neurologial damage were 2.5 times more likely to have been vainated against pertussis in the seven preeding days than the 'ontrols'." 2/5

8 Can we just go bak to the point she makes, in other words that the study was not looking at a wide enough piture. irst of all, is that right in your view or not? The study atually looked at hildren up to 28 days old and divided it up into --- Sorry, do you mean 28 days old or 28 days after the reeipt of the vaine? Twenty-eight days after the reeipt of the vaine and then divided it up into different periods one of whih was up to seven days post vaination, but also beyond that. The risk of having a serious neurologial event in the period beyond seven days was taken to be not statistially signifiantly inreased. So the hane was having a neurologial event seven to 28 days after your vaine was thought to be no different from if you had not had the vaine. It was the period no days to seven days after the vaination that was felt to be signifiant, but they did examine all of that period of 28 days. It is in my referene eleven. In r onegan's file we will find, I think, that tab 8 is empty. I am not making any omplaint about that, I suspet there were referenes available at the ourt, but I do not think they are inluded, as it were, in r onegan's file. It may be beause the file or the paper was too weighty. This was atually a 200 page report. We see this elsewhere, I think, where a report was enormous, it did not find its way into the referene material. Can we just look, please, at tab 11 of your bundle where we do find, I think, the study. If we go to page 119 (and I am using again the original pagination of the artile itself) we are looking at r onegan's words partiularly that the study only looked: "... at the numbers who had been vainated against pertussis in the seven days before the neurologial event. This means that a hild ould have had a serious neurologial reation two or three weeks after pertussis vaination [whih] would not have been inluded in the... figures." So if we just look at this table and you ould help us, please, with how it works. Right. They had two measures: one was time between immunisation and being admitted to hospital with a neurologial event; the other was the time between having the vaination and when it was thought that the neurologial event started beause, of ourse, the neurologial event ould have started a day or two before admission to hospital, but would be a bit more diffiult to objetify. So that is the explanation for there being two tables. The top one is time between immunisation and neurologial event; the seond one is time between immunisation and when the neurologial event first beame manifest in the parents' impression. What they have looked at is the number of ases in this study that fell into eah of a number of time periods and the time periods are the text in the lines above eah table. So immunised within 72 hours prior to admission and then 72 hours to seven days, then seven days to 14 days, and 14 days to 28 days, and then those are the hildren who have not been immunised in the last olumn so there is nothing at all. Transribe UK Lld Can we just take this slowly. irst of all, we are dealing with admission. That is 2/6

9 the first part of the table? So where there is admission to hospital. We an see that of those who are immunised within 72 hours prior to admission there were 14 hildren. Is that right? Whih made up l per ent of the total study hildren. Yes? Immunised more than 72 hours but within seven days prior to admission, twelve hildren, 1.2 per ent. Then ontrary to what r onegan seems to have thought, immunised more than seven days but within 14 days prior to admission, ten hildren or one per ent. Immunised more than 14 days but within 28 days of admission, 22, 2.2 per ent. Then not immunised with TP within 28 days prior to admission, 935 hildren or 94.2 per ent of the study. What, if anything, an one glean from that table? Under the table itself there are two lines of text: "Within 7 days: Relative risk =1.9 p<o.05", and then within 72 hours a similar statement. These statements are saying that the hane of this differene ourring between the ases and the ontrols in those two periods, so that is within seven days and within 72 hours, is very small. This is unlikely to be a hane finding. It is probable that there is a genuine onnetion here. You will see that there are not any figures given beyond seven days, beause it was thought that there was not a signifiant onnetion, and the same for the bottom table. The same priniple exatly. So, is it fair to say this? That the last two lines on r onegan's report whih reveal: "owever, even with this timeframe, it was shown that those with severe neurologial damage were 2.5 times more likely to have been vainated against pertussis in the seven preeding days than the 'ontrols"', was that an aurate omment in fat? Within seven days there was an inreased risk. There are very slightly different figures in slightly different publiations, beause some publiations onsisted of the whole set of data and some only partially, but this is within the right ball game. I am happy with the seven days, yes. er omment: Transribe UK Lld is that aurate or not? "This means that a hild ould have had a serious neurologial reation two or three weeks after pertussis vaination and this would not have been inluded in the 'pertussis vaine' figure", 217

10 No, it is not aurate. The table reflets that. MR STRN: helps. If it helps, if I an just assist, it is aepted that that was an error, if that MR KRK: Thank you: (To the witness) Let me move on. Could we go to page 20, the following page of r onegan's report, and the very bottom of the page dealing with the retrospetive study omparing the inidene of asthma in hildren who had been vainated against pertussis with those who had not. r onegan writes at the bottom of page 20: "In 1994 r...", and is it Mihel Odent? Yes: Transribe UKLld "... published a retrospetive study whih ompared the inidene of asthma in 243 hildren who had been vainated against pertussis with 203 who had not. Vainated hildren were over five times more likely to suffer from asthma and twie as likely to have had ear infetion than unvainated ones... In 1997 another retrospetive study of 1934 patients born between 1975 and 1984 from one general pratie in Oxfordshire showed that hildren vainated against pertussis were 75% more likely to develop asthma, hayfever and ezema later in life... larger prospetive (looking forward study) of 9444 hildren in von failed to show assoiation". Now, I think there are two aspets about this. irst of all, it is the weight that is put on the earlier studies. What an you say, if anything, about those earlier studies? You an rank if you like how reliable, how ertain you an be about the results of a study, depending upon the way it has been done, the way it has been analysed and whether other people have ritiqued it. So if you like the highest standard you ould expet is what is alled a randomised ontrol trial, where you take a group of people, you divide them up at random and you do whatever it is to them and then analyse the outome. The great advantage of that is that, if you had not thought of something that might influene your outome, in a sense it does not matter beause it should be evenly spread around the group. So, that would be the highest standard of researh. Then it would be presented to a journal, who would then send it out to referees who would review it and say yes, or no, I think this is good or bad researh and it ought to be published. This is peer review? This is peer review. Then it would be published in a journal. So, the highest standard would be a randomised ontrol trial that is published in a peer review journal. or many reasons you may not be able to perform a randomised ontrol trial, as has been mentioned in some of the papers here. or example, if one were to suggest a randomised ontrol trial now of say measles vaine, most people would onsider it totally unethial 2/8

11 to deliberately deny a group of hildren that possibility and so you may have to use what you would all seond best methods, whih would be observing what happens in real life. Some hildren did get the vaine, some did not but that may have been through parental hoie, and then you see what happens. The diffiulty with that is that a parent who hooses not to have their hild vainated may have other things that they do differently and you would not then be able to be ertain that the result of your study was just due to the vaine, or ould be due to something else. It is less random? Well, it is not random at all. It is very seletive and you annot be sure that there are not other things that have been not randomly alloated to the two groups. So if we were to go through these studies and look at them in omparison with what I have just said, the study by Mihel Odent was to take a group of people who had not been randomised, but were people he knew of one way or another, and they were asked whether they had had their hildren immunised or not and whether they had had asthma. The figures quoted here are quite aurate. That was the outome. That was published as a letter in a respetable journal, namely lm, whih is referene 14. This is your tab 14, I think? It is bundle 2. When you say bundle 2? MR STRN: It is bundle 1, C2. T WITNSS: I mean Panel undle 2. MR STRN: Yes, it is r onegan's referene. MR KRK: (To the witness) Yes, I think you have also produed it, in fat, but let us have a look at it. So, that gives the aount. Can we just pause while we all find it. I think it is 14? Yes, 14. Is it the letter in the bottom right-hand orner? Yes, that ontinues over the page. Yes, the first page behind tab 14. So, that is the --- So, r onegan's aount aurately reflet the numbers involved in this study and the outome. Mihe1 Odent himself towards the end of the letter, so that is over the page at four lines up from the bottom, says: "urther researh is needed using different methodologies", Transribe UKLld but we wanted to ommuniate thisear1y. Then the next study was a retrospetive study, whih was again reording the fat that 2/9

12 hildren had or had not been immunised and whether they had asthma or not, and so in the same way one ould not be ertain that any differene in outome was due to the vaination beause these were not randomised. This was reported in referene , Ithink it is, ofr onegan's bundle? Oh, I am sorry. It is 15, yes, in a publiation alled PULS, whih is a sort of P newspaper. It itself would not laim to be a sientifi journal. It is more a newspaper. y the nature of it it does not allow you to look at exatly how the study was done and to make a reasonable judgment as to whether it was a good study, and so I would suggest that this is not a soure that one would use as produing an expert report, or writing a sientifi paper. You would use it as an indiation that somebody had said something, but you would go and look up the original data and, if you ould not find that, you would be very irumspet about inluding it. So, these omments by r onegan on page 21 of her report seem to be based on this artile? The line 2 to 5-and-a-half, yes. So, "In 1997 an other retrospetive study..." Yes, and this is an artile by Maggie Verrall in PULS magazine? Yes, that would be a journalist. It omes, it would seem, from the middle olumn: " trend was seen towards less atopy...", is that asthma and hayfever? Yes, it inludes asthma, hayfever, ezema. Yes: "... who had natural measles infetion. The reords of 1,934 hildren born between 1975 and 1984 and registered at one Oxfordshire general pratie were reviewed for vainations, episodes of infetion and treatment...", et: "The results presented at a meeting at the Royal College of Paediatris and Child ealth in York last month showed the risk of atopi disease was inreased by whole-ell pertussis vaination... The study was onduted by researhers at ddenbrook's... Transribe UK Lld Childhood infetious disease experts autioned against reading too muh into the preliminary results. They appointed out that the study was retrospetive and did not prove ausal links". In the right-hand olumn, r Robert ooy said: 2/1O

13 "It'sdefinitely interesting and demands further study. 'The aution is that this should not put people off having their hildren immunised against life-threatening onditions'''. t the bottom of the page: "r darn inn, a senior leturer in immunology and infetious diseases at the University of Sheffield said: 'This sort of study really needs to be ritiised arefully before oming to any onlusions. It's Ju.st an assoiation". Can I just add something? Yes, please do? The fat that it was presented at the Royal College, what would have been the annual sientifi meeting, would mean that there was some peer review into this study, but of ourse what we are reading here is a journalist's report of the study and not the original researher's report ofthe study. So, you are ritial - you are slightly ritial - of the study, as it were, in terms of it is a retrospetive study? It would not be of the gold standard one would need in this sort of irumstane. It is in PULS magazine and so it is the refletions of a journalist about what the study had said? Transribe UKLld Can we look at the other study that is mentioned and that is the larger prospetive (looking forward) study of9,444 hildren in von. That I think is r onegan's tab 16. Now, what do you say about the weight of this partiular study? This is a study that was a group of hildren who were enrolled from birth by researhers in ristol for the purposes of long-term follow up looking at links between health and other fators. It was what you would all an observational study and so to some extent it has the limitations of the others. The parents themselves would have seleted whether their hildren were immunised, or not, and therefore you ould not be ertain that there were not other fators that would influene the outome than just whooping ough immunisation, although they would have tried to allow for some of those beause they had a lot of knowledge about the hildren. The strength of this study is it has been fully peer reviewed and it is published in a journal in some detail, so that one an look at it and say for oneself, well, the way they have done this study is good, bad, indifferent and therefore I should or should not attah a lot of weight to it, and of ourse it is atually a very large study. In terms of weight ompared with the earlier two studies that r onegan has relied on? There is no ontest. This is by far and away the better study with, as I say, some limitations. 2/11

14 With your bakground, of ourse, you reognise that. Would you neessarily expet a lay member of the publi, or a judge, to reognise the differene between those studies? No, and espeially as it is only just a line given to this one large study and the rest of the paragraph is to what I would onsider muh inferior studies. No. Was there in fat a seond study also of a muh larger number of hildren? There was a muh larger study whih I have referred to in my report, and I apologise if I aused some onfusion in some people's mind. This was a large study that was reported in two journal artiles, one as a letter and one as a more detailed artile, and in --- Is it your tabs 13 and 14? That is right, yes. MR KRK: gain, I am sorry, we are again going to have to have r lliman's file. I think r lether ould not find your referene to 2000? I perhaps did not explain it as well as I might have done in my report. So the two referenes refer to the same group of hildren. The first is a letter to the Journal of the merian Medial ssoiation, whih is --- Is this tab 13? Yes, whih is one at the top merian journals. This desribes how a group of hildren were enrolled in a study of whooping ough vaines, and the purpose of the study was to look at the safety and how well the vaines worked. It took a very large group of hildren. You an see the numbers here, getting on for 10,000 hildren in total, and they were randomly divided into four groups. One group of hildren were given diphtheria and tetanus vaine, whih was the standard at the time. The other three groups of hildren were given diphtheria and tetanus vaine, with one of three different sorts of whooping ough vaine. One is, if you like, the onventional vaine that we used to use in this ountry and the other two were newer vaines. t two and a half years old, the parents of these hildren were sent a questionnaire, whih was designed to see whether the hildren had developed atopy; so, asthma, ezema, hayfever. In the letter, it desribes the results of that; namely, that there was no differene between the groups. I think if we look at the right-hand olumn, about two-thirds of the way down the page, we see the words, "We found no signifiant differenes." "etween the TP vaination groups in the proportions of hildren with reported wheezing, ithy rash or sneezing." Transribe UKLld What they are saying is the addition of whooping ough vaine to diphtheria and tetanus vaine makes no differene to whether or not you get asthma, ezema or hayfever. We an see right at the bottom of the page, this was a publiation of JM in Marh of /12

15 Then at tab 14, do we have the report --- Tab 14 is a muh more detailed study where they did skin tests on a subset of the hildren. In a sense, although it is giving a more detailed aount, the more important one in this ontext is the letter, referene 13. It is referring to a larger group? It is referring to the whole group, and it is speifially asking about asthma, ezema and hayfever. Whereas, as I say, this is oning down and doing skin tests on hildren. If we look at tab 14 very briefly, a total of 669 hildren were randomised and those ame from the group that we have just been talking about? There is an editor's note. gain, we have to be autious, perhaps it is only an editor's note, but he writes: "This study should help to allay fears of inreased atopy with pertussis vaine; in fat if that was the reason you used not to immunize, the data on atopy following pertussis vaination should stimulate you to do so." Can Ijust ask you this: how diffiult was it to find these artiles? The JM artile would be very readily available, so that is the letter, the shorter one. The more detailed one, aess would be somewhat more diffiult, and bearing in mind that r onegan did her report five years ago, and there was not quite the aess via the Internet that there is now, that more detailed one would be more diffiult. ow would you --- Ifyou went to a library, a medial library, and said, "Can I do a searh?" that was ertainly possible at that stage and you would probably have had to pay to get a journal. What about PubMed? Would that have been available then? PubMed was available and you would have ome up with this journal, but it is not one of the ones that is so readily easily to get hold of. It would not spring out at you? It would ome up on the PubMed searh. Transribe UKLld I am afraid I am going to use one more example of pertussis. Ifit is any omfort to anybody, there are other diseases where we are only going to use one example, I think. In this one, we are using three. Can I ask you to stay with page 21 and go down to the seond paragraph, starting: "The Swedes abandoned the whole ell pertussis vaine in 1979 beause of worry about side effets and beause of its pereived ineffetiveness as whooping ough swept through its population of whom the majority was fully vainated. The Japanese raised the vaination age to two years in 1975 after a number of reports of severe reations and deaths. This redued the total number of deaths in infants younger than one year. In 1981 Japan introdued the aellular vaine. This is said to be safer than the whole ell one." 2/13

16 irst of all, what do you say about those omments about the Japanese history? The history is as near as makes no differene aurate in that there was a sare in Japan about whooping ough vaine following two hildren dying of ot death in lose temporal assoiation with the vaine. In fat, I think for a very short period they stopped using it, then they introdued it at two years old, then, as you said, they went over to a newer vaine. So that part is - yes. What I take issue with is the redution in number of infant deaths following a essation or the hanging of age of the whooping ough vaine. If you were to go to page 68 of my report, whih is - I have lost the bundle number. It is bundle 4. It is the graph we looked at yesterday, I think. This is a graph that - to be fair, I took offthe Internet, obviously, at the time I wrote my report, so I ould not guarantee that this graph would have been so readily available at the time r onegan wrote her report, but it does give the figures for infant mortality, as you an see, in the period - in Japan - in the period 1960 to What I would suggest that this shows is --- MR KRK: bundle 4. Just pause for a moment. Sorry. It is page 68 of r lliman's report, Panel Transribe UK Lld Sorry, dotor. So this is a graph showing infant mortality, that is mortality in hildren below a year, in Japan, from 1960 to This was obtained from the Japanese Ministry of ealth web site. It shows a ontinuing redution in infant mortality over that period. You an see the arrow shows a hange in age of vaination when hildren stopped being vainated as infants and started being vainated at two yearsold. I would suggest there is no hange in the trend there to suggest there was a hange in infant mortality in any way linked to - well, there was not a hange in infant mortality. It was a irulartrend that was already there. The omment made by r onegan was that this redued the total number of deaths in infants younger than one year. So, first of all, she appears to be orrelating, diretly orrelating, the vaination with the deaths? That was the impression I got from the report. Was that firm evidene of ausality? ven if there was a hange at the same time, it is not evidene of ausality, but there was not a hange at the same time. Seondly, this redued - in other words, the hange of timing - the number of deaths? There was a trend that was already there that I an see no hange in with the hange in vaination. Is there any evidene, that you have seen, to support that assertion this redued the total number of deaths in infants younger than a year? There is none. My next referene over the page shows, in fat, there was a rise in deaths over that period, due to whooping ough. We are going to move on. We are going to deal with tetanus. Could I ask you to go, please, to page 29, in that there is muh that she said I know you do not entirely agree with, but I want to onentrate on a few examples, please. Page 29, right at the top. Perhaps we ought to start at page 27. The heading is "The Vaine." She deals with 2/14

17 listed side effets, and then r onegan goes on to other side effets. Then, right at the bottom of the page, "Some people develop nerve damage ausing either musle weakness or altered sensations." I think you would add the word "rarely" to that? If we go on, please, to the top of page 29, where r onegan stated this: "Vaination of 11 healthy subjets with tetanus toxoid" - meaning the tetanus vaine - "produed a lowering of T-lymphoyte helper/suppressor ratio suh as might be seen in patients with the aquired immunodefiieny syndrome (IS)." Now, if you an, in as simple language as possible, explain what the lowering of the T lymphoyte helper/suppressor ratio is? Right. In your blood stream, you have a number of ells, broadly alled white ells, that are involved in ombating infetion. You an divide those up into various subgroups. You get in some diseases harateristi hanges in those groups, and in the ratios of one to the other, some of whih may have profound signifiane in terms of the ability to ombat infetion. One of the things you see in aquired immunodefiieny syndrome, from IV, is a hange in this helper/suppressor ratio. er omment to the layperson might indiate that the vaination of these healthy subjets had aused a ondition similar to IS. Ifthat were one's understanding of that, what would you say? I would say, like a lot of things, you need to go to the original researh to put it in ontext. The aount r onegan has given is of a hange in this ratio whih has been reported after people being given tetanus vaine, whih is indeed true. What people were looking for is a way whih you might pik up people with IV from testing blood transfusions. This was suggested as a way of doing it, but then some researhers looked at what happened to normal people after they had tetanus vaination and found that, indeed, you do get a temporary hange, and it is important, temporary hange, in this ratio up to 14 days after you have been given the vaine, whih, in their trial, had no signifiane at all, did not ause any inreased illness, and did not persist beyond 14 days. Can we just have a look, please, at the researh, the referene that r onegan gives? It is her referene 9, whih we find at tab 35 of her referenes. It is quite diffiult to read. I will justwait for everybody to get it. Tab 35 ofr onegan's evidene. We are looking at Panel bundle 2. We are looking at the artile, or a letter, bottom right-hand orner of the page. Is that right? That is orret, yes. eaded, "bnormal T-lymphoyte subpopulations in healthy subjets after tetanus booster immunization." Could I ask the Panel to look at about seven lines down, starting with the words: Transribe UK Lld "To study the effet of immunization on the T-lymphoyte helper/suppressor ratio we have given 11 healthy subjets (between 20 and 50 years of age, nine men and two women), who did not 2/15

18 belong to any of the populations known to be at risk for IS, a widely used antigen (tetanus toxoid)." Then it deals with what happened to those various healthy volunteers. We see about halfway down the artile: "The lowest ratio, whih is shown in igure I, appeared between ay 3 and ay 14 after vaination and returned to normal subsequently." Can you just try and give us, again, a bird's-eye view of what this artile is really talking about? Well, if you go,to the bottom of that page, it said: "The suggestion was that blood donors should be examined" --- Stop there. "In the May 26 issue of the Journal"? "The suggestion was made that blood donors should be examined." What they were looking for is: an we do a test whih allows us to pik up people who have got IS and therefore rejet their blood and not put it into the donor pool? The problem was that this may not be speifi for IS, so they then took a group of healthy people and gave them tetanus toxoid and measured these ratios for a period, whih they are not very speifi about, ertainly up to 14 days but longer, and this is one of the diffiulties of relying on a letter, not a detailed proper study. They looked at these ratios. Indeed, they did go down to levels that have been seen in people who have IV infetion, and then they went up again. So it was a temporary effet that lasted ertainly no longer than two weeks, and in those where it ourred mostly less than that, and it did not affet their health at all. Those two points that you have just made (a) it was temporary and (b) it did not affet the patients' health, were those, in your view, important matters oming from the researh? I think they are extremely important, beause one ould go away with the impression that this suggests that tetanus toxoid auses a signifiant problem whih, in some way, might be related to IS. It ould be permanent? That is the impression one would go away with, without having the further details. /... Transribe UKLld Let us move on. Could we go to the graph that we have at page 32. I ask for your assistane on how we should understand it. This is a graph showing notifiation by thousands in the left-hand axis, and dates along the bottom, and we an see where the various vainations were introdued. So we start in Now, first of all, dealing with notifiations, and they have a more general point to make here, in terms of notifiations of disease, has the proess of notifiation got better over the years? The proess has hanged over the years, so for some things it has got better. It is quite ompliated, beause notifiations are dependent upon a linial diagnosis, so a dotor seeing somebody who they think has got the disease. It is not reliant on tests to make sure they have, so for different diseases there may be a greater or lesser auray. 2/16

19 We an see that the graph shows that diphtheria vaination was introdued in around Would that be about right? Vainations some years ago were not introdued in the same way they are now where you usually launh it on a partiular day and the whole ountry does it. They tended to drift in and the diphtheria vaine drifted in in the late 30s, but was part of the national programme by the early 40s. We an see that the graph rather shoots up after vaination had been introdued, but how many years after vaination was it introdued? Well I think the Panel an estimate that as good as I an and it looks as though it is about Several years? The whole ountry was being immunised by about 1942/43. If you are looking at the effet of a vaine upon the population and the number of people who thereafter, in fat, get the disease, what sort of period of time would one normally be looking? I think I should be speifi beause this is a very partiular instane that I think r onegan is referring to and that is that when wild polio was fairly ommon. Someone who had had an intramusular injetion stood a risk of getting polio in that limb within the usual inubation period. So a ouple of months of that happening. So undoubtedly there were ases and there is no ontest that they were due to having an intramusular injetion and then having polio disease on top of that. So in answer to your question if a person is given diphtheria immunisation and there was thought to be a onnetion between that immunisation and getting polio, then you would expet it within a ouple of months. Right. On a population basis, if you introdue something in the early 1940s you would expet the effet in the early 1940s. Transribe UKLld So we have to look fairly arefully using this graph at the temporal line to see what the distane is, as it were, between the introdution of the vaine and the rise of notifiations. gain, just dealing with the rise in notifiations, are ertain diseases ylial? Yes, measles is probably the best example in that alternate years you have muh higher rates than the in-between years. Whooping ough runs on three to four yearly yles. Meningooal disease runs on ten to twelve yearly yles. So, yes. o we see something of those yles in this graph? You do, but I do not know enough about polio epidemiology to say whether that yling pattern at that period was appropriate. We an see also from this graph, I do not want to spend too long on it, the tetanus vaination was introdued to members of the armed fores in 1951 to seleted areas of the ountry --- I think probably r onegan did not mean 1951 for the armed fores, but 2117

20 to seleted areas of the ountry and then 1961 was nationwide. I see. It is perhaps 1961 that we should onentrate on? ither 51 or 61 whih would mean a signifiant proportion of the population was getting it. Then pertussis vaination and that looks again at round 1950? It drifted in so there would have been poor uptake in the very early 50s and then muh better in the mid 50s. Just staying with this graph for a moment, the Salk vaine, S--L-K, is that the inativated --- Yes, that is the dead vaine. Is that the one that is used now or not? The history of the use of polio vaine was firstly the dead salk vaine and then about six years later the live oral vaine and then still in 2002 it would have been a live oral vaine, but from 2004 it is the dead vaine. Just looking at this graph --- T LL SSSSOR: Mr Kark, I just mentioned something to the Chairman and she asked me if I would raise it. When you were talking about when diphtheria vaination was introdued, if one looks at the hart you an see the arrow, whih the atual arrow itself ame under the word "year", and it is getting on for 60, but the beginning of the arrows is the beginning of the 40s, and I had assumed, beause the witness said that the diphtheria vaine was introdued at the beginning of the 40s, that the start of the arrow, if you like, is where the diphtheria vaine is introdued and then one omes to what one is talking about now, the tetanus vainated, introdued to members of the armed fores in 1951, it seems that the tetanus vaination, if I am right about the beginning of the arrow, seems to have been in about 44 or 45 and you were talking about T WITNSS: No, I think there may be, with respet, some onfusion. T LL SSSSOR: There may be some misunderstanding, so ould you lear that up? Transribe UKLld MR KRK: It is a good point to raise. Thank you very muh. (To the witness) I think the answer to it might atually lie slightly earlier in the report, but ould you just give the answer first? You will have to pardon me for trying to interpret what someone else has written, but my understanding is that you were right for the diphtheria vaine, the start of the arrow is roughly where it was started to be introdued in the whole population. or tetanus it started to be introdued into the armed fores, so that is the start of the arrow, in the early/mid 40s. Then in the general population in some areas of the ountry in 1951 and then the whole ountry in Just for total larity, the end of the arrow does not mean the vaination stopped. 2/18

21 Itjust arries on? It just ontinued on off the edge. Ifwe go bak, ould I just suggest we look at page 31, so the page before, on the top paragraph might help. We see the words: "It also oinided with the widespread use of antibiotis whih were initially all injeted intramusularly and massive vaination ampaigns against diphtheria (1940s onwards)" Whih would equate with the beginning of the arrow on the graph and then: "Tetanus (World War Two: armed fores personnel, 1951)" So that is atually what r onegan has written or the maker of the graph has written ertainly and then "nationwide overage 1961". Just dealing with this graph --- I do not think it is a terribly important point, but I think --- You arry on, it does not matter. r onegan has not put a date... well she has put a date atually to the beginning of the armed fores whih is World War ll. I think the ommas and semi-olons have onfused people. Ifwe look and if we step bak from this and now look at the graph, as it were, should we take from the graph that there was (and I do not suggest this was being suggested by r onegan) just so when we look bak at this graph we understand it, was there any inrease, as it were, poliomyelitis notifiations following the introdution of the various vaines? rom that graph there was no indiation of that at all. That was a short point made in a rather lengthy way and an I go on to page 34 and the top of the report again dealing with polio. "s the World ealth Organisation struggles to ahieve its aim of world wide eradiation of polio it is notable that epidemis of paralyti poliomyelitis have ourred in highly vainated populations and, tragially, immediately after a polio vaination has ourred." Then there are various referenes to vaination programmes elsewhere in the world: "India... several ases have been reported of hildren ontrating polio even after reeiving up to a dozen doses of the vaine." Transribe UK Lld In Oman there was an outbreak where the highest attak rate was in the area where there had been a high overage rate. 2119

22 In Israel there was an outbreak in 1988: "... in a highly vainated population. People vainated with inativated polio vaine served as a reservoir for poliovirus multipliation and transmission to suseptible individuals." Just dealing with those various problems from around the world, what relevane, if any, did they have to 2002 in the UK? s you say, there are a number of papers here and there are some general points. One is that polio vaine, of itself, the live polio vaine rarely does ause polio. So you give someone polio vaine as a baby --- Can you keep your voie up, sorry, you are quiet? C Sorry. You give somebody the oral polio vaine as a baby. There is a very, very small risk of the order of one in a million that they will develop polio as a result of that and that is a diret effet of the vaine whih does not happen after the killed injeted vaine. What is being talked about, I think, more here is how well the vaine works at proteting you and some people, in spite of the vaination, still get wild polio. So it is not disease due to the vaine, but disease in spite of the vaine. Indeed, one does find that there are populations where polio still exists, but I would go bak to what I said previously and to know how well the vaine works you need to know how many people have been vainated, what proportion of those have got the disease, and the same for the unvainated population. When referring bak to these papers, I think almost all of them give an estimate of how well the vaine works from about 80 to 90 per ent. So yes, it is not perfet, but it is (I am going to think of a way of saying it that is reordable) a lot better than nothing. What about the relevane to the UK? What sort of vaine was being used in the UK at the time that this judge was being asked to make his deision? This was the oral polio vaine, the live toned-down vaine. id it have a higher poteny than the vaines used elsewhere? It was a different omposition from the vaine used in some ountries and storage would have been better in this ountry. Polio vaine is quite a fragile vaine and needs to be stored in a refrigerator and that has been a reurrent problem in some ountries. In your view, should any of these problems from elsewhere in the world have affeted the judge's deision in relation to the UK in 2002? I think the reality is, if you are talking about the effetiveness of a vaine against an unommon disease, there may not be reent experiene from this ountry. So there may be lessons to be learned from other ountries, but to learn the lessons you need the full piture of exatly what happened and, therefore, how you an apply it to the UK. So just taking the bald statement there were lots of vainated people who got the disease in Oman, by itself is not adequate to answer what we should be doing with three and ten year old hildren in the UK. Transribe UKLld I think, justtaking Oman as an example, the report in fat suggests that the 2120